Study to Investigate Safety, Pharmacokinetic (PK), Pharmacodynamic (PD) and Clinical Activity of Trametinib in Subjects With Cancer or Plexiform Neurofibromas and Trametinib in Combination With Dabrafenib in Subjects With Cancers Harboring V600 Mutations

Sponsor
Novartis Pharmaceuticals (Industry)
Overall Status
Completed
CT.gov ID
NCT02124772
Collaborator
(none)
139
16
13
71.5
8.7
0.1

Study Details

Study Description

Brief Summary

This was a 4-part (Part A, Part B, Part C and Part D), Phase I/IIa, multi-center, open label, study in pediatric subjects with refractory or recurrent tumors.

Part A was a repeat dose, dose escalation and expansion phase that identified the recommended phase II dose (RP2D) of trametinib monotherapy. Part B evaluated the preliminary activity of trametinib monotherapy in 4 disease-specific cohorts of subjects. Part C was aimed to determine the safety, tolerability and preliminary activity of the RP2D of trametinib in combination with a limited dose escalation of dabrafenib. Part D evaluated the preliminary activity of trametinib in combination with dabrafenib in 2 disease-specific cohorts of subjects.

The overall goal of this trial was to efficiently establish safe, pharmacologically relevant dose of trametinib monotherapy and trametinib in combination with dabrafenib in infants, children and adolescents and determine preliminary activity of trametinib monotherapy and trametinib in combination with dabrafenib in selected recurrent, refractory or unresectable childhood tumors.

Condition or Disease Intervention/Treatment Phase
Phase 1/Phase 2

Detailed Description

This was a 4-part (Part A, Part B, Part C and Part D), Phase I/IIa, multi-center, open label, study in pediatric subjects with refractory or recurrent tumors.

Part A was a repeat dose, dose escalation and expansion phase that identified the recommended phase II dose (RP2D) of trametinib monotherapy using a 3 + 3 dose- escalation procedure. The starting dose level of trametinib was 0.0125 mg/kg/day, the second dose level was 0.025 mg/kg/day and the third dose level was 0.040 mg/kg/day. Additionally, in Part A extension an intermediate trametinib dose level of 0.032 mg/kg/day was assessed in subjects under 6 years of age. In all cohorts, the total daily trametinib dose was not to exceed the adult dose (2 mg) in any subject.

Part B evaluated the preliminary activity of trametinib monotherapy in 4 disease-specific cohorts of subjects:

B1: Refractory or relapsed neuroblastoma B2: Recurrent or unresectable low grade glioma (LGG) with BRAF tandem duplication with fusion (glioma fusion) B3: Neurofibromatosis Type -1 associated plexiform neurofibromas (NF-1 with PN) that are unresectable and medically significant B4: BRAF V600 mutant tumors In Part B it was used the RP2D of trametinib (0.025 mg/kg/day) determined in Part A.

Part C was a 3+3 study design to determine the safety, tolerability and preliminary activity of the RP2D of trametinib in combination with a limited dose escalation of dabrafenib. The trametinib dose administered in Part C was based on the trametinib monotherapy RP2D from Part A (0.025 mg/kg/day). For the evaluation of combination therapy in this study, the starting dose of dabrafenib was 50% of the monotherapy RP2D established in a separate study: 2.63 mg/kg/day (<12 years old subjects) and 2.25 mg/kg/day (≥12 years old subjects). The second dose level of dabrafenib was 100% of the monotherapy RP2D: 5.25 mg/kg/day (<12 years old subjects) and 4.5 mg/kg/day (≥12 years old subjects).

Additionally, in Part C extension, the trametinib dose determined from Part A extension (0.032 mg/kg/day) with 100% pediatric RP2D of dabrafenib (5.25 mg/kg/day) was assessed in subjects under 6 years of age.

In all cohorts, the total daily trametinib dose was not to exceed the adult dose (2 mg) in any subject and the total daily dabrafenib dose was not to exceed the adult dose (300 mg) in any subject.

Part D evaluated the preliminary activity of trametinib in combination with dabrafenib in two disease-specific cohorts of subjects diagnosed with low grade glioma (LGG) and Langerhans cell histiocytosis (LCH).

In Part D it was used the RP2D of the combination treatment determined in Part C (0.025 mg/kg/day trametinib and the 100% RP2D of dabrafenib) in subjects 6 years to < 18 years of age. Additionally, once Part C extension had defined the trametinib RP2D for subjects under 6 years of age, this dose was used for the remaining subjects enrolled in Part D (0.032 mg/kg/day trametinib and the 100% RP2D of dabrafenib).

