Dose Escalation Study Investigating the Safety, Tolerability, Pharmacokinetics, Pharmacodynamics of ASP2215 in Patients With Relapsed or Refractory Acute Myeloid Leukemia

Sponsor

Astellas Pharma Global Development, Inc. (Industry)

Overall Status

Completed

CT.gov ID

NCT02014558

Collaborator

(none)

265

Enrollment

Locations

Arms

52.9

Actual Duration (Months)

10.2

Patients Per Site

0.2

Patients Per Site Per Month

Study Details

Study Description

Brief Summary

The objective of this study was to assess the safety and tolerability, including the maximum tolerated dose, of gilteritinib in participants with relapsed or treatment-refractory acute myeloid leukemia (AML). This study also determined the pharmacokinetic (PK) parameters of gilteritinib.

Condition or Disease	Intervention/Treatment	Phase
Acute Myeloid Leukemia	Drug: Gilteritinib Drug: Voriconazole Drug: Midazolam Drug: Cephalexin	Phase 1/Phase 2

Study Design

Study Type:

Interventional

Actual Enrollment :

265 participants

Allocation:

Randomized

Intervention Model:

Parallel Assignment

Masking:

None (Open Label)

Primary Purpose:

Treatment

Official Title:

A Phase 1/2 Open-Label, Dose Escalation Study Investigating the Safety, Tolerability, Pharmacokinetics, and Pharmacodynamics of ASP2215 in Patients With Relapsed or Refractory Acute Myeloid Leukemia

Actual Study Start Date :

Oct 9, 2013

Actual Primary Completion Date :

Aug 4, 2017

Actual Study Completion Date :

Mar 7, 2018

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Gilteritinib 20 mg in Escalation Phase Participants received a single dose of 20 mg gilteritinib orally on day -2 to evaluate pharmacokinetics of gilteritinib. Then starting on day 1 of cycle 1, participants received 20 mg gilteritinib orally once daily in 28-day cycles until disease progression or participant discontinuation in the escalation phase of the study.	Drug: Gilteritinib Participants received gilteritinib oral tablets (10 mg, 40 mg or 100 mg, depending on the dose) once daily without food allowed for at least 2 hours before and 1 hour after dosing starting from day -2 and day of cycle 1, for continuous 28-day cycles. Other Names: ASP2215 Drug: Voriconazole Participants received 200 mg voriconazole tablets daily every 12 hours starting from day 16 of cycle 1 through day 1 of cycle 2.
Experimental: Gilteritinib 40 mg in Escalation Phase Participants received a single dose of 40 mg gilteritinib orally on day -2 to evaluate pharmacokinetics of gilteritinib. Then starting on day 1 of cycle 1, participants received 40 mg gilteritinib orally once daily in 28-day cycles until disease progression or participant discontinuation in the escalation phase of the study.	Drug: Gilteritinib Participants received gilteritinib oral tablets (10 mg, 40 mg or 100 mg, depending on the dose) once daily without food allowed for at least 2 hours before and 1 hour after dosing starting from day -2 and day of cycle 1, for continuous 28-day cycles. Other Names: ASP2215
Experimental: Gilteritinib 80 mg in Escalation Phase Participants received a single dose of 80 mg gilteritinib orally on day -2 to evaluate pharmacokinetics of gilteritinib. Then starting on day 1 of cycle 1, participants received 80 mg gilteritinib orally once daily in 28-day cycles until disease progression or participant discontinuation in the escalation phase of the study.	Drug: Gilteritinib Participants received gilteritinib oral tablets (10 mg, 40 mg or 100 mg, depending on the dose) once daily without food allowed for at least 2 hours before and 1 hour after dosing starting from day -2 and day of cycle 1, for continuous 28-day cycles. Other Names: ASP2215
Experimental: Gilteritinib 120 mg in Escalation Phase Participants received a single dose of 120 mg gilteritinib orally on day -2 to evaluate pharmacokinetics of gilteritinib. Then starting on day 1 of cycle 1, participants received 120 mg gilteritinib orally once daily in 28-day cycles until disease progression or participant discontinuation in the escalation phase of the study.	Drug: Gilteritinib Participants received gilteritinib oral tablets (10 mg, 40 mg or 100 mg, depending on the dose) once daily without food allowed for at least 2 hours before and 1 hour after dosing starting from day -2 and day of cycle 1, for continuous 28-day cycles. Other Names: ASP2215
Experimental: Gilteritinib 200 mg in Escalation Phase Participants received a single dose of 200 mg gilteritinib orally on day -2 to evaluate pharmacokinetics of gilteritinib. Then starting on day 1 of cycle 1, participants received 200 mg gilteritinib orally once daily in 28-day cycles until disease progression or participant discontinuation in the escalation phase of the study.	Drug: Gilteritinib Participants received gilteritinib oral tablets (10 mg, 40 mg or 100 mg, depending on the dose) once daily without food allowed for at least 2 hours before and 1 hour after dosing starting from day -2 and day of cycle 1, for continuous 28-day cycles. Other Names: ASP2215
Experimental: Gilteritinib 300 mg in Escalation Phase Participants received a single dose of 300 mg gilteritinib orally on day -2 to evaluate pharmacokinetics of gilteritinib. Then starting on day 1 of cycle 1, participants received 300 mg gilteritinib orally once daily in 28-day cycles until disease progression or participant discontinuation in the escalation phase of the study.	Drug: Gilteritinib Participants received gilteritinib oral tablets (10 mg, 40 mg or 100 mg, depending on the dose) once daily without food allowed for at least 2 hours before and 1 hour after dosing starting from day -2 and day of cycle 1, for continuous 28-day cycles. Other Names: ASP2215
Experimental: Gilteritinib 450 mg in Escalation Phase Participants received a single dose of 450 mg gilteritinib orally on day -2 to evaluate pharmacokinetics of gilteritinib. Then starting on day 1 of cycle 1, participants received 450 mg gilteritinib orally once daily in 28-day cycles until disease progression or participant discontinuation in the escalation phase of the study.	Drug: Gilteritinib Participants received gilteritinib oral tablets (10 mg, 40 mg or 100 mg, depending on the dose) once daily without food allowed for at least 2 hours before and 1 hour after dosing starting from day -2 and day of cycle 1, for continuous 28-day cycles. Other Names: ASP2215
Experimental: Gilteritinib 20 mg in Expansion Phase Participants received 20 mg gilteritinib orally once daily stating on day 1 of cycle 1 and continued in 28-day cycles until disease progression or participant discontinuation in the expansion phase of the study. Starting on day 16 of cycle 1, participants also received 200 mg voriconazole orally every 12 hours through day 1 of cycle 2.	Drug: Gilteritinib Participants received gilteritinib oral tablets (10 mg, 40 mg or 100 mg, depending on the dose) once daily without food allowed for at least 2 hours before and 1 hour after dosing starting from day -2 and day of cycle 1, for continuous 28-day cycles. Other Names: ASP2215
Experimental: Gilteritinib 40 mg in Expansion Phase Participants received 40 mg gilteritinib orally once daily starting on day 1 of cycle 1 and continued in 28-day cycles until disease progression or participant discontinuation in the expansion phase of the study.	Drug: Gilteritinib Participants received gilteritinib oral tablets (10 mg, 40 mg or 100 mg, depending on the dose) once daily without food allowed for at least 2 hours before and 1 hour after dosing starting from day -2 and day of cycle 1, for continuous 28-day cycles. Other Names: ASP2215
Experimental: Gilteritinib 80 mg in Expansion Phase Participants received 80 mg gilteritinib orally once daily starting on day 1 of cycle 1 and continued in 28-day cycles until disease progression or participant discontinuation in the expansion phase of the study.	Drug: Gilteritinib Participants received gilteritinib oral tablets (10 mg, 40 mg or 100 mg, depending on the dose) once daily without food allowed for at least 2 hours before and 1 hour after dosing starting from day -2 and day of cycle 1, for continuous 28-day cycles. Other Names: ASP2215
Experimental: Gilteritinib 120 mg in Expansion Phase Participants received 120 mg gilteritinib orally once daily starting on day 1 of cycle 1 and continued in 28-day cycles until disease progression or participant discontinuation in the expansion phase of the study.	Drug: Gilteritinib Participants received gilteritinib oral tablets (10 mg, 40 mg or 100 mg, depending on the dose) once daily without food allowed for at least 2 hours before and 1 hour after dosing starting from day -2 and day of cycle 1, for continuous 28-day cycles. Other Names: ASP2215
Experimental: Gilteritinib 200 mg in Expansion Phase Participants received 200 mg gilteritinib orally once daily starting on day 1 of cycle 1 and continued in 28-day cycles until disease progression or participant discontinuation in the expansion phase of the study. On day -1 and day 15 of cycle 1, certain participants also received 500 mg cephalexin as a single oral dose.	Drug: Gilteritinib Participants received gilteritinib oral tablets (10 mg, 40 mg or 100 mg, depending on the dose) once daily without food allowed for at least 2 hours before and 1 hour after dosing starting from day -2 and day of cycle 1, for continuous 28-day cycles. Other Names: ASP2215 Drug: Cephalexin Participants received a single oral dose of 500 mg cephalexin tablet or capsule on day -1 and day 15 of cycle 1.
Experimental: Gilteritinib 300 mg in Expansion Phase Participants received 300 mg gilteritinib orally once daily starting on day 1 of cycle 1 and continued in 28-day cycles until disease progression or participant discontinuation in the expansion phase of the study. On day -1 and day 15 of cycle 1, participants also received 2 mg midazolam as a single oral dose.	Drug: Gilteritinib Participants received gilteritinib oral tablets (10 mg, 40 mg or 100 mg, depending on the dose) once daily without food allowed for at least 2 hours before and 1 hour after dosing starting from day -2 and day of cycle 1, for continuous 28-day cycles. Other Names: ASP2215 Drug: Midazolam Participants received a single oral dose of 2 mg of midazolam syrup on day -1 and day 15 of cycle 1.

Outcome Measures

Primary Outcome Measures

Number of Participants With Dose Limiting Toxicities (DLTs) [From first dose up to end of cycle 1 (30 days)]
To determine the maximum tolerated dose, safety was assessed by DLTs, defined as any grade ≥ 3 non-hematologic or extramedullary toxicity that occurred within 30 days starting with the first dose taken on day -2, and included the first treatment cycle in the dose escalation phase and in the first treatment cycle (28 days) in the dose expansion phase, that was considered to be possibly or probably related to study drug. Exceptions to this were the following: (1) Alopecia, anorexia or fatigue, (2) Grade 3 nausea and/or vomiting if not required tube feeding or total parenteral nutrition, or diarrhea if not required or prolonged hospitalization that was managed to grade ≤ 2 with standard antiemetic or antidiarrheal medications used at prescribed dose within 7 days of onset, (3) Grade 3 fever with neutropenia, with or without infection, (4) Grade 3 infection.
Number of Participants With Adverse Events (AEs) [From first dose of study drug up to 30 days after last dose of study drug (median treatment duration was 69.5 days, minimum of 3 days and maximum of 1320 days)]
Safety was assessed by AEs, which included abnormalities identified during a medical test (e.g. laboratory tests, vital signs, electrocardiogram, etc.) if the abnormality induced clinical signs or symptoms, needed active intervention, interruption or discontinuation of study medication or was clinically significant. A treatment-emergent AE (TEAE) was defined as an AE observed after starting administration of the study drug up to 30 days after last dose of study drug (for participants who underwent hematopoietic stem cell transplantation [HSCT]: defined as AEs observed after starting study drug until the last dose before on study HSCT plus 30 days, and AEs that began after resumption of gilteritinib and within 30 days after the last dose of gilteritinib). AEs were graded using the National Cancer Institute Common Terminology Criteria for Adverse Events Version 4.03 (1-Mild, 2-Moderate, 3-Severe, 4-LifeThreatening, 5-Death).
Area Under the Concentration-time Curve Over the 24-Hour Dosing Interval (AUC24) After Single and Multiple Doses of Gilteritinib [Day -2 and cycle 1 day 15: predose, 0.5, 1, 2, 4, 6, 24 hours postdose]
Plasma samples were used for pharmacokinetic assessments.
Maximum Concentration (Cmax) After Single and Multiple Doses of Gilteritinib [Day -2 and cycle 1 day 15: predose, 0.5, 1, 2, 4, 6, 24 hours postdose]
Plasma samples were used for pharmacokinetic assessments.
Area Under the Concentration-time Curve From the Time of Dosing to the Last Measurable Concentration (AUClast) After Single and Multiple Doses of Gilteritinib [Day -2 and cycle 1 day 15: predose, 0.5, 1, 2, 4, 6, 24 hours postdose]
Plasma samples were used for pharmacokinetic assessments.
Time to Observed Cmax (Tmax) After Single and Multiple Doses of Gilteritinib [Day -2 and cycle 1 day 15: predose, 0.5, 1, 2, 4, 6, 24 hours postdose]
Plasma samples were used for pharmacokinetic assessments.
Terminal Elimination Half-life (t1/2) After Multiple Doses of Gilteritinib [Cycle 1 day 15: predose, 0.5, 1, 2, 4, 6, 24 hours postdose]
Plasma samples were used for pharmacokinetic assessments.
Accumulation Ratio After Multiple Doses of Gilteritinib [Cycle 1 day 15: predose, 0.5, 1, 2, 4, 6, 24 hours postdose]
Plasma samples were used for pharmacokinetic assessments.

Secondary Outcome Measures

Percentage of Participants With Complete Remission (CR) During the First 2 Cycles [During the first 2 cycles (56 days)]
CR was defined according to modified Cheson criteria (2003), using centrally evaluated myeloblast counts from bone marrow aspirate/biopsy assessments and centrally evaluated hematology results; if neither central bone marrow aspirate nor biopsy was available, myeloblast was imputed with locally evaluated bone marrow aspirate/biopsy assessments (derived response). Participants were classified as being in CR when they had bone marrow regenerating normal hematopoietic cells, achieved a morphologic leukemia-free state, had an absolute neutrophil count (ANC) > 1 x 10^9/L, platelet count ≥ 100 x 10^9/L, normal marrow differential with < 5% blasts, had been red blood cell (RBC) and platelet transfusion independent (defined as 1 week without RBC transfusion and 1 week without platelet transfusion), had no presence of Auer rods and no evidence of extramedullary leukemia, and blast counts in peripheral blood had been ≤ 2%. Exact 95% confidence interval was estimated using binomial distribution.
Percentage of Participants With CR During Treatment [Up to end of treatment (median treatment duration was 69.5 days, minimum of 3 days and maximum of 1320 days)]
CR was defined according to modified Cheson criteria (2003), using centrally evaluated myeloblast counts from bone marrow aspirate/biopsy assessments and centrally evaluated hematology results; if neither central bone marrow aspirate nor biopsy was available, myeloblast was imputed with locally evaluated bone marrow aspirate/biopsy assessments (derived response). Participants were classified as being in CR when they had bone marrow regenerating normal hematopoietic cells, achieved a morphologic leukemia-free state, had an absolute neutrophil count (ANC) > 1 x 10^9/L, platelet count ≥ 100 x 10^9/L, normal marrow differential with < 5% blasts, had been red blood cell (RBC) and platelet transfusion independent (defined as 1 week without RBC transfusion and 1 week without platelet transfusion), had no presence of Auer rods and no evidence of extramedullary leukemia, and blast counts in peripheral blood had been ≤ 2%. Exact 95% confidence interval was estimated using binomial distribution.
Percentage of Participants With CR With Incomplete Platelet Recovery (CRp) [Up to end of treatment (median treatment duration was 69.5 days, minimum of 3 days and maximum of 1320 days)]
CRp was defined according to modified Cheson criteria (2003), using centrally evaluated myeloblast counts from bone marrow aspirate/biopsy assessments and centrally evaluated hematology results; if neither central bone marrow aspirate nor biopsy was available, myeloblast was imputed with locally evaluated bone marrow aspirate/biopsy assessments (derived response). Participants were classified as being in CRp when they achieved CR except for incomplete platelet recovery (< 100 x 10^9/L). Exact 95% confidence interval was estimated using the binomial distribution.
Percentage of Participants With CR With Incomplete Hematological Recovery (CRi) [Up to end of treatment (median treatment duration was 69.5 days, minimum of 3 days and maximum of 1320 days)]
CRi was defined according to modified Cheson criteria (2003), using centrally evaluated myeloblast counts from bone marrow aspirate/biopsy assessments and centrally evaluated hematology results; if neither central bone marrow aspirate nor biopsy was available, myeloblast was imputed with locally evaluated bone marrow aspirate/biopsy assessments (derived response). Participants were classified as being in CRi when they fulfilled all the criteria for CR except for incomplete hematological recovery with residual neutropenia < 1 x 10^9/L with or without complete platelet recovery. RBC and platelet transfusion independence were not required. Exact 95% confidence interval was estimated using the binomial distribution.
Percentage of Participants With Complete Remission With Partial Hematologic Recovery (CRh) [Up to end of treatment (median treatment duration was 69.5 days, minimum of 3 days and maximum of 1320 days)]
CRh was defined according to modified Cheson criteria (2003), using centrally evaluated myeloblast counts from bone marrow aspirate/biopsy assessments and centrally evaluated hematology results; if neither central bone marrow aspirate nor biopsy was available, myeloblast was imputed with locally evaluated bone marrow aspirate/biopsy assessments (derived response). Participants were classified as being in CRh when they could not be classified as being in CR and had bone marrow blasts < 5% and partial hematologic recovery ANC >= 0.5 x 10^9/L and platelets >= 50 x 10^9/L. There should not be evidence of extramedullary leukemia. Exact 95% confidence interval was estimated using the binomial distribution. CRh was calculated only for participants who were FLT3 mutation positive.
Percentage of Participants With Composite CR (CRc) [Up to end of treatment (median treatment duration was 69.5 days, minimum of 3 days and maximum of 1320 days)]
CRc was defined according to modified Cheson criteria (2003), using centrally evaluated myeloblast counts from bone marrow aspirate/biopsy assessments and centrally evaluated hematology results; if neither central bone marrow aspirate nor biopsy was available, myeloblast was imputed with locally evaluated bone marrow aspirate/biopsy assessments (derived response). Participants were classified as being in CRc when they had achieved either CR, complete remission with incomplete platelet recovery (CRp, defined as had achieved CR except for incomplete platelet recovery (< 100 x 10^9/L) or complete remission with incomplete hematologic recovery (CRi, defined as had fulfilled all the criteria for CR except for incomplete hematological recovery with residual neutropenia < 1 x 10^9/L with or without complete platelet recovery; RBC platelet transfusion independence not required). Exact 95% confidence interval was estimated using the binomial distribution.
Percentage of Participants With Partial Remission (PR) [Up to end of treatment (median treatment duration was 69.5 days, minimum of 3 days and maximum of 1320 days)]
PR was defined according to modified Cheson criteria (2003), using centrally evaluated myeloblast counts from bone marrow aspirate/biopsy assessments and centrally evaluated hematology results; if neither central bone marrow aspirate nor biopsy was available, myeloblast was imputed with locally evaluated bone marrow aspirate/biopsy assessments (derived response). Participants were classified as being in PR when they had bone marrow regenerating normal hematopoietic cells with evidence of peripheral recovery with no (or only a few regenerating) circulating blasts and with a decrease of at least 50% in the percentage of blasts in the bone marrow aspirate with the total marrow blasts between 5% and 25%. A value of less or equal than 5% blasts was also considered a PR if Auer rods were present. There should be no evidence of extramedullary leukemia. Exact 95% confidence interval was estimated using the binomial distribution.
Percentage of Participants With Best Response [Up to end of treatment (median treatment duration was 69.5 days, minimum of 3 days and maximum of 1320 days)]
Best response was defined according to modified Cheson criteria (2003), using centrally evaluated myeloblast counts from bone marrow aspirate/biopsy assessments and centrally evaluated hematology results; if neither central bone marrow aspirate nor biopsy was available, myeloblast was imputed with locally evaluated bone marrow aspirate/biopsy assessments (derived response). BR was defined as the best measured response for all visits (in the order of CR, CRp, CRi, and PR) post-treatment. Participants who achieved the best response of CR, CRp, CRi or PR were classified as responders. Participants who did not achieve at least PR were considered as non-responders. Exact 95% confidence interval was estimated using the binomial distribution.
Percentage of Participants With Complete Remission and Complete Remission With Partial Hematologic Recovery (CR/CRh) [Up to end of treatment (median treatment duration was 69.5 days, minimum of 3 days and maximum of 1320 days)]
Participants with CR/CRh were defined as participants who achieved either CR or CRh. Participants with CR had bone marrow regenerating normal hematopoietic cells, achieved a morphologic leukemia-free state, had an ANC > 1 x 10^9/L, platelet count ≥ 100 x 10^9/L, and normal marrow differential with < 5% blasts, had been RBC and platelet transfusion independent (defined as 1 week without RBC transfusion and 1 week without platelet transfusion). Also, there had been no presence of Auer rods, no evidence of extramedullary leukemia, and blast counts in peripheral blood had been ≤ 2%. Participants with CRh could not be classified as being in CR and had bone marrow blasts < 5%, partial hematologic recovery ANC >= 0.5 x 10^9/L and platelets >= 50 x 10^9/L. There should not be evidence of extramedullary leukemia. Exact 95% confidence interval was estimated using the binomial distribution. CR/CRh was calculated only for participants who were FLT3 mutation positive.
Duration of CR (DCR) [From date of remission until end of study (median treatment duration was 69.5 days, minimum of 3 days and maximum of 1320 days)]
DCR was defined as the time from the date of first CR until the date of documented relapse for participants who achieved CR. Participants who died without report of relapse were considered non-events and censored at their last relapse-free disease assessment date. Other participants who did not relapse on study were considered non-events and censored at the last relapse-free disease assessment date. DCR was calculated using Kaplan-Meier method and therefore data are estimated.
Duration of CRp (DCRp) [From date of remission until end of study (median treatment duration was 69.5 days, minimum of 3 days and maximum of 1320 days)]
DCRp was defined as the time from the date of first CRp until the date of documented relapse for participants who achieved CRp. Participants who died without report of relapse were considered non-events and censored at their last relapse-free disease assessment date. Other participants who did not relapse on study were considered non-events and censored at the last relapse-free disease assessment date. DCRp was calculated using Kaplan-Meier method and therefore data are estimated.
Duration of CRi (DCRi) [From date of remission until end of study (median treatment duration was 69.5 days, minimum of 3 days and maximum of 1320 days)]
DCRi was defined as the time from the date of first CRi until the date of documented relapse for participants who achieved CRi. Participants who died without report of relapse and participants who did not relapse were considered non-events and censored at the last relapse-free disease assessment date. DCRi was calculated using Kaplan-Meier method and therefore data are estimated.
Duration of CRh (DCRh) [From date of remission until end of study (median treatment duration was 69.5 days, minimum of 3 days and maximum of 1320 days)]
DCRh was defined as the time from the date of first CRh until the date of documented relapse for participants who achieved CRh but did not have a best response of CR. Participants who died without report of relapse and participants who did not relapse were considered non-events and censored at the last relapse-free disease assessment date. DCRh was calculated using Kaplan-Meier method and therefore data are estimated. DCRh was calculated only for participants who were FLT3 mutation positive.
Duration of CRc (DCRc) [From date of remission until end of study (median treatment duration was 69.5 days, minimum of 3 days and maximum of 1320 days)]
DCRc was defined as the time from the date of first CRc until the date of documented relapse for participants who achieved CRc. Participants who died without report of relapse and participants who did not relapse were considered non-events and censored at the last relapse-free disease assessment date. DCRc was calculated using Kaplan-Meier method and therefore data are estimated.
Duration of CR/CRh (DCRCRh) [From date of remission until end of study (median treatment duration was 69.5 days, minimum of 3 days and maximum of 1320 days)]
DCRCRh was defined as the time from the date of first DCRCRh until the date of documented relapse for participants who achieved CR or CRh. For participants who achieved both CR and CRh, the first CR date or CRh date, whichever occurred first, was used. Participants who died without report of relapse and participants who did not relapse were considered non-events and censored at the last relapse-free disease assessment date. DCRCRh was calculated using Kaplan-Meier method and therefore data are estimated. DCRCRh was calculated only for participants who were FLT3 mutation positive.
Duration of Response [From date of remission until end of study (median treatment duration was 69.5 days, minimum of 3 days and maximum of 1320 days)]
Duration of response was defined as the time from the date of either first CRc or PR until the date of documented relapse of any type for participants who achieved CRc or PR. Participants who died without report of relapse were considered non-events and censored at their last relapse-free disease assessment date. Other participants who did not relapse on study are considered non-events and censored at the last relapse-free assessment date. Duration of response was calculated using Kaplan-Meier method and therefore data are estimated.
Time to CR (TTCR) [From first dose of study drug up to end of treatment (median treatment duration was 69.5 days, minimum of 3 days and maximum of 1320 days)]
TTCR was defined as the time from the first dose of study drug until the date of first CR.
Time to CRp (TTCRp) [From first dose of study drug up to end of treatment (median treatment duration was 69.5 days, minimum of 3 days and maximum of 1320 days)]
TTCRp was defined as the time from the first dose of study drug until the date of first CRp. TTCRp was evaluated for participants who achieved CRp.
Time to CRi (TTCRi) [From first dose of study drug up to end of treatment (median treatment duration was 69.5 days, minimum of 3 days and maximum of 1320 days)]
TTCRi was defined as the time from the first dose of study drug until the date of first CRi. TTCRi was evaluated for participants who achieved CRi.
Time to First CR/CRh (TTFCRCRh) [From first dose of study drug up to end of treatment (median treatment duration was 69.5 days, minimum of 3 days and maximum of 1320 days)]
TTFCRCRh was defined as the time from the first dose of study drug until the date of first either CR or CRh. TTFCRCRh was evaluated for participants who achieved CR or CRh. For participants who achieve both CR and CRh, the first CR date or CRh date, whichever occurs first was used. TTFCRCRh was calculated only for participants who were FLT3 mutation positive.
Time to Best CR/CRh (TTBCRCRh) [From first dose of study drug up to end of treatment (median treatment duration was 69.5 days, minimum of 3 days and maximum of 1320 days)]
TTBCRCRh was defined as the time from the first dose of study drug until the first date that the best response of CR or CRh was achieved. TTBCRCRh was evaluated for participants who achieved CR or CRh. For participants who achieve both CR and CRh, the first CR date was used. TTBCRCRh was calculated only for participants who were FLT3 mutation positive.
Time to CRc (TTCRc) [From first dose of study drug up to end of treatment (median treatment duration was 69.5 days, minimum of 3 days and maximum of 1320 days)]
TTCRc was defined as the time from the first dose of study drug until the date of first CRc. TTCRc was evaluated for participants who achieved CRc.
Time to Response (TTR) [From first dose of study drug up to end of treatment (median treatment duration was 69.5 days, minimum of 3 days and maximum of 1320 days)]
TTR was defined as the time from the first dose of study drug until the date of either first CRc or PR. TTR was evaluated for participants who achieved CRc or PR.
Time to Best Response (TTBR) [From first dose of study drug up to end of treatment (median treatment duration was 69.5 days, minimum of 3 days and maximum of 1320 days)]
TTBR was defined as the time from the first dose of study drug until the first disease assessment date when participant achieved best response. TTBR was evaluated in participants who achieved best response of CR, CRp, CRi, or PR.
Overall Survival (OS) [From first dose of study drug up to end of study (median time on study was 157.0 days, minimum of 5 days and maximum of 1320 days)]
The time from the date of first dose of study drug until the date of death from any cause. For a participant who was not known to have died by the end of study follow-up, OS was censored at the date of last contact. OS was calculated using Kaplan-Meier method and therefore data are estimated.
Event Free Survival (EFS) [From first dose of study drug up to end of study (median time on study was 157.0 days, minimum of 5 days and maximum of 1320 days)]
EFS was defined as the time from the date of first dose of study drug until the date of documented relapse, treatment failure or death from any cause, whichever occurred first. For a participant with none of these events, EFS was censored at the date of last relapse-free disease assessment. A participant without post-treatment disease assessment was censored at randomization date. Treatment failure included those participants who discontinued the treatment due to "progressive disease" or "lack of efficacy" without a previous response of CR, CRp, CRi or PR. Treatment failure date referred to the start of new anti-leukemia therapy or the last treatment evaluation date when new anti-leukemia therapy date was not available. For participants who were censored, last relapse-free disease assessment date referred to the participant's last disease assessment date. EFS was calculated using Kaplan-Meier method and therefore data are estimated.
Leukemia Free Survival (LFS) [From first dose of study drug up to end of study (median time on study was 157.0 days, minimum of 5 days and maximum of 1320 days)]
LFS was defined as the time from the date of first CRc until the date of documented relapse or death for participants who achieved CRc. For a participant who was not known to have relapsed or died, LFS was censored on the date of last relapse-free disease assessment date. LFS was calculated using Kaplan-Meier method and therefore data are estimated.
Percentage of Participants Who Achieved Transfusion Conversion [Baseline (28 days prior to first dose until 28 days after the first dose) and postbaseline (from 29 days after first dose date until last dose date); median treatment duration was 69.5 days, minimum of 3 days and maximum of 1320 days]
Participants who achieved transfusion conversion were defined as the number of participants who were transfusion dependent at baseline period but became transfusion independent at post-baseline period divided by the total number of participants who were transfusion dependent at baseline period. Participants were considered baseline transfusion dependent if there were RBC or platelet transfusions within the baseline period. Participants were considered post-baseline transfusion independent if they were on treatment >=84 days, and if there was one consecutive 56 days without any RBC or platelet transfusion within post-baseline period. If participants were on treatment >28 days but <84 days, and there was no RBC or platelet transfusion within post-baseline period, or on treatment <=28 days, post-baseline transfusion status was not evaluable. Exact 95% confidence interval was estimated using the binomial distribution.
Percentage of Participants Who Achieved Transfusion Maintenance [Baseline (28 days prior to first dose until 28 days after the first dose) and postbaseline (from 29 days after first dose date until last dose date); median treatment duration was 69.5 days, minimum of 3 days and maximum of 1320 days]
Participants who achieved transfusion maintenance were defined as the number of participants who were transfusion independent at baseline period and still maintained transfusion independent at post-baseline period divided by the total number of participants who were transfusion independent at baseline period.
AUC24 of Gilteritinib in Co-administration With Voriconazole [Cycle 1 Day 15 and Cycle 2 Day 1: predose, 0.5, 1, 2, 4, 6, 24 hours postdose (gilteritinib)]
Plasma samples were used for pharmacokinetic assessments.
Cmax of Gilteritinib in Co-administration With Voriconazole [Cycle 1 Day 15 and Cycle 2 Day 1: predose, 0.5, 1, 2, 4, 6, 24 hours postdose (gilteritinib)]
Plasma samples were used for pharmacokinetic assessments.
AUClast of Gilteritinib in Co-administration With Voriconazole [Cycle 1 Day 15 and Cycle 2 Day 1: predose, 0.5, 1, 2, 4, 6, 24 hours postdose (gilteritinib)]
Plasma samples were used for pharmacokinetic assessments.
Tmax of Gilteritinib in Co-administration With Voriconazole [Cycle 1 Day 15 and Cycle 2 Day 1: predose, 0.5, 1, 2, 4, 6, 24 hours postdose (gilteritinib)]
Plasma samples were used for pharmacokinetic assessments.
AUC24 of Midazolam Administered With and Without Gilteritinib [Day -1 and cycle 1 day 15: predose, 0.5, 1, 2, 4, 6, 24 hours postdose (midazolam)]
Plasma samples were used for pharmacokinetic assessments.
AUC24 of Metabolite 1-Hydroxymidazolam After Administration of Midazolam With and Without Gilteritinib [Day -1 and cycle 1 day 15: predose, 0.5, 1, 2, 4, 6, 24 hours postdose (midazolam)]
Plasma samples were used for pharmacokinetic assessments.
Cmax of Midazolam Administered With and Without Gilteritinib [Day -1 and cycle 1 day 15: predose, 0.5, 1, 2, 4, 6, 24 hours postdose (midazolam)]
Plasma samples were used for pharmacokinetic assessments.
Cmax of 1-Hydroxymidazolam After Administration of Midazolam With and Without Gilteritinib [Day -1 and cycle 1 day 15: predose, 0.5, 1, 2, 4, 6, 24 hours postdose (midazolam)]
Plasma samples were used for pharmacokinetic assessments.
AUClast of Midazolam Administered With and Without Gilteritinib [Day -1 and cycle 1 day 15: predose, 0.5, 1, 2, 4, 6, 24 hours postdose (midazolam)]
Plasma samples were used for pharmacokinetic assessments.
AUClast of 1-Hydroxymidazolam After Administration of Midazolam With and Without Gilteritinib [Day -1 and cycle 1 day 15: predose, 0.5, 1, 2, 4, 6, 24 hours postdose (midazolam)]
Plasma samples were used for pharmacokinetic assessments.
Tmax of Midazolam Administered With and Without Gilteritinib [Day -1 and cycle 1 day 15: predose, 0.5, 1, 2, 4, 6, 24 hours postdose (midazolam)]
Plasma samples were used for pharmacokinetic assessments.
Tmax of 1-Hydroxymidazolam After Administration of Midazolam With and Without Gilteritinib [Day -1 and cycle 1 day 15: predose, 0.5, 1, 2, 4, 6, 24 hours postdose (midazolam)]
Plasma samples were used for pharmacokinetic assessments.
Area Under the Concentration-time Curve From the Time of Dosing Extrapolated to Time Infinity (AUCinf) of Cephalexin Administered With and Without Gilteritinib [Day -1 and cycle 1 day 15: predose, 0.5, 1, 1.5, 2, 3, 4, 6, 24 hours postdose (cephalexin)]
Plasma samples were used for pharmacokinetic assessments.
Cmax of Cephalexin Administered With and Without Gilteritinib [Day -1 and cycle 1 day 15: predose, 0.5, 1, 1.5, 2, 3, 4, 6, 24 hours postdose (cephalexin)]
Plasma samples were used for pharmacokinetic assessments.
AUClast of Cephalexin Administered With and Without Gilteritinib [Day -1 and cycle 1 day 15: predose, 0.5, 1, 1.5, 2, 3, 4, 6, 24 hours postdose (cephalexin)]
Plasma samples were used for pharmacokinetic assessments.
Tmax of Cephalexin Administered With and Without Gilteritinib [Day -1 and cycle 1 day 15: predose, 0.5, 1, 1.5, 2, 3, 4, 6, 24 hours postdose (cephalexin)]
Plasma samples were used for pharmacokinetic assessments.
T1/2 of Cephalexin Administered With and Without Gilteritinib [Day -1 and cycle 1 day 15: predose, 0.5, 1, 1.5, 2, 3, 4, 6, 24 hours postdose (cephalexin)]
Plasma samples were used for pharmacokinetic assessments.
Apparent Total Systemic Clearance After Single or Multiple Extravascular Dosing (CL/F) of Cephalexin Administered With and Without Gilteritinib [Day -1 and cycle 1 day 15: predose, 0.5, 1, 1.5, 2, 3, 4, 6, 24 hours postdose (cephalexin)]
Plasma samples were used for pharmacokinetic assessments.
Apparent Volume of Distribution During the Terminal Elimination Phase After Single Extravascular Dosing (Vz/F) of Cephalexin Administered With and Without Gilteritinib [Day -1 and cycle 1 day 15: predose, 0.5, 1, 1.5, 2, 3, 4, 6, 24 hours postdose (cephalexin)]
Plasma samples were used for pharmacokinetic assessments.
Amount of Drug Excreted in Urine (Aelast) of Cephalexin Administered With and Without Gilteritinib [Day -1 and cycle 1 day 15: 0-3 hours, 3-6 hours, 6-24 hours postdose (cephalexin)]
Urine samples were used for pharmacokinetic assessments.
Fraction of Drug Excreted Into Urine in Percentage (%Ae) of Cephalexin Administered With and Without Gilteritinib [Day -1 and cycle 1 day 15: 0-3 hours, 3-6 hours, 6-24 hours postdose (cephalexin)]
Urine samples were used for pharmacokinetic assessments.
Renal Clearance (CLr) of Cephalexin in Administered With and Without Gilteritinib [Day -1 and cycle 1 day 15: 0-3 hours, 3-6 hours, 6-24 hours postdose (cephalexin)]
Urine samples were used for pharmacokinetic assessments.

Eligibility Criteria

Criteria

Ages Eligible for Study:

18 Years and Older

Sexes Eligible for Study:

All

Accepts Healthy Volunteers:

Inclusion Criteria:

Subject is defined as morphologically documented primary or secondary AML by the World

Health Organization (WHO) criteria (2008) and fulfills one of the following:

Refractory to at least 1 cycle of induction chemotherapy
Relapsed after achieving remission with a prior therapy
Subject has an Eastern Cooperative Oncology Group (ECOG) performance status ≤ 2.
Subject's interval from prior treatment to time of study drug administration is at least 2 weeks for cytotoxic agents (except hydroxyurea given for controlling blast cells), or at least 5 half-lives for prior experimental agents or noncytotoxic agents.
Subject must meet the following criteria as indicated on the clinical laboratory tests*:
Serum aspartate aminotransferase (AST) and alanine aminotransferase (ALT) <2.5 x institutional upper limit normal (ULN)
Total serum bilirubin < 1.5x institutional ULN
Serum creatinine < 1.5 x institutional ULN or an estimated glomerular filtration rate (eGFR) of > 50 ml/min as calculated by the Modification of Diet in Renal Disease (MDRD) equation.
Subject agrees not to participate in another interventional study while on treatment.