The overall goal of this trial was to efficiently establish safe, pharmacologically relevant dose of trametinib monotherapy and trametinib in combination with dabrafenib in infants, children and adolescents and determine preliminary activity of trametinib monotherapy and trametinib in combination with dabrafenib in selected recurrent, refractory or unresectable childhood tumors.

Study Design

Study Type:
Interventional
Actual Enrollment :
139 participants
Allocation:
Non-Randomized
Intervention Model:
Parallel Assignment
Masking:
None (Open Label)
Primary Purpose:
Treatment
Official Title:
An Open-Label, Dose-Escalation, Phase I/II Study to Investigate the Safety, Pharmacokinetics, Pharmacodynamics and Clinical Activity of the MEK Inhibitor Trametinib in Children and Adolescents Subjects With Cancer or Plexiform Neurofibromas and Trametinib in Combination With Dabrafenib in Children and Adolescents With Cancers Harboring V600 Mutations
Actual Study Start Date :
Jan 15, 2015
Actual Primary Completion Date :
Dec 29, 2020
Actual Study Completion Date :
Dec 29, 2020

Arms and Interventions

Arm Intervention/Treatment
Experimental: Part A - TMT 0.0125 mg/kg/day

Participants treated with trametinib 0.0125 mg/kg/day

Drug: Trametinib
Trametinib was administered orally, once daily. It was available in tablets (0.125 mg, 0.5 mg, 2 mg dose) as well as in powder form for oral solution (0.05 mg/mL dose).

Experimental: Part A - TMT 0.025 mg/kg/day

Participants treated with trametinib 0.025 mg/kg/day

Drug: Trametinib
Trametinib was administered orally, once daily. It was available in tablets (0.125 mg, 0.5 mg, 2 mg dose) as well as in powder form for oral solution (0.05 mg/mL dose).

Experimental: Part A - TMT 0.032 mg/kg/day

Participants under 6 years of age treated with trametinib 0.032 mg/kg/day

Drug: Trametinib
Trametinib was administered orally, once daily. It was available in tablets (0.125 mg, 0.5 mg, 2 mg dose) as well as in powder form for oral solution (0.05 mg/mL dose).

Experimental: Part A - TMT 0.04 mg/kg/day

Participants treated with trametinib 0.04 mg/kg/day

Drug: Trametinib
Trametinib was administered orally, once daily. It was available in tablets (0.125 mg, 0.5 mg, 2 mg dose) as well as in powder form for oral solution (0.05 mg/mL dose).

Experimental: Part B - Neuroblastoma

Participants with refractory or relapsed neuroblastoma treated with trametinib 0.025 mg/kg/day

Drug: Trametinib
Trametinib was administered orally, once daily. It was available in tablets (0.125 mg, 0.5 mg, 2 mg dose) as well as in powder form for oral solution (0.05 mg/mL dose).

Experimental: Part B - LGG fusion

Participants with refractory or relapsed neuroblastoma treated with trametinib 0.025 mg/kg/day

Drug: Trametinib
Trametinib was administered orally, once daily. It was available in tablets (0.125 mg, 0.5 mg, 2 mg dose) as well as in powder form for oral solution (0.05 mg/mL dose).

Experimental: Part B - NF-1 with PN

Participants with neurofibromatosis Type -1 associated plexiform neurofibromas (NF-1 with PN) treated with trametinib 0.025 mg/kg/day

Drug: Trametinib
Trametinib was administered orally, once daily. It was available in tablets (0.125 mg, 0.5 mg, 2 mg dose) as well as in powder form for oral solution (0.05 mg/mL dose).

Experimental: Part B - BRAF V600 mutant solid tumor

Participants with BRAF V600 mutant solid tumors treated with trametinib 0.025 mg/kg/day

Drug: Trametinib
Trametinib was administered orally, once daily. It was available in tablets (0.125 mg, 0.5 mg, 2 mg dose) as well as in powder form for oral solution (0.05 mg/mL dose).

Experimental: Part C - TMT 0.025 mg/kg/day + 50% DRB RP2D

Participants treated with a combination therapy of trametinib (0.025 mg/kg/day) plus 50% of the recommended phase II dose (RP2D) of dabrafenib monotherapy (2.63 mg/kg/day for <12 years old subjects and 2.25 mg/kg/day for ≥12 years old subjects)

Drug: Trametinib
Trametinib was administered orally, once daily. It was available in tablets (0.125 mg, 0.5 mg, 2 mg dose) as well as in powder form for oral solution (0.05 mg/mL dose).