Exclusion Criteria:

Subject was diagnosed as acute promyelocytic leukemia (APL).
Subject has BCR-ABL-positive leukemia (chronic myelogenous leukemia in blast crisis).
Subject has active malignant tumors other than AML or Myelodysplastic syndrome (MDS).
Subject has persistent nonhematological toxicities of >= Grade 2 (Common Terminology Criteria for Adverse Events v4), with symptoms and objective findings, from prior AML treatment (including chemotherapy, kinase inhibitors, immunotherapy, experimental agents, radiation, or surgery).
Subject has had hematopoietic stem cell transplant (HSCT) and meets any of the following:
Is within 2 months of transplant from C1D1
Has clinically significant graft-versus-host disease requiring treatment
Has >= Grade 2 persistent non-hematological toxicity related to the transplant. Donor lymphocytes infusion (DLI) is not permitted <= 30 days prior to study registration or during the first cycle of treatment on the study in Cohort 1 and first two cycles of the treatment in Cohort 2
Subject has clinically active central nervous system leukemia
Subject has disseminated intravascular coagulation abnormality (DIC)
Subject has had major surgery within 4 weeks prior to the first study dose.
Subject has had radiation therapy within 4 weeks prior to the first study dose
Subject has congestive heart failure New York Heart Association (NYHA) class 3 or 4, or subject with a history of congestive heart failure NYHA class 3 or 4 in the past, unless a screening echocardiogram performed within 3 months prior to study entry results in a left ventricular ejection fraction that is ≥ 45%
Subject requires treatment with concomitant drugs that are strong inhibitors or inducers of Cytochrome P450-isozyme3A4 (CYP3A4) with the exception of antibiotics, antifungals, and antivirals that are used as standard of care post-transplant or to prevent or treat infections and other such drugs that are considered absolutely essential for the care of the subject
Subject required treatment with concomitant drugs that target serotonin 5HT1R or 5HT2BR receptors or sigma nonspecific receptor with the exception of drugs that are considered absolutely essential for the care of the subject.
Subject has an active uncontrolled infection
Subject is known to have human immunodeficiency virus infection
Subject has active hepatitis B or C, or other active hepatic disorder

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Site US10021	Birmingham	Alabama	United States	35294
2	Site US10023	Scottsdale	Arizona	United States	85259
3	Site US10022	Duarte	California	United States	91010
4	Site US10008	Los Angeles	California	United States	90095-1678
5	Site US10005	San Francisco	California	United States	94143
6	Site US10001	Chicago	Illinois	United States	60611
7	Site US10015	Chicago	Illinois	United States	60637
8	Site US10012	Baltimore	Maryland	United States	21201
9	Site US10003	Baltimore	Maryland	United States	21287
10	Site US10006	Minneapolis	Minnesota	United States	55455
11	Site US10011	Rochester	Minnesota	United States	55905
12	Site US10020	Hackensack	New Jersey	United States	07601
13	Site US10010	Buffalo	New York	United States	14263
14	Site US10009	New York	New York	United States	10022
15	Site US10013	New York	New York	United States	10032
16	Site US10019	New York	New York	United States	10065
17	Site US10014	Cleveland	Ohio	United States	44195
18	Site US10018	Hershey	Pennsylvania	United States	17033
19	Site US10004	Philadelphia	Pennsylvania	United States	19104
20	Site US10017	Charleston	South Carolina	United States	29425-8900
21	Site US10007	Nashville	Tennessee	United States	37232
22	Site US10002	Houston	Texas	United States	77030
23	Site US10026	Fairfax	Virginia	United States	22031
24	Site DE49002	Berlin		Germany	12203
25	Site DE49004	Dresden		Germany	01307
26	Site IT39001	Bologna		Italy	40138

Sponsors and Collaborators

Astellas Pharma Global Development, Inc.

Investigators

Study Director: Executive Medical Director, Astellas Pharma Global Development

Study Documents (Full-Text)

More Information

Additional Information:

Link to results on the Astellas Clinical Study Results website

Publications

None provided.

Responsible Party:

Astellas Pharma Global Development, Inc.

ClinicalTrials.gov Identifier:

NCT02014558

Other Study ID Numbers:

2215-CL-0101

First Posted:

Dec 18, 2013

Last Update Posted:

May 23, 2019

Last Verified:

May 1, 2019

Individual Participant Data (IPD) Sharing Statement:

Yes

Plan to Share IPD:

Yes

Keywords provided by Astellas Pharma Global Development, Inc.

Acute Myeloid Leukemia

Gilteritinib

ASP2215

Additional relevant MeSH terms:

Leukemia

Leukemia, Myeloid

Leukemia, Myeloid, Acute

Voriconazole

Cephalexin

Midazolam

Study Results

Participant Flow

Recruitment Details	This dose-escalation/dose-expansion study was conducted in sites in the United States, France, Germany and Italy. The study had 7 dose-escalation cohorts with ≥3 participants enrolled at each dose level. Following escalation to the next dose cohort, additional participants were enrolled to the dose-expansion cohorts per protocol-specified criteria.
Pre-assignment Detail	Participants with acute myeloid leukemia (AML) who relapsed after or were refractory to induction or salvage treatment were selected for this study. Five participants were re-enrolled into the dose-expansion cohorts as they discontinued treatment for reasons other than toxicity or disease progression, as long as they met the eligibility criteria.

Arm/Group Title	Gilteritinib 20 mg in Escalation Phase	Gilteritinib 40 mg in Escalation Phase	Gilteritinib 80 mg in Escalation Phase	Gilteritinib 120 mg in Escalation Phase	Gilteritinib 200 mg in Escalation Phase	Gilteritinib 300 mg in Escalation Phase	Gilteritinib 450 mg in Escalation Phase	Gilteritinib 20 mg in Expansion Phase	Gilteritinib 40 mg in Expansion Phase	Gilteritinib 80 mg in Expansion Phase	Gilteritinib 120 mg in Expansion Phase	Gilteritinib 200 mg in Expansion Phase	Gilteritinib 300 mg in Expansion Phase
Arm/Group Description	Participants received a single dose of 20 mg gilteritinib orally on day -2 to evaluate pharmacokinetics of gilteritinib. Then starting on day 1 of cycle 1, participants received 20 mg gilteritinib orally once daily in 28-day cycles until disease progression or participant discontinuation in the escalation phase of the study.	Participants received a single dose of 40 mg gilteritinib orally on day -2 to evaluate pharmacokinetics of gilteritinib. Then starting on day 1 of cycle 1, participants received 40 mg gilteritinib orally once daily in 28-day cycles until disease progression or participant discontinuation in the escalation phase of the study.	Participants received a single dose of 80 mg gilteritinib orally on day -2 to evaluate pharmacokinetics of gilteritinib. Then starting on day 1 of cycle 1, participants received 80 mg gilteritinib orally once daily in 28-day cycles until disease progression or participant discontinuation in the escalation phase of the study.	Participants received a single dose of 120 mg gilteritinib orally on day -2 to evaluate pharmacokinetics of gilteritinib. Then starting on day 1 of cycle 1, participants received 120 mg gilteritinib orally once daily in 28-day cycles until disease progression or participant discontinuation in the escalation phase of the study.	Participants received a single dose of 200 mg gilteritinib orally on day -2 to evaluate pharmacokinetics of gilteritinib. Then starting on day 1 of cycle 1, participants received 200 mg gilteritinib orally once daily in 28-day cycles until disease progression or participant discontinuation in the escalation phase of the study.	Participants received a single dose of 300 mg gilteritinib orally on day -2 to evaluate pharmacokinetics of gilteritinib. Then starting on day 1 of cycle 1, participants received 300 mg gilteritinib orally once daily in 28-day cycles until disease progression or participant discontinuation in the escalation phase of the study.	Participants received a single dose of 450 mg gilteritinib orally on day -2 to evaluate pharmacokinetics of gilteritinib. Then starting on day 1 of cycle 1, participants received 450 mg gilteritinib orally once daily in 28-day cycles until disease progression or participant discontinuation in the escalation phase of the study.	Participants received 20 mg gilteritinib orally once daily stating on day 1 of cycle 1 and continued in 28-day cycles until disease progression or participant discontinuation in the expansion phase of the study. Starting on day 16 of cycle 1, participants also received 200 mg voriconazole orally every 12 hours through day 1 of cycle 2.	Participants received 40 mg gilteritinib orally once daily starting on day 1 of cycle 1 and continued in 28-day cycles until disease progression or participant discontinuation in the expansion phase of the study.	Participants received 80 mg gilteritinib orally once daily starting on day 1 of cycle 1 and continued in 28-day cycles until disease progression or participant discontinuation in the expansion phase of the study.	Participants received 120 mg gilteritinib orally once daily starting on day 1 of cycle 1 and continued in 28-day cycles until disease progression or participant discontinuation in the expansion phase of the study.	Participants received 200 mg gilteritinib orally once daily starting on day 1 of cycle 1 and continued in 28-day cycles until disease progression or participant discontinuation in the expansion phase of the study. On day -1 and day 15 of cycle 1, certain participants also received 500 mg cephalexin as a single oral dose.	Participants received 300 mg gilteritinib orally once daily starting on day 1 of cycle 1 and continued in 28-day cycles until disease progression or participant discontinuation in the expansion phase of the study. On day -1 and day 15 of cycle 1, participants also received 2 mg midazolam as a single oral dose.
Period Title: Overall Study
STARTED	5	3	3	3	4	3	4	11	15	21	69	102	17
Treated	5	3	3	3	3	3	3	12	13	21	66	100	17
COMPLETED	0	0	0	0	0	0	0	0	0	0	0	0	0
NOT COMPLETED	5	3	3	3	4	3	4	11	15	21	69	102	17

Baseline Characteristics

Arm/Group Title	Gilteritinib 20 mg in Escalation Phase	Gilteritinib 40 mg in Escalation Phase	Gilteritinib 80 mg in Escalation Phase	Gilteritinib 120 mg in Escalation Phase	Gilteritinib 200 mg in Escalation Phase	Gilteritinib 300 mg in Escalation Phase	Gilteritinib 450 mg in Escalation Phase	Gilteritinib 20 mg in Expansion Phase	Gilteritinib 40 mg in Expansion Phase	Gilteritinib 80 mg in Expansion Phase	Gilteritinib 120 mg in Expansion Phase	Gilteritinib 200 mg in Expansion Phase	Gilteritinib 300 mg in Expansion Phase	Total
Arm/Group Description	Participants received a single dose of 20 mg gilteritinib orally on day -2 to evaluate pharmacokinetics of gilteritinib. Then starting on day 1 of cycle 1, participants received 20 mg gilteritinib orally once daily in 28-day cycles until disease progression or participant discontinuation in the escalation phase of the study.	Participants received a single dose of 40 mg gilteritinib orally on day -2 to evaluate pharmacokinetics of gilteritinib. Then starting on day 1 of cycle 1, participants received 40 mg gilteritinib orally once daily in 28-day cycles until disease progression or participant discontinuation in the escalation phase of the study.	Participants received a single dose of 80 mg gilteritinib orally on day -2 to evaluate pharmacokinetics of gilteritinib. Then starting on day 1 of cycle 1, participants received 80 mg gilteritinib orally once daily in 28-day cycles until disease progression or participant discontinuation in the escalation phase of the study.	Participants received a single dose of 120 mg gilteritinib orally on day -2 to evaluate pharmacokinetics of gilteritinib. Then starting on day 1 of cycle 1, participants received 120 mg gilteritinib orally once daily in 28-day cycles until disease progression or participant discontinuation in the escalation phase of the study.	Participants received a single dose of 200 mg gilteritinib orally on day -2 to evaluate pharmacokinetics of gilteritinib. Then starting on day 1 of cycle 1, participants received 200 mg gilteritinib orally once daily in 28-day cycles until disease progression or participant discontinuation in the escalation phase of the study.	Participants received a single dose of 300 mg gilteritinib orally on day -2 to evaluate pharmacokinetics of gilteritinib. Then starting on day 1 of cycle 1, participants received 300 mg gilteritinib orally once daily in 28-day cycles until disease progression or participant discontinuation in the escalation phase of the study.	Participants received a single dose of 450 mg gilteritinib orally on day -2 to evaluate pharmacokinetics of gilteritinib. Then starting on day 1 of cycle 1, participants received 450 mg gilteritinib orally once daily in 28-day cycles until disease progression or participant discontinuation in the escalation phase of the study.	Participants received 20 mg gilteritinib orally once daily stating on day 1 of cycle 1 and continued in 28-day cycles until disease progression or participant discontinuation in the expansion phase of the study. Starting on day 16 of cycle 1, participants also received 200 mg voriconazole orally every 12 hours through day 1 of cycle 2.	Participants received 40 mg gilteritinib orally once daily starting on day 1 of cycle 1 and continued in 28-day cycles until disease progression or participant discontinuation in the expansion phase of the study.	Participants received 80 mg gilteritinib orally once daily starting on day 1 of cycle 1 and continued in 28-day cycles until disease progression or participant discontinuation in the expansion phase of the study.	Participants received 120 mg gilteritinib orally once daily starting on day 1 of cycle 1 and continued in 28-day cycles until disease progression or participant discontinuation in the expansion phase of the study.	Participants received 200 mg gilteritinib orally once daily starting on day 1 of cycle 1 and continued in 28-day cycles until disease progression or participant discontinuation in the expansion phase of the study. On day -1 and day 15 of cycle 1, certain participants also received 500 mg cephalexin as a single oral dose.	Participants received 300 mg gilteritinib orally once daily starting on day 1 of cycle 1 and continued in 28-day cycles until disease progression or participant discontinuation in the expansion phase of the study. On day -1 and day 15 of cycle 1, participants also received 2 mg midazolam as a single oral dose.	Total of all reporting groups
Overall Participants	5	3	3	3	3	3	3	12	13	21	66	100	17	252
Age (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	65.8 (6.8)	56.7 (6.7)	61 (8.7)	61.7 (6)	64 (1)	55.3 (25)	61.7 (10.7)	59.3 (15.6)	59.6 (14)	56.3 (18.1)	58.3 (16.7)	59.8 (14.6)	57.7 (15.9)	59 (15.1)
Sex: Female, Male (Count of Participants)
Female	2 40%	1 33.3%	1 33.3%	1 33.3%	2 66.7%	1 33.3%	0 0%	8 66.7%	4 30.8%	12 57.1%	37 56.1%	49 49%	5 29.4%	123 48.8%
Male	3 60%	2 66.7%	2 66.7%	2 66.7%	1 33.3%	2 66.7%	3 100%	4 33.3%	9 69.2%	9 42.9%	29 43.9%	51 51%	12 70.6%	129 51.2%
Race/Ethnicity, Customized (Count of Participants)
Black or African American	0 0%	0 0%	0 0%	1 33.3%	1 33.3%	0 0%	0 0%	1 8.3%	0 0%	4 19%	2 3%	4 4%	3 17.6%	16 6.3%
White	5 100%	2 66.7%	3 100%	2 66.7%	1 33.3%	3 100%	3 100%	10 83.3%	9 69.2%	14 66.7%	57 86.4%	91 91%	13 76.5%	213 84.5%
Asian	0 0%	1 33.3%	0 0%	0 0%	1 33.3%	0 0%	0 0%	0 0%	0 0%	0 0%	1 1.5%	4 4%	0 0%	7 2.8%
Other	0 0%	0 0%	0 0%	0 0%	0 0%	0 0%	0 0%	1 8.3%	4 30.8%	3 14.3%	6 9.1%	1 1%	1 5.9%	16 6.3%
Ethnicity (Count of Participants)
Not Hispanic or Latino	5 100%	3 100%	2 66.7%	3 100%	3 100%	3 100%	3 100%	11 91.7%	12 92.3%	20 95.2%	62 93.9%	97 97%	17 100%	241 95.6%
Hispanic or Latino	0 0%	0 0%	1 33.3%	0 0%	0 0%	0 0%	0 0%	1 8.3%	1 7.7%	1 4.8%	4 6.1%	3 3%	0 0%	11 4.4%
Duration of Disease (AML) (months) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [months]	19.70 (24.62)	10.81 (8.58)	62.46 (6.97)	49.53 (72.17)	9.46 (2.23)	19.75 (NA)	7.21 (4.27)	11.3 (6.61)	10.53 (11.22)	16.3 (9.85)	12.65 (11.33)	10.9 (9.94)	12.09 (17.76)	13.16 (14.97)
Local FLT3 Mutation Status (Count of Participants)
Negative	1 20%	0 0%	0 0%	1 33.3%	1 33.3%	1 33.3%	1 33.3%	1 8.3%	8 61.5%	12 57.1%	13 19.7%	10 10%	9 52.9%	58 23%
Positive	4 80%	3 100%	3 100%	2 66.7%	2 66.7%	2 66.7%	2 66.7%	11 91.7%	5 38.5%	9 42.9%	53 80.3%	90 90%	8 47.1%	194 77%

Outcome Measures

1. Primary Outcome

Title	Number of Participants With Dose Limiting Toxicities (DLTs)
Description	To determine the maximum tolerated dose, safety was assessed by DLTs, defined as any grade ≥ 3 non-hematologic or extramedullary toxicity that occurred within 30 days starting with the first dose taken on day -2, and included the first treatment cycle in the dose escalation phase and in the first treatment cycle (28 days) in the dose expansion phase, that was considered to be possibly or probably related to study drug. Exceptions to this were the following: (1) Alopecia, anorexia or fatigue, (2) Grade 3 nausea and/or vomiting if not required tube feeding or total parenteral nutrition, or diarrhea if not required or prolonged hospitalization that was managed to grade ≤ 2 with standard antiemetic or antidiarrheal medications used at prescribed dose within 7 days of onset, (3) Grade 3 fever with neutropenia, with or without infection, (4) Grade 3 infection.
Time Frame	From first dose up to end of cycle 1 (30 days)

Outcome Measure Data

Analysis Population Description
The analysis population was the SAF. Only evaluable participants (defined as participants who received at least 80% of the intended dose during cycle 1 [received at least 23 daily doses in escalation phase or 22 daily doses in expansion phase during cycle 1] or participants who developed DLT within cycle 1) were included.

Arm/Group Title	Gilteritinib 20 mg in Escalation Phase	Gilteritinib 40 mg in Escalation Phase	Gilteritinib 80 mg in Escalation Phase	Gilteritinib 120 mg in Escalation Phase	Gilteritinib 200 mg in Escalation Phase	Gilteritinib 300 mg in Escalation Phase	Gilteritinib 450 mg in Escalation Phase	Gilteritinib 20 mg in Expansion Phase	Gilteritinib 40 mg in Expansion Phase	Gilteritinib 80 mg in Expansion Phase	Gilteritinib 120 mg in Expansion Phase	Gilteritinib 200 mg in Expansion Phase	Gilteritinib 300 mg in Expansion Phase
Arm/Group Description	Participants received a single dose of 20 mg gilteritinib orally on day -2 to evaluate pharmacokinetics of gilteritinib. Then starting on day 1 of cycle 1, participants received 20 mg gilteritinib orally once daily in 28-day cycles until disease progression or participant discontinuation in the escalation phase of the study.	Participants received a single dose of 40 mg gilteritinib orally on day -2 to evaluate pharmacokinetics of gilteritinib. Then starting on day 1 of cycle 1, participants received 40 mg gilteritinib orally once daily in 28-day cycles until disease progression or participant discontinuation in the escalation phase of the study.	Participants received a single dose of 80 mg gilteritinib orally on day -2 to evaluate pharmacokinetics of gilteritinib. Then starting on day 1 of cycle 1, participants received 80 mg gilteritinib orally once daily in 28-day cycles until disease progression or participant discontinuation in the escalation phase of the study.	Participants received a single dose of 120 mg gilteritinib orally on day -2 to evaluate pharmacokinetics of gilteritinib. Then starting on day 1 of cycle 1, participants received 120 mg gilteritinib orally once daily in 28-day cycles until disease progression or participant discontinuation.	Participants received a single dose of 200 mg gilteritinib orally on day -2 to evaluate pharmacokinetics of gilteritinib. Then starting on day 1 of cycle 1, participants received 200 mg gilteritinib orally once daily in 28-day cycles until disease progression or participant discontinuation in the escalation phase of the study.	Participants received a single dose of 300 mg gilteritinib orally on day -2 to evaluate pharmacokinetics of gilteritinib. Then starting on day 1 of cycle 1, participants received 300 mg gilteritinib orally once daily in 28-day cycles until disease progression or participant discontinuation in the escalation phase of the study.	Participants received a single dose of 450 mg gilteritinib orally on day -2 to evaluate pharmacokinetics of gilteritinib. Then starting on day 1 of cycle 1, participants received 450 mg gilteritinib orally once daily in 28-day cycles until disease progression or participant discontinuation in the escalation phase of the study.	Participants received 20 mg gilteritinib orally once daily stating on day 1 of cycle 1 and continued in 28-day cycles until disease progression or participant discontinuation in the expansion phase of the study. Starting on day 16 of cycle 1, participants also received 200 mg voriconazole orally every 12 hours through day 1 of cycle 2.	Participants received 40 mg gilteritinib orally once daily stating on day 1 of cycle 1 and continued in 28-day cycles until disease progression or participant discontinuation in the expansion phase of the study.	Participants received 80 mg gilteritinib orally once daily stating on day 1 of cycle 1 and continued in 28-day cycles until disease progression or participant discontinuation in the expansion phase of the study.	Participants received 120 mg gilteritinib orally once daily stating on day 1 of cycle 1 and continued in 28-day cycles until disease progression or participant discontinuation in the expansion phase of the study.	Participants received 200 mg gilteritinib orally once daily stating on day 1 of cycle 1 and continued in 28-day cycles until disease progression or participant discontinuation in the expansion phase of the study. On day -1 and day 15 of cycle 1, certain participants also received 500 mg cephalexin as a single oral dose.	Participants received 300 mg gilteritinib orally once daily stating on day 1 of cycle 1 and continued in 28-day cycles until disease progression or participant discontinuation in the expansion phase of the study. On day -1 and day 15 of cycle 1, participants also received 2 mg midazolam as a single oral dose.
Measure Participants	3	3	3	3	3	3	3	9	11	18	62	87	13
Any DLT	0 0%	0 0%	0 0%	0 0%	0 0%	0 0%	2 66.7%	1 8.3%	1 7.7%	2 9.5%	7 10.6%	15 15%	3 17.6%
Blood and lymphatic system disorders	0 0%	0 0%	0 0%	0 0%	0 0%	0 0%	0 0%	0 0%	0 0%	0 0%	0 0%	0 0%	1 5.9%
Cardiac disorders	0 0%	0 0%	0 0%	0 0%	0 0%	0 0%	0 0%	0 0%	0 0%	0 0%	1 1.5%	0 0%	0 0%
Eye disorders	0 0%	0 0%	0 0%	0 0%	0 0%	0 0%	0 0%	0 0%	0 0%	1 4.8%	0 0%	0 0%	0 0%
Gastrointestinal disorders	0 0%	0 0%	0 0%	0 0%	0 0%	0 0%	1 33.3%	0 0%	0 0%	0 0%	1 1.5%	4 4%	1 5.9%
General disorders & administration site conditions	0 0%	0 0%	0 0%	0 0%	0 0%	0 0%	0 0%	0 0%	0 0%	0 0%	0 0%	1 1%	0 0%
Hepatobiliary disorders	0 0%	0 0%	0 0%	0 0%	0 0%	0 0%	0 0%	0 0%	0 0%	0 0%	1 1.5%	0 0%	0 0%
Infections and infestations	0 0%	0 0%	0 0%	0 0%	0 0%	0 0%	0 0%	0 0%	1 7.7%	1 4.8%	0 0%	0 0%	0 0%
Investigations	0 0%	0 0%	0 0%	0 0%	0 0%	0 0%	1 33.3%	0 0%	0 0%	0 0%	2 3%	6 6%	2 11.8%
Metabolism and nutrition disorders	0 0%	0 0%	0 0%	0 0%	0 0%	0 0%	0 0%	0 0%	0 0%	0 0%	0 0%	2 2%	0 0%
Musculoskeletal and connective tissue disorders	0 0%	0 0%	0 0%	0 0%	0 0%	0 0%	0 0%	0 0%	0 0%	0 0%	0 0%	1 1%	1 5.9%
Nervous system disorders	0 0%	0 0%	0 0%	0 0%	0 0%	0 0%	0 0%	1 8.3%	0 0%	0 0%	0 0%	3 3%	0 0%
Renal and urinary disorders	0 0%	0 0%	0 0%	0 0%	0 0%	0 0%	0 0%	0 0%	0 0%	0 0%	1 1.5%	0 0%	0 0%
Reproductive system and breast disorders	0 0%	0 0%	0 0%	0 0%	0 0%	0 0%	0 0%	0 0%	0 0%	0 0%	0 0%	1 1%	0 0%
Respiratory, thoracic and mediastinal disorders	0 0%	0 0%	0 0%	0 0%	0 0%	0 0%	0 0%	0 0%	0 0%	0 0%	1 1.5%	2 2%	1 5.9%
Vascular disorders	0 0%	0 0%	0 0%	0 0%	0 0%	0 0%	0 0%	0 0%	0 0%	0 0%	0 0%	2 2%	1 5.9%

2. Primary Outcome

Title	Number of Participants With Adverse Events (AEs)
Description	Safety was assessed by AEs, which included abnormalities identified during a medical test (e.g. laboratory tests, vital signs, electrocardiogram, etc.) if the abnormality induced clinical signs or symptoms, needed active intervention, interruption or discontinuation of study medication or was clinically significant. A treatment-emergent AE (TEAE) was defined as an AE observed after starting administration of the study drug up to 30 days after last dose of study drug (for participants who underwent hematopoietic stem cell transplantation [HSCT]: defined as AEs observed after starting study drug until the last dose before on study HSCT plus 30 days, and AEs that began after resumption of gilteritinib and within 30 days after the last dose of gilteritinib). AEs were graded using the National Cancer Institute Common Terminology Criteria for Adverse Events Version 4.03 (1-Mild, 2-Moderate, 3-Severe, 4-LifeThreatening, 5-Death).
Time Frame	From first dose of study drug up to 30 days after last dose of study drug (median treatment duration was 69.5 days, minimum of 3 days and maximum of 1320 days)

Outcome Measure Data

Analysis Population Description
The analysis population was the SAF.

Arm/Group Title	Gilteritinib 20 mg in Escalation Phase	Gilteritinib 40 mg in Escalation Phase	Gilteritinib 80 mg in Escalation Phase	Gilteritinib 120 mg in Escalation Phase	Gilteritinib 200 mg in Escalation Phase	Gilteritinib 300 mg in Escalation Phase	Gilteritinib 450 mg in Escalation Phase	Gilteritinib 20 mg in Expansion Phase	Gilteritinib 40 mg in Expansion Phase	Gilteritinib 80 mg in Expansion Phase	Gilteritinib 120 mg in Expansion Phase	Gilteritinib 200 mg in Expansion Phase	Gilteritinib 300 mg in Expansion Phase
Arm/Group Description	Participants received a single dose of 20 mg gilteritinib orally on day -2 to evaluate pharmacokinetics of gilteritinib. Then starting on day 1 of cycle 1, participants received 20 mg gilteritinib orally once daily in 28-day cycles until disease progression or participant discontinuation in the escalation phase of the study.	Participants received a single dose of 40 mg gilteritinib orally on day -2 to evaluate pharmacokinetics of gilteritinib. Then starting on day 1 of cycle 1, participants received 40 mg gilteritinib orally once daily in 28-day cycles until disease progression or participant discontinuation in the escalation phase of the study.	Participants received a single dose of 80 mg gilteritinib orally on day -2 to evaluate pharmacokinetics of gilteritinib. Then starting on day 1 of cycle 1, participants received 80 mg gilteritinib orally once daily in 28-day cycles until disease progression or participant discontinuation in the escalation phase of the study.	Participants received a single dose of 120 mg gilteritinib orally on day -2 to evaluate pharmacokinetics of gilteritinib. Then starting on day 1 of cycle 1, participants received 120 mg gilteritinib orally once daily in 28-day cycles until disease progression or participant discontinuation in the escalation phase of the study.	Participants received a single dose of 200 mg gilteritinib orally on day -2 to evaluate pharmacokinetics of gilteritinib. Then starting on day 1 of cycle 1, participants received 200 mg gilteritinib orally once daily in 28-day cycles until disease progression or participant discontinuation in the escalation phase of the study.	Participants received a single dose of 300 mg gilteritinib orally on day -2 to evaluate pharmacokinetics of gilteritinib. Then starting on day 1 of cycle 1, participants received 300 mg gilteritinib orally once daily in 28-day cycles until disease progression or participant discontinuation in the escalation phase of the study.	Participants received a single dose of 450 mg gilteritinib orally on day -2 to evaluate pharmacokinetics of gilteritinib. Then starting on day 1 of cycle 1, participants received 450 mg gilteritinib orally once daily in 28-day cycles until disease progression or participant discontinuation in the escalation phase of the study.	Participants received 20 mg gilteritinib orally once daily stating on day 1 of cycle 1 and continued in 28-day cycles until disease progression or participant discontinuation in the expansion phase of the study. Starting on day 16 of cycle 1, participants also received 200 mg voriconazole orally every 12 hours through day 1 of cycle 2.	Participants received 40 mg gilteritinib orally once daily stating on day 1 of cycle 1 and continued in 28-day cycles until disease progression or participant discontinuation in the expansion phase of the study.	Participants received 80 mg gilteritinib orally once daily stating on day 1 of cycle 1 and continued in 28-day cycles until disease progression or participant discontinuation in the expansion phase of the study.	Participants received 120 mg gilteritinib orally once daily stating on day 1 of cycle 1 and continued in 28-day cycles until disease progression or participant discontinuation in the expansion phase of the study.	Participants received 200 mg gilteritinib orally once daily stating on day 1 of cycle 1 and continued in 28-day cycles until disease progression or participant discontinuation in the expansion phase of the study. On day -1 and day 15 of cycle 1, certain participants also received 500 mg cephalexin as a single oral dose.	Participants received 300 mg gilteritinib orally once daily stating on day 1 of cycle 1 and continued in 28-day cycles until disease progression or participant discontinuation in the expansion phase of the study. On day -1 and day 15 of cycle 1, participants also received 2 mg midazolam as a single oral dose.
Measure Participants	5	3	3	3	3	3	3	12	13	21	66	100	17
AEs	5 100%	3 100%	3 100%	3 100%	3 100%	3 100%	3 100%	12 100%	13 100%	20 95.2%	64 97%	100 100%	17 100%
Drug-Related AEs	3 60%	2 66.7%	1 33.3%	3 100%	3 100%	2 66.7%	3 100%	7 58.3%	6 46.2%	17 81%	52 78.8%	77 77%	13 76.5%
Deaths	2 40%	2 66.7%	0 0%	1 33.3%	1 33.3%	1 33.3%	1 33.3%	3 25%	4 30.8%	11 52.4%	23 34.8%	49 49%	7 41.2%
Serious AEs	2 40%	2 66.7%	2 66.7%	1 33.3%	2 66.7%	2 66.7%	2 66.7%	8 66.7%	12 92.3%	19 90.5%	52 78.8%	92 92%	14 82.4%
Drug-Related Serious AEs	0 0%	0 0%	0 0%	1 33.3%	1 33.3%	0 0%	2 66.7%	2 16.7%	1 7.7%	10 47.6%	19 28.8%	36 36%	4 23.5%
AEs Leading to Discontinuation of Study Drug	2 40%	0 0%	1 33.3%	0 0%	1 33.3%	0 0%	1 33.3%	2 16.7%	5 38.5%	11 52.4%	12 18.2%	46 46%	6 35.3%
Drug-Related AEs Leading to Discont. of Study Drug	0 0%	0 0%	0 0%	0 0%	0 0%	0 0%	0 0%	1 8.3%	1 7.7%	4 19%	5 7.6%	10 10%	3 17.6%
Grade 3 or Higher TEAEs	3 60%	2 66.7%	2 66.7%	1 33.3%	2 66.7%	2 66.7%	3 100%	9 75%	13 100%	20 95.2%	59 89.4%	99 99%	14 82.4%
AEs During On-Study HSCT Period	0 0%	0 0%	0 0%	0 0%	0 0%	0 0%	0 0%	0 0%	0 0%	0 0%	3 4.5%	7 7%	0 0%
Serious AEs During On-Study HSCT	0 0%	0 0%	0 0%	0 0%	0 0%	0 0%	0 0%	0 0%	0 0%	0 0%	0 0%	3 3%	0 0%

3. Primary Outcome

Title	Area Under the Concentration-time Curve Over the 24-Hour Dosing Interval (AUC24) After Single and Multiple Doses of Gilteritinib
Description	Plasma samples were used for pharmacokinetic assessments.
Time Frame	Day -2 and cycle 1 day 15: predose, 0.5, 1, 2, 4, 6, 24 hours postdose

Outcome Measure Data

Analysis Population Description
Pharmacokinetics analysis set (PKAS) - consisted of the subset of the SAF for which sufficient plasma concentration data were available to facilitate derivation of at least 1 pharmacokinetic parameter and for whom the time of dosing on the day of sampling was known. Participants with available data were included in the analysis.

Arm/Group Title	Gilteritinib 20 mg in Escalation Phase	Gilteritinib 40 mg in Escalation Phase	Gilteritinib 80 mg in Escalation Phase	Gilteritinib 120 mg in Escalation Phase	Gilteritinib 200 mg in Escalation Phase	Gilteritinib 300 mg in Escalation Phase	Gilteritinib 450 mg in Escalation Phase
Arm/Group Description	Participants received a single dose of 20 mg gilteritinib orally on day -2 to evaluate pharmacokinetics of gilteritinib. Then starting on day 1 of cycle 1, participants received 20 mg gilteritinib orally once daily in 28-day cycles until disease progression or participant discontinuation in the escalation phase of the study.	Participants received a single dose of 40 mg gilteritinib orally on day -2 to evaluate pharmacokinetics of gilteritinib. Then starting on day 1 of cycle 1, participants received 40 mg gilteritinib orally once daily in 28-day cycles until disease progression or participant discontinuation in the escalation phase of the study.	Participants received a single dose of 80 mg gilteritinib orally on day -2 to evaluate pharmacokinetics of gilteritinib. Then starting on day 1 of cycle 1, participants received 80 mg gilteritinib orally once daily in 28-day cycles until disease progression or participant discontinuation in the escalation phase of the study.	Participants received a single dose of 120 mg gilteritinib orally on day -2 to evaluate pharmacokinetics of gilteritinib. Then starting on day 1 of cycle 1, participants received 120 mg gilteritinib orally once daily in 28-day cycles until disease progression or participant discontinuation in the escalation phase of the study.	Participants received a single dose of 200 mg gilteritinib orally on day -2 to evaluate pharmacokinetics of gilteritinib. Then starting on day 1 of cycle 1, participants received 200 mg gilteritinib orally once daily in 28-day cycles until disease progression or participant discontinuation in the escalation phase of the study.	Participants received a single dose of 300 mg gilteritinib orally on day -2 to evaluate pharmacokinetics of gilteritinib. Then starting on day 1 of cycle 1, participants received 300 mg gilteritinib orally once daily in 28-day cycles until disease progression or participant discontinuation in the escalation phase of the study.	Participants received a single dose of 450 mg gilteritinib orally on day -2 to evaluate pharmacokinetics of gilteritinib. Then starting on day 1 of cycle 1, participants received 450 mg gilteritinib orally once daily in 28-day cycles until disease progression or participant discontinuation in the escalation phase of the study.
Measure Participants	5	3	3	3	3	3	3
Day -2	302.1 (207.0)	360.0 (223.5)	1216 (472.6)	2480 (1972)	3022 (843.6)	4163 (3178)	3324 (221.1)
Cycle 1 Day 15	1299 (1006)	2482 (33.28)	6958 (3273)	6943 (3221)	31428 (21412)	31005 (10068)	34768 (NA)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Gilteritinib 20 mg in Escalation Phase, Gilteritinib 40 mg in Escalation Phase, Gilteritinib 80 mg in Escalation Phase, Gilteritinib 120 mg in Escalation Phase, Gilteritinib 200 mg in Escalation Phase, Gilteritinib 300 mg in Escalation Phase, Gilteritinib 450 mg in Escalation Phase
	Comments	Dose Proportionality (Single Dose / Day -2) was evaluated using the power model.
	Type of Statistical Test	Other
	Comments

Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments

Method of Estimation	Estimation Parameter	Slope
	Estimated Value	0.990
	Confidence Interval	(2-Sided) 90% 0.788 to 1.19
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Gilteritinib 20 mg in Escalation Phase, Gilteritinib 40 mg in Escalation Phase, Gilteritinib 80 mg in Escalation Phase, Gilteritinib 120 mg in Escalation Phase, Gilteritinib 200 mg in Escalation Phase, Gilteritinib 300 mg in Escalation Phase, Gilteritinib 450 mg in Escalation Phase
	Comments	Dose Proportionality (Multiple Dose / Cycle 1 Day 15) was evaluated using the power model.
	Type of Statistical Test	Other
	Comments

Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments

Method of Estimation	Estimation Parameter	Slope
	Estimated Value	1.22
	Confidence Interval	(2-Sided) 90% 1.00 to 1.43
	Parameter Dispersion	Type: Value:
	Estimation Comments

4. Primary Outcome

Title	Maximum Concentration (Cmax) After Single and Multiple Doses of Gilteritinib
Description	Plasma samples were used for pharmacokinetic assessments.
Time Frame	Day -2 and cycle 1 day 15: predose, 0.5, 1, 2, 4, 6, 24 hours postdose

Outcome Measure Data

Analysis Population Description
The analysis population was the PKAS with available data.

Arm/Group Title	Gilteritinib 20 mg in Escalation Phase	Gilteritinib 40 mg in Escalation Phase	Gilteritinib 80 mg in Escalation Phase	Gilteritinib 120 mg in Escalation Phase	Gilteritinib 200 mg in Escalation Phase	Gilteritinib 300 mg in Escalation Phase	Gilteritinib 450 mg in Escalation Phase
Arm/Group Description	Participants received a single dose of 20 mg gilteritinib orally on day -2 to evaluate pharmacokinetics of gilteritinib. Then starting on day 1 of cycle 1, participants received 20 mg gilteritinib orally once daily in 28-day cycles until disease progression or participant discontinuation in the escalation phase of the study..	Participants received a single dose of 40 mg gilteritinib orally on day -2 to evaluate pharmacokinetics of gilteritinib. Then starting on day 1 of cycle 1, participants received 40 mg gilteritinib orally once daily in 28-day cycles until disease progression or participant discontinuation in the escalation phase of the study..	Participants received a single dose of 80 mg gilteritinib orally on day -2 to evaluate pharmacokinetics of gilteritinib. Then starting on day 1 of cycle 1, participants received 80 mg gilteritinib orally once daily in 28-day cycles until disease progression or participant discontinuation in the escalation phase of the study.	Participants received a single dose of 120 mg gilteritinib orally on day -2 to evaluate pharmacokinetics of gilteritinib. Then starting on day 1 of cycle 1, participants received 120 mg gilteritinib orally once daily in 28-day cycles until disease progression or participant discontinuation in the escalation phase of the study.	Participants received a single dose of 200 mg gilteritinib orally on day -2 to evaluate pharmacokinetics of gilteritinib. Then starting on day 1 of cycle 1, participants received 200 mg gilteritinib orally once daily in 28-day cycles until disease progression or participant discontinuation in the escalation phase of the study.	Participants received a single dose of 300 mg gilteritinib orally on day -2 to evaluate pharmacokinetics of gilteritinib. Then starting on day 1 of cycle 1, participants received 300 mg gilteritinib orally once daily in 28-day cycles until disease progression or participant discontinuation in the escalation phase of the study.	Participants received a single dose of 450 mg gilteritinib orally on day -2 to evaluate pharmacokinetics of gilteritinib. Then starting on day 1 of cycle 1, participants received 450 mg gilteritinib orally once daily in 28-day cycles until disease progression or participant discontinuation in the escalation phase of the study.
Measure Participants	5	3	3	3	3	3	3
Day -2	28.13 (21.49)	24.98 (14.58)	75.29 (25.22)	136.7 (94.37)	168.2 (45.34)	204.3 (136.4)	207.6 (51.81)
Cycle 1 day 15	64.64 (48.77)	107.6 (31.92)	376.4 (150.5)	374.2 (190.1)	1462 (815.1)	1525 (664.6)	1528 (NA)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Gilteritinib 20 mg in Escalation Phase, Gilteritinib 40 mg in Escalation Phase, Gilteritinib 80 mg in Escalation Phase, Gilteritinib 120 mg in Escalation Phase, Gilteritinib 200 mg in Escalation Phase, Gilteritinib 300 mg in Escalation Phase, Gilteritinib 450 mg in Escalation Phase
	Comments	Dose Proportionality (Single Dose / Day -2) was evaluated using the power model.
	Type of Statistical Test	Other
	Comments

Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments

Method of Estimation	Estimation Parameter	Slope
	Estimated Value	0.808
	Confidence Interval	(2-Sided) 90% 0.629 to 0.988
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Gilteritinib 20 mg in Escalation Phase, Gilteritinib 40 mg in Escalation Phase, Gilteritinib 80 mg in Escalation Phase, Gilteritinib 120 mg in Escalation Phase, Gilteritinib 200 mg in Escalation Phase, Gilteritinib 300 mg in Escalation Phase, Gilteritinib 450 mg in Escalation Phase
	Comments	Dose Proportionality (Multiple Dose / Cycle 1 Day 15) was evaluated using the power model.
	Type of Statistical Test	Other
	Comments

Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments

Method of Estimation	Estimation Parameter	Slope
	Estimated Value	1.21
	Confidence Interval	(2-Sided) 90% 1.02 to 1.41
	Parameter Dispersion	Type: Value:
	Estimation Comments

5. Primary Outcome

Title	Area Under the Concentration-time Curve From the Time of Dosing to the Last Measurable Concentration (AUClast) After Single and Multiple Doses of Gilteritinib
Description	Plasma samples were used for pharmacokinetic assessments.
Time Frame	Day -2 and cycle 1 day 15: predose, 0.5, 1, 2, 4, 6, 24 hours postdose

Outcome Measure Data

Analysis Population Description
The analysis population was the PKAS with available data.

Arm/Group Title	Gilteritinib 20 mg in Escalation Phase	Gilteritinib 40 mg in Escalation Phase	Gilteritinib 80 mg in Escalation Phase	Gilteritinib 120 mg in Escalation Phase	Gilteritinib 200 mg in Escalation Phase	Gilteritinib 300 mg in Escalation Phase	Gilteritinib 450 mg in Escalation Phase
Arm/Group Description	Participants received a single dose of 20 mg gilteritinib orally on day -2 to evaluate pharmacokinetics of gilteritinib. Then starting on day 1 of cycle 1, participants received 20 mg gilteritinib orally once daily in 28-day cycles until disease progression or participant discontinuation in the escalation phase of the study.	Participants received a single dose of 40 mg gilteritinib orally on day -2 to evaluate pharmacokinetics of gilteritinib. Then starting on day 1 of cycle 1, participants received 40 mg gilteritinib orally once daily in 28-day cycles until disease progression or participant discontinuation in the escalation phase of the study.	Participants received a single dose of 80 mg gilteritinib orally on day -2 to evaluate pharmacokinetics of gilteritinib. Then starting on day 1 of cycle 1, participants received 80 mg gilteritinib orally once daily in 28-day cycles until disease progression or participant discontinuation in the escalation phase of the study.	Participants received a single dose of 120 mg gilteritinib orally on day -2 to evaluate pharmacokinetics of gilteritinib. Then starting on day 1 of cycle 1, participants received 120 mg gilteritinib orally once daily in 28-day cycles until disease progression or participant discontinuation in the escalation phase of the study.	Participants received a single dose of 200 mg gilteritinib orally on day -2 to evaluate pharmacokinetics of gilteritinib. Then starting on day 1 of cycle 1, participants received 200 mg gilteritinib orally once daily in 28-day cycles until disease progression or participant discontinuation in the escalation phase of the study.	Participants received a single dose of 300 mg gilteritinib orally on day -2 to evaluate pharmacokinetics of gilteritinib. Then starting on day 1 of cycle 1, participants received 300 mg gilteritinib orally once daily in 28-day cycles until disease progression or participant discontinuation in the escalation phase of the study.	Participants received a single dose of 450 mg gilteritinib orally on day -2 to evaluate pharmacokinetics of gilteritinib. Then starting on day 1 of cycle 1, participants received 450 mg gilteritinib orally once daily in 28-day cycles until disease progression or participant discontinuation in the escalation phase of the study.
Measure Participants	5	3	3	3	3	3	3
Day -2	303.0 (207.1)	360.4 (224.1)	1216 (472.6)	2480 (1972)	3024 (846.2)	4181 (3189)	2544 (1427)
Cycle 1 day -15	1030 (984.2)	1990 (1422)	7111 (3525)	6943 (3221)	32248 (22571)	31749 (10090)	35506 (NA)

6. Primary Outcome

Title	Time to Observed Cmax (Tmax) After Single and Multiple Doses of Gilteritinib
Description	Plasma samples were used for pharmacokinetic assessments.
Time Frame	Day -2 and cycle 1 day 15: predose, 0.5, 1, 2, 4, 6, 24 hours postdose

Outcome Measure Data

Analysis Population Description
The analysis population was the PKAS with available data.

Arm/Group Title	Gilteritinib 20 mg in Escalation Phase	Gilteritinib 40 mg in Escalation Phase	Gilteritinib 80 mg in Escalation Phase	Gilteritinib 120 mg in Escalation Phase	Gilteritinib 200 mg in Escalation Phase	Gilteritinib 300 mg in Escalation Phase	Gilteritinib 450 mg in Escalation Phase
Arm/Group Description	Participants received a single dose of 20 mg gilteritinib orally on day -2 to evaluate pharmacokinetics of gilteritinib. Then starting on day 1 of cycle 1, participants received 20 mg gilteritinib orally once daily in 28-day cycles until disease progression or participant discontinuation in the escalation phase of the study.	Participants received a single dose of 40 mg gilteritinib orally on day -2 to evaluate pharmacokinetics of gilteritinib. Then starting on day 1 of cycle 1, participants received 40 mg gilteritinib orally once daily in 28-day cycles until disease progression or participant discontinuation in the escalation phase of the study.	Participants received a single dose of 80 mg gilteritinib orally on day -2 to evaluate pharmacokinetics of gilteritinib. Then starting on day 1 of cycle 1, participants received 80 mg gilteritinib orally once daily in 28-day cycles until disease progression or participant discontinuation in the escalation phase of the study.	Participants received a single dose of 120 mg gilteritinib orally on day -2 to evaluate pharmacokinetics of gilteritinib. Then starting on day 1 of cycle 1, participants received 120 mg gilteritinib orally once daily in 28-day cycles until disease progression or participant discontinuation in the escalation phase of the study.	Participants received a single dose of 200 mg gilteritinib orally on day -2 to evaluate pharmacokinetics of gilteritinib. Then starting on day 1 of cycle 1, participants received 200 mg gilteritinib orally once daily in 28-day cycles until disease progression or participant discontinuation in the escalation phase of the study.	Participants received a single dose of 300 mg gilteritinib orally on day -2 to evaluate pharmacokinetics of gilteritinib. Then starting on day 1 of cycle 1, participants received 300 mg gilteritinib orally once daily in 28-day cycles until disease progression or participant discontinuation in the escalation phase of the study.	Participants received a single dose of 450 mg gilteritinib orally on day -2 to evaluate pharmacokinetics of gilteritinib. Then starting on day 1 of cycle 1, participants received 450 mg gilteritinib orally once daily in 28-day cycles until disease progression or participant discontinuation in the escalation phase of the study.
Measure Participants	5	3	3	3	3	3	3
Day -2	2.00	5.983	4.000	2.083	5.233	6.067	5.783
Cycle 1 day 15	4.008	3.867	4.333	2.167	6.033	6.050	5.933

7. Primary Outcome

Title	Terminal Elimination Half-life (t1/2) After Multiple Doses of Gilteritinib
Description	Plasma samples were used for pharmacokinetic assessments.
Time Frame	Cycle 1 day 15: predose, 0.5, 1, 2, 4, 6, 24 hours postdose

Outcome Measure Data

Analysis Population Description
The analysis population was the PKAS with available data.

Arm/Group Title	Gilteritinib 20 mg in Escalation Phase	Gilteritinib 40 mg in Escalation Phase	Gilteritinib 80 mg in Escalation Phase	Gilteritinib 120 mg in Escalation Phase	Gilteritinib 200 mg in Escalation Phase	Gilteritinib 300 mg in Escalation Phase	Gilteritinib 450 mg in Escalation Phase
Arm/Group Description	Participants received a single dose of 20 mg gilteritinib orally on day -2 to evaluate pharmacokinetics of gilteritinib. Then starting on day 1 of cycle 1, participants received 20 mg gilteritinib orally once daily in 28-day cycles until disease progression or participant discontinuation in the escalation phase of the study.	Participants received a single dose of 40 mg gilteritinib orally on day -2 to evaluate pharmacokinetics of gilteritinib. Then starting on day 1 of cycle 1, participants received 40 mg gilteritinib orally once daily in 28-day cycles until disease progression or participant discontinuation in the escalation phase of the study.	Participants received a single dose of 80 mg gilteritinib orally on day -2 to evaluate pharmacokinetics of gilteritinib. Then starting on day 1 of cycle 1, participants received 80 mg gilteritinib orally once daily in 28-day cycles until disease progression or participant discontinuation in the escalation phase of the study.	Participants received a single dose of 120 mg gilteritinib orally on day -2 to evaluate pharmacokinetics of gilteritinib. Then starting on day 1 of cycle 1, participants received 120 mg gilteritinib orally once daily in 28-day cycles until disease progression or participant discontinuation in the escalation phase of the study.	Participants received a single dose of 200 mg gilteritinib orally on day -2 to evaluate pharmacokinetics of gilteritinib. Then starting on day 1 of cycle 1, participants received 200 mg gilteritinib orally once daily in 28-day cycles until disease progression or participant discontinuation in the escalation phase of the study.	Participants received a single dose of 300 mg gilteritinib orally on day -2 to evaluate pharmacokinetics of gilteritinib. Then starting on day 1 of cycle 1, participants received 300 mg gilteritinib orally once daily in 28-day cycles until disease progression or participant discontinuation in the escalation phase of the study.	Participants received a single dose of 450 mg gilteritinib orally on day -2 to evaluate pharmacokinetics of gilteritinib. Then starting on day 1 of cycle 1, participants received 450 mg gilteritinib orally once daily in 28-day cycles until disease progression or participant discontinuation in the escalation phase of the study.
Measure Participants	3	2	3	3	2	3	0
Mean (Standard Deviation) [hours]	62.14 (17.88)	151.8 (129.2)	86.11 (24.08)	45.85 (18.83)	141.9 (61.51)	142.2 (55.04)

8. Primary Outcome

Title	Accumulation Ratio After Multiple Doses of Gilteritinib
Description	Plasma samples were used for pharmacokinetic assessments.
Time Frame	Cycle 1 day 15: predose, 0.5, 1, 2, 4, 6, 24 hours postdose

Outcome Measure Data

Analysis Population Description
The analysis population was the PKAS with available data.

Arm/Group Title	Gilteritinib 20 mg in Escalation Phase	Gilteritinib 40 mg in Escalation Phase	Gilteritinib 80 mg in Escalation Phase	Gilteritinib 120 mg in Escalation Phase	Gilteritinib 200 mg in Escalation Phase	Gilteritinib 300 mg in Escalation Phase	Gilteritinib 450 mg in Escalation Phase
Arm/Group Description	Participants received a single dose of 20 mg gilteritinib orally on day -2 to evaluate pharmacokinetics of gilteritinib. Then starting on day 1 of cycle 1, participants received 20 mg gilteritinib orally once daily in 28-day cycles until disease progression or participant discontinuation in the escalation phase of the study.	Participants received a single dose of 40 mg gilteritinib orally on day -2 to evaluate pharmacokinetics of gilteritinib. Then starting on day 1 of cycle 1, participants received 40 mg gilteritinib orally once daily in 28-day cycles until disease progression or participant discontinuation in the escalation phase of the study.	Participants received a single dose of 80 mg gilteritinib orally on day -2 to evaluate pharmacokinetics of gilteritinib. Then starting on day 1 of cycle 1, participants received 80 mg gilteritinib orally once daily in 28-day cycles until disease progression or participant discontinuation in the escalation phase of the study.	Participants received a single dose of 120 mg gilteritinib orally on day -2 to evaluate pharmacokinetics of gilteritinib. Then starting on day 1 of cycle 1, participants received 120 mg gilteritinib orally once daily in 28-day cycles until disease progression or participant discontinuation in the escalation phase of the study.	Participants received a single dose of 200 mg gilteritinib orally on day -2 to evaluate pharmacokinetics of gilteritinib. Then starting on day 1 of cycle 1, participants received 200 mg gilteritinib orally once daily in 28-day cycles until disease progression or participant discontinuation in the escalation phase of the study.	Participants received a single dose of 300 mg gilteritinib orally on day -2 to evaluate pharmacokinetics of gilteritinib. Then starting on day 1 of cycle 1, participants received 300 mg gilteritinib orally once daily in 28-day cycles until disease progression or participant discontinuation in the escalation phase of the study.	Participants received a single dose of 450 mg gilteritinib orally on day -2 to evaluate pharmacokinetics of gilteritinib. Then starting on day 1 of cycle 1, participants received 450 mg gilteritinib orally once daily in in the escalation phase of the study.28-day cycles until disease progression or participant discontinuation in the escalation phase of the study.
Measure Participants	3	2	3	3	2	3	0
Mean (Standard Deviation) [ratio]	4.259 (1.069)	9.640 (7.754)	5.693 (1.442)	3.290 (1.118)	9.041 (3.693)	9.057 (3.303)

9. Secondary Outcome

Title	Percentage of Participants With Complete Remission (CR) During the First 2 Cycles
Description	CR was defined according to modified Cheson criteria (2003), using centrally evaluated myeloblast counts from bone marrow aspirate/biopsy assessments and centrally evaluated hematology results; if neither central bone marrow aspirate nor biopsy was available, myeloblast was imputed with locally evaluated bone marrow aspirate/biopsy assessments (derived response). Participants were classified as being in CR when they had bone marrow regenerating normal hematopoietic cells, achieved a morphologic leukemia-free state, had an absolute neutrophil count (ANC) > 1 x 10^9/L, platelet count ≥ 100 x 10^9/L, normal marrow differential with < 5% blasts, had been red blood cell (RBC) and platelet transfusion independent (defined as 1 week without RBC transfusion and 1 week without platelet transfusion), had no presence of Auer rods and no evidence of extramedullary leukemia, and blast counts in peripheral blood had been ≤ 2%. Exact 95% confidence interval was estimated using binomial distribution.
Time Frame	During the first 2 cycles (56 days)

Outcome Measure Data

Analysis Population Description
Full analysis set (FAS) - consisted of all participants who were enrolled, took at least 1 dose of study drug and who had at least 1 posttreatment data point. Re-enrolled participants and participants from one site due to concerns with this site's GCP compliance were excluded. Participants were summarized under planned reporting groups in the FAS.

Arm/Group Title	Gilteritinib 20 mg	Gilteritinib 40 mg	Gilteritinib 80 mg	Gilteritinib 120 mg	Gilteritinib 200 mg	Gilteritinib 300 mg	Gilteritinib 450 mg
Arm/Group Description	Participants received 20 mg gilteritinib orally once on day -2, and starting on day 1 of cycle 1, participants received 20 mg gilteritinib orally once daily in 28-day cycles until disease progression or participant discontinuation.	Participants received 40 mg gilteritinib orally once on day -2, and starting on day 1 of cycle 1, participants received 40 mg gilteritinib orally once daily in 28-day cycles until disease progression or participant discontinuation.	Participants received 80 mg gilteritinib orally once on day -2, and starting on day 1 of cycle 1, participants received 80 mg gilteritinib orally once daily in 28-day cycles until disease progression or participant discontinuation.	Participants received 120 mg gilteritinib orally once on day -2, and starting on day 1 of cycle 1, participants received 120 mg gilteritinib orally once daily in 28-day cycles until disease progression or participant discontinuation.	Participants received 200 mg gilteritinib orally once on day -2, and starting on day 1 of cycle 1, participants received 200 mg gilteritinib orally once daily in 28-day cycles until disease progression or participant discontinuation.	Participants received 300 mg gilteritinib orally once on day -2, and starting on day 1 of cycle 1, participants received 300 mg gilteritinib orally once daily in 28-day cycles until disease progression or participant discontinuation.	Participants received 450 mg gilteritinib orally once on day -2, and starting on day 1 of cycle 1, participants received 450 mg gilteritinib orally once daily in 28-day cycles until disease progression or participant discontinuation.
Measure Participants	16	16	24	70	100	20	3
FLT3 Mutation Positive	0 0%	0 0%	8.3 276.7%	3.6 120%	3.4 113.3%	10 333.3%	0 0%
FLT3 Mutation Negative	50.0 1000%	0 0%	0 0%	0 0%	0 0%	0 0%	0 0%
All Participants	6.3 126%	0 0%	4.2 140%	2.9 96.7%	3.0 100%	5.0 166.7%	0 0%

10. Secondary Outcome

Title	Percentage of Participants With CR During Treatment
Description	CR was defined according to modified Cheson criteria (2003), using centrally evaluated myeloblast counts from bone marrow aspirate/biopsy assessments and centrally evaluated hematology results; if neither central bone marrow aspirate nor biopsy was available, myeloblast was imputed with locally evaluated bone marrow aspirate/biopsy assessments (derived response). Participants were classified as being in CR when they had bone marrow regenerating normal hematopoietic cells, achieved a morphologic leukemia-free state, had an absolute neutrophil count (ANC) > 1 x 10^9/L, platelet count ≥ 100 x 10^9/L, normal marrow differential with < 5% blasts, had been red blood cell (RBC) and platelet transfusion independent (defined as 1 week without RBC transfusion and 1 week without platelet transfusion), had no presence of Auer rods and no evidence of extramedullary leukemia, and blast counts in peripheral blood had been ≤ 2%. Exact 95% confidence interval was estimated using binomial distribution.
Time Frame	Up to end of treatment (median treatment duration was 69.5 days, minimum of 3 days and maximum of 1320 days)

Outcome Measure Data

Analysis Population Description
The analysis population was the FAS.

Arm/Group Title	Gilteritinib 20 mg	Gilteritinib 40 mg	Gilteritinib 80 mg	Gilteritinib 120 mg	Gilteritinib 200 mg	Gilteritinib 300 mg	Gilteritinib 450 mg
Arm/Group Description	Participants received 20 mg gilteritinib orally once on day -2, and starting on day 1 of cycle 1, participants received 20 mg gilteritinib orally once daily in 28-day cycles until disease progression or participant discontinuation.	Participants received 40 mg gilteritinib orally once on day -2, and starting on day 1 of cycle 1, participants received 40 mg gilteritinib orally once daily in 28-day cycles until disease progression or participant discontinuation.	Participants received 80 mg gilteritinib orally once on day -2, and starting on day 1 of cycle 1, participants received 80 mg gilteritinib orally once daily in 28-day cycles until disease progression or participant discontinuation.	Participants received 120 mg gilteritinib orally once on day -2, and starting on day 1 of cycle 1, participants received 120 mg gilteritinib orally once daily in 28-day cycles until disease progression or participant discontinuation.	Participants received 200 mg gilteritinib orally once on day -2, and starting on day 1 of cycle 1, participants received 200 mg gilteritinib orally once daily in 28-day cycles until disease progression or participant discontinuation.	Participants received 300 mg gilteritinib orally once on day -2, and starting on day 1 of cycle 1, participants received 300 mg gilteritinib orally once daily in 28-day cycles until disease progression or participant discontinuation.	Participants received 450 mg gilteritinib orally once on day -2, and starting on day 1 of cycle 1, participants received 450 mg gilteritinib orally once daily in 28-day cycles until disease progression or participant discontinuation.
Measure Participants	16	16	24	70	100	20	3
FLT3 Mutation Positive	0 0%	0 0%	16.7 556.7%	12.5 416.7%	11.2 373.3%	10.0 333.3%	0 0%
FLT3 Mutation Negative	50.0 1000%	0 0%	0 0%	0 0%	0 0%	0 0%	0 0%
All Participants	6.3 126%	0 0%	8.3 276.7%	10.0 333.3%	10.0 333.3%	5.0 166.7%	0 0%

11. Secondary Outcome

Title	Percentage of Participants With CR With Incomplete Platelet Recovery (CRp)
Description	CRp was defined according to modified Cheson criteria (2003), using centrally evaluated myeloblast counts from bone marrow aspirate/biopsy assessments and centrally evaluated hematology results; if neither central bone marrow aspirate nor biopsy was available, myeloblast was imputed with locally evaluated bone marrow aspirate/biopsy assessments (derived response). Participants were classified as being in CRp when they achieved CR except for incomplete platelet recovery (< 100 x 10^9/L). Exact 95% confidence interval was estimated using the binomial distribution.
Time Frame	Up to end of treatment (median treatment duration was 69.5 days, minimum of 3 days and maximum of 1320 days)

Outcome Measure Data

Analysis Population Description
The analysis population was the FAS.

Arm/Group Title	Gilteritinib 20 mg	Gilteritinib 40 mg	Gilteritinib 80 mg	Gilteritinib 120 mg	Gilteritinib 200 mg	Gilteritinib 300 mg	Gilteritinib 450 mg
Arm/Group Description	Participants received 20 mg gilteritinib orally once on day -2, and starting on day 1 of cycle 1, participants received 20 mg gilteritinib orally once daily in 28-day cycles until disease progression or participant discontinuation.	Participants received 40 mg gilteritinib orally once on day -2, and starting on day 1 of cycle 1, participants received 40 mg gilteritinib orally once daily in 28-day cycles until disease progression or participant discontinuation.	Participants received 80 mg gilteritinib orally once on day -2, and starting on day 1 of cycle 1, participants received 80 mg gilteritinib orally once daily in 28-day cycles until disease progression or participant discontinuation.	Participants received 120 mg gilteritinib orally once on day -2, and starting on day 1 of cycle 1, participants received 120 mg gilteritinib orally once daily in 28-day cycles until disease progression or participant discontinuation.	Participants received 200 mg gilteritinib orally once on day -2, and starting on day 1 of cycle 1, participants received 200 mg gilteritinib orally once daily in 28-day cycles until disease progression or participant discontinuation.	Participants received 300 mg gilteritinib orally once on day -2, and starting on day 1 of cycle 1, participants received 300 mg gilteritinib orally once daily in 28-day cycles until disease progression or participant discontinuation.	Participants received 450 mg gilteritinib orally once on day -2, and starting on day 1 of cycle 1, participants received 450 mg gilteritinib orally once daily in 28-day cycles until disease progression or participant discontinuation.
Measure Participants	16	16	24	70	100	20	3
FLT3 Mutation Positive	0 0%	0 0%	0 0%	3.6 120%	9.0 300%	10.0 333.3%	0 0%
FLT3 Mutation Negative	0 0%	0 0%	0 0%	0 0%	0 0%	0 0%	0 0%
All Participants	0 0%	0 0%	0 0%	2.9 96.7%	8.0 266.7%	5.0 166.7%	0 0%

12. Secondary Outcome

Title	Percentage of Participants With CR With Incomplete Hematological Recovery (CRi)
Description	CRi was defined according to modified Cheson criteria (2003), using centrally evaluated myeloblast counts from bone marrow aspirate/biopsy assessments and centrally evaluated hematology results; if neither central bone marrow aspirate nor biopsy was available, myeloblast was imputed with locally evaluated bone marrow aspirate/biopsy assessments (derived response). Participants were classified as being in CRi when they fulfilled all the criteria for CR except for incomplete hematological recovery with residual neutropenia < 1 x 10^9/L with or without complete platelet recovery. RBC and platelet transfusion independence were not required. Exact 95% confidence interval was estimated using the binomial distribution.
Time Frame	Up to end of treatment (median treatment duration was 69.5 days, minimum of 3 days and maximum of 1320 days)

Outcome Measure Data

Analysis Population Description
The analysis population was the FAS.

Arm/Group Title	Gilteritinib 20 mg	Gilteritinib 40 mg	Gilteritinib 80 mg	Gilteritinib 120 mg	Gilteritinib 200 mg	Gilteritinib 300 mg	Gilteritinib 450 mg
Arm/Group Description	Participants received 20 mg gilteritinib orally once on day -2, and starting on day 1 of cycle 1, participants received 20 mg gilteritinib orally once daily in 28-day cycles until disease progression or participant discontinuation.	Participants received 40 mg gilteritinib orally once on day -2, and starting on day 1 of cycle 1, participants received 40 mg gilteritinib orally once daily in 28-day cycles until disease progression or participant discontinuation.	Participants received 80 mg gilteritinib orally once on day -2, and starting on day 1 of cycle 1, participants received 80 mg gilteritinib orally once daily in 28-day cycles until disease progression or participant discontinuation.	Participants received 120 mg gilteritinib orally once on day -2, and starting on day 1 of cycle 1, participants received 120 mg gilteritinib orally once daily in 28-day cycles until disease progression or participant discontinuation.	Participants received 200 mg gilteritinib orally once on day -2, and starting on day 1 of cycle 1, participants received 200 mg gilteritinib orally once daily in 28-day cycles until disease progression or participant discontinuation.	Participants received 300 mg gilteritinib orally once on day -2, and starting on day 1 of cycle 1, participants received 300 mg gilteritinib orally once daily in 28-day cycles until disease progression or participant discontinuation.	Participants received 450 mg gilteritinib orally once on day -2, and starting on day 1 of cycle 1, participants received 450 mg gilteritinib orally once daily in 28-day cycles until disease progression or participant discontinuation.
Measure Participants	16	16	24	70	100	20	3
FLT3 Mutation Positive	7.1 142%	0 0%	25.0 833.3%	30.4 1013.3%	20.2 673.3%	10.0 333.3%	0 0%
FLT3 Mutation Negative	0 0%	0 0%	16.7 556.7%	7.1 236.7%	9.1 303.3%	0 0%	0 0%
All Participants	6.3 126%	0 0%	20.8 693.3%	25.7 856.7%	19.0 633.3%	5.0 166.7%	0 0%

13. Secondary Outcome

Title	Percentage of Participants With Complete Remission With Partial Hematologic Recovery (CRh)
Description	CRh was defined according to modified Cheson criteria (2003), using centrally evaluated myeloblast counts from bone marrow aspirate/biopsy assessments and centrally evaluated hematology results; if neither central bone marrow aspirate nor biopsy was available, myeloblast was imputed with locally evaluated bone marrow aspirate/biopsy assessments (derived response). Participants were classified as being in CRh when they could not be classified as being in CR and had bone marrow blasts < 5% and partial hematologic recovery ANC >= 0.5 x 10^9/L and platelets >= 50 x 10^9/L. There should not be evidence of extramedullary leukemia. Exact 95% confidence interval was estimated using the binomial distribution. CRh was calculated only for participants who were FLT3 mutation positive.
Time Frame	Up to end of treatment (median treatment duration was 69.5 days, minimum of 3 days and maximum of 1320 days)

Outcome Measure Data

Analysis Population Description
The analysis population was the FAS, with participants who were FLT3 mutation positive.

Arm/Group Title	Gilteritinib 20 mg	Gilteritinib 40 mg	Gilteritinib 80 mg	Gilteritinib 120 mg	Gilteritinib 200 mg	Gilteritinib 300 mg	Gilteritinib 450 mg
Arm/Group Description	Participants received 20 mg gilteritinib orally once on day -2, and starting on day 1 of cycle 1, participants received 20 mg gilteritinib orally once daily in 28-day cycles until disease progression or participant discontinuation.	Participants received 40 mg gilteritinib orally once on day -2, and starting on day 1 of cycle 1, participants received 40 mg gilteritinib orally once daily in 28-day cycles until disease progression or participant discontinuation.	Participants received 80 mg gilteritinib orally once on day -2, and starting on day 1 of cycle 1, participants received 80 mg gilteritinib orally once daily in 28-day cycles until disease progression or participant discontinuation.	Participants received 120 mg gilteritinib orally once on day -2, and starting on day 1 of cycle 1, participants received 120 mg gilteritinib orally once daily in 28-day cycles until disease progression or participant discontinuation.	Participants received 200 mg gilteritinib orally once on day -2, and starting on day 1 of cycle 1, participants received 200 mg gilteritinib orally once daily in 28-day cycles until disease progression or participant discontinuation.	Participants received 300 mg gilteritinib orally once on day -2, and starting on day 1 of cycle 1, participants received 300 mg gilteritinib orally once daily in 28-day cycles until disease progression or participant discontinuation.	Participants received 450 mg gilteritinib orally once on day -2, and starting on day 1 of cycle 1, participants received 450 mg gilteritinib orally once daily in 28-day cycles until disease progression or participant discontinuation.
Measure Participants	14	8	12	56	89	10	2
Number (95% Confidence Interval) [percentage of participants]	7.1 142%	0 0%	8.3 276.7%	10.7 356.7%	7.9 263.3%	20.0 666.7%	0 0%

14. Secondary Outcome

Title	Percentage of Participants With Composite CR (CRc)
Description	CRc was defined according to modified Cheson criteria (2003), using centrally evaluated myeloblast counts from bone marrow aspirate/biopsy assessments and centrally evaluated hematology results; if neither central bone marrow aspirate nor biopsy was available, myeloblast was imputed with locally evaluated bone marrow aspirate/biopsy assessments (derived response). Participants were classified as being in CRc when they had achieved either CR, complete remission with incomplete platelet recovery (CRp, defined as had achieved CR except for incomplete platelet recovery (< 100 x 10^9/L) or complete remission with incomplete hematologic recovery (CRi, defined as had fulfilled all the criteria for CR except for incomplete hematological recovery with residual neutropenia < 1 x 10^9/L with or without complete platelet recovery; RBC platelet transfusion independence not required). Exact 95% confidence interval was estimated using the binomial distribution.
Time Frame	Up to end of treatment (median treatment duration was 69.5 days, minimum of 3 days and maximum of 1320 days)

Outcome Measure Data

Analysis Population Description
The analysis population was the FAS.

Arm/Group Title	Gilteritinib 20 mg	Gilteritinib 40 mg	Gilteritinib 80 mg	Gilteritinib 120 mg	Gilteritinib 200 mg	Gilteritinib 300 mg	Gilteritinib 450 mg
Arm/Group Description	Participants received 20 mg gilteritinib orally once on day -2, and starting on day 1 of cycle 1, participants received 20 mg gilteritinib orally once daily in 28-day cycles until disease progression or participant discontinuation.	Participants received 40 mg gilteritinib orally once on day -2, and starting on day 1 of cycle 1, participants received 40 mg gilteritinib orally once daily in 28-day cycles until disease progression or participant discontinuation.	Participants received 80 mg gilteritinib orally once on day -2, and starting on day 1 of cycle 1, participants received 80 mg gilteritinib orally once daily in 28-day cycles until disease progression or participant discontinuation.	Participants received 120 mg gilteritinib orally once on day -2, and starting on day 1 of cycle 1, participants received 120 mg gilteritinib orally once daily in 28-day cycles until disease progression or participant discontinuation.	Participants received 200 mg gilteritinib orally once on day -2, and starting on day 1 of cycle 1, participants received 200 mg gilteritinib orally once daily in 28-day cycles until disease progression or participant discontinuation.	Participants received 300 mg gilteritinib orally once on day -2, and starting on day 1 of cycle 1, participants received 300 mg gilteritinib orally once daily in 28-day cycles until disease progression or participant discontinuation.	Participants received 450 mg gilteritinib orally once on day -2, and starting on day 1 of cycle 1, participants received 450 mg gilteritinib orally once daily in 28-day cycles until disease progression or participant discontinuation.
Measure Participants	16	16	24	70	100	20	3
FLT3 Mutation Positive	7.1 142%	0 0%	41.7 1390%	46.4 1546.7%	40.4 1346.7%	30.0 1000%	0 0%
FLT3 Mutation Negative	50.0 1000%	0 0%	16.7 556.7%	7.1 236.7%	9.1 303.3%	0 0%	0 0%
All Participants	12.5 250%	0 0%	29.2 973.3%	38.6 1286.7%	37.0 1233.3%	15.0 500%	0 0%

15. Secondary Outcome

Title	Percentage of Participants With Partial Remission (PR)
Description	PR was defined according to modified Cheson criteria (2003), using centrally evaluated myeloblast counts from bone marrow aspirate/biopsy assessments and centrally evaluated hematology results; if neither central bone marrow aspirate nor biopsy was available, myeloblast was imputed with locally evaluated bone marrow aspirate/biopsy assessments (derived response). Participants were classified as being in PR when they had bone marrow regenerating normal hematopoietic cells with evidence of peripheral recovery with no (or only a few regenerating) circulating blasts and with a decrease of at least 50% in the percentage of blasts in the bone marrow aspirate with the total marrow blasts between 5% and 25%. A value of less or equal than 5% blasts was also considered a PR if Auer rods were present. There should be no evidence of extramedullary leukemia. Exact 95% confidence interval was estimated using the binomial distribution.
Time Frame	Up to end of treatment (median treatment duration was 69.5 days, minimum of 3 days and maximum of 1320 days)

Outcome Measure Data

Analysis Population Description
The analysis population was the FAS.

Arm/Group Title	Gilteritinib 20 mg	Gilteritinib 40 mg	Gilteritinib 80 mg	Gilteritinib 120 mg	Gilteritinib 200 mg	Gilteritinib 300 mg	Gilteritinib 450 mg
Arm/Group Description	Participants received 20 mg gilteritinib orally once on day -2, and starting on day 1 of cycle 1, participants received 20 mg gilteritinib orally once daily in 28-day cycles until disease progression or participant discontinuation.	Participants received 40 mg gilteritinib orally once on day -2, and starting on day 1 of cycle 1, participants received 40 mg gilteritinib orally once daily in 28-day cycles until disease progression or participant discontinuation.	Participants received 80 mg gilteritinib orally once on day -2, and starting on day 1 of cycle 1, participants received 80 mg gilteritinib orally once daily in 28-day cycles until disease progression or participant discontinuation.	Participants received 120 mg gilteritinib orally once on day -2, and starting on day 1 of cycle 1, participants received 120 mg gilteritinib orally once daily in 28-day cycles until disease progression or participant discontinuation.	Participants received 200 mg gilteritinib orally once on day -2, and starting on day 1 of cycle 1, participants received 200 mg gilteritinib orally once daily in 28-day cycles until disease progression or participant discontinuation.	Participants received 300 mg gilteritinib orally once on day -2, and starting on day 1 of cycle 1, participants received 300 mg gilteritinib orally once daily in 28-day cycles until disease progression or participant discontinuation.	Participants received 450 mg gilteritinib orally once on day -2, and starting on day 1 of cycle 1, participants received 450 mg gilteritinib orally once daily in 28-day cycles until disease progression or participant discontinuation.
Measure Participants	16	16	24	70	100	20	3
FLT3 Mutation Positive	7.1 142%	37.5 1250%	25.0 833.3%	7.1 236.7%	7.9 263.3%	30.0 1000%	50.0 1666.7%
FLT3 Mutation Negative	0 0%	0 0%	0 0%	7.1 236.7%	9.1 303.3%	0 0%	0 0%
All Participants	6.3 126%	18.8 626.7%	12.5 416.7%	7.1 236.7%	8.0 266.7%	15.0 500%	33.3 1110%

16. Secondary Outcome

Title	Percentage of Participants With Best Response
Description	Best response was defined according to modified Cheson criteria (2003), using centrally evaluated myeloblast counts from bone marrow aspirate/biopsy assessments and centrally evaluated hematology results; if neither central bone marrow aspirate nor biopsy was available, myeloblast was imputed with locally evaluated bone marrow aspirate/biopsy assessments (derived response). BR was defined as the best measured response for all visits (in the order of CR, CRp, CRi, and PR) post-treatment. Participants who achieved the best response of CR, CRp, CRi or PR were classified as responders. Participants who did not achieve at least PR were considered as non-responders. Exact 95% confidence interval was estimated using the binomial distribution.
Time Frame	Up to end of treatment (median treatment duration was 69.5 days, minimum of 3 days and maximum of 1320 days)

Outcome Measure Data

Analysis Population Description
The analysis population was the FAS.

Arm/Group Title	Gilteritinib 20 mg	Gilteritinib 40 mg	Gilteritinib 80 mg	Gilteritinib 120 mg	Gilteritinib 200 mg	Gilteritinib 300 mg	Gilteritinib 450 mg
Arm/Group Description	Participants received 20 mg gilteritinib orally once on day -2, and starting on day 1 of cycle 1, participants received 20 mg gilteritinib orally once daily in 28-day cycles until disease progression or participant discontinuation.	Participants received 40 mg gilteritinib orally once on day -2, and starting on day 1 of cycle 1, participants received 40 mg gilteritinib orally once daily in 28-day cycles until disease progression or participant discontinuation.	Participants received 80 mg gilteritinib orally once on day -2, and starting on day 1 of cycle 1, participants received 80 mg gilteritinib orally once daily in 28-day cycles until disease progression or participant discontinuation.	Participants received 120 mg gilteritinib orally once on day -2, and starting on day 1 of cycle 1, participants received 120 mg gilteritinib orally once daily in 28-day cycles until disease progression or participant discontinuation.	Participants received 200 mg gilteritinib orally once on day -2, and starting on day 1 of cycle 1, participants received 200 mg gilteritinib orally once daily in 28-day cycles until disease progression or participant discontinuation.	Participants received 300 mg gilteritinib orally once on day -2, and starting on day 1 of cycle 1, participants received 300 mg gilteritinib orally once daily in 28-day cycles until disease progression or participant discontinuation.	Participants received 450 mg gilteritinib orally once on day -2, and starting on day 1 of cycle 1, participants received 450 mg gilteritinib orally once daily in 28-day cycles until disease progression or participant discontinuation.
Measure Participants	16	16	24	70	100	20	3
FLT3 Mutation Positive	14.3 286%	37.5 1250%	66.7 2223.3%	53.6 1786.7%	48.3 1610%	60.0 2000%	50.0 1666.7%
FLT3 Mutation Negative	50.0 1000%	0 0%	16.7 556.7%	14.3 476.7%	18.2 606.7%	0 0%	0 0%
All Participants	18.8 376%	18.8 626.7%	41.7 1390%	45.7 1523.3%	45.0 1500%	30.0 1000%	33.3 1110%

17. Secondary Outcome

Title	Percentage of Participants With Complete Remission and Complete Remission With Partial Hematologic Recovery (CR/CRh)
Description	Participants with CR/CRh were defined as participants who achieved either CR or CRh. Participants with CR had bone marrow regenerating normal hematopoietic cells, achieved a morphologic leukemia-free state, had an ANC > 1 x 10^9/L, platelet count ≥ 100 x 10^9/L, and normal marrow differential with < 5% blasts, had been RBC and platelet transfusion independent (defined as 1 week without RBC transfusion and 1 week without platelet transfusion). Also, there had been no presence of Auer rods, no evidence of extramedullary leukemia, and blast counts in peripheral blood had been ≤ 2%. Participants with CRh could not be classified as being in CR and had bone marrow blasts < 5%, partial hematologic recovery ANC >= 0.5 x 10^9/L and platelets >= 50 x 10^9/L. There should not be evidence of extramedullary leukemia. Exact 95% confidence interval was estimated using the binomial distribution. CR/CRh was calculated only for participants who were FLT3 mutation positive.
Time Frame	Up to end of treatment (median treatment duration was 69.5 days, minimum of 3 days and maximum of 1320 days)

Outcome Measure Data

Analysis Population Description
The analysis population was the FAS, with participants who were FLT3 mutation positive.

Arm/Group Title	Gilteritinib 20 mg	Gilteritinib 40 mg	Gilteritinib 80 mg	Gilteritinib 120 mg	Gilteritinib 200 mg	Gilteritinib 300 mg	Gilteritinib 450 mg
Arm/Group Description	Participants received 20 mg gilteritinib orally once on day -2, and starting on day 1 of cycle 1, participants received 20 mg gilteritinib orally once daily in 28-day cycles until disease progression or participant discontinuation.	Participants received 40 mg gilteritinib orally once on day -2, and starting on day 1 of cycle 1, participants received 40 mg gilteritinib orally once daily in 28-day cycles until disease progression or participant discontinuation.	Participants received 80 mg gilteritinib orally once on day -2, and starting on day 1 of cycle 1, participants received 80 mg gilteritinib orally once daily in 28-day cycles until disease progression or participant discontinuation.	Participants received 120 mg gilteritinib orally once on day -2, and starting on day 1 of cycle 1, participants received 120 mg gilteritinib orally once daily in 28-day cycles until disease progression or participant discontinuation.	Participants received 200 mg gilteritinib orally once on day -2, and starting on day 1 of cycle 1, participants received 200 mg gilteritinib orally once daily in 28-day cycles until disease progression or participant discontinuation.	Participants received 300 mg gilteritinib orally once on day -2, and starting on day 1 of cycle 1, participants received 300 mg gilteritinib orally once daily in 28-day cycles until disease progression or participant discontinuation.	Participants received 450 mg gilteritinib orally once on day -2, and starting on day 1 of cycle 1, participants received 450 mg gilteritinib orally once daily in 28-day cycles until disease progression or participant discontinuation.
Measure Participants	14	8	12	56	89	10	2
Number (95% Confidence Interval) [percentage of participants]	7.1 142%	0 0%	25.0 833.3%	23.2 773.3%	19.1 636.7%	30.0 1000%	0 0%

18. Secondary Outcome

Title	Duration of CR (DCR)
Description	DCR was defined as the time from the date of first CR until the date of documented relapse for participants who achieved CR. Participants who died without report of relapse were considered non-events and censored at their last relapse-free disease assessment date. Other participants who did not relapse on study were considered non-events and censored at the last relapse-free disease assessment date. DCR was calculated using Kaplan-Meier method and therefore data are estimated.
Time Frame	From date of remission until end of study (median treatment duration was 69.5 days, minimum of 3 days and maximum of 1320 days)

Outcome Measure Data

Analysis Population Description
The analysis population was the FAS. Only participants who achieved CR were included in the analysis.

Arm/Group Title	Gilteritinib 20 mg	Gilteritinib 40 mg	Gilteritinib 80 mg	Gilteritinib 120 mg	Gilteritinib 200 mg	Gilteritinib 300 mg	Gilteritinib 450 mg
Arm/Group Description	Participants received 20 mg gilteritinib orally once on day -2, and starting on day 1 of cycle 1, participants received 20 mg gilteritinib orally once daily in 28-day cycles until disease progression or participant discontinuation.	Participants received 40 mg gilteritinib orally once on day -2, and starting on day 1 of cycle 1, participants received 40 mg gilteritinib orally once daily in 28-day cycles until disease progression or participant discontinuation.	Participants received 80 mg gilteritinib orally once on day -2, and starting on day 1 of cycle 1, participants received 80 mg gilteritinib orally once daily in 28-day cycles until disease progression or participant discontinuation.	Participants received 120 mg gilteritinib orally once on day -2, and starting on day 1 of cycle 1, participants received 120 mg gilteritinib orally once daily in 28-day cycles until disease progression or participant discontinuation.	Participants received 200 mg gilteritinib orally once on day -2, and starting on day 1 of cycle 1, participants received 200 mg gilteritinib orally once daily in 28-day cycles until disease progression or participant discontinuation.	Participants received 300 mg gilteritinib orally once on day -2, and starting on day 1 of cycle 1, participants received 300 mg gilteritinib orally once daily in 28-day cycles until disease progression or participant discontinuation.	Participants received 450 mg gilteritinib orally once on day -2, and starting on day 1 of cycle 1, participants received 450 mg gilteritinib orally once daily in 28-day cycles until disease progression or participant discontinuation.
Measure Participants	1	0	2	7	10	1	0
FLT3 Mutation Positive	NA	NA	419.0	NA
FLT3 Mutation Negative	NA
All Participants	NA	NA	NA	419.0	NA

19. Secondary Outcome

Title	Duration of CRp (DCRp)
Description	DCRp was defined as the time from the date of first CRp until the date of documented relapse for participants who achieved CRp. Participants who died without report of relapse were considered non-events and censored at their last relapse-free disease assessment date. Other participants who did not relapse on study were considered non-events and censored at the last relapse-free disease assessment date. DCRp was calculated using Kaplan-Meier method and therefore data are estimated.
Time Frame	From date of remission until end of study (median treatment duration was 69.5 days, minimum of 3 days and maximum of 1320 days)

Outcome Measure Data

Analysis Population Description
The analysis population was the FAS. Only participants who achieved CRp were included in the analysis.

Arm/Group Title	Gilteritinib 20 mg	Gilteritinib 40 mg	Gilteritinib 80 mg	Gilteritinib 120 mg	Gilteritinib 200 mg	Gilteritinib 300 mg	Gilteritinib 450 mg
Arm/Group Description	Participants received 20 mg gilteritinib orally once on day -2, and starting on day 1 of cycle 1, participants received 20 mg gilteritinib orally once daily in 28-day cycles until disease progression or participant discontinuation.	Participants received 40 mg gilteritinib orally once on day -2, and starting on day 1 of cycle 1, participants received 40 mg gilteritinib orally once daily in 28-day cycles until disease progression or participant discontinuation.	Participants received 80 mg gilteritinib orally once on day -2, and starting on day 1 of cycle 1, participants received 80 mg gilteritinib orally once daily in 28-day cycles until disease progression or participant discontinuation.	Participants received 120 mg gilteritinib orally once on day -2, and starting on day 1 of cycle 1, participants received 120 mg gilteritinib orally once daily in 28-day cycles until disease progression or participant discontinuation.	Participants received 200 mg gilteritinib orally once on day -2, and starting on day 1 of cycle 1, participants received 200 mg gilteritinib orally once daily in 28-day cycles until disease progression or participant discontinuation.	Participants received 300 mg gilteritinib orally once on day -2, and starting on day 1 of cycle 1, participants received 300 mg gilteritinib orally once daily in 28-day cycles until disease progression or participant discontinuation.	Participants received 450 mg gilteritinib orally once on day -2, and starting on day 1 of cycle 1, participants received 450 mg gilteritinib orally once daily in 28-day cycles until disease progression or participant discontinuation.
Measure Participants	0	0	1	6	12	2	0
FLT3 Mutation Positive	NA	NA	450.0	NA
All Participants	NA	NA	450.0	NA

20. Secondary Outcome

Title	Duration of CRi (DCRi)
Description	DCRi was defined as the time from the date of first CRi until the date of documented relapse for participants who achieved CRi. Participants who died without report of relapse and participants who did not relapse were considered non-events and censored at the last relapse-free disease assessment date. DCRi was calculated using Kaplan-Meier method and therefore data are estimated.
Time Frame	From date of remission until end of study (median treatment duration was 69.5 days, minimum of 3 days and maximum of 1320 days)

Outcome Measure Data

Analysis Population Description
The analysis population was the FAS. Only participants who achieved CRi were included in the analysis.

Arm/Group Title	Gilteritinib 20 mg	Gilteritinib 40 mg	Gilteritinib 80 mg	Gilteritinib 120 mg	Gilteritinib 200 mg	Gilteritinib 300 mg	Gilteritinib 450 mg
Arm/Group Description	Participants received 20 mg gilteritinib orally once on day -2, and starting on day 1 of cycle 1, participants received 20 mg gilteritinib orally once daily in 28-day cycles until disease progression or participant discontinuation.	Participants received 40 mg gilteritinib orally once on day -2, and starting on day 1 of cycle 1, participants received 40 mg gilteritinib orally once daily in 28-day cycles until disease progression or participant discontinuation.	Participants received 80 mg gilteritinib orally once on day -2, and starting on day 1 of cycle 1, participants received 80 mg gilteritinib orally once daily in 28-day cycles until disease progression or participant discontinuation.	Participants received 120 mg gilteritinib orally once on day -2, and starting on day 1 of cycle 1, participants received 120 mg gilteritinib orally once daily in 28-day cycles until disease progression or participant discontinuation.	Participants received 200 mg gilteritinib orally once on day -2, and starting on day 1 of cycle 1, participants received 200 mg gilteritinib orally once daily in 28-day cycles until disease progression or participant discontinuation.	Participants received 300 mg gilteritinib orally once on day -2, and starting on day 1 of cycle 1, participants received 300 mg gilteritinib orally once daily in 28-day cycles until disease progression or participant discontinuation.	Participants received 450 mg gilteritinib orally once on day -2, and starting on day 1 of cycle 1, participants received 450 mg gilteritinib orally once daily in 28-day cycles until disease progression or participant discontinuation.
Measure Participants	1	0	7	24	31	1	0
FLT3 Mutation Positive	NA	NA	120.0	191.0	NA
FLT3 Mutation Negative	41.0	99.0
All Participants	NA	79.0	120.0	191.0	NA

21. Secondary Outcome

Title	Duration of CRh (DCRh)
Description	DCRh was defined as the time from the date of first CRh until the date of documented relapse for participants who achieved CRh but did not have a best response of CR. Participants who died without report of relapse and participants who did not relapse were considered non-events and censored at the last relapse-free disease assessment date. DCRh was calculated using Kaplan-Meier method and therefore data are estimated. DCRh was calculated only for participants who were FLT3 mutation positive.
Time Frame	From date of remission until end of study (median treatment duration was 69.5 days, minimum of 3 days and maximum of 1320 days)

Outcome Measure Data

Analysis Population Description
The analysis population was the FAS. Only participants who achieved CRh were included in the analysis.

Arm/Group Title	Gilteritinib 20 mg	Gilteritinib 40 mg	Gilteritinib 80 mg	Gilteritinib 120 mg	Gilteritinib 200 mg	Gilteritinib 300 mg	Gilteritinib 450 mg
Arm/Group Description	Participants received 20 mg gilteritinib orally once on day -2, and starting on day 1 of cycle 1, participants received 20 mg gilteritinib orally once daily in 28-day cycles until disease progression or participant discontinuation.	Participants received 40 mg gilteritinib orally once on day -2, and starting on day 1 of cycle 1, participants received 40 mg gilteritinib orally once daily in 28-day cycles until disease progression or participant discontinuation.	Participants received 80 mg gilteritinib orally once on day -2, and starting on day 1 of cycle 1, participants received 80 mg gilteritinib orally once daily in 28-day cycles until disease progression or participant discontinuation.	Participants received 120 mg gilteritinib orally once on day -2, and starting on day 1 of cycle 1, participants received 120 mg gilteritinib orally once daily in 28-day cycles until disease progression or participant discontinuation.	Participants received 200 mg gilteritinib orally once on day -2, and starting on day 1 of cycle 1, participants received 200 mg gilteritinib orally once daily in 28-day cycles until disease progression or participant discontinuation.	Participants received 300 mg gilteritinib orally once on day -2, and starting on day 1 of cycle 1, participants received 300 mg gilteritinib orally once daily in 28-day cycles until disease progression or participant discontinuation.	Participants received 450 mg gilteritinib orally once on day -2, and starting on day 1 of cycle 1, participants received 450 mg gilteritinib orally once daily in 28-day cycles until disease progression or participant discontinuation.
Measure Participants	1	0	1	6	7	2	0
Median (95% Confidence Interval) [days]	NA	NA	64.0	101.0	NA

22. Secondary Outcome

Title	Duration of CRc (DCRc)
Description	DCRc was defined as the time from the date of first CRc until the date of documented relapse for participants who achieved CRc. Participants who died without report of relapse and participants who did not relapse were considered non-events and censored at the last relapse-free disease assessment date. DCRc was calculated using Kaplan-Meier method and therefore data are estimated.
Time Frame	From date of remission until end of study (median treatment duration was 69.5 days, minimum of 3 days and maximum of 1320 days)

Outcome Measure Data

Analysis Population Description
The analysis population was the FAS. Only participants who achieved CRc were included in the analysis.

Arm/Group Title	Gilteritinib 20 mg	Gilteritinib 40 mg	Gilteritinib 80 mg	Gilteritinib 120 mg	Gilteritinib 200 mg	Gilteritinib 300 mg	Gilteritinib 450 mg
Arm/Group Description	Participants received 20 mg gilteritinib orally once on day -2, and starting on day 1 of cycle 1, participants received 20 mg gilteritinib orally once daily in 28-day cycles until disease progression or participant discontinuation.	Participants received 40 mg gilteritinib orally once on day -2, and starting on day 1 of cycle 1, participants received 40 mg gilteritinib orally once daily in 28-day cycles until disease progression or participant discontinuation.	Participants received 80 mg gilteritinib orally once on day -2, and starting on day 1 of cycle 1, participants received 80 mg gilteritinib orally once daily in 28-day cycles until disease progression or participant discontinuation.	Participants received 120 mg gilteritinib orally once on day -2, and starting on day 1 of cycle 1, participants received 120 mg gilteritinib orally once daily in 28-day cycles until disease progression or participant discontinuation.	Participants received 200 mg gilteritinib orally once on day -2, and starting on day 1 of cycle 1, participants received 200 mg gilteritinib orally once daily in 28-day cycles until disease progression or participant discontinuation.	Participants received 300 mg gilteritinib orally once on day -2, and starting on day 1 of cycle 1, participants received 300 mg gilteritinib orally once daily in 28-day cycles until disease progression or participant discontinuation.	Participants received 450 mg gilteritinib orally once on day -2, and starting on day 1 of cycle 1, participants received 450 mg gilteritinib orally once daily in 28-day cycles until disease progression or participant discontinuation.
Measure Participants	2	0	7	27	37	3	0
FLT3 Mutation Positive	NA	NA	98.0	191.0	NA
FLT3 Mutation Negative	NA	41.0	99.0	NA
All Participants	NA	79.0	99.0	191.0	NA

23. Secondary Outcome

Title	Duration of CR/CRh (DCRCRh)
Description	DCRCRh was defined as the time from the date of first DCRCRh until the date of documented relapse for participants who achieved CR or CRh. For participants who achieved both CR and CRh, the first CR date or CRh date, whichever occurred first, was used. Participants who died without report of relapse and participants who did not relapse were considered non-events and censored at the last relapse-free disease assessment date. DCRCRh was calculated using Kaplan-Meier method and therefore data are estimated. DCRCRh was calculated only for participants who were FLT3 mutation positive.
Time Frame	From date of remission until end of study (median treatment duration was 69.5 days, minimum of 3 days and maximum of 1320 days)

Outcome Measure Data

Analysis Population Description
The analysis population was the FAS. Only participants who achieved CR or CRh were included in the analysis.

Arm/Group Title	Gilteritinib 20 mg	Gilteritinib 40 mg	Gilteritinib 80 mg	Gilteritinib 120 mg	Gilteritinib 200 mg	Gilteritinib 300 mg	Gilteritinib 450 mg
Arm/Group Description	Participants received 20 mg gilteritinib orally once on day -2, and starting on day 1 of cycle 1, participants received 20 mg gilteritinib orally once daily in 28-day cycles until disease progression or participant discontinuation.	Participants received 40 mg gilteritinib orally once on day -2, and starting on day 1 of cycle 1, participants received 40 mg gilteritinib orally once daily in 28-day cycles until disease progression or participant discontinuation.	Participants received 80 mg gilteritinib orally once on day -2, and starting on day 1 of cycle 1, participants received 80 mg gilteritinib orally once daily in 28-day cycles until disease progression or participant discontinuation.	Participants received 120 mg gilteritinib orally once on day -2, and starting on day 1 of cycle 1, participants received 120 mg gilteritinib orally once daily in 28-day cycles until disease progression or participant discontinuation.	Participants received 200 mg gilteritinib orally once on day -2, and starting on day 1 of cycle 1, participants received 200 mg gilteritinib orally once daily in 28-day cycles until disease progression or participant discontinuation.	Participants received 300 mg gilteritinib orally once on day -2, and starting on day 1 of cycle 1, participants received 300 mg gilteritinib orally once daily in 28-day cycles until disease progression or participant discontinuation.	Participants received 450 mg gilteritinib orally once on day -2, and starting on day 1 of cycle 1, participants received 450 mg gilteritinib orally once daily in 28-day cycles until disease progression or participant discontinuation.
Measure Participants	1	0	3	13	17	3	0
Median (95% Confidence Interval) [days]	NA	NA	307.0	308.0	NA

24. Secondary Outcome

Title	Duration of Response
Description	Duration of response was defined as the time from the date of either first CRc or PR until the date of documented relapse of any type for participants who achieved CRc or PR. Participants who died without report of relapse were considered non-events and censored at their last relapse-free disease assessment date. Other participants who did not relapse on study are considered non-events and censored at the last relapse-free assessment date. Duration of response was calculated using Kaplan-Meier method and therefore data are estimated.
Time Frame	From date of remission until end of study (median treatment duration was 69.5 days, minimum of 3 days and maximum of 1320 days)

Outcome Measure Data

Analysis Population Description
The analysis population was the FAS. Only participants who achieved CRc or PR were included in the analysis.

Arm/Group Title	Gilteritinib 20 mg	Gilteritinib 40 mg	Gilteritinib 80 mg	Gilteritinib 120 mg	Gilteritinib 200 mg	Gilteritinib 300 mg	Gilteritinib 450 mg
Arm/Group Description	Participants received 20 mg gilteritinib orally once on day -2, and starting on day 1 of cycle 1, participants received 20 mg gilteritinib orally once daily in 28-day cycles until disease progression or participant discontinuation.	Participants received 40 mg gilteritinib orally once on day -2, and starting on day 1 of cycle 1, participants received 40 mg gilteritinib orally once daily in 28-day cycles until disease progression or participant discontinuation.	Participants received 80 mg gilteritinib orally once on day -2, and starting on day 1 of cycle 1, participants received 80 mg gilteritinib orally once daily in 28-day cycles until disease progression or participant discontinuation.	Participants received 120 mg gilteritinib orally once on day -2, and starting on day 1 of cycle 1, participants received 120 mg gilteritinib orally once daily in 28-day cycles until disease progression or participant discontinuation.	Participants received 200 mg gilteritinib orally once on day -2, and starting on day 1 of cycle 1, participants received 200 mg gilteritinib orally once daily in 28-day cycles until disease progression or participant discontinuation.	Participants received 300 mg gilteritinib orally once on day -2, and starting on day 1 of cycle 1, participants received 300 mg gilteritinib orally once daily in 28-day cycles until disease progression or participant discontinuation.	Participants received 450 mg gilteritinib orally once on day -2, and starting on day 1 of cycle 1, participants received 450 mg gilteritinib orally once daily in 28-day cycles until disease progression or participant discontinuation.
Measure Participants	3	3	10	32	45	6	1
FLT3 Mutation Positive	NA	NA	88.0	141.0	220.0	59.0	NA
FLT3 Mutation Negative	NA	41.0	109.5	85.0
All Participants	NA	NA	79.0	126.0	220.0	59.0	NA

25. Secondary Outcome

Title	Time to CR (TTCR)
Description	TTCR was defined as the time from the first dose of study drug until the date of first CR.
Time Frame	From first dose of study drug up to end of treatment (median treatment duration was 69.5 days, minimum of 3 days and maximum of 1320 days)

Outcome Measure Data

Analysis Population Description
The analysis population was the FAS. Only participants who achieved CR were included in the analysis.

Arm/Group Title	Gilteritinib 20 mg	Gilteritinib 40 mg	Gilteritinib 80 mg	Gilteritinib 120 mg	Gilteritinib 200 mg	Gilteritinib 300 mg	Gilteritinib 450 mg
Arm/Group Description	Participants received 20 mg gilteritinib orally once on day -2, and starting on day 1 of cycle 1, participants received 20 mg gilteritinib orally once daily in 28-day cycles until disease progression or participant discontinuation.	Participants received 40 mg gilteritinib orally once on day -2, and starting on day 1 of cycle 1, participants received 40 mg gilteritinib orally once daily in 28-day cycles until disease progression or participant discontinuation.	Participants received 80 mg gilteritinib orally once on day -2, and starting on day 1 of cycle 1, participants received 80 mg gilteritinib orally once daily in 28-day cycles until disease progression or participant discontinuation.	Participants received 120 mg gilteritinib orally once on day -2, and starting on day 1 of cycle 1, participants received 120 mg gilteritinib orally once daily in 28-day cycles until disease progression or participant discontinuation.	Participants received 200 mg gilteritinib orally once on day -2, and starting on day 1 of cycle 1, participants received 200 mg gilteritinib orally once daily in 28-day cycles until disease progression or participant discontinuation.	Participants received 300 mg gilteritinib orally once on day -2, and starting on day 1 of cycle 1, participants received 300 mg gilteritinib orally once daily in 28-day cycles until disease progression or participant discontinuation.	Participants received 450 mg gilteritinib orally once on day -2, and starting on day 1 of cycle 1, participants received 450 mg gilteritinib orally once daily in 28-day cycles until disease progression or participant discontinuation.
Measure Participants	1	0	2	7	10	1	0
FLT3 Mutation Positive	171.5	141.0	93.0	56.0
FLT3 Mutation Negative	30.0
All Participants	30.0	171.5	141.0	93.0	56.0

26. Secondary Outcome

Title	Time to CRp (TTCRp)
Description	TTCRp was defined as the time from the first dose of study drug until the date of first CRp. TTCRp was evaluated for participants who achieved CRp.
Time Frame	From first dose of study drug up to end of treatment (median treatment duration was 69.5 days, minimum of 3 days and maximum of 1320 days)

Outcome Measure Data

Analysis Population Description
The analysis population was the FAS. Only participants who achieved CRp were included in the analysis.

Arm/Group Title	Gilteritinib 20 mg	Gilteritinib 40 mg	Gilteritinib 80 mg	Gilteritinib 120 mg	Gilteritinib 200 mg	Gilteritinib 300 mg	Gilteritinib 450 mg
Arm/Group Description	Participants received 20 mg gilteritinib orally once on day -2, and starting on day 1 of cycle 1, participants received 20 mg gilteritinib orally once daily in 28-day cycles until disease progression or participant discontinuation.	Participants received 40 mg gilteritinib orally once on day -2, and starting on day 1 of cycle 1, participants received 40 mg gilteritinib orally once daily in 28-day cycles until disease progression or participant discontinuation.	Participants received 80 mg gilteritinib orally once on day -2, and starting on day 1 of cycle 1, participants received 80 mg gilteritinib orally once daily in 28-day cycles until disease progression or participant discontinuation.	Participants received 120 mg gilteritinib orally once on day -2, and starting on day 1 of cycle 1, participants received 120 mg gilteritinib orally once daily in 28-day cycles until disease progression or participant discontinuation.	Participants received 200 mg gilteritinib orally once on day -2, and starting on day 1 of cycle 1, participants received 200 mg gilteritinib orally once daily in 28-day cycles until disease progression or participant discontinuation.	Participants received 300 mg gilteritinib orally once on day -2, and starting on day 1 of cycle 1, participants received 300 mg gilteritinib orally once daily in 28-day cycles until disease progression or participant discontinuation.	Participants received 450 mg gilteritinib orally once on day -2, and starting on day 1 of cycle 1, participants received 450 mg gilteritinib orally once daily in 28-day cycles until disease progression or participant discontinuation.
Measure Participants	0	0	1	6	12	2	0
FLT3 Mutation Positive	140.0	195.0	84.5	29.0
All Participants	140.0	195.0	84.5	29.0

27. Secondary Outcome

Title	Time to CRi (TTCRi)
Description	TTCRi was defined as the time from the first dose of study drug until the date of first CRi. TTCRi was evaluated for participants who achieved CRi.
Time Frame	From first dose of study drug up to end of treatment (median treatment duration was 69.5 days, minimum of 3 days and maximum of 1320 days)

Outcome Measure Data

Analysis Population Description
The analysis population was the FAS. Only participants who achieved CRi were included in the analysis.

Arm/Group Title	Gilteritinib 20 mg	Gilteritinib 40 mg	Gilteritinib 80 mg	Gilteritinib 120 mg	Gilteritinib 200 mg	Gilteritinib 300 mg	Gilteritinib 450 mg
Arm/Group Description	Participants received 20 mg gilteritinib orally once on day -2, and starting on day 1 of cycle 1, participants received 20 mg gilteritinib orally once daily in 28-day cycles until disease progression or participant discontinuation.	Participants received 40 mg gilteritinib orally once on day -2, and starting on day 1 of cycle 1, participants received 40 mg gilteritinib orally once daily in 28-day cycles until disease progression or participant discontinuation.	Participants received 80 mg gilteritinib orally once on day -2, and starting on day 1 of cycle 1, participants received 80 mg gilteritinib orally once daily in 28-day cycles until disease progression or participant discontinuation.	Participants received 120 mg gilteritinib orally once on day -2, and starting on day 1 of cycle 1, participants received 120 mg gilteritinib orally once daily in 28-day cycles until disease progression or participant discontinuation.	Participants received 200 mg gilteritinib orally once on day -2, and starting on day 1 of cycle 1, participants received 200 mg gilteritinib orally once daily in 28-day cycles until disease progression or participant discontinuation.	Participants received 300 mg gilteritinib orally once on day -2, and starting on day 1 of cycle 1, participants received 300 mg gilteritinib orally once daily in 28-day cycles until disease progression or participant discontinuation.	Participants received 450 mg gilteritinib orally once on day -2, and starting on day 1 of cycle 1, participants received 450 mg gilteritinib orally once daily in 28-day cycles until disease progression or participant discontinuation.
Measure Participants	1	0	7	24	31	1	0
FLT3 Mutation Positive	57.0	57.0	57.0	39.5	28.0
FLT3 Mutation Negative	71.5	30.0	30.0
All Participants	57.0	64.0	43.5	35.0	28.0

28. Secondary Outcome

Title	Time to First CR/CRh (TTFCRCRh)
Description	TTFCRCRh was defined as the time from the first dose of study drug until the date of first either CR or CRh. TTFCRCRh was evaluated for participants who achieved CR or CRh. For participants who achieve both CR and CRh, the first CR date or CRh date, whichever occurs first was used. TTFCRCRh was calculated only for participants who were FLT3 mutation positive.
Time Frame	From first dose of study drug up to end of treatment (median treatment duration was 69.5 days, minimum of 3 days and maximum of 1320 days)

Outcome Measure Data

Analysis Population Description
The analysis population was the FAS. Only participants who achieved CR or CRh were included in the analysis.

Arm/Group Title	Gilteritinib 20 mg	Gilteritinib 40 mg	Gilteritinib 80 mg	Gilteritinib 120 mg	Gilteritinib 200 mg	Gilteritinib 300 mg	Gilteritinib 450 mg
Arm/Group Description	Participants received 20 mg gilteritinib orally once on day -2, and starting on day 1 of cycle 1, participants received 20 mg gilteritinib orally once daily in 28-day cycles until disease progression or participant discontinuation.	Participants received 40 mg gilteritinib orally once on day -2, and starting on day 1 of cycle 1, participants received 40 mg gilteritinib orally once daily in 28-day cycles until disease progression or participant discontinuation.	Participants received 80 mg gilteritinib orally once on day -2, and starting on day 1 of cycle 1, participants received 80 mg gilteritinib orally once daily in 28-day cycles until disease progression or participant discontinuation.	Participants received 120 mg gilteritinib orally once on day -2, and starting on day 1 of cycle 1, participants received 120 mg gilteritinib orally once daily in 28-day cycles until disease progression or participant discontinuation.	Participants received 200 mg gilteritinib orally once on day -2, and starting on day 1 of cycle 1, participants received 200 mg gilteritinib orally once daily in 28-day cycles until disease progression or participant discontinuation.	Participants received 300 mg gilteritinib orally once on day -2, and starting on day 1 of cycle 1, participants received 300 mg gilteritinib orally once daily in 28-day cycles until disease progression or participant discontinuation.	Participants received 450 mg gilteritinib orally once on day -2, and starting on day 1 of cycle 1, participants received 450 mg gilteritinib orally once daily in 28-day cycles until disease progression or participant discontinuation.
Measure Participants	1	0	3	13	17	3	0
Median (Full Range) [days]	57.0	57.0	59.0	57.0	28.0

29. Secondary Outcome

Title	Time to Best CR/CRh (TTBCRCRh)
Description	TTBCRCRh was defined as the time from the first dose of study drug until the first date that the best response of CR or CRh was achieved. TTBCRCRh was evaluated for participants who achieved CR or CRh. For participants who achieve both CR and CRh, the first CR date was used. TTBCRCRh was calculated only for participants who were FLT3 mutation positive.
Time Frame	From first dose of study drug up to end of treatment (median treatment duration was 69.5 days, minimum of 3 days and maximum of 1320 days)

Outcome Measure Data

Analysis Population Description
The analysis population was the FAS. Participants who achieved CR or CRh were included in the analysis.

Arm/Group Title	Gilteritinib 20 mg	Gilteritinib 40 mg	Gilteritinib 80 mg	Gilteritinib 120 mg	Gilteritinib 200 mg	Gilteritinib 300 mg	Gilteritinib 450 mg
Arm/Group Description	Participants received 20 mg gilteritinib orally once on day -2, and starting on day 1 of cycle 1, participants received 20 mg gilteritinib orally once daily in 28-day cycles until disease progression or participant discontinuation.	Participants received 40 mg gilteritinib orally once on day -2, and starting on day 1 of cycle 1, participants received 40 mg gilteritinib orally once daily in 28-day cycles until disease progression or participant discontinuation.	Participants received 80 mg gilteritinib orally once on day -2, and starting on day 1 of cycle 1, participants received 80 mg gilteritinib orally once daily in 28-day cycles until disease progression or participant discontinuation.	Participants received 120 mg gilteritinib orally once on day -2, and starting on day 1 of cycle 1, participants received 120 mg gilteritinib orally once daily in 28-day cycles until disease progression or participant discontinuation.	Participants received 200 mg gilteritinib orally once on day -2, and starting on day 1 of cycle 1, participants received 200 mg gilteritinib orally once daily in 28-day cycles until disease progression or participant discontinuation.	Participants received 300 mg gilteritinib orally once on day -2, and starting on day 1 of cycle 1, participants received 300 mg gilteritinib orally once daily in 28-day cycles until disease progression or participant discontinuation.	Participants received 450 mg gilteritinib orally once on day -2, and starting on day 1 of cycle 1, participants received 450 mg gilteritinib orally once daily in 28-day cycles until disease progression or participant discontinuation.
Measure Participants	1	0	3	13	17	3	0
Median (Full Range) [days]	57.0	57.0	63.0	88.0	30.0

30. Secondary Outcome

Title	Time to CRc (TTCRc)
Description	TTCRc was defined as the time from the first dose of study drug until the date of first CRc. TTCRc was evaluated for participants who achieved CRc.
Time Frame	From first dose of study drug up to end of treatment (median treatment duration was 69.5 days, minimum of 3 days and maximum of 1320 days)

Outcome Measure Data

Analysis Population Description
The analysis population was the FAS. Only participants who achieved CRc were included in the analysis.

Arm/Group Title	Gilteritinib 20 mg	Gilteritinib 40 mg	Gilteritinib 80 mg	Gilteritinib 120 mg	Gilteritinib 200 mg	Gilteritinib 300 mg	Gilteritinib 450 mg
Arm/Group Description	Participants received 20 mg gilteritinib orally once on day -2, and starting on day 1 of cycle 1, participants received 20 mg gilteritinib orally once daily in 28-day cycles until disease progression or participant discontinuation.	Participants received 40 mg gilteritinib orally once on day -2, and starting on day 1 of cycle 1, participants received 40 mg gilteritinib orally once daily in 28-day cycles until disease progression or participant discontinuation.	Participants received 80 mg gilteritinib orally once on day -2, and starting on day 1 of cycle 1, participants received 80 mg gilteritinib orally once daily in 28-day cycles until disease progression or participant discontinuation.	Participants received 120 mg gilteritinib orally once on day -2, and starting on day 1 of cycle 1, participants received 120 mg gilteritinib orally once daily in 28-day cycles until disease progression or participant discontinuation.	Participants received 200 mg gilteritinib orally once on day -2, and starting on day 1 of cycle 1, participants received 200 mg gilteritinib orally once daily in 28-day cycles until disease progression or participant discontinuation.	Participants received 300 mg gilteritinib orally once on day -2, and starting on day 1 of cycle 1, participants received 300 mg gilteritinib orally once daily in 28-day cycles until disease progression or participant discontinuation.	Participants received 450 mg gilteritinib orally once on day -2, and starting on day 1 of cycle 1, participants received 450 mg gilteritinib orally once daily in 28-day cycles until disease progression or participant discontinuation.
Measure Participants	2	0	7	27	37	3	0
FLT3 Mutation Positive	57.0	56.0	30.0	31.5	28.0
FLT3 Mutation Negative	30.0	71.5	30.0	30.0
All Participants	43.5	57.0	30.0	31.0	28.0

31. Secondary Outcome

Title	Time to Response (TTR)
Description	TTR was defined as the time from the first dose of study drug until the date of either first CRc or PR. TTR was evaluated for participants who achieved CRc or PR.
Time Frame	From first dose of study drug up to end of treatment (median treatment duration was 69.5 days, minimum of 3 days and maximum of 1320 days)

Outcome Measure Data

Analysis Population Description
The analysis population was the FAS. Only participants who achieved CRc or PR were included in the analysis.

Arm/Group Title	Gilteritinib 20 mg	Gilteritinib 40 mg	Gilteritinib 80 mg	Gilteritinib 120 mg	Gilteritinib 200 mg	Gilteritinib 300 mg	Gilteritinib 450 mg
Arm/Group Description	Participants received 20 mg gilteritinib orally once on day -2, and starting on day 1 of cycle 1, participants received 20 mg gilteritinib orally once daily in 28-day cycles until disease progression or participant discontinuation.	Participants received 40 mg gilteritinib orally once on day -2, and starting on day 1 of cycle 1, participants received 40 mg gilteritinib orally once daily in 28-day cycles until disease progression or participant discontinuation.	Participants received 80 mg gilteritinib orally once on day -2, and starting on day 1 of cycle 1, participants received 80 mg gilteritinib orally once daily in 28-day cycles until disease progression or participant discontinuation.	Participants received 120 mg gilteritinib orally once on day -2, and starting on day 1 of cycle 1, participants received 120 mg gilteritinib orally once daily in 28-day cycles until disease progression or participant discontinuation.	Participants received 200 mg gilteritinib orally once on day -2, and starting on day 1 of cycle 1, participants received 200 mg gilteritinib orally once daily in 28-day cycles until disease progression or participant discontinuation.	Participants received 300 mg gilteritinib orally once on day -2, and starting on day 1 of cycle 1, participants received 300 mg gilteritinib orally once daily in 28-day cycles until disease progression or participant discontinuation.	Participants received 450 mg gilteritinib orally once on day -2, and starting on day 1 of cycle 1, participants received 450 mg gilteritinib orally once daily in 28-day cycles until disease progression or participant discontinuation.
Measure Participants	3	3	10	32	45	6	1
FLT3 Mutation Positive	61.5	57.0	31.0	29.0	29.0	28.0	31.0
FLT3 Mutation Negative	30.0	71.5	29.5	29.5
All Participants	30.0	57.0	43.5	29.0	29.0	28.0	31.0

32. Secondary Outcome

Title	Time to Best Response (TTBR)
Description	TTBR was defined as the time from the first dose of study drug until the first disease assessment date when participant achieved best response. TTBR was evaluated in participants who achieved best response of CR, CRp, CRi, or PR.
Time Frame	From first dose of study drug up to end of treatment (median treatment duration was 69.5 days, minimum of 3 days and maximum of 1320 days)

Outcome Measure Data

Analysis Population Description
The analysis population was the FAS. Only participants who achieved CR, CRp, CRi, or PR were included in the analysis.

Arm/Group Title	Gilteritinib 20 mg	Gilteritinib 40 mg	Gilteritinib 80 mg	Gilteritinib 120 mg	Gilteritinib 200 mg	Gilteritinib 300 mg	Gilteritinib 450 mg
Arm/Group Description	Participants received 20 mg gilteritinib orally once on day -2, and starting on day 1 of cycle 1, participants received 20 mg gilteritinib orally once daily in 28-day cycles until disease progression or participant discontinuation.	Participants received 40 mg gilteritinib orally once on day -2, and starting on day 1 of cycle 1, participants received 40 mg gilteritinib orally once daily in 28-day cycles until disease progression or participant discontinuation.	Participants received 80 mg gilteritinib orally once on day -2, and starting on day 1 of cycle 1, participants received 80 mg gilteritinib orally once daily in 28-day cycles until disease progression or participant discontinuation.	Participants received 120 mg gilteritinib orally once on day -2, and starting on day 1 of cycle 1, participants received 120 mg gilteritinib orally once daily in 28-day cycles until disease progression or participant discontinuation.	Participants received 200 mg gilteritinib orally once on day -2, and starting on day 1 of cycle 1, participants received 200 mg gilteritinib orally once daily in 28-day cycles until disease progression or participant discontinuation.	Participants received 300 mg gilteritinib orally once on day -2, and starting on day 1 of cycle 1, participants received 300 mg gilteritinib orally once daily in 28-day cycles until disease progression or participant discontinuation.	Participants received 450 mg gilteritinib orally once on day -2, and starting on day 1 of cycle 1, participants received 450 mg gilteritinib orally once daily in 28-day cycles until disease progression or participant discontinuation.
Measure Participants	3	3	10	32	45	6	1
FLT3 Mutation Positive	75.5	57.0	44.0	43.5	57.0	29.0	31.0
FLT3 Mutation Negative	30.0	71.5	29.5	29.5
All Participants	57.0	57.0	58.0	30.0	56.0	29.0	31.0

33. Secondary Outcome

Title	Overall Survival (OS)
Description	The time from the date of first dose of study drug until the date of death from any cause. For a participant who was not known to have died by the end of study follow-up, OS was censored at the date of last contact. OS was calculated using Kaplan-Meier method and therefore data are estimated.
Time Frame	From first dose of study drug up to end of study (median time on study was 157.0 days, minimum of 5 days and maximum of 1320 days)

Outcome Measure Data

Analysis Population Description
The analysis population was the FAS.

Arm/Group Title	Gilteritinib 20 mg	Gilteritinib 40 mg	Gilteritinib 80 mg	Gilteritinib 120 mg	Gilteritinib 200 mg	Gilteritinib 300 mg	Gilteritinib 450 mg
Arm/Group Description	Participants received 20 mg gilteritinib orally once on day -2, and starting on day 1 of cycle 1, participants received 20 mg gilteritinib orally once daily in 28-day cycles until disease progression or participant discontinuation.	Participants received 40 mg gilteritinib orally once on day -2, and starting on day 1 of cycle 1, participants received 40 mg gilteritinib orally once daily in 28-day cycles until disease progression or participant discontinuation.	Participants received 80 mg gilteritinib orally once on day -2, and starting on day 1 of cycle 1, participants received 80 mg gilteritinib orally once daily in 28-day cycles until disease progression or participant discontinuation.	Participants received 120 mg gilteritinib orally once on day -2, and starting on day 1 of cycle 1, participants received 120 mg gilteritinib orally once daily in 28-day cycles until disease progression or participant discontinuation.	Participants received 200 mg gilteritinib orally once on day -2, and starting on day 1 of cycle 1, participants received 200 mg gilteritinib orally once daily in 28-day cycles until disease progression or participant discontinuation.	Participants received 300 mg gilteritinib orally once on day -2, and starting on day 1 of cycle 1, participants received 300 mg gilteritinib orally once daily in 28-day cycles until disease progression or participant discontinuation.	Participants received 450 mg gilteritinib orally once on day -2, and starting on day 1 of cycle 1, participants received 450 mg gilteritinib orally once daily in 28-day cycles until disease progression or participant discontinuation.
Measure Participants	16	16	24	70	100	20	3
FLT3 Mutation Positive	123.0	199.5	197.5	246.0	214.0	157.0	204.0
FLT3 Mutation Negative	NA	71.5	136.0	144.0	67.0	68.0	89.0
All Participants	149.5	95.0	154.0	216.0	176.0	128.5	89.0

34. Secondary Outcome

Title	Event Free Survival (EFS)
Description	EFS was defined as the time from the date of first dose of study drug until the date of documented relapse, treatment failure or death from any cause, whichever occurred first. For a participant with none of these events, EFS was censored at the date of last relapse-free disease assessment. A participant without post-treatment disease assessment was censored at randomization date. Treatment failure included those participants who discontinued the treatment due to "progressive disease" or "lack of efficacy" without a previous response of CR, CRp, CRi or PR. Treatment failure date referred to the start of new anti-leukemia therapy or the last treatment evaluation date when new anti-leukemia therapy date was not available. For participants who were censored, last relapse-free disease assessment date referred to the participant's last disease assessment date. EFS was calculated using Kaplan-Meier method and therefore data are estimated.
Time Frame	From first dose of study drug up to end of study (median time on study was 157.0 days, minimum of 5 days and maximum of 1320 days)

Outcome Measure Data

Analysis Population Description
The analysis population was the FAS.

Arm/Group Title	Gilteritinib 20 mg	Gilteritinib 40 mg	Gilteritinib 80 mg	Gilteritinib 120 mg	Gilteritinib 200 mg	Gilteritinib 300 mg	Gilteritinib 450 mg
Arm/Group Description	Participants received 20 mg gilteritinib orally once on day -2, and starting on day 1 of cycle 1, participants received 20 mg gilteritinib orally once daily in 28-day cycles until disease progression or participant discontinuation.	Participants received 40 mg gilteritinib orally once on day -2, and starting on day 1 of cycle 1, participants received 40 mg gilteritinib orally once daily in 28-day cycles until disease progression or participant discontinuation.	Participants received 80 mg gilteritinib orally once on day -2, and starting on day 1 of cycle 1, participants received 80 mg gilteritinib orally once daily in 28-day cycles until disease progression or participant discontinuation.	Participants received 120 mg gilteritinib orally once on day -2, and starting on day 1 of cycle 1, participants received 120 mg gilteritinib orally once daily in 28-day cycles until disease progression or participant discontinuation.	Participants received 200 mg gilteritinib orally once on day -2, and starting on day 1 of cycle 1, participants received 200 mg gilteritinib orally once daily in 28-day cycles until disease progression or participant discontinuation.	Participants received 300 mg gilteritinib orally once on day -2, and starting on day 1 of cycle 1, participants received 300 mg gilteritinib orally once daily in 28-day cycles until disease progression or participant discontinuation.	Participants received 450 mg gilteritinib orally once on day -2, and starting on day 1 of cycle 1, participants received 450 mg gilteritinib orally once daily in 28-day cycles until disease progression or participant discontinuation.
Measure Participants	16	16	24	70	100	20	3
FLT3 Mutation Positive	52.0	109.0	93.5	112.0	121.0	85.0	86.0
FLT3 Mutation Negative	58.0	39.0	74.0	85.5	45.0	43.0	71.0
All Participants	58.0	55.5	76.0	108.0	118.0	65.0	71.0

35. Secondary Outcome

Title	Leukemia Free Survival (LFS)
Description	LFS was defined as the time from the date of first CRc until the date of documented relapse or death for participants who achieved CRc. For a participant who was not known to have relapsed or died, LFS was censored on the date of last relapse-free disease assessment date. LFS was calculated using Kaplan-Meier method and therefore data are estimated.
Time Frame	From first dose of study drug up to end of study (median time on study was 157.0 days, minimum of 5 days and maximum of 1320 days)

Outcome Measure Data

Analysis Population Description
The analysis population was the FAS. Only participants who achieved CRc were included in the analysis.

Arm/Group Title	Gilteritinib 20 mg	Gilteritinib 40 mg	Gilteritinib 80 mg	Gilteritinib 120 mg	Gilteritinib 200 mg	Gilteritinib 300 mg	Gilteritinib 450 mg
Arm/Group Description	Participants received 20 mg gilteritinib orally once on day -2, and starting on day 1 of cycle 1, participants received 20 mg gilteritinib orally once daily in 28-day cycles until disease progression or participant discontinuation.	Participants received 40 mg gilteritinib orally once on day -2, and starting on day 1 of cycle 1, participants received 40 mg gilteritinib orally once daily in 28-day cycles until disease progression or participant discontinuation.	Participants received 80 mg gilteritinib orally once on day -2, and starting on day 1 of cycle 1, participants received 80 mg gilteritinib orally once daily in 28-day cycles until disease progression or participant discontinuation.	Participants received 120 mg gilteritinib orally once on day -2, and starting on day 1 of cycle 1, participants received 120 mg gilteritinib orally once daily in 28-day cycles until disease progression or participant discontinuation.	Participants received 200 mg gilteritinib orally once on day -2, and starting on day 1 of cycle 1, participants received 200 mg gilteritinib orally once daily in 28-day cycles until disease progression or participant discontinuation.	Participants received 300 mg gilteritinib orally once on day -2, and starting on day 1 of cycle 1, participants received 300 mg gilteritinib orally once daily in 28-day cycles until disease progression or participant discontinuation.	Participants received 450 mg gilteritinib orally once on day -2, and starting on day 1 of cycle 1, participants received 450 mg gilteritinib orally once daily in 28-day cycles until disease progression or participant discontinuation.
Measure Participants	2	0	7	27	37	3	0
FLT3 Mutation Positive	242.0	98.0	98.0	146.0	296.0
FLT3 Mutation Negative	NA	41.0	99.0	38.0
All Participants	242.0	79.0	98.0	146.0	296.0

36. Secondary Outcome

Title	Percentage of Participants Who Achieved Transfusion Conversion
Description	Participants who achieved transfusion conversion were defined as the number of participants who were transfusion dependent at baseline period but became transfusion independent at post-baseline period divided by the total number of participants who were transfusion dependent at baseline period. Participants were considered baseline transfusion dependent if there were RBC or platelet transfusions within the baseline period. Participants were considered post-baseline transfusion independent if they were on treatment >=84 days, and if there was one consecutive 56 days without any RBC or platelet transfusion within post-baseline period. If participants were on treatment >28 days but <84 days, and there was no RBC or platelet transfusion within post-baseline period, or on treatment <=28 days, post-baseline transfusion status was not evaluable. Exact 95% confidence interval was estimated using the binomial distribution.
Time Frame	Baseline (28 days prior to first dose until 28 days after the first dose) and postbaseline (from 29 days after first dose date until last dose date); median treatment duration was 69.5 days, minimum of 3 days and maximum of 1320 days

Outcome Measure Data

Analysis Population Description
The analysis population was the FAS. Participants who were transfusion dependent at baseline and had evaluable post-baseline transfusion status were included in the analysis.

Arm/Group Title	Gilteritinib 20 mg	Gilteritinib 40 mg	Gilteritinib 80 mg	Gilteritinib 120 mg	Gilteritinib 200 mg	Gilteritinib 300 mg	Gilteritinib 450 mg
Arm/Group Description	Participants received 20 mg gilteritinib orally once on day -2, and starting on day 1 of cycle 1, participants received 20 mg gilteritinib orally once daily in 28-day cycles until disease progression or participant discontinuation.	Participants received 40 mg gilteritinib orally once on day -2, and starting on day 1 of cycle 1, participants received 40 mg gilteritinib orally once daily in 28-day cycles until disease progression or participant discontinuation.	Participants received 80 mg gilteritinib orally once on day -2, and starting on day 1 of cycle 1, participants received 80 mg gilteritinib orally once daily in 28-day cycles until disease progression or participant discontinuation.	Participants received 120 mg gilteritinib orally once on day -2, and starting on day 1 of cycle 1, participants received 120 mg gilteritinib orally once daily in 28-day cycles until disease progression or participant discontinuation.	Participants received 200 mg gilteritinib orally once on day -2, and starting on day 1 of cycle 1, participants received 200 mg gilteritinib orally once daily in 28-day cycles until disease progression or participant discontinuation.	Participants received 300 mg gilteritinib orally once on day -2, and starting on day 1 of cycle 1, participants received 300 mg gilteritinib orally once daily in 28-day cycles until disease progression or participant discontinuation.	Participants received 450 mg gilteritinib orally once on day -2, and starting on day 1 of cycle 1, participants received 450 mg gilteritinib orally once daily in 28-day cycles until disease progression or participant discontinuation.
Measure Participants	7	8	16	49	63	8	2
FLT3 Mutation Positive	0 0%	0 0%	37.5 1250%	27.5 916.7%	40.4 1346.7%	NA NaN	NA NaN
FLT3 Mutation Negative	NA NaN	NA NaN	12.5 416.7%	22.2 740%	33.3 1110%	NA NaN	NA NaN
All Participants	NA NaN	NA NaN	25.0 833.3%	26.5 883.3%	39.7 1323.3%	NA NaN	NA NaN

37. Secondary Outcome

Title	Percentage of Participants Who Achieved Transfusion Maintenance
Description	Participants who achieved transfusion maintenance were defined as the number of participants who were transfusion independent at baseline period and still maintained transfusion independent at post-baseline period divided by the total number of participants who were transfusion independent at baseline period.
Time Frame	Baseline (28 days prior to first dose until 28 days after the first dose) and postbaseline (from 29 days after first dose date until last dose date); median treatment duration was 69.5 days, minimum of 3 days and maximum of 1320 days

Outcome Measure Data

Analysis Population Description
The analysis population was the FAS. Participants who were transfusion independent at baseline and had evaluable post-baseline transfusion status were included in the analysis.

Arm/Group Title	Gilteritinib 20 mg	Gilteritinib 40 mg	Gilteritinib 80 mg	Gilteritinib 120 mg	Gilteritinib 200 mg	Gilteritinib 300 mg	Gilteritinib 450 mg
Arm/Group Description	Participants received 20 mg gilteritinib orally once on day -2, and starting on day 1 of cycle 1, participants received 20 mg gilteritinib orally once daily in 28-day cycles until disease progression or participant discontinuation.	Participants received 40 mg gilteritinib orally once on day -2, and starting on day 1 of cycle 1, participants received 40 mg gilteritinib orally once daily in 28-day cycles until disease progression or participant discontinuation.	Participants received 80 mg gilteritinib orally once on day -2, and starting on day 1 of cycle 1, participants received 80 mg gilteritinib orally once daily in 28-day cycles until disease progression or participant discontinuation.	Participants received 120 mg gilteritinib orally once on day -2, and starting on day 1 of cycle 1, participants received 120 mg gilteritinib orally once daily in 28-day cycles until disease progression or participant discontinuation.	Participants received 200 mg gilteritinib orally once on day -2, and starting on day 1 of cycle 1, participants received 200 mg gilteritinib orally once daily in 28-day cycles until disease progression or participant discontinuation.	Participants received 300 mg gilteritinib orally once on day -2, and starting on day 1 of cycle 1, participants received 300 mg gilteritinib orally once daily in 28-day cycles until disease progression or participant discontinuation.	Participants received 450 mg gilteritinib orally once on day -2, and starting on day 1 of cycle 1, participants received 450 mg gilteritinib orally once daily in 28-day cycles until disease progression or participant discontinuation.
Measure Participants	0	0	1	7	10	0	1
FLT3 Mutation Positive	100.0 2000%	75.0 2500%	80.0 2666.7%	100.0 3333.3%
FLT3 Mutation Negative	33.3 666%
All Participants	100.0 2000%	57.1 1903.3%	80.0 2666.7%	100.0 3333.3%

38. Secondary Outcome

Title	AUC24 of Gilteritinib in Co-administration With Voriconazole
Description	Plasma samples were used for pharmacokinetic assessments.
Time Frame	Cycle 1 Day 15 and Cycle 2 Day 1: predose, 0.5, 1, 2, 4, 6, 24 hours postdose (gilteritinib)

Outcome Measure Data

Analysis Population Description
The analysis population was the PKAS, with participants administered 20 mg gilteritinib and voriconazole.

Arm/Group Title	Gilteritinib 20 mg in Expansion Phase
Arm/Group Description	Participants received 20 mg gilteritinib orally once daily stating on day 1 of cycle 1 and continued in 28-day cycles until disease progression or participant discontinuation in the expansion phase of the study. Starting on day 16 of cycle 1, participants also received 200 mg voriconazole orally every 12 hours through day 1 of cycle 2.
Measure Participants	1
Mean (Standard Deviation) [ng*h/mL]	919.3 (NA)

39. Secondary Outcome

Title	Cmax of Gilteritinib in Co-administration With Voriconazole
Description	Plasma samples were used for pharmacokinetic assessments.
Time Frame	Cycle 1 Day 15 and Cycle 2 Day 1: predose, 0.5, 1, 2, 4, 6, 24 hours postdose (gilteritinib)

Outcome Measure Data

Analysis Population Description
The analysis population was the PKAS, with participants administered 20 mg gilteritinib and voriconazole.

Arm/Group Title	Gilteritinib 20 mg in Expansion Phase
Arm/Group Description	Participants received 20 mg gilteritinib orally once daily stating on day 1 of cycle 1 and continued in 28-day cycles until disease progression or participant discontinuation in the expansion phase of the study. Starting on day 16 of cycle 1, participants also received 200 mg voriconazole orally every 12 hours through day 1 of cycle 2.
Measure Participants	1
Mean (Standard Deviation) [ng/mL]	63.79 (NA)

40. Secondary Outcome

Title	AUClast of Gilteritinib in Co-administration With Voriconazole
Description	Plasma samples were used for pharmacokinetic assessments.
Time Frame	Cycle 1 Day 15 and Cycle 2 Day 1: predose, 0.5, 1, 2, 4, 6, 24 hours postdose (gilteritinib)

Outcome Measure Data

Analysis Population Description
The analysis population was the PKAS, with participants administered 20 mg gilteritinib and voriconazole.

Arm/Group Title	Gilteritinib 20 mg in Expansion Phase
Arm/Group Description	Participants received 20 mg gilteritinib orally once daily stating on day 1 of cycle 1 and continued in 28-day cycles until disease progression or participant discontinuation in the expansion phase of the study. Starting on day 16 of cycle 1, participants also received 200 mg voriconazole orally every 12 hours through day 1 of cycle 2.
Measure Participants	1
Mean (Standard Deviation) [ng*h/mL]	919.3 (NA)

41. Secondary Outcome

Title	Tmax of Gilteritinib in Co-administration With Voriconazole
Description	Plasma samples were used for pharmacokinetic assessments.
Time Frame	Cycle 1 Day 15 and Cycle 2 Day 1: predose, 0.5, 1, 2, 4, 6, 24 hours postdose (gilteritinib)

Outcome Measure Data

Analysis Population Description
The analysis population was the PKAS, with participants administered 20 mg gilteritinib and voriconazole.

Arm/Group Title	Gilteritinib 20 mg in Expansion Phase
Arm/Group Description	Participants received 20 mg gilteritinib orally once daily stating on day 1 of cycle 1 and continued in 28-day cycles until disease progression or participant discontinuation in the expansion phase of the study. Starting on day 16 of cycle 1, participants also received 200 mg voriconazole orally every 12 hours through day 1 of cycle 2.
Measure Participants	1
Median (Full Range) [hours]	2.08

42. Secondary Outcome

Title	AUC24 of Midazolam Administered With and Without Gilteritinib
Description	Plasma samples were used for pharmacokinetic assessments.
Time Frame	Day -1 and cycle 1 day 15: predose, 0.5, 1, 2, 4, 6, 24 hours postdose (midazolam)

Outcome Measure Data

Analysis Population Description
The analysis population was the PKAS, with participants administered 300 mg gilteritinib and midazolam.

Arm/Group Title	Gilteritinib 300 mg in Expansion Phase
Arm/Group Description	Participants received 300 mg gilteritinib orally once daily stating on day 1 of cycle 1 and continued in 28-day cycles until disease progression or participant discontinuation in the expansion phase of the study. On day -1 and day 15 of cycle 1, participants also received 2 mg midazolam as a single oral dose.
Measure Participants	17
Midazolam Alone (Day -1)	66.55 (57.70)
Midazolam + Gilteritinib (Cycle 1 Day 15)	81.56 (65.84)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Gilteritinib 20 mg in Escalation Phase
	Comments	Statistical Comparison of Midazolam Exposure after Administration of Midazolam Alone or Coadministered with Gilteritinib: The difference of least squares (LS) means of log-transformed pharmacokinetic parameters between midazolam alone and midazolam + gilteritinib and its 90% CI are backtransformed to the raw scale and are expressed as percent.
	Type of Statistical Test	Other
	Comments

Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments

Method of Estimation	Estimation Parameter	Geometric LS Mean Ratio
	Estimated Value	109.46
	Confidence Interval	(2-Sided) 90% 49.82 to 240.48
	Parameter Dispersion	Type: Value:
	Estimation Comments

43. Secondary Outcome

Title	AUC24 of Metabolite 1-Hydroxymidazolam After Administration of Midazolam With and Without Gilteritinib
Description	Plasma samples were used for pharmacokinetic assessments.
Time Frame	Day -1 and cycle 1 day 15: predose, 0.5, 1, 2, 4, 6, 24 hours postdose (midazolam)

Outcome Measure Data

Analysis Population Description
The analysis population was the PKAS, with participants administered 300 mg gilteritinib and midazolam.

Arm/Group Title	Gilteritinib 300 mg in Expansion Phase
Arm/Group Description	Participants received 300 mg gilteritinib orally once daily stating on day 1 of cycle 1 and continued in 28-day cycles until disease progression or participant discontinuation in the expansion phase of the study. On day -1 and day 15 of cycle 1, participants also received 2 mg midazolam as a single oral dose.
Measure Participants	17
Midazolam Alone (Day -1)	20.44 (24.80)
Midazolam + Gilteritinib (Cycle 1 Day 15)	23.10 (21.64)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Gilteritinib 20 mg in Escalation Phase
	Comments	Statistical Comparison of Midazolam Exposure after Administration of Midazolam Alone or Coadministered with Gilteritinib: The difference of LS means of log-transformed pharmacokinetic parameters between 1-hydroxymidazolam alone and 1-hydroxymidazolam + gilteritinib and its 90% CI are backtransformed to the raw scale and are expressed as percent.
	Type of Statistical Test	Other
	Comments

Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments

Method of Estimation	Estimation Parameter	Geometric LS Mean Ratio
	Estimated Value	149.90
	Confidence Interval	() 90% 74.88 to 300.06
	Parameter Dispersion	Type: Value:
	Estimation Comments

44. Secondary Outcome

Title	Cmax of Midazolam Administered With and Without Gilteritinib
Description	Plasma samples were used for pharmacokinetic assessments.
Time Frame	Day -1 and cycle 1 day 15: predose, 0.5, 1, 2, 4, 6, 24 hours postdose (midazolam)

Outcome Measure Data

Analysis Population Description
The analysis population was the PKAS, with participants administered 300 mg gilteritinib and midazolam.

Arm/Group Title	Gilteritinib 300 mg in Expansion Phase
Arm/Group Description	Participants received 300 mg gilteritinib orally once daily stating on day 1 of cycle 1 and continued in 28-day cycles until disease progression or participant discontinuation in the expansion phase of the study. On day -1 and day 15 of cycle 1, participants also received 2 mg midazolam as a single oral dose.
Measure Participants	17
Midazolam Alone (Day -1)	14.68 (8.923)
Midazolam + Gilteritinib (Cycle 1 Day 15)	18.45 (9.452)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Gilteritinib 20 mg in Escalation Phase
	Comments	Statistical Comparison of Midazolam Exposure after Administration of Midazolam Alone or Coadministered with Gilteritinib: The difference of LS means of log-transformed pharmacokinetic parameters between midazolam alone and midazolam + gilteritinib and its 90% CI are backtransformed to the raw scale and are expressed as percent.
	Type of Statistical Test	Other
	Comments

Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments

Method of Estimation	Estimation Parameter	Geometric LS Mean Ratio
	Estimated Value	111.64
	Confidence Interval	(2-Sided) 90% 69.54 to 179.25
	Parameter Dispersion	Type: Value:
	Estimation Comments

45. Secondary Outcome

Title	Cmax of 1-Hydroxymidazolam After Administration of Midazolam With and Without Gilteritinib
Description	Plasma samples were used for pharmacokinetic assessments.
Time Frame	Day -1 and cycle 1 day 15: predose, 0.5, 1, 2, 4, 6, 24 hours postdose (midazolam)

Outcome Measure Data

Analysis Population Description
The analysis population was the PKAS, with participants administered 300 mg gilteritinib and midazolam.

Arm/Group Title	Gilteritinib 300 mg in Expansion Phase
Arm/Group Description	Participants received 300 mg gilteritinib orally once daily stating on day 1 of cycle 1 and continued in 28-day cycles until disease progression or participant discontinuation in the expansion phase of the study. On day -1 and day 15 of cycle 1, participants also received 2 mg midazolam as a single oral dose.
Measure Participants	17
Midazolam Alone (Day -1)	4.562 (2.858)
Midazolam + Gilteritinib (Cycle 1 Day 15)	5.053 (3.158)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Gilteritinib 20 mg in Escalation Phase
	Comments	Statistical Comparison of Midazolam Exposure after Administration of Midazolam Alone or Coadministered with Gilteritinib: The difference of LS means of log-transformed pharmacokinetic parameters between 1-hydroxymidazolam/midazolam alone and 1-hydroxymidazolam/midazolam + gilteritinib and its 90% CI are backtransformed to the raw scale and are expressed as percent.
	Type of Statistical Test	Other
	Comments

Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments

Method of Estimation	Estimation Parameter	Geometric LS Mean Ratio
	Estimated Value	123.47
	Confidence Interval	(2-Sided) 90% 72.41 to 210.52
	Parameter Dispersion	Type: Value:
	Estimation Comments

46. Secondary Outcome

Title	AUClast of Midazolam Administered With and Without Gilteritinib
Description	Plasma samples were used for pharmacokinetic assessments.
Time Frame	Day -1 and cycle 1 day 15: predose, 0.5, 1, 2, 4, 6, 24 hours postdose (midazolam)

Outcome Measure Data

Analysis Population Description
The analysis population was the PKAS, with participants administered 300 mg gilteritinib and midazolam.

Arm/Group Title	Gilteritinib 300 mg in Expansion Phase
Arm/Group Description	Participants received 300 mg gilteritinib orally once daily stating on day 1 of cycle 1 and continued in 28-day cycles until disease progression or participant discontinuation in the expansion phase of the study. On day -1 and day 15 of cycle 1, participants also received 2 mg midazolam as a single oral dose.
Measure Participants	17
Midazolam Alone (Day -1)	59.48 (59.49)
Midazolam + Gilteritinib (Cycle 1 Day 15)	82.44 (64.25)

47. Secondary Outcome

Title	AUClast of 1-Hydroxymidazolam After Administration of Midazolam With and Without Gilteritinib
Description	Plasma samples were used for pharmacokinetic assessments.
Time Frame	Day -1 and cycle 1 day 15: predose, 0.5, 1, 2, 4, 6, 24 hours postdose (midazolam)

Outcome Measure Data

Analysis Population Description
The analysis population was the PKAS, with participants administered 300 mg gilteritinib and midazolam.

Arm/Group Title	Gilteritinib 300 mg in Expansion Phase
Arm/Group Description	Participants received 300 mg gilteritinib orally once daily stating on day 1 of cycle 1 and continued in 28-day cycles until disease progression or participant discontinuation in the expansion phase of the study. On day -1 and day 15 of cycle 1, participants also received 2 mg midazolam as a single oral dose.
Measure Participants	17
Midazolam Alone (Day -1)	17.05 (24.70)
Midazolam + Gilteritinib (Cycle 1 Day 15)	23.58 (22.07)

48. Secondary Outcome

Title	Tmax of Midazolam Administered With and Without Gilteritinib
Description	Plasma samples were used for pharmacokinetic assessments.
Time Frame	Day -1 and cycle 1 day 15: predose, 0.5, 1, 2, 4, 6, 24 hours postdose (midazolam)

Outcome Measure Data

Analysis Population Description
The analysis population was the PKAS, with participants administered 300 mg gilteritinib and midazolam.

Arm/Group Title	Gilteritinib 300 mg in Expansion Phase
Arm/Group Description	Participants received 300 mg gilteritinib orally once daily stating on day 1 of cycle 1 and continued in 28-day cycles until disease progression or participant discontinuation in the expansion phase of the study. On day -1 and day 15 of cycle 1, participants also received 2 mg midazolam as a single oral dose.
Measure Participants	17
Midazolam Alone (Day -1)	0.5000
Midazolam + Gilteritinib (Cycle 1 Day 15)	1.00

49. Secondary Outcome

Title	Tmax of 1-Hydroxymidazolam After Administration of Midazolam With and Without Gilteritinib
Description	Plasma samples were used for pharmacokinetic assessments.
Time Frame	Day -1 and cycle 1 day 15: predose, 0.5, 1, 2, 4, 6, 24 hours postdose (midazolam)

Outcome Measure Data

Analysis Population Description
The analysis population was the PKAS, with participants administered 300 mg gilteritinib and midazolam.

Arm/Group Title	Gilteritinib 300 mg in Expansion Phase
Arm/Group Description	Participants received 300 mg gilteritinib orally once daily stating on day 1 of cycle 1 and continued in 28-day cycles until disease progression or participant discontinuation in the expansion phase of the study. On day -1 and day 15 of cycle 1, participants also received 2 mg midazolam as a single oral dose.
Measure Participants	17
Midazolam Alone (Day -1)	0.5583
Midazolam + Gilteritinib (Cycle 1 Day 15)	1.00

50. Secondary Outcome

Title	Area Under the Concentration-time Curve From the Time of Dosing Extrapolated to Time Infinity (AUCinf) of Cephalexin Administered With and Without Gilteritinib
Description	Plasma samples were used for pharmacokinetic assessments.
Time Frame	Day -1 and cycle 1 day 15: predose, 0.5, 1, 1.5, 2, 3, 4, 6, 24 hours postdose (cephalexin)

Outcome Measure Data

Analysis Population Description
The analysis population was the PKAS, with participants administered 200 mg gilteritinib and cephalexin.

Arm/Group Title	Gilteritinib 200 mg in Expansion Phase
Arm/Group Description	Participants received 200 mg gilteritinib orally once daily stating on day 1 of cycle 1 and continued in 28-day cycles until disease progression or participant discontinuation in the expansion phase of the study. On day -1 and day 15 of cycle 1, certain participants also received 500 mg cephalexin as a single oral dose.
Measure Participants	100
Cephalexin Alone (Day -1)	57650 (20386)
Cephalexin + Gilteritinib (Cycle 1 Day 15)	51873 (18819)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Gilteritinib 20 mg in Escalation Phase
	Comments	Statistical Assessment of the Effect of Gilteritinib on Cephalexin Pharmacokinetics after Administration of Cephalexin Alone or Coadministered with Gilteritinib: The difference of LS means of log-transformed pharmacokinetic parameters between cephalexin alone and cephalexin + gilteritinib and its 90% CI are backtransformed to the raw scale and are expressed as percent.
	Type of Statistical Test	Other
	Comments

Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments

Method of Estimation	Estimation Parameter	Geometric LS Mean Ratio
	Estimated Value	93.96
	Confidence Interval	(2-Sided) 90% 75.29 to 117.26
	Parameter Dispersion	Type: Value:
	Estimation Comments

51. Secondary Outcome

Title	Cmax of Cephalexin Administered With and Without Gilteritinib
Description	Plasma samples were used for pharmacokinetic assessments.
Time Frame	Day -1 and cycle 1 day 15: predose, 0.5, 1, 1.5, 2, 3, 4, 6, 24 hours postdose (cephalexin)

Outcome Measure Data

Analysis Population Description
The analysis population was the PKAS, with participants administered 200 mg gilteritinib and cephalexin.

Arm/Group Title	Gilteritinib 200 mg in Expansion Phase
Arm/Group Description	Participants received 200 mg gilteritinib orally once daily stating on day 1 of cycle 1 and continued in 28-day cycles until disease progression or participant discontinuation in the expansion phase of the study. On day -1 and day 15 of cycle 1, certain participants also received 500 mg cephalexin as a single oral dose.
Measure Participants	100
Cephalexin Alone (Day -1)	17688 (6680)
Cephalexin + Gilteritinib (Cycle 1 day 15)	16075 (4606)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Gilteritinib 20 mg in Escalation Phase
	Comments	Statistical Assessment of the Effect of Gilteritinib on Cephalexin Pharmacokinetics after Administration of Cephalexin Alone or Coadministered with Gilteritinib: The difference of LS means of log-transformed pharmacokinetic parameters between cephalexin alone and cephalexin + gilteritinib and its 90% CI are backtransformed to the raw scale and are expressed as percent.
	Type of Statistical Test	Other
	Comments

Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments

Method of Estimation	Estimation Parameter	Geometric LS Mean Ratio
	Estimated Value	91.46
	Confidence Interval	(2-Sided) 90% 74.60 to 112.12
	Parameter Dispersion	Type: Value:
	Estimation Comments

52. Secondary Outcome

Title	AUClast of Cephalexin Administered With and Without Gilteritinib
Description	Plasma samples were used for pharmacokinetic assessments.
Time Frame	Day -1 and cycle 1 day 15: predose, 0.5, 1, 1.5, 2, 3, 4, 6, 24 hours postdose (cephalexin)

Outcome Measure Data

Analysis Population Description
The analysis population was the PKAS, with participants administered 200 mg gilteritinib and cephalexin.

Arm/Group Title	Gilteritinib 200 mg in Expansion Phase
Arm/Group Description	Participants received 200 mg gilteritinib orally once daily stating on day 1 of cycle 1 and continued in 28-day cycles until disease progression or participant discontinuation in the expansion phase of the study. On day -1 and day 15 of cycle 1, certain participants also received 500 mg cephalexin as a single oral dose.
Measure Participants	100
Cephalexin Alone (Day -1)	53183 (26877)
Cephalexin + Gilteritinib (Cycle 1 Day 15)	54963 (29531)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Gilteritinib 20 mg in Escalation Phase
	Comments	Statistical Assessment of the Effect of Gilteritinib on Cephalexin Pharmacokinetics after Administration of Cephalexin Alone or Coadministered with Gilteritinib: The difference of LS means of log-transformed pharmacokinetic parameters between cephalexin alone and cephalexin + gilteritinib and its 90% CI are backtransformed to the raw scale and are expressed as percent.
	Type of Statistical Test	Other
	Comments

Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments

Method of Estimation	Estimation Parameter	Geometric LS Mean Ratio
	Estimated Value	97.71
	Confidence Interval	(2-Sided) 90% 74.19 to 128.70
	Parameter Dispersion	Type: Value:
	Estimation Comments

53. Secondary Outcome

Title	Tmax of Cephalexin Administered With and Without Gilteritinib
Description	Plasma samples were used for pharmacokinetic assessments.
Time Frame	Day -1 and cycle 1 day 15: predose, 0.5, 1, 1.5, 2, 3, 4, 6, 24 hours postdose (cephalexin)

Outcome Measure Data

Analysis Population Description
The analysis population was the PKAS, with participants administered 200 mg gilteritinib and cephalexin.

Arm/Group Title	Gilteritinib 200 mg in Expansion Phase
Arm/Group Description	Participants received 200 mg gilteritinib orally once daily stating on day 1 of cycle 1 and continued in 28-day cycles until disease progression or participant discontinuation in the expansion phase of the study. On day -1 and day 15 of cycle 1, certain participants also received 500 mg cephalexin as a single oral dose.
Measure Participants	100
Cephalexin Alone (Day -1)	1.500
Cephalexin + Gilteritinib (Cycle 1 Day 15)	1.483

54. Secondary Outcome

Title	T1/2 of Cephalexin Administered With and Without Gilteritinib
Description	Plasma samples were used for pharmacokinetic assessments.
Time Frame	Day -1 and cycle 1 day 15: predose, 0.5, 1, 1.5, 2, 3, 4, 6, 24 hours postdose (cephalexin)

Outcome Measure Data

Analysis Population Description
The analysis population was the PKAS, with participants administered 200 mg gilteritinib and cephalexin.

Arm/Group Title	Gilteritinib 200 mg in Expansion Phase
Arm/Group Description	Participants received 200 mg gilteritinib orally once daily stating on day 1 of cycle 1 and continued in 28-day cycles until disease progression or participant discontinuation in the expansion phase of the study. On day -1 and day 15 of cycle 1, certain participants also received 500 mg cephalexin as a single oral dose.
Measure Participants	100
Cephalexin Alone (Day -1)	1.822 (0.5914)
Cephalexin + Gilteritinib (Cycle 1 Day 15)	1.827 (0.7175)

55. Secondary Outcome

Title	Apparent Total Systemic Clearance After Single or Multiple Extravascular Dosing (CL/F) of Cephalexin Administered With and Without Gilteritinib
Description	Plasma samples were used for pharmacokinetic assessments.
Time Frame	Day -1 and cycle 1 day 15: predose, 0.5, 1, 1.5, 2, 3, 4, 6, 24 hours postdose (cephalexin)

Outcome Measure Data

Analysis Population Description
The analysis population was the PKAS, with participants administered 200 mg gilteritinib and cephalexin.

Arm/Group Title	Gilteritinib 200 mg in Expansion Phase
Arm/Group Description	Participants received 200 mg gilteritinib orally once daily stating on day 1 of cycle 1 and continued in 28-day cycles until disease progression or participant discontinuation in the expansion phase of the study. On day -1 and day 15 of cycle 1, certain participants also received 500 mg cephalexin as a single oral dose.
Measure Participants	100
Cephalexin Alone (Day -1)	9.713 (3.319)
Cephalexin + Gilteritinib (Cycle 1 Day 15)	10.58 (2.977)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Gilteritinib 20 mg in Escalation Phase
	Comments	Statistical Assessment of the Effect of Gilteritinib on Cephalexin Pharmacokinetics after Administration of Cephalexin Alone or Coadministered with Gilteritinib: The difference of LS means of log-transformed pharmacokinetic parameters between cephalexin alone and cephalexin + gilteritinib and its 90% CI are backtransformed to the raw scale and are expressed as percent.
	Type of Statistical Test	Other
	Comments

Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments

Method of Estimation	Estimation Parameter	Geometric LS Mean Ratio
	Estimated Value	106.42
	Confidence Interval	(2-Sided) 90% 85.28 to 132.81
	Parameter Dispersion	Type: Value:
	Estimation Comments

56. Secondary Outcome

Title	Apparent Volume of Distribution During the Terminal Elimination Phase After Single Extravascular Dosing (Vz/F) of Cephalexin Administered With and Without Gilteritinib
Description	Plasma samples were used for pharmacokinetic assessments.
Time Frame	Day -1 and cycle 1 day 15: predose, 0.5, 1, 1.5, 2, 3, 4, 6, 24 hours postdose (cephalexin)

Outcome Measure Data

Analysis Population Description
The analysis population was the PKAS, with participants administered 200 mg gilteritinib and cephalexin.

Arm/Group Title	Gilteritinib 200 mg in Expansion Phase
Arm/Group Description	Participants received 200 mg gilteritinib orally once daily stating on day 1 of cycle 1 and continued in 28-day cycles until disease progression or participant discontinuation in the expansion phase of the study. On day -1 and day 15 of cycle 1, certain participants also received 500 mg cephalexin as a single oral dose.
Measure Participants	100
Cephalexin Alone (Day -1)	24.07 (7.173)
Cephalexin + Gilteritinib (Cycle 1 Day 15)	25.86 (5.346)

57. Secondary Outcome

Title	Amount of Drug Excreted in Urine (Aelast) of Cephalexin Administered With and Without Gilteritinib
Description	Urine samples were used for pharmacokinetic assessments.
Time Frame	Day -1 and cycle 1 day 15: 0-3 hours, 3-6 hours, 6-24 hours postdose (cephalexin)

Outcome Measure Data

Analysis Population Description
The analysis population was the PKAS, with participants administered 200 mg gilteritinib and cephalexin.

Arm/Group Title	Gilteritinib 200 mg in Expansion Phase
Arm/Group Description	Participants received 200 mg gilteritinib orally once daily stating on day 1 of cycle 1 and continued in 28-day cycles until disease progression or participant discontinuation in the expansion phase of the study. On day -1 and day 15 of cycle 1, certain participants also received 500 mg cephalexin as a single oral dose.
Measure Participants	100
Cephalexin Alone (Day -1)	548.9 (523.7)
Cephalexin + Gilteritinib (Cycle 1 Day 15)	448.8 (306.1)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Gilteritinib 20 mg in Escalation Phase
	Comments	Statistical Assessment of the Effect of Gilteritinib on Cephalexin Pharmacokinetics after Administration of Cephalexin Alone or Coadministered with Gilteritinib: The difference of LS means of log-transformed pharmacokinetic parameters between cephalexin alone and cephalexin + gilteritinib and its 90% CI are backtransformed to the raw scale and are expressed as percent.
	Type of Statistical Test	Other
	Comments

Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments

Method of Estimation	Estimation Parameter	Geometric LS Mean Ratio
	Estimated Value	83.93
	Confidence Interval	(2-Sided) 90% 46.53 to 151.39
	Parameter Dispersion	Type: Value:
	Estimation Comments

58. Secondary Outcome

Title	Fraction of Drug Excreted Into Urine in Percentage (%Ae) of Cephalexin Administered With and Without Gilteritinib
Description	Urine samples were used for pharmacokinetic assessments.
Time Frame	Day -1 and cycle 1 day 15: 0-3 hours, 3-6 hours, 6-24 hours postdose (cephalexin)

Outcome Measure Data

Analysis Population Description
The analysis population was the PKAS, with participants administered 200 mg gilteritinib and cephalexin.

Arm/Group Title	Gilteritinib 200 mg in Expansion Phase
Arm/Group Description	Participants received 200 mg gilteritinib orally once daily stating on day 1 of cycle 1 and continued in 28-day cycles until disease progression or participant discontinuation in the expansion phase of the study. On day -1 and day 15 of cycle 1, certain participants also received 500 mg cephalexin as a single oral dose.
Measure Participants	100
Cephalexin Alone (Day -1)	109.8 (104.7)
Cephalexin + Gilteritinib (Cycle 1 Day 15)	89.75 (61.21)

59. Secondary Outcome

Title	Renal Clearance (CLr) of Cephalexin in Administered With and Without Gilteritinib
Description	Urine samples were used for pharmacokinetic assessments.
Time Frame	Day -1 and cycle 1 day 15: 0-3 hours, 3-6 hours, 6-24 hours postdose (cephalexin)

Outcome Measure Data

Analysis Population Description
The analysis population was the PKAS, with participants administered 200 mg gilteritinib and cephalexin.

Arm/Group Title	Gilteritinib 200 mg in Expansion Phase
Arm/Group Description	Participants received 200 mg gilteritinib orally once daily stating on day 1 of cycle 1 and continued in 28-day cycles until disease progression or participant discontinuation in the expansion phase of the study. On day -1 and day 15 of cycle 1, certain participants also received 500 mg cephalexin as a single oral dose.
Measure Participants	100
Cephalexin Alone (Day -1)	8.784 (8.727)
Cephalexin + Gilteritinib (Cycle 1 Day 15)	11.04 (8.430)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Gilteritinib 20 mg in Escalation Phase
	Comments	Statistical Assessment of the Effect of Gilteritinib on Cephalexin Pharmacokinetics after Administration of Cephalexin Alone or Coadministered with Gilteritinib: The difference of LS means of log-transformed pharmacokinetic parameters between cephalexin alone and cephalexin + gilteritinib and its 90% CI are backtransformed to the raw scale and are expressed as percent.
	Type of Statistical Test	Other
	Comments

Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments

Method of Estimation	Estimation Parameter	Geometric LS Mean Ratio
	Estimated Value	82.84
	Confidence Interval	(2-Sided) 90% 40.25 to 170.48
	Parameter Dispersion	Type: Value:
	Estimation Comments

Adverse Events

	Gilterinib 20 mg in Escalation Phase		Gilterinib 40 mg in Escalation Phase		Gilterinib 80 mg in Escalation Phase		Gilterinib 120 mg in Escalation Phase		Gilterinib 200 mg in Escalation Phase		Gilterinib 300 mg in Escalation Phase		Gilterinib 450 mg in Escalation Phase		Gilterinib 20 mg in Expansion Phase		Gilterinib 40 mg in Expansion Phase		Gilterinib 80 mg in Expansion Phase		Gilterinib 120 mg in Expansion Phase		Gilterinib 200 mg in Expansion Phase		Gilterinib 300 mg in Expansion Phase
Time Frame	From first dose of study drug up to 30 days after last dose of study drug (median treatment duration was 69.5 days, minimum of 3 days and maximum of 1320 days)
Adverse Event Reporting Description	The total number of deaths (all causes) includes deaths reported after the time frame above.

Arm/Group Title	Gilterinib 20 mg in Escalation Phase		Gilterinib 40 mg in Escalation Phase		Gilterinib 80 mg in Escalation Phase		Gilterinib 120 mg in Escalation Phase		Gilterinib 200 mg in Escalation Phase		Gilterinib 300 mg in Escalation Phase		Gilterinib 450 mg in Escalation Phase		Gilterinib 20 mg in Expansion Phase		Gilterinib 40 mg in Expansion Phase		Gilterinib 80 mg in Expansion Phase		Gilterinib 120 mg in Expansion Phase		Gilterinib 200 mg in Expansion Phase		Gilterinib 300 mg in Expansion Phase
Arm/Group Description	Participants received a single dose of 20 mg gilteritinib orally on day -2 to evaluate pharmacokinetics of gilteritinib. Then starting on day 1 of cycle 1, participants received 20 mg gilteritinib orally once daily in 28-day cycles until disease progression or participant discontinuation in the escalation phase of the study.		Participants received a single dose of 40 mg gilteritinib orally on day -2 to evaluate pharmacokinetics of gilteritinib. Then starting on day 1 of cycle 1, participants received 40 mg gilteritinib orally once daily in 28-day cycles until disease progression or participant discontinuation in the escalation phase of the study.		Participants received a single dose of 80 mg gilteritinib orally on day -2 to evaluate pharmacokinetics of gilteritinib. Then starting on day 1 of cycle 1, participants received 80 mg gilteritinib orally once daily in 28-day cycles until disease progression or participant discontinuation in the escalation phase of the study.		Participants received a single dose of 120 mg gilteritinib orally on day -2 to evaluate pharmacokinetics of gilteritinib. Then starting on day 1 of cycle 1, participants received 120 mg gilteritinib orally once daily in 28-day cycles until disease progression or participant discontinuation in the escalation phase of the study.		Participants received a single dose of 200 mg gilteritinib orally on day -2 to evaluate pharmacokinetics of gilteritinib. Then starting on day 1 of cycle 1, participants received 200 mg gilteritinib orally once daily in 28-day cycles until disease progression or participant discontinuation in the escalation phase of the study.		Participants received a single dose of 300 mg gilteritinib orally on day -2 to evaluate pharmacokinetics of gilteritinib. Then starting on day 1 of cycle 1, participants received 300 mg gilteritinib orally once daily in 28-day cycles until disease progression or participant discontinuation in the escalation phase of the study.		Participants received a single dose of 450 mg gilteritinib orally on day -2 to evaluate pharmacokinetics of gilteritinib. Then starting on day 1 of cycle 1, participants received 450 mg gilteritinib orally once daily in 28-day cycles until disease progression or participant discontinuation in the escalation phase of the study.		Participants received 20 mg gilteritinib orally once daily stating on day 1 of cycle 1 and continued in 28-day cycles until disease progression or participant discontinuation in the expansion phase of the study. Starting on day 16 of cycle 1, participants also received 200 mg voriconazole orally every 12 hours through day 1 of cycle 2.		Participants received 40 mg gilteritinib orally once daily starting on day 1 of cycle 1 and continued in 28-day cycles until disease progression or participant discontinuation in the expansion phase of the study.		Participants received 80 mg gilteritinib orally once daily starting on day 1 of cycle 1 and continued in 28-day cycles until disease progression or participant discontinuation in the expansion phase of the study.		Participants received 120 mg gilteritinib orally once daily starting on day 1 of cycle 1 and continued in 28-day cycles until disease progression or participant discontinuation in the expansion phase of the study.		Participants received 200 mg gilteritinib orally once daily starting on day 1 of cycle 1 and continued in 28-day cycles until disease progression or participant discontinuation in the expansion phase of the study. On day -1 and day 15 of cycle 1, certain participants also received 500 mg cephalexin as a single oral dose.		Participants received 300 mg gilteritinib orally once daily starting on day 1 of cycle 1 and continued in 28-day cycles until disease progression or participant discontinuation in the expansion phase of the study. On day -1 and day 15 of cycle 1, participants also received 2 mg midazolam as a single oral dose.
All Cause Mortality
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	4/5 (80%)		2/3 (66.7%)		3/3 (100%)		3/3 (100%)		2/3 (66.7%)		3/3 (100%)		3/3 (100%)		10/12 (83.3%)		13/13 (100%)		21/21 (100%)		53/66 (80.3%)		82/100 (82%)		16/17 (94.1%)
Serious Adverse Events
	Gilterinib 20 mg in Escalation Phase		Gilterinib 40 mg in Escalation Phase		Gilterinib 80 mg in Escalation Phase		Gilterinib 120 mg in Escalation Phase		Gilterinib 200 mg in Escalation Phase		Gilterinib 300 mg in Escalation Phase		Gilterinib 450 mg in Escalation Phase		Gilterinib 20 mg in Expansion Phase		Gilterinib 40 mg in Expansion Phase		Gilterinib 80 mg in Expansion Phase		Gilterinib 120 mg in Expansion Phase		Gilterinib 200 mg in Expansion Phase		Gilterinib 300 mg in Expansion Phase
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	2/5 (40%)		2/3 (66.7%)		2/3 (66.7%)		1/3 (33.3%)		2/3 (66.7%)		2/3 (66.7%)		2/3 (66.7%)		8/12 (66.7%)		12/13 (92.3%)		19/21 (90.5%)		52/66 (78.8%)		92/100 (92%)		14/17 (82.4%)
Blood and lymphatic system disorders
Anaemia	0/5 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	1/3 (33.3%)	1	0/12 (0%)	0	0/13 (0%)	0	1/21 (4.8%)	1	0/66 (0%)	0	4/100 (4%)	6	0/17 (0%)	0
Disseminated intravascular coagulation	0/5 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/12 (0%)	0	0/13 (0%)	0	0/21 (0%)	0	0/66 (0%)	0	1/100 (1%)	1	1/17 (5.9%)	1
Febrile neutropenia	0/5 (0%)	0	1/3 (33.3%)	1	1/3 (33.3%)	1	1/3 (33.3%)	1	2/3 (66.7%)	6	2/3 (66.7%)	5	0/3 (0%)	0	4/12 (33.3%)	6	7/13 (53.8%)	7	5/21 (23.8%)	11	18/66 (27.3%)	28	35/100 (35%)	58	4/17 (23.5%)	4
Haemolytic anaemia	0/5 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/12 (0%)	0	0/13 (0%)	0	1/21 (4.8%)	1	0/66 (0%)	0	0/100 (0%)	0	0/17 (0%)	0
Leukocytosis	1/5 (20%)	1	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/12 (0%)	0	0/13 (0%)	0	0/21 (0%)	0	2/66 (3%)	2	3/100 (3%)	3	1/17 (5.9%)	1
Neutropenia	0/5 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/12 (0%)	0	0/13 (0%)	0	0/21 (0%)	0	1/66 (1.5%)	2	2/100 (2%)	2	0/17 (0%)	0
Pancytopenia	0/5 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/12 (0%)	0	0/13 (0%)	0	0/21 (0%)	0	0/66 (0%)	0	2/100 (2%)	2	0/17 (0%)	0
Thrombocytopenia	0/5 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/12 (0%)	0	0/13 (0%)	0	0/21 (0%)	0	0/66 (0%)	0	2/100 (2%)	2	0/17 (0%)	0
Cardiac disorders
Acute myocardial infarction	0/5 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/12 (0%)	0	0/13 (0%)	0	1/21 (4.8%)	1	0/66 (0%)	0	1/100 (1%)	1	0/17 (0%)	0
Atrial fibrillation	0/5 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/12 (0%)	0	0/13 (0%)	0	0/21 (0%)	0	3/66 (4.5%)	3	3/100 (3%)	4	0/17 (0%)	0
Atrial thrombosis	0/5 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/12 (0%)	0	0/13 (0%)	0	0/21 (0%)	0	1/66 (1.5%)	1	0/100 (0%)	0	0/17 (0%)	0
Atrioventricular block second degree	0/5 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/12 (0%)	0	0/13 (0%)	0	1/21 (4.8%)	1	0/66 (0%)	0	0/100 (0%)	0	0/17 (0%)	0
Cardiac arrest	0/5 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	1/3 (33.3%)	1	0/12 (0%)	0	0/13 (0%)	0	1/21 (4.8%)	1	0/66 (0%)	0	0/100 (0%)	0	0/17 (0%)	0
Cardiac failure	0/5 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/12 (0%)	0	0/13 (0%)	0	0/21 (0%)	0	0/66 (0%)	0	1/100 (1%)	1	0/17 (0%)	0
Cardiac failure congestive	0/5 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/12 (0%)	0	0/13 (0%)	0	1/21 (4.8%)	1	0/66 (0%)	0	2/100 (2%)	4	0/17 (0%)	0
Myocardial infarction	0/5 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/12 (0%)	0	0/13 (0%)	0	0/21 (0%)	0	0/66 (0%)	0	1/100 (1%)	1	0/17 (0%)	0
Myocarditis	0/5 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/12 (0%)	0	0/13 (0%)	0	0/21 (0%)	0	0/66 (0%)	0	2/100 (2%)	2	0/17 (0%)	0
Pericardial effusion	0/5 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/12 (0%)	0	0/13 (0%)	0	0/21 (0%)	0	1/66 (1.5%)	1	1/100 (1%)	1	0/17 (0%)	0
Pericarditis	0/5 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/12 (0%)	0	0/13 (0%)	0	0/21 (0%)	0	0/66 (0%)	0	1/100 (1%)	1	0/17 (0%)	0
Supraventricular tachycardia	0/5 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/12 (0%)	0	0/13 (0%)	0	0/21 (0%)	0	1/66 (1.5%)	1	2/100 (2%)	2	0/17 (0%)	0
Tachycardia	0/5 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/12 (0%)	0	0/13 (0%)	0	0/21 (0%)	0	1/66 (1.5%)	1	0/100 (0%)	0	0/17 (0%)	0
Ventricular fibrillation	0/5 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/12 (0%)	0	0/13 (0%)	0	0/21 (0%)	0	1/66 (1.5%)	2	0/100 (0%)	0	0/17 (0%)	0
Ventricular tachycardia	0/5 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/12 (0%)	0	0/13 (0%)	0	0/21 (0%)	0	0/66 (0%)	0	1/100 (1%)	1	0/17 (0%)	0
Endocrine disorders
Diabetes insipidus	0/5 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/12 (0%)	0	0/13 (0%)	0	0/21 (0%)	0	1/66 (1.5%)	1	0/100 (0%)	0	0/17 (0%)	0
Eye disorders
Conjunctival oedema	0/5 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/12 (0%)	0	0/13 (0%)	0	1/21 (4.8%)	1	0/66 (0%)	0	0/100 (0%)	0	0/17 (0%)	0
Papilloedema	0/5 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/12 (0%)	0	0/13 (0%)	0	0/21 (0%)	0	1/66 (1.5%)	1	0/100 (0%)	0	0/17 (0%)	0
Gastrointestinal disorders
Colitis	0/5 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/12 (0%)	0	0/13 (0%)	0	0/21 (0%)	0	0/66 (0%)	0	1/100 (1%)	2	0/17 (0%)	0
Diarrhoea	0/5 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	1/3 (33.3%)	1	0/12 (0%)	0	0/13 (0%)	0	1/21 (4.8%)	1	5/66 (7.6%)	5	5/100 (5%)	5	0/17 (0%)	0
Dysphagia	0/5 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/12 (0%)	0	0/13 (0%)	0	0/21 (0%)	0	0/66 (0%)	0	0/100 (0%)	0	1/17 (5.9%)	1
Enteritis	0/5 (0%)	0	1/3 (33.3%)	1	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/12 (0%)	0	0/13 (0%)	0	0/21 (0%)	0	0/66 (0%)	0	0/100 (0%)	0	0/17 (0%)	0
Enterocolitis	0/5 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/12 (0%)	0	1/13 (7.7%)	1	0/21 (0%)	0	0/66 (0%)	0	0/100 (0%)	0	0/17 (0%)	0
Gastric haemorrhage	0/5 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/12 (0%)	0	0/13 (0%)	0	0/21 (0%)	0	0/66 (0%)	0	1/100 (1%)	1	0/17 (0%)	0
Gastrointestinal haemorrhage	0/5 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/12 (0%)	0	0/13 (0%)	0	1/21 (4.8%)	1	2/66 (3%)	4	2/100 (2%)	4	1/17 (5.9%)	1
Haematemesis	0/5 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/12 (0%)	0	0/13 (0%)	0	0/21 (0%)	0	0/66 (0%)	0	1/100 (1%)	1	0/17 (0%)	0
Haematochezia	0/5 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/12 (0%)	0	0/13 (0%)	0	0/21 (0%)	0	0/66 (0%)	0	1/100 (1%)	1	0/17 (0%)	0
Intestinal obstruction	0/5 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/12 (0%)	0	0/13 (0%)	0	0/21 (0%)	0	0/66 (0%)	0	1/100 (1%)	1	0/17 (0%)	0
Intestinal perforation	0/5 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/12 (0%)	0	0/13 (0%)	0	0/21 (0%)	0	0/66 (0%)	0	1/100 (1%)	1	0/17 (0%)	0
Large intestinal ulcer	0/5 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/12 (0%)	0	0/13 (0%)	0	0/21 (0%)	0	0/66 (0%)	0	1/100 (1%)	1	0/17 (0%)	0
Lower gastrointestinal haemorrhage	0/5 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/12 (0%)	0	0/13 (0%)	0	0/21 (0%)	0	2/66 (3%)	3	0/100 (0%)	0	0/17 (0%)	0
Malabsorption	0/5 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/12 (0%)	0	0/13 (0%)	0	0/21 (0%)	0	0/66 (0%)	0	1/100 (1%)	1	0/17 (0%)	0
Nausea	0/5 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/12 (0%)	0	0/13 (0%)	0	0/21 (0%)	0	1/66 (1.5%)	1	3/100 (3%)	3	0/17 (0%)	0
Neutropenic colitis	0/5 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/12 (0%)	0	0/13 (0%)	0	0/21 (0%)	0	2/66 (3%)	3	0/100 (0%)	0	0/17 (0%)	0
Pancreatitis	0/5 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/12 (0%)	0	0/13 (0%)	0	0/21 (0%)	0	0/66 (0%)	0	1/100 (1%)	1	0/17 (0%)	0
Pancreatitis acute	0/5 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/12 (0%)	0	0/13 (0%)	0	0/21 (0%)	0	0/66 (0%)	0	1/100 (1%)	1	0/17 (0%)	0
Rectal haemorrhage	0/5 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/12 (0%)	0	0/13 (0%)	0	0/21 (0%)	0	0/66 (0%)	0	1/100 (1%)	1	0/17 (0%)	0
Rectal tenesmus	0/5 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/12 (0%)	0	0/13 (0%)	0	0/21 (0%)	0	0/66 (0%)	0	1/100 (1%)	1	0/17 (0%)	0
Small intestinal obstruction	0/5 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/12 (0%)	0	0/13 (0%)	0	1/21 (4.8%)	1	0/66 (0%)	0	1/100 (1%)	1	1/17 (5.9%)	1
Stomatitis	0/5 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/12 (0%)	0	0/13 (0%)	0	0/21 (0%)	0	0/66 (0%)	0	1/100 (1%)	1	0/17 (0%)	0
Swollen tongue	0/5 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/12 (0%)	0	0/13 (0%)	0	0/21 (0%)	0	1/66 (1.5%)	1	0/100 (0%)	0	0/17 (0%)	0
Upper gastrointestinal haemorrhage	0/5 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/12 (0%)	0	0/13 (0%)	0	0/21 (0%)	0	0/66 (0%)	0	0/100 (0%)	0	1/17 (5.9%)	1
Vomiting	0/5 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/12 (0%)	0	0/13 (0%)	0	1/21 (4.8%)	1	2/66 (3%)	2	2/100 (2%)	2	0/17 (0%)	0
General disorders
Asthenia	0/5 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/12 (0%)	0	0/13 (0%)	0	1/21 (4.8%)	1	0/66 (0%)	0	0/100 (0%)	0	0/17 (0%)	0
Chills	0/5 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/12 (0%)	0	0/13 (0%)	0	1/21 (4.8%)	1	0/66 (0%)	0	0/100 (0%)	0	0/17 (0%)	0
Death	0/5 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/12 (0%)	0	0/13 (0%)	0	0/21 (0%)	0	2/66 (3%)	2	1/100 (1%)	1	0/17 (0%)	0
Fatigue	0/5 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/12 (0%)	0	0/13 (0%)	0	0/21 (0%)	0	2/66 (3%)	2	1/100 (1%)	1	0/17 (0%)	0
Mucosal inflammation	0/5 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	1/3 (33.3%)	1	0/3 (0%)	0	0/12 (0%)	0	0/13 (0%)	0	0/21 (0%)	0	0/66 (0%)	0	1/100 (1%)	1	1/17 (5.9%)	1
Multiple organ dysfunction syndrome	0/5 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/12 (0%)	0	1/13 (7.7%)	1	0/21 (0%)	0	1/66 (1.5%)	2	4/100 (4%)	6	0/17 (0%)	0
Oedema peripheral	0/5 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/12 (0%)	0	0/13 (0%)	0	0/21 (0%)	0	0/66 (0%)	0	1/100 (1%)	1	0/17 (0%)	0
Pyrexia	0/5 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	1/3 (33.3%)	1	1/3 (33.3%)	1	1/3 (33.3%)	1	0/3 (0%)	0	0/12 (0%)	0	0/13 (0%)	0	0/21 (0%)	0	9/66 (13.6%)	10	9/100 (9%)	13	1/17 (5.9%)	1
Sudden death	0/5 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/12 (0%)	0	0/13 (0%)	0	0/21 (0%)	0	0/66 (0%)	0	1/100 (1%)	1	0/17 (0%)	0
Systemic inflammatory response syndrome	0/5 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/12 (0%)	0	0/13 (0%)	0	0/21 (0%)	0	0/66 (0%)	0	1/100 (1%)	1	0/17 (0%)	0
Hepatobiliary disorders
Cholecystitis	0/5 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	1/3 (33.3%)	1	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/12 (0%)	0	0/13 (0%)	0	0/21 (0%)	0	0/66 (0%)	0	0/100 (0%)	0	0/17 (0%)	0
Hepatic failure	0/5 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/12 (0%)	0	0/13 (0%)	0	0/21 (0%)	0	0/66 (0%)	0	1/100 (1%)	1	0/17 (0%)	0
Hyperbilirubinaemia	0/5 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/12 (0%)	0	0/13 (0%)	0	0/21 (0%)	0	1/66 (1.5%)	1	2/100 (2%)	2	0/17 (0%)	0
Immune system disorders
Acute graft versus host disease	0/5 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/12 (0%)	0	0/13 (0%)	0	0/21 (0%)	0	0/66 (0%)	0	1/100 (1%)	1	0/17 (0%)	0
Acute graft versus host disease in intestine	0/5 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/12 (0%)	0	0/13 (0%)	0	0/21 (0%)	0	0/66 (0%)	0	1/100 (1%)	1	0/17 (0%)	0
Acute graft versus host disease in skin	0/5 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/12 (0%)	0	0/13 (0%)	0	0/21 (0%)	0	1/66 (1.5%)	1	3/100 (3%)	4	0/17 (0%)	0
Anaphylactic reaction	0/5 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/12 (0%)	0	0/13 (0%)	0	0/21 (0%)	0	1/66 (1.5%)	1	1/100 (1%)	1	0/17 (0%)	0
Chronic graft versus host disease in skin	0/5 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/12 (0%)	0	0/13 (0%)	0	0/21 (0%)	0	0/66 (0%)	0	1/100 (1%)	1	0/17 (0%)	0
Graft versus host disease in skin	0/5 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/12 (0%)	0	0/13 (0%)	0	1/21 (4.8%)	1	0/66 (0%)	0	0/100 (0%)	0	0/17 (0%)	0
Infections and infestations
Abscess limb	0/5 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	1/12 (8.3%)	2	0/13 (0%)	0	0/21 (0%)	0	0/66 (0%)	0	0/100 (0%)	0	0/17 (0%)	0
Arthritis bacterial	0/5 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/12 (0%)	0	0/13 (0%)	0	1/21 (4.8%)	2	1/66 (1.5%)	1	0/100 (0%)	0	0/17 (0%)	0
Bacteraemia	1/5 (20%)	1	0/3 (0%)	0	1/3 (33.3%)	1	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/12 (0%)	0	0/13 (0%)	0	5/21 (23.8%)	9	2/66 (3%)	2	5/100 (5%)	7	0/17 (0%)	0
Bacterial infection	0/5 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/12 (0%)	0	0/13 (0%)	0	0/21 (0%)	0	1/66 (1.5%)	2	0/100 (0%)	0	0/17 (0%)	0
Bronchopulmonary aspergillosis	0/5 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/12 (0%)	0	0/13 (0%)	0	0/21 (0%)	0	1/66 (1.5%)	2	3/100 (3%)	4	0/17 (0%)	0
Cellulitis	0/5 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/12 (0%)	0	0/13 (0%)	0	0/21 (0%)	0	4/66 (6.1%)	4	4/100 (4%)	4	0/17 (0%)	0
Clostridial infection	0/5 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/12 (0%)	0	0/13 (0%)	0	0/21 (0%)	0	0/66 (0%)	0	0/100 (0%)	0	1/17 (5.9%)	1
Clostridium bacteraemia	0/5 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/12 (0%)	0	0/13 (0%)	0	0/21 (0%)	0	0/66 (0%)	0	2/100 (2%)	3	0/17 (0%)	0
Clostridium difficile colitis	0/5 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/12 (0%)	0	0/13 (0%)	0	0/21 (0%)	0	1/66 (1.5%)	1	6/100 (6%)	6	0/17 (0%)	0
Clostridium difficile infection	0/5 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/12 (0%)	0	0/13 (0%)	0	0/21 (0%)	0	1/66 (1.5%)	1	2/100 (2%)	2	1/17 (5.9%)	1
Corona virus infection	0/5 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/12 (0%)	0	0/13 (0%)	0	0/21 (0%)	0	0/66 (0%)	0	0/100 (0%)	0	1/17 (5.9%)	1
Device related infection	0/5 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/12 (0%)	0	0/13 (0%)	0	0/21 (0%)	0	0/66 (0%)	0	1/100 (1%)	1	0/17 (0%)	0
Diverticulitis	0/5 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/12 (0%)	0	0/13 (0%)	0	0/21 (0%)	0	0/66 (0%)	0	1/100 (1%)	1	0/17 (0%)	0
Encephalitis viral	0/5 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/12 (0%)	0	0/13 (0%)	0	0/21 (0%)	0	1/66 (1.5%)	1	0/100 (0%)	0	0/17 (0%)	0
Enterococcal bacteraemia	0/5 (0%)	0	1/3 (33.3%)	1	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/12 (0%)	0	0/13 (0%)	0	0/21 (0%)	0	0/66 (0%)	0	2/100 (2%)	2	0/17 (0%)	0
Enterococcal infection	0/5 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/12 (0%)	0	0/13 (0%)	0	0/21 (0%)	0	0/66 (0%)	0	0/100 (0%)	0	1/17 (5.9%)	1
Enterocolitis infectious	0/5 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/12 (0%)	0	0/13 (0%)	0	0/21 (0%)	0	1/66 (1.5%)	1	0/100 (0%)	0	0/17 (0%)	0
Epiglottitis	0/5 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/12 (0%)	0	0/13 (0%)	0	0/21 (0%)	0	1/66 (1.5%)	1	0/100 (0%)	0	0/17 (0%)	0
Escherichia bacteraemia	0/5 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/12 (0%)	0	0/13 (0%)	0	0/21 (0%)	0	1/66 (1.5%)	1	1/100 (1%)	1	0/17 (0%)	0
Escherichia sepsis	0/5 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/12 (0%)	0	0/13 (0%)	0	1/21 (4.8%)	1	0/66 (0%)	0	0/100 (0%)	0	0/17 (0%)	0
Escherichia urinary tract infection	0/5 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/12 (0%)	0	0/13 (0%)	0	0/21 (0%)	0	1/66 (1.5%)	1	0/100 (0%)	0	0/17 (0%)	0
Fungaemia	0/5 (0%)	0	1/3 (33.3%)	1	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/12 (0%)	0	0/13 (0%)	0	0/21 (0%)	0	0/66 (0%)	0	0/100 (0%)	0	0/17 (0%)	0
Gastroenteritis viral	0/5 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/12 (0%)	0	0/13 (0%)	0	0/21 (0%)	0	1/66 (1.5%)	1	0/100 (0%)	0	0/17 (0%)	0
Hepatic infection	0/5 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/12 (0%)	0	0/13 (0%)	0	0/21 (0%)	0	1/66 (1.5%)	2	0/100 (0%)	0	0/17 (0%)	0
Herpes zoster	0/5 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/12 (0%)	0	0/13 (0%)	0	0/21 (0%)	0	1/66 (1.5%)	1	0/100 (0%)	0	0/17 (0%)	0
Infection	0/5 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/12 (0%)	0	0/13 (0%)	0	0/21 (0%)	0	0/66 (0%)	0	2/100 (2%)	2	0/17 (0%)	0
Influenza	0/5 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/12 (0%)	0	0/13 (0%)	0	0/21 (0%)	0	1/66 (1.5%)	1	0/100 (0%)	0	1/17 (5.9%)	1
Klebsiella bacteraemia	0/5 (0%)	0	0/3 (0%)	0	1/3 (33.3%)	1	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/12 (0%)	0	0/13 (0%)	0	0/21 (0%)	0	0/66 (0%)	0	2/100 (2%)	2	0/17 (0%)	0
Lung infection	0/5 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/12 (0%)	0	0/13 (0%)	0	0/21 (0%)	0	2/66 (3%)	2	7/100 (7%)	10	0/17 (0%)	0
Oral infection	0/5 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/12 (0%)	0	1/13 (7.7%)	1	0/21 (0%)	0	0/66 (0%)	0	0/100 (0%)	0	0/17 (0%)	0
Osteomyelitis	0/5 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/12 (0%)	0	0/13 (0%)	0	0/21 (0%)	0	0/66 (0%)	0	1/100 (1%)	1	0/17 (0%)	0
Otitis externa	0/5 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/12 (0%)	0	0/13 (0%)	0	0/21 (0%)	0	0/66 (0%)	0	1/100 (1%)	1	0/17 (0%)	0
Parainfluenzae virus infection	0/5 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/12 (0%)	0	0/13 (0%)	0	0/21 (0%)	0	1/66 (1.5%)	1	1/100 (1%)	1	0/17 (0%)	0
Periodontitis	0/5 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/12 (0%)	0	0/13 (0%)	0	0/21 (0%)	0	0/66 (0%)	0	1/100 (1%)	1	0/17 (0%)	0
Periorbital infection	0/5 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/12 (0%)	0	0/13 (0%)	0	1/21 (4.8%)	1	0/66 (0%)	0	0/100 (0%)	0	0/17 (0%)	0
Pneumonia	0/5 (0%)	0	1/3 (33.3%)	1	0/3 (0%)	0	0/3 (0%)	0	2/3 (66.7%)	2	0/3 (0%)	0	0/3 (0%)	0	1/12 (8.3%)	2	1/13 (7.7%)	1	2/21 (9.5%)	2	13/66 (19.7%)	15	12/100 (12%)	15	1/17 (5.9%)	1
Pneumonia fungal	0/5 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	1/3 (33.3%)	1	0/3 (0%)	0	0/12 (0%)	0	0/13 (0%)	0	0/21 (0%)	0	5/66 (7.6%)	5	5/100 (5%)	5	0/17 (0%)	0
Pneumonia haemophilus	0/5 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/12 (0%)	0	0/13 (0%)	0	0/21 (0%)	0	1/66 (1.5%)	1	0/100 (0%)	0	0/17 (0%)	0
Pneumonia parainfluenzae viral	0/5 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/12 (0%)	0	0/13 (0%)	0	0/21 (0%)	0	1/66 (1.5%)	1	0/100 (0%)	0	0/17 (0%)	0
Pneumonia viral	0/5 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/12 (0%)	0	0/13 (0%)	0	0/21 (0%)	0	1/66 (1.5%)	1	0/100 (0%)	0	0/17 (0%)	0
Post procedural cellulitis	0/5 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/12 (0%)	0	0/13 (0%)	0	0/21 (0%)	0	0/66 (0%)	0	1/100 (1%)	1	0/17 (0%)	0
Pseudomonas infection	0/5 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/12 (0%)	0	0/13 (0%)	0	0/21 (0%)	0	0/66 (0%)	0	1/100 (1%)	1	0/17 (0%)	0
Pyelonephritis	0/5 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/12 (0%)	0	0/13 (0%)	0	0/21 (0%)	0	0/66 (0%)	0	1/100 (1%)	1	0/17 (0%)	0
Respiratory syncytial virus infection	0/5 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/12 (0%)	0	0/13 (0%)	0	0/21 (0%)	0	2/66 (3%)	2	0/100 (0%)	0	0/17 (0%)	0
Sepsis	0/5 (0%)	0	0/3 (0%)	0	1/3 (33.3%)	1	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/12 (0%)	0	2/13 (15.4%)	2	7/21 (33.3%)	8	10/66 (15.2%)	10	19/100 (19%)	25	0/17 (0%)	0
Septic shock	0/5 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/12 (0%)	0	0/13 (0%)	0	3/21 (14.3%)	4	0/66 (0%)	0	4/100 (4%)	6	0/17 (0%)	0
Sinusitis	0/5 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/12 (0%)	0	0/13 (0%)	0	1/21 (4.8%)	1	1/66 (1.5%)	1	0/100 (0%)	0	1/17 (5.9%)	1
Sinusitis fungal	0/5 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/12 (0%)	0	0/13 (0%)	0	0/21 (0%)	0	0/66 (0%)	0	1/100 (1%)	1	0/17 (0%)	0
Skin bacterial infection	0/5 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/12 (0%)	0	0/13 (0%)	0	0/21 (0%)	0	0/66 (0%)	0	1/100 (1%)	1	0/17 (0%)	0
Skin infection	0/5 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/12 (0%)	0	0/13 (0%)	0	1/21 (4.8%)	1	1/66 (1.5%)	1	2/100 (2%)	2	0/17 (0%)	0
Soft tissue infection	0/5 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/12 (0%)	0	0/13 (0%)	0	0/21 (0%)	0	2/66 (3%)	2	0/100 (0%)	0	0/17 (0%)	0
Staphylococcal bacteraemia	0/5 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/12 (0%)	0	0/13 (0%)	0	1/21 (4.8%)	1	0/66 (0%)	0	1/100 (1%)	1	0/17 (0%)	0
Staphylococcal sepsis	0/5 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/12 (0%)	0	0/13 (0%)	0	0/21 (0%)	0	0/66 (0%)	0	2/100 (2%)	4	0/17 (0%)	0
Streptococcal bacteraemia	0/5 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/12 (0%)	0	0/13 (0%)	0	0/21 (0%)	0	2/66 (3%)	3	1/100 (1%)	1	1/17 (5.9%)	1
Streptococcal sepsis	0/5 (0%)	0	0/3 (0%)	0	1/3 (33.3%)	1	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/12 (0%)	0	0/13 (0%)	0	0/21 (0%)	0	0/66 (0%)	0	1/100 (1%)	1	0/17 (0%)	0
Systemic candida	0/5 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/12 (0%)	0	0/13 (0%)	0	0/21 (0%)	0	0/66 (0%)	0	0/100 (0%)	0	1/17 (5.9%)	1
Systemic mycosis	0/5 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/12 (0%)	0	1/13 (7.7%)	1	0/21 (0%)	0	0/66 (0%)	0	0/100 (0%)	0	0/17 (0%)	0
Tooth abscess	0/5 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/12 (0%)	0	0/13 (0%)	0	0/21 (0%)	0	0/66 (0%)	0	1/100 (1%)	1	0/17 (0%)	0
Tooth infection	0/5 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/12 (0%)	0	0/13 (0%)	0	0/21 (0%)	0	0/66 (0%)	0	1/100 (1%)	1	0/17 (0%)	0
Toxic shock syndrome	0/5 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/12 (0%)	0	1/13 (7.7%)	1	0/21 (0%)	0	0/66 (0%)	0	0/100 (0%)	0	0/17 (0%)	0
Upper respiratory tract infection	0/5 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/12 (0%)	0	0/13 (0%)	0	1/21 (4.8%)	1	3/66 (4.5%)	3	0/100 (0%)	0	0/17 (0%)	0
Urinary tract infection	0/5 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	1/3 (33.3%)	1	0/3 (0%)	0	0/12 (0%)	0	0/13 (0%)	0	2/21 (9.5%)	2	3/66 (4.5%)	4	2/100 (2%)	4	0/17 (0%)	0
Urinary tract infection bacterial	0/5 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/12 (0%)	0	0/13 (0%)	0	0/21 (0%)	0	1/66 (1.5%)	2	0/100 (0%)	0	0/17 (0%)	0
Urinary tract infection enterococcal	0/5 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/12 (0%)	0	0/13 (0%)	0	0/21 (0%)	0	1/66 (1.5%)	1	0/100 (0%)	0	0/17 (0%)	0
Urosepsis	0/5 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/12 (0%)	0	0/13 (0%)	0	1/21 (4.8%)	1	0/66 (0%)	0	1/100 (1%)	1	0/17 (0%)	0
Injury, poisoning and procedural complications
Facial bones fracture	0/5 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/12 (0%)	0	0/13 (0%)	0	0/21 (0%)	0	0/66 (0%)	0	1/100 (1%)	1	0/17 (0%)	0
Fall	0/5 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/12 (0%)	0	0/13 (0%)	0	0/21 (0%)	0	2/66 (3%)	2	2/100 (2%)	2	0/17 (0%)	0
Hip fracture	0/5 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/12 (0%)	0	0/13 (0%)	0	0/21 (0%)	0	0/66 (0%)	0	0/100 (0%)	0	1/17 (5.9%)	1
Pelvic fracture	0/5 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/12 (0%)	0	0/13 (0%)	0	1/21 (4.8%)	1	0/66 (0%)	0	0/100 (0%)	0	0/17 (0%)	0
Post procedural haemorrhage	0/5 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/12 (0%)	0	0/13 (0%)	0	0/21 (0%)	0	1/66 (1.5%)	1	0/100 (0%)	0	0/17 (0%)	0
Road traffic accident	0/5 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/12 (0%)	0	0/13 (0%)	0	0/21 (0%)	0	0/66 (0%)	0	1/100 (1%)	1	0/17 (0%)	0
Subdural haematoma	0/5 (0%)	0	1/3 (33.3%)	1	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/12 (0%)	0	0/13 (0%)	0	1/21 (4.8%)	1	1/66 (1.5%)	1	2/100 (2%)	2	1/17 (5.9%)	1
Tendon rupture	0/5 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/12 (0%)	0	0/13 (0%)	0	1/21 (4.8%)	1	0/66 (0%)	0	0/100 (0%)	0	0/17 (0%)	0
Wound complication	0/5 (0%)	0	0/3 (0%)	0	1/3 (33.3%)	1	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/12 (0%)	0	0/13 (0%)	0	0/21 (0%)	0	0/66 (0%)	0	0/100 (0%)	0	0/17 (0%)	0
Investigations
Alanine aminotransferase increased	0/5 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/12 (0%)	0	0/13 (0%)	0	0/21 (0%)	0	0/66 (0%)	0	2/100 (2%)	2	0/17 (0%)	0
Aspartate aminotransferase increased	0/5 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	1/3 (33.3%)	1	0/12 (0%)	0	0/13 (0%)	0	0/21 (0%)	0	0/66 (0%)	0	2/100 (2%)	2	1/17 (5.9%)	1
Blood bilirubin increased	0/5 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/12 (0%)	0	0/13 (0%)	0	0/21 (0%)	0	2/66 (3%)	3	2/100 (2%)	3	0/17 (0%)	0
Blood creatine phosphokinase increased	0/5 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/12 (0%)	0	0/13 (0%)	0	0/21 (0%)	0	2/66 (3%)	2	3/100 (3%)	3	0/17 (0%)	0
Blood creatinine increased	0/5 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/12 (0%)	0	0/13 (0%)	0	0/21 (0%)	0	1/66 (1.5%)	1	2/100 (2%)	4	0/17 (0%)	0
Blood lactate dehydrogenase increased	0/5 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/12 (0%)	0	0/13 (0%)	0	0/21 (0%)	0	0/66 (0%)	0	1/100 (1%)	1	0/17 (0%)	0
Blood uric acid increased	0/5 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/12 (0%)	0	0/13 (0%)	0	0/21 (0%)	0	0/66 (0%)	0	1/100 (1%)	1	0/17 (0%)	0
Ejection fraction decreased	0/5 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	1/12 (8.3%)	1	1/13 (7.7%)	1	0/21 (0%)	0	1/66 (1.5%)	1	0/100 (0%)	0	0/17 (0%)	0
Electrocardiogram QT prolonged	0/5 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/12 (0%)	0	0/13 (0%)	0	0/21 (0%)	0	1/66 (1.5%)	1	0/100 (0%)	0	0/17 (0%)	0
Liver function test increased	0/5 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	1/3 (33.3%)	1	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/12 (0%)	0	0/13 (0%)	0	0/21 (0%)	0	1/66 (1.5%)	1	0/100 (0%)	0	0/17 (0%)	0
Platelet count decreased	0/5 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/12 (0%)	0	0/13 (0%)	0	0/21 (0%)	0	0/66 (0%)	0	2/100 (2%)	2	0/17 (0%)	0
Transaminases increased	0/5 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/12 (0%)	0	0/13 (0%)	0	1/21 (4.8%)	1	0/66 (0%)	0	1/100 (1%)	1	0/17 (0%)	0
Troponin I increased	0/5 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/12 (0%)	0	0/13 (0%)	0	0/21 (0%)	0	0/66 (0%)	0	1/100 (1%)	1	0/17 (0%)	0
White blood cell count increased	0/5 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/12 (0%)	0	0/13 (0%)	0	0/21 (0%)	0	0/66 (0%)	0	1/100 (1%)	1	0/17 (0%)	0
Metabolism and nutrition disorders
Dehydration	0/5 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/12 (0%)	0	0/13 (0%)	0	0/21 (0%)	0	1/66 (1.5%)	1	1/100 (1%)	1	1/17 (5.9%)	1
Diabetic ketoacidosis	0/5 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/12 (0%)	0	0/13 (0%)	0	1/21 (4.8%)	1	0/66 (0%)	0	0/100 (0%)	0	0/17 (0%)	0
Failure to thrive	0/5 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/12 (0%)	0	0/13 (0%)	0	0/21 (0%)	0	1/66 (1.5%)	1	1/100 (1%)	1	0/17 (0%)	0
Hyperkalaemia	0/5 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/12 (0%)	0	0/13 (0%)	0	0/21 (0%)	0	0/66 (0%)	0	1/100 (1%)	1	0/17 (0%)	0
Hyperuricaemia	0/5 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/12 (0%)	0	0/13 (0%)	0	0/21 (0%)	0	0/66 (0%)	0	1/100 (1%)	1	0/17 (0%)	0
Hypocalcaemia	0/5 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/12 (0%)	0	0/13 (0%)	0	0/21 (0%)	0	0/66 (0%)	0	1/100 (1%)	1	0/17 (0%)	0
Hyponatraemia	0/5 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/12 (0%)	0	0/13 (0%)	0	1/21 (4.8%)	1	2/66 (3%)	4	1/100 (1%)	1	0/17 (0%)	0
Tumour lysis syndrome	0/5 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/12 (0%)	0	0/13 (0%)	0	0/21 (0%)	0	0/66 (0%)	0	1/100 (1%)	1	0/17 (0%)	0
Musculoskeletal and connective tissue disorders
Arthralgia	0/5 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/12 (0%)	0	0/13 (0%)	0	0/21 (0%)	0	0/66 (0%)	0	1/100 (1%)	1	0/17 (0%)	0
Back pain	0/5 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/12 (0%)	0	0/13 (0%)	0	0/21 (0%)	0	1/66 (1.5%)	1	1/100 (1%)	1	0/17 (0%)	0
Joint effusion	0/5 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/12 (0%)	0	0/13 (0%)	0	0/21 (0%)	0	0/66 (0%)	0	0/100 (0%)	0	1/17 (5.9%)	1
Muscular weakness	0/5 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/12 (0%)	0	0/13 (0%)	0	0/21 (0%)	0	2/66 (3%)	2	0/100 (0%)	0	0/17 (0%)	0
Musculoskeletal chest pain	0/5 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/12 (0%)	0	0/13 (0%)	0	0/21 (0%)	0	1/66 (1.5%)	1	0/100 (0%)	0	0/17 (0%)	0
Myalgia	0/5 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/12 (0%)	0	0/13 (0%)	0	0/21 (0%)	0	0/66 (0%)	0	1/100 (1%)	1	0/17 (0%)	0
Myositis	0/5 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/12 (0%)	0	0/13 (0%)	0	0/21 (0%)	0	1/66 (1.5%)	1	0/100 (0%)	0	0/17 (0%)	0
Neck pain	0/5 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/12 (0%)	0	0/13 (0%)	0	0/21 (0%)	0	0/66 (0%)	0	1/100 (1%)	1	0/17 (0%)	0
Necrotising myositis	0/5 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	1/3 (33.3%)	1	0/3 (0%)	0	0/3 (0%)	0	0/12 (0%)	0	0/13 (0%)	0	0/21 (0%)	0	0/66 (0%)	0	0/100 (0%)	0	0/17 (0%)	0
Osteonecrosis	0/5 (0%)	0	0/3 (0%)	0	1/3 (33.3%)	1	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/12 (0%)	0	0/13 (0%)	0	0/21 (0%)	0	0/66 (0%)	0	0/100 (0%)	0	0/17 (0%)	0
Pain in extremity	0/5 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/12 (0%)	0	0/13 (0%)	0	0/21 (0%)	0	1/66 (1.5%)	2	1/100 (1%)	1	0/17 (0%)	0
Rhabdomyolysis	0/5 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/12 (0%)	0	0/13 (0%)	0	0/21 (0%)	0	0/66 (0%)	0	0/100 (0%)	0	1/17 (5.9%)	1
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Acute myeloid leukaemia	1/5 (20%)	1	2/3 (66.7%)	2	0/3 (0%)	0	1/3 (33.3%)	1	0/3 (0%)	0	1/3 (33.3%)	1	0/3 (0%)	0	2/12 (16.7%)	2	3/13 (23.1%)	3	5/21 (23.8%)	8	9/66 (13.6%)	10	20/100 (20%)	25	4/17 (23.5%)	5
Acute myeloid leukaemia recurrent	0/5 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/12 (0%)	0	0/13 (0%)	0	1/21 (4.8%)	1	0/66 (0%)	0	0/100 (0%)	0	0/17 (0%)	0
Basal cell carcinoma	0/5 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/12 (0%)	0	0/13 (0%)	0	0/21 (0%)	0	1/66 (1.5%)	1	0/100 (0%)	0	0/17 (0%)	0
Central nervous system leukaemia	0/5 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/12 (0%)	0	0/13 (0%)	0	0/21 (0%)	0	0/66 (0%)	0	1/100 (1%)	1	0/17 (0%)	0
Leukaemia	0/5 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/12 (0%)	0	0/13 (0%)	0	0/21 (0%)	0	0/66 (0%)	0	1/100 (1%)	1	0/17 (0%)	0
Squamous cell carcinoma	0/5 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/12 (0%)	0	0/13 (0%)	0	0/21 (0%)	0	2/66 (3%)	2	1/100 (1%)	1	0/17 (0%)	0
Squamous cell carcinoma of skin	0/5 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/12 (0%)	0	0/13 (0%)	0	0/21 (0%)	0	0/66 (0%)	0	2/100 (2%)	2	0/17 (0%)	0
Nervous system disorders
Aphasia	0/5 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/12 (0%)	0	0/13 (0%)	0	0/21 (0%)	0	0/66 (0%)	0	1/100 (1%)	1	0/17 (0%)	0
Cerebral ischaemia	0/5 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/12 (0%)	0	0/13 (0%)	0	0/21 (0%)	0	0/66 (0%)	0	1/100 (1%)	2	0/17 (0%)	0
Cerebrovascular accident	0/5 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/12 (0%)	0	0/13 (0%)	0	0/21 (0%)	0	0/66 (0%)	0	1/100 (1%)	1	0/17 (0%)	0
Coordination abnormal	0/5 (0%)	0	1/3 (33.3%)	1	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/12 (0%)	0	0/13 (0%)	0	0/21 (0%)	0	0/66 (0%)	0	0/100 (0%)	0	0/17 (0%)	0
Encephalopathy	0/5 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/12 (0%)	0	0/13 (0%)	0	0/21 (0%)	0	0/66 (0%)	0	1/100 (1%)	1	0/17 (0%)	0
Haemorrhage intracranial	1/5 (20%)	2	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	1/3 (33.3%)	2	0/3 (0%)	0	0/3 (0%)	0	1/12 (8.3%)	1	0/13 (0%)	0	0/21 (0%)	0	1/66 (1.5%)	1	0/100 (0%)	0	0/17 (0%)	0
Headache	0/5 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/12 (0%)	0	0/13 (0%)	0	0/21 (0%)	0	0/66 (0%)	0	0/100 (0%)	0	1/17 (5.9%)	1
Intracranial pressure increased	0/5 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/12 (0%)	0	0/13 (0%)	0	0/21 (0%)	0	1/66 (1.5%)	1	0/100 (0%)	0	0/17 (0%)	0
Lethargy	0/5 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/12 (0%)	0	0/13 (0%)	0	1/21 (4.8%)	1	0/66 (0%)	0	0/100 (0%)	0	0/17 (0%)	0
Loss of consciousness	0/5 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/12 (0%)	0	0/13 (0%)	0	0/21 (0%)	0	0/66 (0%)	0	1/100 (1%)	1	0/17 (0%)	0
Neuralgia	0/5 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/12 (0%)	0	0/13 (0%)	0	0/21 (0%)	0	1/66 (1.5%)	1	0/100 (0%)	0	0/17 (0%)	0
Posterior reversible encephalopathy syndrome	0/5 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/12 (0%)	0	0/13 (0%)	0	0/21 (0%)	0	1/66 (1.5%)	1	1/100 (1%)	1	0/17 (0%)	0
Presyncope	0/5 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/12 (0%)	0	0/13 (0%)	0	0/21 (0%)	0	0/66 (0%)	0	1/100 (1%)	2	0/17 (0%)	0
Radicular pain	0/5 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/12 (0%)	0	0/13 (0%)	0	1/21 (4.8%)	1	0/66 (0%)	0	0/100 (0%)	0	0/17 (0%)	0
Seizure	0/5 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/12 (0%)	0	0/13 (0%)	0	0/21 (0%)	0	1/66 (1.5%)	1	2/100 (2%)	2	0/17 (0%)	0
Syncope	0/5 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/12 (0%)	0	0/13 (0%)	0	0/21 (0%)	0	1/66 (1.5%)	1	5/100 (5%)	6	0/17 (0%)	0
Psychiatric disorders
Confusional state	0/5 (0%)	0	1/3 (33.3%)	1	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/12 (0%)	0	0/13 (0%)	0	0/21 (0%)	0	0/66 (0%)	0	1/100 (1%)	2	0/17 (0%)	0
Mental status changes	0/5 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/12 (0%)	0	0/13 (0%)	0	1/21 (4.8%)	1	0/66 (0%)	0	1/100 (1%)	1	0/17 (0%)	0
Renal and urinary disorders
Acute kidney injury	0/5 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	1/12 (8.3%)	1	3/13 (23.1%)	3	3/21 (14.3%)	4	5/66 (7.6%)	5	14/100 (14%)	16	1/17 (5.9%)	1
Renal failure	0/5 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/12 (0%)	0	0/13 (0%)	0	0/21 (0%)	0	1/66 (1.5%)	1	1/100 (1%)	1	1/17 (5.9%)	2
Renal injury	0/5 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/12 (0%)	0	1/13 (7.7%)	1	0/21 (0%)	0	0/66 (0%)	0	0/100 (0%)	0	0/17 (0%)	0
Renal tubular necrosis	0/5 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/12 (0%)	0	0/13 (0%)	0	1/21 (4.8%)	1	1/66 (1.5%)	1	0/100 (0%)	0	0/17 (0%)	0
Urinary retention	0/5 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	1/3 (33.3%)	1	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/12 (0%)	0	0/13 (0%)	0	0/21 (0%)	0	1/66 (1.5%)	1	0/100 (0%)	0	0/17 (0%)	0
Respiratory, thoracic and mediastinal disorders
Acute promyelocytic leukaemia differentiation syndrome	0/5 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/12 (0%)	0	0/13 (0%)	0	0/21 (0%)	0	0/66 (0%)	0	1/100 (1%)	1	0/17 (0%)	0
Acute respiratory distress syndrome	0/5 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/12 (0%)	0	0/13 (0%)	0	1/21 (4.8%)	1	0/66 (0%)	0	0/100 (0%)	0	0/17 (0%)	0
Acute respiratory failure	0/5 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/12 (0%)	0	0/13 (0%)	0	0/21 (0%)	0	0/66 (0%)	0	3/100 (3%)	4	0/17 (0%)	0
Aspiration	0/5 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/12 (0%)	0	0/13 (0%)	0	0/21 (0%)	0	1/66 (1.5%)	1	0/100 (0%)	0	0/17 (0%)	0
Dyspnoea	0/5 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/12 (0%)	0	1/13 (7.7%)	1	0/21 (0%)	0	1/66 (1.5%)	1	2/100 (2%)	2	0/17 (0%)	0
Epistaxis	0/5 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/12 (0%)	0	0/13 (0%)	0	1/21 (4.8%)	1	0/66 (0%)	0	1/100 (1%)	1	0/17 (0%)	0
Haemoptysis	0/5 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/12 (0%)	0	0/13 (0%)	0	1/21 (4.8%)	2	0/66 (0%)	0	0/100 (0%)	0	0/17 (0%)	0
Hypoxia	0/5 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/12 (0%)	0	1/13 (7.7%)	1	1/21 (4.8%)	1	2/66 (3%)	2	3/100 (3%)	4	0/17 (0%)	0
Laryngeal mass	0/5 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/12 (0%)	0	1/13 (7.7%)	1	0/21 (0%)	0	0/66 (0%)	0	0/100 (0%)	0	0/17 (0%)	0
Lung infiltration	0/5 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/12 (0%)	0	0/13 (0%)	0	0/21 (0%)	0	0/66 (0%)	0	1/100 (1%)	1	0/17 (0%)	0
Pleural effusion	0/5 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/12 (0%)	0	0/13 (0%)	0	0/21 (0%)	0	2/66 (3%)	2	2/100 (2%)	3	0/17 (0%)	0
Pneumonitis	0/5 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/12 (0%)	0	0/13 (0%)	0	0/21 (0%)	0	1/66 (1.5%)	1	0/100 (0%)	0	0/17 (0%)	0
Pulmonary embolism	0/5 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/12 (0%)	0	0/13 (0%)	0	0/21 (0%)	0	1/66 (1.5%)	1	0/100 (0%)	0	1/17 (5.9%)	1
Pulmonary haemorrhage	0/5 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/12 (0%)	0	0/13 (0%)	0	0/21 (0%)	0	0/66 (0%)	0	1/100 (1%)	1	0/17 (0%)	0
Respiratory distress	0/5 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/12 (0%)	0	0/13 (0%)	0	0/21 (0%)	0	2/66 (3%)	2	2/100 (2%)	2	0/17 (0%)	0
Respiratory failure	0/5 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	1/3 (33.3%)	1	0/3 (0%)	0	0/12 (0%)	0	0/13 (0%)	0	1/21 (4.8%)	2	1/66 (1.5%)	1	11/100 (11%)	13	1/17 (5.9%)	1
Skin and subcutaneous tissue disorders
Acute febrile neutrophilic dermatosis	0/5 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/12 (0%)	0	0/13 (0%)	0	0/21 (0%)	0	2/66 (3%)	2	2/100 (2%)	2	0/17 (0%)	0
Angioedema	0/5 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/12 (0%)	0	0/13 (0%)	0	0/21 (0%)	0	1/66 (1.5%)	1	1/100 (1%)	1	0/17 (0%)	0
Rash papular	0/5 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/12 (0%)	0	0/13 (0%)	0	1/21 (4.8%)	1	0/66 (0%)	0	0/100 (0%)	0	0/17 (0%)	0
Skin lesion	0/5 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/12 (0%)	0	0/13 (0%)	0	0/21 (0%)	0	0/66 (0%)	0	1/100 (1%)	1	0/17 (0%)	0
Vascular disorders
Deep vein thrombosis	0/5 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/12 (0%)	0	0/13 (0%)	0	0/21 (0%)	0	0/66 (0%)	0	1/100 (1%)	1	0/17 (0%)	0
Embolism	0/5 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	1/3 (33.3%)	1	0/12 (0%)	0	0/13 (0%)	0	0/21 (0%)	0	0/66 (0%)	0	0/100 (0%)	0	0/17 (0%)	0
Haematoma	0/5 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	1/3 (33.3%)	2	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/12 (0%)	0	0/13 (0%)	0	0/21 (0%)	0	1/66 (1.5%)	1	1/100 (1%)	1	0/17 (0%)	0
Haemorrhage	0/5 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/12 (0%)	0	0/13 (0%)	0	0/21 (0%)	0	0/66 (0%)	0	1/100 (1%)	1	0/17 (0%)	0
Hypertension	0/5 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/12 (0%)	0	0/13 (0%)	0	0/21 (0%)	0	0/66 (0%)	0	0/100 (0%)	0	1/17 (5.9%)	1
Hypotension	0/5 (0%)	0	0/3 (0%)	0	1/3 (33.3%)	1	0/3 (0%)	0	1/3 (33.3%)	1	0/3 (0%)	0	0/3 (0%)	0	1/12 (8.3%)	1	0/13 (0%)	0	0/21 (0%)	0	3/66 (4.5%)	4	4/100 (4%)	4	0/17 (0%)	0
Orthostatic hypotension	0/5 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/12 (0%)	0	0/13 (0%)	0	0/21 (0%)	0	0/66 (0%)	0	1/100 (1%)	1	0/17 (0%)	0
Phlebitis deep	0/5 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/12 (0%)	0	0/13 (0%)	0	0/21 (0%)	0	1/66 (1.5%)	1	0/100 (0%)	0	0/17 (0%)	0
Other (Not Including Serious) Adverse Events
	Gilterinib 20 mg in Escalation Phase		Gilterinib 40 mg in Escalation Phase		Gilterinib 80 mg in Escalation Phase		Gilterinib 120 mg in Escalation Phase		Gilterinib 200 mg in Escalation Phase		Gilterinib 300 mg in Escalation Phase		Gilterinib 450 mg in Escalation Phase		Gilterinib 20 mg in Expansion Phase		Gilterinib 40 mg in Expansion Phase		Gilterinib 80 mg in Expansion Phase		Gilterinib 120 mg in Expansion Phase		Gilterinib 200 mg in Expansion Phase		Gilterinib 300 mg in Expansion Phase
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	5/5 (100%)		2/3 (66.7%)		3/3 (100%)		3/3 (100%)		3/3 (100%)		3/3 (100%)		3/3 (100%)		12/12 (100%)		12/13 (92.3%)		20/21 (95.2%)		62/66 (93.9%)		97/100 (97%)		16/17 (94.1%)
Blood and lymphatic system disorders
Anaemia	2/5 (40%)	2	0/3 (0%)	0	1/3 (33.3%)	3	0/3 (0%)	0	0/3 (0%)	0	1/3 (33.3%)	1	0/3 (0%)	0	2/12 (16.7%)	4	4/13 (30.8%)	4	7/21 (33.3%)	10	27/66 (40.9%)	84	33/100 (33%)	65	6/17 (35.3%)	6
Febrile neutropenia	1/5 (20%)	1	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	2/12 (16.7%)	2	0/13 (0%)	0	1/21 (4.8%)	1	7/66 (10.6%)	8	15/100 (15%)	20	3/17 (17.6%)	3
Hyperfibrinogenaemia	0/5 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/12 (0%)	0	0/13 (0%)	0	0/21 (0%)	0	0/66 (0%)	0	0/100 (0%)	0	1/17 (5.9%)	1
Leukocytosis	1/5 (20%)	1	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/12 (0%)	0	1/13 (7.7%)	1	1/21 (4.8%)	1	4/66 (6.1%)	4	4/100 (4%)	6	2/17 (11.8%)	2
Lymphadenopathy	0/5 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/12 (0%)	0	0/13 (0%)	0	0/21 (0%)	0	1/66 (1.5%)	1	0/100 (0%)	0	1/17 (5.9%)	1
Neutropenia	0/5 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/12 (0%)	0	0/13 (0%)	0	0/21 (0%)	0	5/66 (7.6%)	28	12/100 (12%)	29	2/17 (11.8%)	2
Thrombocytopenia	0/5 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	1/3 (33.3%)	1	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/12 (0%)	0	1/13 (7.7%)	1	3/21 (14.3%)	6	12/66 (18.2%)	27	19/100 (19%)	44	2/17 (11.8%)	2
Cardiac disorders
Angina pectoris	0/5 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	2/12 (16.7%)	3	0/13 (0%)	0	0/21 (0%)	0	0/66 (0%)	0	2/100 (2%)	2	0/17 (0%)	0
Atrial fibrillation	0/5 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/12 (0%)	0	0/13 (0%)	0	1/21 (4.8%)	1	3/66 (4.5%)	3	5/100 (5%)	5	0/17 (0%)	0
Atrial flutter	0/5 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/12 (0%)	0	1/13 (7.7%)	1	0/21 (0%)	0	0/66 (0%)	0	0/100 (0%)	0	0/17 (0%)	0
Palpitations	0/5 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/12 (0%)	0	0/13 (0%)	0	2/21 (9.5%)	2	0/66 (0%)	0	3/100 (3%)	3	0/17 (0%)	0
Pericardial effusion	0/5 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	1/12 (8.3%)	1	0/13 (0%)	0	1/21 (4.8%)	1	1/66 (1.5%)	1	3/100 (3%)	3	0/17 (0%)	0
Sinus bradycardia	0/5 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	1/3 (33.3%)	1	0/12 (0%)	0	0/13 (0%)	0	1/21 (4.8%)	1	0/66 (0%)	0	2/100 (2%)	2	0/17 (0%)	0
Sinus tachycardia	0/5 (0%)	0	1/3 (33.3%)	1	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	1/12 (8.3%)	1	2/13 (15.4%)	2	1/21 (4.8%)	2	2/66 (3%)	2	6/100 (6%)	7	0/17 (0%)	0
Tachycardia	0/5 (0%)	0	0/3 (0%)	0	1/3 (33.3%)	1	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	1/12 (8.3%)	1	0/13 (0%)	0	1/21 (4.8%)	1	1/66 (1.5%)	1	12/100 (12%)	13	0/17 (0%)	0
Ear and labyrinth disorders
Ear discomfort	0/5 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	1/12 (8.3%)	1	0/13 (0%)	0	0/21 (0%)	0	0/66 (0%)	0	0/100 (0%)	0	0/17 (0%)	0
Ear pain	1/5 (20%)	1	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	2/12 (16.7%)	2	0/13 (0%)	0	0/21 (0%)	0	0/66 (0%)	0	3/100 (3%)	3	0/17 (0%)	0
Endocrine disorders
Hypothyroidism	1/5 (20%)	1	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/12 (0%)	0	0/13 (0%)	0	0/21 (0%)	0	1/66 (1.5%)	1	3/100 (3%)	3	0/17 (0%)	0
Eye disorders
Blepharitis	0/5 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/12 (0%)	0	0/13 (0%)	0	0/21 (0%)	0	4/66 (6.1%)	4	2/100 (2%)	2	0/17 (0%)	0
Cataract	0/5 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/12 (0%)	0	0/13 (0%)	0	0/21 (0%)	0	4/66 (6.1%)	6	0/100 (0%)	0	0/17 (0%)	0
Cataract nuclear	0/5 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/12 (0%)	0	1/13 (7.7%)	1	0/21 (0%)	0	1/66 (1.5%)	1	0/100 (0%)	0	0/17 (0%)	0
Conjunctival haemorrhage	0/5 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	1/12 (8.3%)	1	0/13 (0%)	0	4/21 (19%)	4	0/66 (0%)	0	3/100 (3%)	3	0/17 (0%)	0
Dry eye	0/5 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	1/3 (33.3%)	1	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/12 (0%)	0	0/13 (0%)	0	1/21 (4.8%)	1	8/66 (12.1%)	10	6/100 (6%)	7	0/17 (0%)	0
Eye oedema	0/5 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	1/3 (33.3%)	1	0/12 (0%)	0	0/13 (0%)	0	0/21 (0%)	0	0/66 (0%)	0	1/100 (1%)	1	0/17 (0%)	0
Eye pruritus	0/5 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/12 (0%)	0	0/13 (0%)	0	0/21 (0%)	0	1/66 (1.5%)	1	1/100 (1%)	1	1/17 (5.9%)	1
Glaucoma	0/5 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/12 (0%)	0	1/13 (7.7%)	1	0/21 (0%)	0	0/66 (0%)	0	0/100 (0%)	0	0/17 (0%)	0
Lacrimation increased	0/5 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	1/3 (33.3%)	1	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/12 (0%)	0	0/13 (0%)	0	0/21 (0%)	0	2/66 (3%)	3	0/100 (0%)	0	0/17 (0%)	0
Periorbital oedema	0/5 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/12 (0%)	0	0/13 (0%)	0	2/21 (9.5%)	2	3/66 (4.5%)	3	5/100 (5%)	9	0/17 (0%)	0
Retinal exudates	0/5 (0%)	0	0/3 (0%)	0	1/3 (33.3%)	1	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/12 (0%)	0	0/13 (0%)	0	0/21 (0%)	0	0/66 (0%)	0	0/100 (0%)	0	0/17 (0%)	0
Retinal haemorrhage	0/5 (0%)	0	0/3 (0%)	0	1/3 (33.3%)	1	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/12 (0%)	0	0/13 (0%)	0	0/21 (0%)	0	3/66 (4.5%)	3	0/100 (0%)	0	0/17 (0%)	0
Vision blurred	1/5 (20%)	1	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/12 (0%)	0	0/13 (0%)	0	1/21 (4.8%)	1	5/66 (7.6%)	8	6/100 (6%)	6	0/17 (0%)	0
Vitreous detachment	1/5 (20%)	1	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/12 (0%)	0	0/13 (0%)	0	0/21 (0%)	0	1/66 (1.5%)	1	0/100 (0%)	0	0/17 (0%)	0
Vitreous floaters	1/5 (20%)	1	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/12 (0%)	0	0/13 (0%)	0	0/21 (0%)	0	4/66 (6.1%)	4	3/100 (3%)	3	0/17 (0%)	0
Gastrointestinal disorders
Abdominal distension	0/5 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	1/12 (8.3%)	1	0/13 (0%)	0	0/21 (0%)	0	1/66 (1.5%)	1	7/100 (7%)	8	1/17 (5.9%)	1
Abdominal pain	1/5 (20%)	1	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	1/3 (33.3%)	1	0/3 (0%)	0	1/3 (33.3%)	1	1/12 (8.3%)	1	1/13 (7.7%)	1	1/21 (4.8%)	1	5/66 (7.6%)	6	15/100 (15%)	19	0/17 (0%)	0
Abdominal pain lower	0/5 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	1/3 (33.3%)	1	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/12 (0%)	0	0/13 (0%)	0	0/21 (0%)	0	1/66 (1.5%)	1	0/100 (0%)	0	0/17 (0%)	0
Abdominal pain upper	0/5 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	1/12 (8.3%)	1	0/13 (0%)	0	0/21 (0%)	0	3/66 (4.5%)	3	1/100 (1%)	1	1/17 (5.9%)	1
Abdominal tenderness	0/5 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	1/12 (8.3%)	1	0/13 (0%)	0	0/21 (0%)	0	0/66 (0%)	0	0/100 (0%)	0	0/17 (0%)	0
Aphthous ulcer	0/5 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/12 (0%)	0	0/13 (0%)	0	0/21 (0%)	0	0/66 (0%)	0	0/100 (0%)	0	1/17 (5.9%)	1
Colitis	0/5 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	1/3 (33.3%)	1	0/3 (0%)	0	0/3 (0%)	0	1/3 (33.3%)	1	0/12 (0%)	0	0/13 (0%)	0	0/21 (0%)	0	2/66 (3%)	2	2/100 (2%)	2	0/17 (0%)	0
Constipation	1/5 (20%)	1	1/3 (33.3%)	1	1/3 (33.3%)	1	2/3 (66.7%)	2	1/3 (33.3%)	1	1/3 (33.3%)	1	0/3 (0%)	0	1/12 (8.3%)	2	1/13 (7.7%)	1	5/21 (23.8%)	5	12/66 (18.2%)	14	32/100 (32%)	36	1/17 (5.9%)	1
Diarrhoea	0/5 (0%)	0	0/3 (0%)	0	1/3 (33.3%)	1	1/3 (33.3%)	1	0/3 (0%)	0	1/3 (33.3%)	2	1/3 (33.3%)	2	1/12 (8.3%)	1	2/13 (15.4%)	2	5/21 (23.8%)	12	27/66 (40.9%)	44	45/100 (45%)	71	5/17 (29.4%)	6
Dry mouth	0/5 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	1/12 (8.3%)	1	1/13 (7.7%)	1	2/21 (9.5%)	2	4/66 (6.1%)	4	10/100 (10%)	10	1/17 (5.9%)	1
Dyspepsia	0/5 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	1/12 (8.3%)	1	0/13 (0%)	0	0/21 (0%)	0	3/66 (4.5%)	3	3/100 (3%)	3	0/17 (0%)	0
Dysphagia	0/5 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	1/12 (8.3%)	1	0/13 (0%)	0	0/21 (0%)	0	2/66 (3%)	2	7/100 (7%)	8	2/17 (11.8%)	2
Gastrointestinal haemorrhage	0/5 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	1/3 (33.3%)	1	0/3 (0%)	0	0/12 (0%)	0	0/13 (0%)	0	1/21 (4.8%)	1	0/66 (0%)	0	4/100 (4%)	5	0/17 (0%)	0
Gingival bleeding	0/5 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	1/3 (33.3%)	1	0/3 (0%)	0	0/12 (0%)	0	1/13 (7.7%)	2	1/21 (4.8%)	1	2/66 (3%)	2	2/100 (2%)	2	0/17 (0%)	0
Gingival pain	0/5 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/12 (0%)	0	1/13 (7.7%)	1	0/21 (0%)	0	1/66 (1.5%)	1	1/100 (1%)	1	0/17 (0%)	0
Haemorrhoids	0/5 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	1/12 (8.3%)	1	1/13 (7.7%)	1	1/21 (4.8%)	1	1/66 (1.5%)	1	6/100 (6%)	8	0/17 (0%)	0
Melaena	0/5 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	1/12 (8.3%)	1	0/13 (0%)	0	1/21 (4.8%)	1	0/66 (0%)	0	1/100 (1%)	1	0/17 (0%)	0
Mouth haemorrhage	0/5 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	1/3 (33.3%)	1	1/3 (33.3%)	1	0/12 (0%)	0	0/13 (0%)	0	1/21 (4.8%)	1	2/66 (3%)	2	8/100 (8%)	9	0/17 (0%)	0
Mouth ulceration	0/5 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/12 (0%)	0	0/13 (0%)	0	1/21 (4.8%)	1	4/66 (6.1%)	5	4/100 (4%)	5	1/17 (5.9%)	1
Nausea	2/5 (40%)	3	0/3 (0%)	0	2/3 (66.7%)	3	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	1/12 (8.3%)	1	3/13 (23.1%)	3	4/21 (19%)	5	15/66 (22.7%)	22	28/100 (28%)	37	1/17 (5.9%)	1
Oesophagitis	0/5 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/12 (0%)	0	0/13 (0%)	0	0/21 (0%)	0	1/66 (1.5%)	1	1/100 (1%)	1	1/17 (5.9%)	1
Oral mucosal blistering	0/5 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/12 (0%)	0	0/13 (0%)	0	2/21 (9.5%)	2	2/66 (3%)	2	1/100 (1%)	3	1/17 (5.9%)	1
Oral pain	1/5 (20%)	1	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/12 (0%)	0	0/13 (0%)	0	0/21 (0%)	0	1/66 (1.5%)	1	2/100 (2%)	3	0/17 (0%)	0
Proctalgia	1/5 (20%)	1	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/12 (0%)	0	0/13 (0%)	0	0/21 (0%)	0	1/66 (1.5%)	1	0/100 (0%)	0	0/17 (0%)	0
Rectal haemorrhage	0/5 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	1/12 (8.3%)	1	0/13 (0%)	0	0/21 (0%)	0	1/66 (1.5%)	1	4/100 (4%)	4	0/17 (0%)	0
Salivary hypersecretion	0/5 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/12 (0%)	0	1/13 (7.7%)	1	0/21 (0%)	0	0/66 (0%)	0	0/100 (0%)	0	0/17 (0%)	0
Stomatitis	0/5 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	1/3 (33.3%)	1	1/3 (33.3%)	1	1/12 (8.3%)	1	1/13 (7.7%)	1	0/21 (0%)	0	8/66 (12.1%)	9	14/100 (14%)	15	1/17 (5.9%)	1
Tongue coated	0/5 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	1/12 (8.3%)	2	0/13 (0%)	0	0/21 (0%)	0	0/66 (0%)	0	1/100 (1%)	1	0/17 (0%)	0
Vomiting	1/5 (20%)	1	0/3 (0%)	0	2/3 (66.7%)	2	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	2/12 (16.7%)	3	1/13 (7.7%)	1	5/21 (23.8%)	6	13/66 (19.7%)	16	22/100 (22%)	31	1/17 (5.9%)	1
General disorders
Asthenia	1/5 (20%)	1	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	1/3 (33.3%)	2	0/3 (0%)	0	2/12 (16.7%)	2	0/13 (0%)	0	3/21 (14.3%)	3	6/66 (9.1%)	8	19/100 (19%)	20	0/17 (0%)	0
Chills	0/5 (0%)	0	0/3 (0%)	0	1/3 (33.3%)	1	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	1/12 (8.3%)	1	0/13 (0%)	0	1/21 (4.8%)	1	5/66 (7.6%)	5	12/100 (12%)	15	0/17 (0%)	0
Face oedema	0/5 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	1/3 (33.3%)	1	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	1/12 (8.3%)	1	0/13 (0%)	0	2/21 (9.5%)	3	2/66 (3%)	2	2/100 (2%)	2	0/17 (0%)	0
Fatigue	1/5 (20%)	1	0/3 (0%)	0	1/3 (33.3%)	2	0/3 (0%)	0	3/3 (100%)	6	1/3 (33.3%)	2	1/3 (33.3%)	3	4/12 (33.3%)	5	5/13 (38.5%)	6	8/21 (38.1%)	11	27/66 (40.9%)	38	32/100 (32%)	47	4/17 (23.5%)	4
Gait disturbance	0/5 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	1/3 (33.3%)	1	0/12 (0%)	0	0/13 (0%)	0	0/21 (0%)	0	0/66 (0%)	0	1/100 (1%)	1	0/17 (0%)	0
Generalised oedema	1/5 (20%)	1	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/12 (0%)	0	0/13 (0%)	0	0/21 (0%)	0	1/66 (1.5%)	1	2/100 (2%)	2	1/17 (5.9%)	1
Local swelling	0/5 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/12 (0%)	0	0/13 (0%)	0	0/21 (0%)	0	0/66 (0%)	0	0/100 (0%)	0	1/17 (5.9%)	1
Localised oedema	0/5 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/12 (0%)	0	0/13 (0%)	0	1/21 (4.8%)	1	1/66 (1.5%)	2	5/100 (5%)	5	0/17 (0%)	0
Malaise	0/5 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/12 (0%)	0	0/13 (0%)	0	0/21 (0%)	0	2/66 (3%)	3	5/100 (5%)	5	0/17 (0%)	0
Mucosal inflammation	0/5 (0%)	0	1/3 (33.3%)	1	1/3 (33.3%)	1	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/12 (0%)	0	0/13 (0%)	0	0/21 (0%)	0	7/66 (10.6%)	9	11/100 (11%)	13	0/17 (0%)	0
Nodule	0/5 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/12 (0%)	0	0/13 (0%)	0	1/21 (4.8%)	1	1/66 (1.5%)	2	0/100 (0%)	0	1/17 (5.9%)	1
Oedema	0/5 (0%)	0	0/3 (0%)	0	1/3 (33.3%)	1	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	1/12 (8.3%)	1	0/13 (0%)	0	3/21 (14.3%)	5	3/66 (4.5%)	5	6/100 (6%)	7	0/17 (0%)	0
Oedema peripheral	0/5 (0%)	0	1/3 (33.3%)	1	0/3 (0%)	0	1/3 (33.3%)	1	0/3 (0%)	0	1/3 (33.3%)	1	1/3 (33.3%)	1	4/12 (33.3%)	4	2/13 (15.4%)	2	5/21 (23.8%)	11	17/66 (25.8%)	22	31/100 (31%)	48	1/17 (5.9%)	2
Pain	0/5 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/12 (0%)	0	0/13 (0%)	0	0/21 (0%)	0	6/66 (9.1%)	7	6/100 (6%)	9	0/17 (0%)	0
Peripheral swelling	0/5 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	1/12 (8.3%)	1	0/13 (0%)	0	1/21 (4.8%)	2	3/66 (4.5%)	4	4/100 (4%)	6	0/17 (0%)	0
Pyrexia	0/5 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	1/12 (8.3%)	1	3/13 (23.1%)	3	3/21 (14.3%)	3	18/66 (27.3%)	25	24/100 (24%)	33	3/17 (17.6%)	3
Serositis	0/5 (0%)	0	0/3 (0%)	0	1/3 (33.3%)	1	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/12 (0%)	0	0/13 (0%)	0	0/21 (0%)	0	0/66 (0%)	0	0/100 (0%)	0	0/17 (0%)	0
Hepatobiliary disorders
Hyperbilirubinaemia	0/5 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/12 (0%)	0	0/13 (0%)	0	2/21 (9.5%)	2	2/66 (3%)	2	6/100 (6%)	12	0/17 (0%)	0
Immune system disorders
Graft versus host disease	0/5 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	1/12 (8.3%)	1	0/13 (0%)	0	0/21 (0%)	0	3/66 (4.5%)	4	0/100 (0%)	0	0/17 (0%)	0
Seasonal allergy	0/5 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	1/12 (8.3%)	1	0/13 (0%)	0	1/21 (4.8%)	1	1/66 (1.5%)	1	1/100 (1%)	1	0/17 (0%)	0
Infections and infestations
Abscess limb	0/5 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	1/12 (8.3%)	1	0/13 (0%)	0	0/21 (0%)	0	0/66 (0%)	0	0/100 (0%)	0	0/17 (0%)	0
Bacteraemia	0/5 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/12 (0%)	0	0/13 (0%)	0	2/21 (9.5%)	2	3/66 (4.5%)	3	2/100 (2%)	2	0/17 (0%)	0
Candida infection	0/5 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/12 (0%)	0	0/13 (0%)	0	0/21 (0%)	0	4/66 (6.1%)	4	2/100 (2%)	2	0/17 (0%)	0
Cellulitis	0/5 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/12 (0%)	0	0/13 (0%)	0	2/21 (9.5%)	3	5/66 (7.6%)	6	1/100 (1%)	1	0/17 (0%)	0
Clostridium difficile infection	0/5 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/12 (0%)	0	1/13 (7.7%)	1	1/21 (4.8%)	1	4/66 (6.1%)	4	2/100 (2%)	2	0/17 (0%)	0
Enterococcal bacteraemia	0/5 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/12 (0%)	0	0/13 (0%)	0	0/21 (0%)	0	1/66 (1.5%)	1	2/100 (2%)	2	1/17 (5.9%)	1
Gingivitis	0/5 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/12 (0%)	0	1/13 (7.7%)	1	0/21 (0%)	0	0/66 (0%)	0	0/100 (0%)	0	0/17 (0%)	0
Herpes virus infection	0/5 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	1/12 (8.3%)	1	0/13 (0%)	0	0/21 (0%)	0	0/66 (0%)	0	1/100 (1%)	1	0/17 (0%)	0
Herpes zoster	0/5 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/12 (0%)	0	1/13 (7.7%)	1	0/21 (0%)	0	0/66 (0%)	0	1/100 (1%)	1	0/17 (0%)	0
Influenza	0/5 (0%)	0	0/3 (0%)	0	1/3 (33.3%)	1	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/12 (0%)	0	0/13 (0%)	0	0/21 (0%)	0	1/66 (1.5%)	1	5/100 (5%)	5	0/17 (0%)	0
Laryngitis fungal	0/5 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	1/12 (8.3%)	1	0/13 (0%)	0	0/21 (0%)	0	0/66 (0%)	0	0/100 (0%)	0	0/17 (0%)	0
Lip infection	1/5 (20%)	1	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/12 (0%)	0	0/13 (0%)	0	0/21 (0%)	0	0/66 (0%)	0	1/100 (1%)	1	0/17 (0%)	0
Lung infection	0/5 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/12 (0%)	0	1/13 (7.7%)	1	0/21 (0%)	0	2/66 (3%)	2	5/100 (5%)	5	0/17 (0%)	0
Oral candidiasis	0/5 (0%)	0	0/3 (0%)	0	1/3 (33.3%)	1	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	1/12 (8.3%)	1	0/13 (0%)	0	1/21 (4.8%)	1	0/66 (0%)	0	2/100 (2%)	2	0/17 (0%)	0
Oral herpes	0/5 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	1/12 (8.3%)	1	0/13 (0%)	0	0/21 (0%)	0	1/66 (1.5%)	2	0/100 (0%)	0	0/17 (0%)	0
Pharyngitis	0/5 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	1/12 (8.3%)	2	0/13 (0%)	0	0/21 (0%)	0	0/66 (0%)	0	1/100 (1%)	1	0/17 (0%)	0
Pneumonia	0/5 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	1/3 (33.3%)	1	0/3 (0%)	0	0/12 (0%)	0	0/13 (0%)	0	1/21 (4.8%)	2	5/66 (7.6%)	6	5/100 (5%)	6	0/17 (0%)	0
Sinusitis	0/5 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	1/3 (33.3%)	1	1/12 (8.3%)	1	0/13 (0%)	0	1/21 (4.8%)	1	2/66 (3%)	2	1/100 (1%)	1	0/17 (0%)	0
Skin infection	0/5 (0%)	0	0/3 (0%)	0	1/3 (33.3%)	1	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/12 (0%)	0	1/13 (7.7%)	1	1/21 (4.8%)	1	3/66 (4.5%)	3	3/100 (3%)	3	0/17 (0%)	0
Upper respiratory tract infection	0/5 (0%)	0	0/3 (0%)	0	1/3 (33.3%)	2	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/12 (0%)	0	2/13 (15.4%)	2	1/21 (4.8%)	1	7/66 (10.6%)	9	5/100 (5%)	11	0/17 (0%)	0
Urinary tract infection	0/5 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	1/3 (33.3%)	1	0/3 (0%)	0	0/12 (0%)	0	0/13 (0%)	0	2/21 (9.5%)	2	9/66 (13.6%)	9	5/100 (5%)	7	0/17 (0%)	0
Urinary tract infection bacterial	0/5 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/12 (0%)	0	0/13 (0%)	0	1/21 (4.8%)	1	4/66 (6.1%)	7	3/100 (3%)	4	0/17 (0%)	0
Urinary tract infection enterococcal	0/5 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	2/12 (16.7%)	2	0/13 (0%)	0	0/21 (0%)	0	0/66 (0%)	0	1/100 (1%)	1	0/17 (0%)	0
Injury, poisoning and procedural complications
Contusion	0/5 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	1/3 (33.3%)	1	1/12 (8.3%)	1	1/13 (7.7%)	1	3/21 (14.3%)	3	3/66 (4.5%)	3	10/100 (10%)	11	0/17 (0%)	0
Fall	0/5 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	1/3 (33.3%)	1	1/12 (8.3%)	1	0/13 (0%)	0	2/21 (9.5%)	2	11/66 (16.7%)	15	18/100 (18%)	22	0/17 (0%)	0
Incision site pain	0/5 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	1/12 (8.3%)	1	0/13 (0%)	0	0/21 (0%)	0	0/66 (0%)	0	0/100 (0%)	0	0/17 (0%)	0
Infusion related reaction	1/5 (20%)	1	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/12 (0%)	0	0/13 (0%)	0	0/21 (0%)	0	0/66 (0%)	0	3/100 (3%)	5	0/17 (0%)	0
Periorbital haemorrhage	0/5 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/12 (0%)	0	0/13 (0%)	0	1/21 (4.8%)	1	0/66 (0%)	0	0/100 (0%)	0	1/17 (5.9%)	1
Post procedural haemorrhage	0/5 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	1/3 (33.3%)	1	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/12 (0%)	0	0/13 (0%)	0	1/21 (4.8%)	1	0/66 (0%)	0	0/100 (0%)	0	0/17 (0%)	0
Procedural pain	0/5 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/12 (0%)	0	0/13 (0%)	0	0/21 (0%)	0	1/66 (1.5%)	1	1/100 (1%)	1	1/17 (5.9%)	1
Stoma site pain	0/5 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	1/12 (8.3%)	2	0/13 (0%)	0	0/21 (0%)	0	0/66 (0%)	0	0/100 (0%)	0	0/17 (0%)	0
Transfusion reaction	0/5 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	1/3 (33.3%)	2	0/3 (0%)	0	0/12 (0%)	0	0/13 (0%)	0	1/21 (4.8%)	1	3/66 (4.5%)	3	1/100 (1%)	1	1/17 (5.9%)	1
Investigations
Activated partial thromboplastin time prolonged	0/5 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	1/3 (33.3%)	1	1/12 (8.3%)	2	0/13 (0%)	0	0/21 (0%)	0	1/66 (1.5%)	1	4/100 (4%)	5	0/17 (0%)	0
Alanine aminotransferase increased	0/5 (0%)	0	0/3 (0%)	0	1/3 (33.3%)	1	0/3 (0%)	0	0/3 (0%)	0	1/3 (33.3%)	1	1/3 (33.3%)	1	1/12 (8.3%)	2	1/13 (7.7%)	1	3/21 (14.3%)	9	16/66 (24.2%)	26	25/100 (25%)	46	2/17 (11.8%)	3
Aspartate aminotransferase increased	0/5 (0%)	0	0/3 (0%)	0	1/3 (33.3%)	1	0/3 (0%)	0	1/3 (33.3%)	1	1/3 (33.3%)	1	2/3 (66.7%)	4	1/12 (8.3%)	3	1/13 (7.7%)	1	3/21 (14.3%)	9	20/66 (30.3%)	33	35/100 (35%)	61	1/17 (5.9%)	2
Blood alkaline phosphatase increased	1/5 (20%)	1	0/3 (0%)	0	1/3 (33.3%)	1	0/3 (0%)	0	0/3 (0%)	0	1/3 (33.3%)	1	1/3 (33.3%)	1	1/12 (8.3%)	1	0/13 (0%)	0	3/21 (14.3%)	12	10/66 (15.2%)	12	15/100 (15%)	19	0/17 (0%)	0
Blood bilirubin increased	0/5 (0%)	0	0/3 (0%)	0	1/3 (33.3%)	1	1/3 (33.3%)	1	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	1/12 (8.3%)	2	2/13 (15.4%)	3	3/21 (14.3%)	3	1/66 (1.5%)	1	12/100 (12%)	22	0/17 (0%)	0
Blood creatine phosphokinase increased	0/5 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	1/3 (33.3%)	1	0/12 (0%)	0	0/13 (0%)	0	0/21 (0%)	0	5/66 (7.6%)	9	15/100 (15%)	27	1/17 (5.9%)	1
Blood creatinine increased	0/5 (0%)	0	0/3 (0%)	0	1/3 (33.3%)	1	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	1/12 (8.3%)	1	2/13 (15.4%)	2	4/21 (19%)	9	13/66 (19.7%)	23	19/100 (19%)	40	1/17 (5.9%)	1
Blood lactate dehydrogenase increased	0/5 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/12 (0%)	0	1/13 (7.7%)	1	0/21 (0%)	0	3/66 (4.5%)	4	7/100 (7%)	9	0/17 (0%)	0
Blood phosphorus decreased	0/5 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/12 (0%)	0	1/13 (7.7%)	1	0/21 (0%)	0	1/66 (1.5%)	1	0/100 (0%)	0	0/17 (0%)	0
Blood thyroid stimulating hormone increased	1/5 (20%)	1	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/12 (0%)	0	0/13 (0%)	0	0/21 (0%)	0	0/66 (0%)	0	0/100 (0%)	0	0/17 (0%)	0
Blood urea increased	0/5 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/12 (0%)	0	0/13 (0%)	0	0/21 (0%)	0	0/66 (0%)	0	2/100 (2%)	2	1/17 (5.9%)	1
Cardiac murmur	0/5 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/12 (0%)	0	0/13 (0%)	0	2/21 (9.5%)	2	1/66 (1.5%)	1	0/100 (0%)	0	0/17 (0%)	0
Chest X-ray abnormal	0/5 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/12 (0%)	0	1/13 (7.7%)	1	0/21 (0%)	0	0/66 (0%)	0	1/100 (1%)	1	0/17 (0%)	0
Electrocardiogram QT prolonged	0/5 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	1/3 (33.3%)	1	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/12 (0%)	0	0/13 (0%)	0	1/21 (4.8%)	1	9/66 (13.6%)	13	9/100 (9%)	11	0/17 (0%)	0
International normalised ratio increased	0/5 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	1/12 (8.3%)	1	1/13 (7.7%)	2	1/21 (4.8%)	1	4/66 (6.1%)	7	5/100 (5%)	7	1/17 (5.9%)	1
Liver function test increased	0/5 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/12 (0%)	0	0/13 (0%)	0	1/21 (4.8%)	2	1/66 (1.5%)	1	3/100 (3%)	4	1/17 (5.9%)	1
Neutrophil count decreased	1/5 (20%)	1	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	1/3 (33.3%)	2	0/3 (0%)	0	2/12 (16.7%)	4	0/13 (0%)	0	1/21 (4.8%)	1	8/66 (12.1%)	16	14/100 (14%)	29	0/17 (0%)	0
Platelet count decreased	1/5 (20%)	3	0/3 (0%)	0	1/3 (33.3%)	1	0/3 (0%)	0	0/3 (0%)	0	1/3 (33.3%)	2	1/3 (33.3%)	1	2/12 (16.7%)	8	3/13 (23.1%)	4	1/21 (4.8%)	1	12/66 (18.2%)	26	17/100 (17%)	37	1/17 (5.9%)	1
Transaminases increased	0/5 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	1/3 (33.3%)	1	0/3 (0%)	0	1/3 (33.3%)	1	0/3 (0%)	0	0/12 (0%)	0	0/13 (0%)	0	1/21 (4.8%)	1	5/66 (7.6%)	5	5/100 (5%)	6	1/17 (5.9%)	1
Ultrasound liver abnormal	0/5 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/12 (0%)	0	0/13 (0%)	0	0/21 (0%)	0	0/66 (0%)	0	0/100 (0%)	0	1/17 (5.9%)	1
Volume blood increased	0/5 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/12 (0%)	0	1/13 (7.7%)	1	0/21 (0%)	0	0/66 (0%)	0	0/100 (0%)	0	0/17 (0%)	0
Weight decreased	0/5 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	1/12 (8.3%)	1	1/13 (7.7%)	1	0/21 (0%)	0	3/66 (4.5%)	3	6/100 (6%)	7	0/17 (0%)	0
Weight increased	0/5 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/12 (0%)	0	0/13 (0%)	0	0/21 (0%)	0	2/66 (3%)	5	12/100 (12%)	18	0/17 (0%)	0
White blood cell count decreased	0/5 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/12 (0%)	0	0/13 (0%)	0	0/21 (0%)	0	4/66 (6.1%)	14	13/100 (13%)	30	0/17 (0%)	0
Metabolism and nutrition disorders
Decreased appetite	0/5 (0%)	0	0/3 (0%)	0	2/3 (66.7%)	3	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	1/12 (8.3%)	1	1/13 (7.7%)	1	3/21 (14.3%)	4	11/66 (16.7%)	13	19/100 (19%)	21	1/17 (5.9%)	1
Dehydration	0/5 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/12 (0%)	0	1/13 (7.7%)	2	0/21 (0%)	0	1/66 (1.5%)	1	10/100 (10%)	10	0/17 (0%)	0
Fluid overload	0/5 (0%)	0	1/3 (33.3%)	1	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/12 (0%)	0	0/13 (0%)	0	0/21 (0%)	0	2/66 (3%)	2	2/100 (2%)	2	0/17 (0%)	0
Fluid retention	0/5 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	1/3 (33.3%)	1	0/3 (0%)	0	0/12 (0%)	0	0/13 (0%)	0	0/21 (0%)	0	0/66 (0%)	0	2/100 (2%)	2	0/17 (0%)	0
Hypercalcaemia	0/5 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/12 (0%)	0	1/13 (7.7%)	1	0/21 (0%)	0	0/66 (0%)	0	0/100 (0%)	0	0/17 (0%)	0
Hyperglycaemia	1/5 (20%)	1	0/3 (0%)	0	0/3 (0%)	0	1/3 (33.3%)	1	0/3 (0%)	0	0/3 (0%)	0	2/3 (66.7%)	2	0/12 (0%)	0	0/13 (0%)	0	0/21 (0%)	0	5/66 (7.6%)	7	14/100 (14%)	16	0/17 (0%)	0
Hyperkalaemia	0/5 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	1/3 (33.3%)	1	0/12 (0%)	0	1/13 (7.7%)	1	1/21 (4.8%)	2	5/66 (7.6%)	6	9/100 (9%)	10	0/17 (0%)	0
Hyperphosphataemia	0/5 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	1/12 (8.3%)	1	0/13 (0%)	0	1/21 (4.8%)	2	2/66 (3%)	2	1/100 (1%)	1	0/17 (0%)	0
Hyperuricaemia	0/5 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/12 (0%)	0	2/13 (15.4%)	2	0/21 (0%)	0	4/66 (6.1%)	4	10/100 (10%)	11	0/17 (0%)	0
Hypoalbuminaemia	0/5 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	1/3 (33.3%)	1	1/12 (8.3%)	2	1/13 (7.7%)	1	4/21 (19%)	15	7/66 (10.6%)	15	18/100 (18%)	28	1/17 (5.9%)	2
Hypocalcaemia	0/5 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	1/3 (33.3%)	1	1/12 (8.3%)	1	2/13 (15.4%)	2	3/21 (14.3%)	17	11/66 (16.7%)	23	23/100 (23%)	50	1/17 (5.9%)	1
Hypochloraemia	0/5 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/12 (0%)	0	0/13 (0%)	0	0/21 (0%)	0	0/66 (0%)	0	0/100 (0%)	0	1/17 (5.9%)	1
Hypoglycaemia	0/5 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	1/12 (8.3%)	1	0/13 (0%)	0	0/21 (0%)	0	2/66 (3%)	2	3/100 (3%)	4	0/17 (0%)	0
Hypokalaemia	1/5 (20%)	1	0/3 (0%)	0	1/3 (33.3%)	1	0/3 (0%)	0	0/3 (0%)	0	1/3 (33.3%)	1	0/3 (0%)	0	5/12 (41.7%)	9	2/13 (15.4%)	3	2/21 (9.5%)	11	10/66 (15.2%)	20	25/100 (25%)	33	0/17 (0%)	0
Hypomagnesaemia	1/5 (20%)	1	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	1/12 (8.3%)	2	1/13 (7.7%)	1	3/21 (14.3%)	3	13/66 (19.7%)	19	17/100 (17%)	25	0/17 (0%)	0
Hyponatraemia	0/5 (0%)	0	0/3 (0%)	0	1/3 (33.3%)	2	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/12 (0%)	0	1/13 (7.7%)	1	2/21 (9.5%)	8	8/66 (12.1%)	16	20/100 (20%)	26	1/17 (5.9%)	1
Hypophosphataemia	1/5 (20%)	2	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	1/12 (8.3%)	1	0/13 (0%)	0	1/21 (4.8%)	1	6/66 (9.1%)	10	11/100 (11%)	13	2/17 (11.8%)	2
Hypoproteinaemia	0/5 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	1/3 (33.3%)	1	0/3 (0%)	0	0/12 (0%)	0	0/13 (0%)	0	0/21 (0%)	0	0/66 (0%)	0	2/100 (2%)	2	0/17 (0%)	0
Hypovolaemia	0/5 (0%)	0	0/3 (0%)	0	1/3 (33.3%)	1	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/12 (0%)	0	0/13 (0%)	0	0/21 (0%)	0	0/66 (0%)	0	2/100 (2%)	2	0/17 (0%)	0
Iron overload	0/5 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/12 (0%)	0	0/13 (0%)	0	0/21 (0%)	0	4/66 (6.1%)	4	0/100 (0%)	0	0/17 (0%)	0
Musculoskeletal and connective tissue disorders
Arthralgia	0/5 (0%)	0	0/3 (0%)	0	1/3 (33.3%)	1	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/12 (0%)	0	0/13 (0%)	0	4/21 (19%)	4	12/66 (18.2%)	15	16/100 (16%)	23	1/17 (5.9%)	1
Back pain	0/5 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	1/12 (8.3%)	2	0/13 (0%)	0	2/21 (9.5%)	2	8/66 (12.1%)	9	9/100 (9%)	11	0/17 (0%)	0
Bone pain	1/5 (20%)	1	0/3 (0%)	0	1/3 (33.3%)	1	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	1/12 (8.3%)	1	0/13 (0%)	0	1/21 (4.8%)	1	1/66 (1.5%)	1	7/100 (7%)	7	0/17 (0%)	0
Flank pain	0/5 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	1/3 (33.3%)	1	0/12 (0%)	0	0/13 (0%)	0	0/21 (0%)	0	0/66 (0%)	0	1/100 (1%)	1	0/17 (0%)	0
Muscle spasms	0/5 (0%)	0	1/3 (33.3%)	1	0/3 (0%)	0	0/3 (0%)	0	1/3 (33.3%)	1	0/3 (0%)	0	0/3 (0%)	0	0/12 (0%)	0	0/13 (0%)	0	1/21 (4.8%)	1	3/66 (4.5%)	4	4/100 (4%)	4	0/17 (0%)	0
Muscular weakness	0/5 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	1/3 (33.3%)	1	0/12 (0%)	0	1/13 (7.7%)	1	0/21 (0%)	0	7/66 (10.6%)	7	4/100 (4%)	4	0/17 (0%)	0
Musculoskeletal chest pain	0/5 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/12 (0%)	0	1/13 (7.7%)	1	0/21 (0%)	0	1/66 (1.5%)	1	0/100 (0%)	0	0/17 (0%)	0
Musculoskeletal pain	0/5 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/12 (0%)	0	0/13 (0%)	0	1/21 (4.8%)	1	2/66 (3%)	2	7/100 (7%)	7	0/17 (0%)	0
Myalgia	0/5 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	1/3 (33.3%)	1	0/3 (0%)	0	0/3 (0%)	0	1/12 (8.3%)	1	1/13 (7.7%)	1	0/21 (0%)	0	5/66 (7.6%)	5	12/100 (12%)	14	0/17 (0%)	0
Myopathy	0/5 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/12 (0%)	0	0/13 (0%)	0	0/21 (0%)	0	0/66 (0%)	0	0/100 (0%)	0	1/17 (5.9%)	1
Neck pain	0/5 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/12 (0%)	0	1/13 (7.7%)	1	0/21 (0%)	0	4/66 (6.1%)	5	3/100 (3%)	3	0/17 (0%)	0
Pain in extremity	0/5 (0%)	0	1/3 (33.3%)	1	0/3 (0%)	0	1/3 (33.3%)	1	1/3 (33.3%)	1	1/3 (33.3%)	1	1/3 (33.3%)	1	1/12 (8.3%)	1	0/13 (0%)	0	2/21 (9.5%)	3	10/66 (15.2%)	13	11/100 (11%)	15	0/17 (0%)	0
Pain in jaw	0/5 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	2/12 (16.7%)	2	0/13 (0%)	0	1/21 (4.8%)	1	1/66 (1.5%)	1	0/100 (0%)	0	0/17 (0%)	0
Nervous system disorders
Cognitive disorder	0/5 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	1/3 (33.3%)	1	0/3 (0%)	0	0/3 (0%)	0	0/12 (0%)	0	0/13 (0%)	0	0/21 (0%)	0	0/66 (0%)	0	2/100 (2%)	2	0/17 (0%)	0
Dizziness	0/5 (0%)	0	1/3 (33.3%)	1	1/3 (33.3%)	1	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	1/12 (8.3%)	1	1/13 (7.7%)	1	5/21 (23.8%)	6	17/66 (25.8%)	19	26/100 (26%)	34	0/17 (0%)	0
Dysaesthesia	1/5 (20%)	1	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/12 (0%)	0	0/13 (0%)	0	0/21 (0%)	0	4/66 (6.1%)	6	9/100 (9%)	10	0/17 (0%)	0
Dysgeusia	0/5 (0%)	0	1/3 (33.3%)	1	1/3 (33.3%)	1	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	2/12 (16.7%)	2	1/13 (7.7%)	1	1/21 (4.8%)	1	9/66 (13.6%)	9	11/100 (11%)	12	2/17 (11.8%)	2
Headache	0/5 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	1/3 (33.3%)	2	0/3 (0%)	0	1/3 (33.3%)	1	0/3 (0%)	0	2/12 (16.7%)	2	1/13 (7.7%)	1	3/21 (14.3%)	4	10/66 (15.2%)	14	14/100 (14%)	20	0/17 (0%)	0
Hyperaesthesia	0/5 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	1/3 (33.3%)	1	0/3 (0%)	0	0/3 (0%)	0	0/12 (0%)	0	0/13 (0%)	0	0/21 (0%)	0	2/66 (3%)	2	4/100 (4%)	4	0/17 (0%)	0
Lethargy	1/5 (20%)	1	0/3 (0%)	0	1/3 (33.3%)	1	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/12 (0%)	0	0/13 (0%)	0	2/21 (9.5%)	2	1/66 (1.5%)	1	3/100 (3%)	3	1/17 (5.9%)	1
Memory impairment	1/5 (20%)	1	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/12 (0%)	0	0/13 (0%)	0	0/21 (0%)	0	0/66 (0%)	0	0/100 (0%)	0	0/17 (0%)	0
Neuropathy peripheral	0/5 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	1/3 (33.3%)	2	0/12 (0%)	0	0/13 (0%)	0	1/21 (4.8%)	1	7/66 (10.6%)	9	5/100 (5%)	6	2/17 (11.8%)	2
Paraesthesia	0/5 (0%)	0	0/3 (0%)	0	1/3 (33.3%)	1	0/3 (0%)	0	1/3 (33.3%)	1	0/3 (0%)	0	0/3 (0%)	0	0/12 (0%)	0	0/13 (0%)	0	0/21 (0%)	0	6/66 (9.1%)	7	7/100 (7%)	12	1/17 (5.9%)	1
Peripheral sensory neuropathy	0/5 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	1/12 (8.3%)	1	0/13 (0%)	0	0/21 (0%)	0	0/66 (0%)	0	1/100 (1%)	1	0/17 (0%)	0
Presyncope	1/5 (20%)	1	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/12 (0%)	0	0/13 (0%)	0	0/21 (0%)	0	3/66 (4.5%)	3	7/100 (7%)	8	0/17 (0%)	0
Sciatica	0/5 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/12 (0%)	0	1/13 (7.7%)	1	0/21 (0%)	0	0/66 (0%)	0	0/100 (0%)	0	0/17 (0%)	0
Somnolence	0/5 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/12 (0%)	0	1/13 (7.7%)	1	1/21 (4.8%)	1	1/66 (1.5%)	1	2/100 (2%)	2	0/17 (0%)	0
Syncope	0/5 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	1/3 (33.3%)	1	0/3 (0%)	0	0/12 (0%)	0	0/13 (0%)	0	0/21 (0%)	0	2/66 (3%)	3	6/100 (6%)	6	0/17 (0%)	0
Tremor	1/5 (20%)	1	0/3 (0%)	0	1/3 (33.3%)	1	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/12 (0%)	0	0/13 (0%)	0	0/21 (0%)	0	1/66 (1.5%)	2	6/100 (6%)	7	0/17 (0%)	0
Product Issues
Device occlusion	0/5 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/12 (0%)	0	0/13 (0%)	0	0/21 (0%)	0	0/66 (0%)	0	0/100 (0%)	0	1/17 (5.9%)	1
Psychiatric disorders
Agitation	0/5 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/12 (0%)	0	1/13 (7.7%)	1	1/21 (4.8%)	1	0/66 (0%)	0	3/100 (3%)	3	0/17 (0%)	0
Anxiety	0/5 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	1/12 (8.3%)	1	1/13 (7.7%)	1	1/21 (4.8%)	1	5/66 (7.6%)	5	6/100 (6%)	6	0/17 (0%)	0
Confusional state	0/5 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/12 (0%)	0	1/13 (7.7%)	2	3/21 (14.3%)	3	4/66 (6.1%)	4	10/100 (10%)	12	1/17 (5.9%)	1
Depression	0/5 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/12 (0%)	0	0/13 (0%)	0	1/21 (4.8%)	1	3/66 (4.5%)	3	6/100 (6%)	6	0/17 (0%)	0
Disorientation	0/5 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/12 (0%)	0	1/13 (7.7%)	1	0/21 (0%)	0	0/66 (0%)	0	1/100 (1%)	1	0/17 (0%)	0
Insomnia	0/5 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	1/3 (33.3%)	1	0/3 (0%)	0	2/12 (16.7%)	2	1/13 (7.7%)	1	3/21 (14.3%)	3	8/66 (12.1%)	9	13/100 (13%)	14	1/17 (5.9%)	1
Mental status changes	0/5 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	1/3 (33.3%)	1	0/3 (0%)	0	0/12 (0%)	0	1/13 (7.7%)	1	2/21 (9.5%)	2	0/66 (0%)	0	2/100 (2%)	2	1/17 (5.9%)	1
Sleep disorder	0/5 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/12 (0%)	0	0/13 (0%)	0	2/21 (9.5%)	2	0/66 (0%)	0	0/100 (0%)	0	0/17 (0%)	0
Renal and urinary disorders
Dysuria	0/5 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	1/3 (33.3%)	1	0/3 (0%)	0	0/12 (0%)	0	0/13 (0%)	0	1/21 (4.8%)	1	3/66 (4.5%)	3	7/100 (7%)	8	0/17 (0%)	0
Haematuria	0/5 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/12 (0%)	0	0/13 (0%)	0	1/21 (4.8%)	2	3/66 (4.5%)	4	6/100 (6%)	6	0/17 (0%)	0
Pollakiuria	0/5 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	2/3 (66.7%)	2	0/3 (0%)	0	0/12 (0%)	0	1/13 (7.7%)	1	0/21 (0%)	0	0/66 (0%)	0	7/100 (7%)	7	0/17 (0%)	0
Urinary incontinence	1/5 (20%)	1	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/12 (0%)	0	0/13 (0%)	0	1/21 (4.8%)	1	5/66 (7.6%)	6	4/100 (4%)	5	0/17 (0%)	0
Urinary retention	0/5 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/12 (0%)	0	0/13 (0%)	0	1/21 (4.8%)	2	0/66 (0%)	0	7/100 (7%)	8	0/17 (0%)	0
Reproductive system and breast disorders
Nipple pain	0/5 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	1/3 (33.3%)	1	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/12 (0%)	0	1/13 (7.7%)	1	0/21 (0%)	0	0/66 (0%)	0	0/100 (0%)	0	0/17 (0%)	0
Respiratory, thoracic and mediastinal disorders
Atelectasis	0/5 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	1/12 (8.3%)	1	0/13 (0%)	0	0/21 (0%)	0	0/66 (0%)	0	1/100 (1%)	1	0/17 (0%)	0
Cough	1/5 (20%)	1	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	1/3 (33.3%)	1	0/3 (0%)	0	0/3 (0%)	0	2/12 (16.7%)	3	1/13 (7.7%)	1	7/21 (33.3%)	7	18/66 (27.3%)	27	26/100 (26%)	29	3/17 (17.6%)	3
Dysphonia	0/5 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	1/3 (33.3%)	2	0/3 (0%)	0	0/12 (0%)	0	0/13 (0%)	0	0/21 (0%)	0	1/66 (1.5%)	1	2/100 (2%)	2	1/17 (5.9%)	1
Dyspnoea	0/5 (0%)	0	0/3 (0%)	0	1/3 (33.3%)	1	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	3/12 (25%)	4	5/13 (38.5%)	5	4/21 (19%)	5	19/66 (28.8%)	23	28/100 (28%)	38	2/17 (11.8%)	2
Dyspnoea exertional	0/5 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/12 (0%)	0	0/13 (0%)	0	1/21 (4.8%)	1	6/66 (9.1%)	7	3/100 (3%)	3	1/17 (5.9%)	1
Epistaxis	0/5 (0%)	0	1/3 (33.3%)	1	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	1/3 (33.3%)	1	1/3 (33.3%)	1	3/12 (25%)	3	3/13 (23.1%)	3	3/21 (14.3%)	3	16/66 (24.2%)	18	20/100 (20%)	24	4/17 (23.5%)	4
Haemoptysis	0/5 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	1/3 (33.3%)	1	0/3 (0%)	0	0/12 (0%)	0	0/13 (0%)	0	0/21 (0%)	0	2/66 (3%)	2	2/100 (2%)	2	0/17 (0%)	0
Hypoxia	0/5 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	1/3 (33.3%)	1	0/3 (0%)	0	1/12 (8.3%)	1	1/13 (7.7%)	1	2/21 (9.5%)	2	5/66 (7.6%)	8	11/100 (11%)	14	0/17 (0%)	0
Nasal congestion	0/5 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	1/3 (33.3%)	1	0/12 (0%)	0	0/13 (0%)	0	3/21 (14.3%)	4	3/66 (4.5%)	4	9/100 (9%)	9	0/17 (0%)	0
Oropharyngeal pain	0/5 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	2/12 (16.7%)	2	2/13 (15.4%)	2	0/21 (0%)	0	5/66 (7.6%)	6	8/100 (8%)	11	0/17 (0%)	0
Pharyngeal disorder	0/5 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/12 (0%)	0	1/13 (7.7%)	1	0/21 (0%)	0	0/66 (0%)	0	0/100 (0%)	0	0/17 (0%)	0
Pleural effusion	0/5 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	1/3 (33.3%)	1	0/3 (0%)	0	1/12 (8.3%)	1	0/13 (0%)	0	1/21 (4.8%)	1	2/66 (3%)	2	10/100 (10%)	14	0/17 (0%)	0
Rales	0/5 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	1/12 (8.3%)	1	0/13 (0%)	0	0/21 (0%)	0	1/66 (1.5%)	1	1/100 (1%)	1	0/17 (0%)	0
Rhinorrhoea	0/5 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	1/3 (33.3%)	1	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/12 (0%)	0	0/13 (0%)	0	0/21 (0%)	0	0/66 (0%)	0	1/100 (1%)	1	0/17 (0%)	0
Sinus pain	0/5 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	1/12 (8.3%)	1	0/13 (0%)	0	0/21 (0%)	0	0/66 (0%)	0	0/100 (0%)	0	0/17 (0%)	0
Tachypnoea	0/5 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	1/3 (33.3%)	2	0/3 (0%)	0	0/12 (0%)	0	0/13 (0%)	0	0/21 (0%)	0	0/66 (0%)	0	1/100 (1%)	1	0/17 (0%)	0
Upper-airway cough syndrome	0/5 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/12 (0%)	0	0/13 (0%)	0	0/21 (0%)	0	4/66 (6.1%)	4	2/100 (2%)	3	0/17 (0%)	0
Wheezing	0/5 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	1/12 (8.3%)	1	0/13 (0%)	0	0/21 (0%)	0	2/66 (3%)	2	5/100 (5%)	6	0/17 (0%)	0
Skin and subcutaneous tissue disorders
Alopecia	0/5 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	1/12 (8.3%)	1	0/13 (0%)	0	0/21 (0%)	0	5/66 (7.6%)	6	0/100 (0%)	0	0/17 (0%)	0
Blood blister	0/5 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	1/3 (33.3%)	1	0/3 (0%)	0	0/3 (0%)	0	0/12 (0%)	0	0/13 (0%)	0	0/21 (0%)	0	1/66 (1.5%)	1	2/100 (2%)	2	1/17 (5.9%)	1
Decubitus ulcer	0/5 (0%)	0	0/3 (0%)	0	1/3 (33.3%)	1	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/12 (0%)	0	0/13 (0%)	0	1/21 (4.8%)	1	1/66 (1.5%)	1	2/100 (2%)	3	0/17 (0%)	0
Dermatitis acneiform	0/5 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/12 (0%)	0	1/13 (7.7%)	1	0/21 (0%)	0	0/66 (0%)	0	0/100 (0%)	0	0/17 (0%)	0
Drug eruption	0/5 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/12 (0%)	0	0/13 (0%)	0	1/21 (4.8%)	1	5/66 (7.6%)	5	4/100 (4%)	4	0/17 (0%)	0
Dry skin	1/5 (20%)	1	1/3 (33.3%)	1	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/12 (0%)	0	0/13 (0%)	0	2/21 (9.5%)	4	3/66 (4.5%)	3	3/100 (3%)	5	0/17 (0%)	0
Ecchymosis	0/5 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	1/3 (33.3%)	1	0/3 (0%)	0	1/12 (8.3%)	1	0/13 (0%)	0	2/21 (9.5%)	3	3/66 (4.5%)	3	8/100 (8%)	8	1/17 (5.9%)	1
Eccrine squamous syringometaplasia	0/5 (0%)	0	1/3 (33.3%)	1	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/12 (0%)	0	0/13 (0%)	0	0/21 (0%)	0	0/66 (0%)	0	0/100 (0%)	0	0/17 (0%)	0
Erythema	0/5 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/12 (0%)	0	0/13 (0%)	0	2/21 (9.5%)	2	3/66 (4.5%)	4	4/100 (4%)	4	1/17 (5.9%)	1
Erythema multiforme	0/5 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	1/12 (8.3%)	1	0/13 (0%)	0	0/21 (0%)	0	0/66 (0%)	0	1/100 (1%)	1	0/17 (0%)	0
Hyperhidrosis	0/5 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/12 (0%)	0	0/13 (0%)	0	3/21 (14.3%)	4	1/66 (1.5%)	1	4/100 (4%)	4	0/17 (0%)	0
Pain of skin	0/5 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	1/3 (33.3%)	1	0/3 (0%)	0	0/12 (0%)	0	0/13 (0%)	0	0/21 (0%)	0	1/66 (1.5%)	1	5/100 (5%)	5	1/17 (5.9%)	1
Petechiae	0/5 (0%)	0	0/3 (0%)	0	1/3 (33.3%)	1	0/3 (0%)	0	1/3 (33.3%)	1	0/3 (0%)	0	0/3 (0%)	0	2/12 (16.7%)	4	0/13 (0%)	0	0/21 (0%)	0	0/66 (0%)	0	14/100 (14%)	14	1/17 (5.9%)	1
Photosensitivity reaction	0/5 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/12 (0%)	0	1/13 (7.7%)	1	0/21 (0%)	0	1/66 (1.5%)	1	1/100 (1%)	1	0/17 (0%)	0
Pigmentation disorder	0/5 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	1/12 (8.3%)	1	0/13 (0%)	0	0/21 (0%)	0	0/66 (0%)	0	1/100 (1%)	1	0/17 (0%)	0
Pruritus	0/5 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	1/3 (33.3%)	1	0/3 (0%)	0	0/3 (0%)	0	1/12 (8.3%)	1	0/13 (0%)	0	2/21 (9.5%)	2	0/66 (0%)	0	7/100 (7%)	12	0/17 (0%)	0
Rash	0/5 (0%)	0	1/3 (33.3%)	1	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	1/3 (33.3%)	1	0/12 (0%)	0	1/13 (7.7%)	1	0/21 (0%)	0	11/66 (16.7%)	11	11/100 (11%)	13	0/17 (0%)	0
Rash maculo-papular	0/5 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	2/12 (16.7%)	2	1/13 (7.7%)	1	1/21 (4.8%)	1	3/66 (4.5%)	3	7/100 (7%)	9	0/17 (0%)	0
Rash papular	0/5 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/12 (0%)	0	1/13 (7.7%)	2	0/21 (0%)	0	0/66 (0%)	0	0/100 (0%)	0	1/17 (5.9%)	1
Skin lesion	0/5 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/12 (0%)	0	0/13 (0%)	0	1/21 (4.8%)	1	1/66 (1.5%)	1	5/100 (5%)	5	2/17 (11.8%)	4
Swelling face	0/5 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	1/3 (33.3%)	1	0/3 (0%)	0	0/3 (0%)	0	0/12 (0%)	0	0/13 (0%)	0	0/21 (0%)	0	2/66 (3%)	2	0/100 (0%)	0	0/17 (0%)	0
Vascular disorders
Flushing	0/5 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	1/12 (8.3%)	1	0/13 (0%)	0	0/21 (0%)	0	0/66 (0%)	0	1/100 (1%)	1	1/17 (5.9%)	1
Haematoma	0/5 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	1/3 (33.3%)	1	0/3 (0%)	0	1/12 (8.3%)	1	0/13 (0%)	0	1/21 (4.8%)	1	2/66 (3%)	2	6/100 (6%)	8	0/17 (0%)	0
Hot flush	1/5 (20%)	1	0/3 (0%)	0	1/3 (33.3%)	1	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/12 (0%)	0	0/13 (0%)	0	0/21 (0%)	0	2/66 (3%)	2	2/100 (2%)	2	0/17 (0%)	0
Hypertension	0/5 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	1/12 (8.3%)	1	1/13 (7.7%)	1	1/21 (4.8%)	1	7/66 (10.6%)	7	16/100 (16%)	34	1/17 (5.9%)	2
Hypotension	0/5 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	1/12 (8.3%)	1	0/13 (0%)	0	3/21 (14.3%)	4	10/66 (15.2%)	11	25/100 (25%)	32	1/17 (5.9%)	1
Orthostatic hypotension	0/5 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/12 (0%)	0	0/13 (0%)	0	1/21 (4.8%)	2	3/66 (4.5%)	3	8/100 (8%)	8	0/17 (0%)	0
Pallor	0/5 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/12 (0%)	0	0/13 (0%)	0	2/21 (9.5%)	2	1/66 (1.5%)	1	0/100 (0%)	0	0/17 (0%)	0

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

Principal Investigators are NOT employed by the organization sponsoring the study.

Institute and/or Principal Investigator may publish trial data generated at their specific study site after Sponsor publication of the multi-center data. Sponsor must receive a site's manuscript prior to publication for review and comment as specified in the Investigator Agreement.

Results Point of Contact

Name/Title	Clinical Trial Disclosure
Organization	Astellas Pharma Global Development, Inc.
Phone	800-888-7704
Email	astellas.resultsdisclosure@astellas.com

Responsible Party:

Astellas Pharma Global Development, Inc.

ClinicalTrials.gov Identifier:

NCT02014558

Other Study ID Numbers:

2215-CL-0101

First Posted:

Dec 18, 2013

Last Update Posted:

May 23, 2019

Last Verified:

May 1, 2019