Drug: Dabrafenib
Dabrafenib was administered orally, twice daily. The daily dose was divided into two equal doses. It was available in capsules (50 mg and 75 mg), dispersible tablets (10 mg) and powder for oral suspension (10 mg/mL dose).

Experimental: Part C - TMT 0.025 mg/kg/day + 100% DRB RP2D

Participants treated with a combination therapy of trametinib (0.025 mg/kg/day) plus 100% of the recommended phase II dose (RP2D) of dabrafenib monotherapy (5.25 mg/kg/day for <12 years old subjects and 4.5 mg/kg/day for ≥12 years old subjects)

Drug: Trametinib
Trametinib was administered orally, once daily. It was available in tablets (0.125 mg, 0.5 mg, 2 mg dose) as well as in powder form for oral solution (0.05 mg/mL dose).

Drug: Dabrafenib
Dabrafenib was administered orally, twice daily. The daily dose was divided into two equal doses. It was available in capsules (50 mg and 75 mg), dispersible tablets (10 mg) and powder for oral suspension (10 mg/mL dose).

Experimental: Part C - TMT 0.032 mg/kg/day + 100% DRB RP2D

Participants under 6 years of age treated with a combination therapy of trametinib (0.032 mg/kg/day) with 100% of the recommended phase II dose (RP2D) of dabrafenib monotherapy (5.25 mg/kg/day)

Drug: Trametinib
Trametinib was administered orally, once daily. It was available in tablets (0.125 mg, 0.5 mg, 2 mg dose) as well as in powder form for oral solution (0.05 mg/mL dose).

Drug: Dabrafenib
Dabrafenib was administered orally, twice daily. The daily dose was divided into two equal doses. It was available in capsules (50 mg and 75 mg), dispersible tablets (10 mg) and powder for oral suspension (10 mg/mL dose).

Experimental: Part D - LGG

Participants with low grade glioma (LGG) treated with a combination therapy of trametinib (0.032 mg/kg/day for < 6 years old subjects and 0.025 mg/kg/day for ≥ 6 years old subjects) plus 100% of the recommended phase II dose (RP2D) of dabrafenib monotherapy (5.25 mg/kg/day for <12 years old subjects and 4.5 mg/kg/day for ≥12 years old subjects)

Drug: Trametinib
Trametinib was administered orally, once daily. It was available in tablets (0.125 mg, 0.5 mg, 2 mg dose) as well as in powder form for oral solution (0.05 mg/mL dose).

Drug: Dabrafenib
Dabrafenib was administered orally, twice daily. The daily dose was divided into two equal doses. It was available in capsules (50 mg and 75 mg), dispersible tablets (10 mg) and powder for oral suspension (10 mg/mL dose).

Experimental: Part D - LCH

Participants with Langerhans cell histiocytosis (LCH) treated with a combination therapy of trametinib (0.032 mg/kg/day for < 6 years old subjects and 0.025 mg/kg/day for ≥ 6 years old subjects) plus 100% of the recommended phase II dose (RP2D) of dabrafenib monotherapy (5.25 mg/kg/day for <12 years old subjects and 4.5 mg/kg/day for ≥12 years old subjects)

Drug: Trametinib
Trametinib was administered orally, once daily. It was available in tablets (0.125 mg, 0.5 mg, 2 mg dose) as well as in powder form for oral solution (0.05 mg/mL dose).

Drug: Dabrafenib
Dabrafenib was administered orally, twice daily. The daily dose was divided into two equal doses. It was available in capsules (50 mg and 75 mg), dispersible tablets (10 mg) and powder for oral suspension (10 mg/mL dose).

Outcome Measures

Primary Outcome Measures

  1. Incidence of Treatment Emergent Adverse Events in Subjects Treated With Trametinib Monotherapy [From the day of the first dose of trametinib up to 30 days after the last dose, up to maximum duration of 64 months]

    Incidence of treatment emergent adverse events is defined as number of participants with adverse events (AEs) and serious adverse events (SAEs), including changes from baseline in vital signs and laboratory results qualifying and reported as AEs. The number of participants in each category is reported in the table.

  2. Average Steady State Plasma Concentration (Cavg) of Trametinib When Administered Alone (Monotherapy) [pre dose, 1, 2, 4, 7, 10 and 24 hours post trametinib dose on Cycle 1 Day 15. The duration of 1 cycle was 28 days.]

    Pharmacokinetic (PK) parameters were calculated based on trametinib plasma concentrations by using non-compartmental methods. The average steady state plasma concentration (Cavg) of trametinib was calculated as the ratio of area under the curve (AUC)/tau, where tau = 24 h for trametinib.

Secondary Outcome Measures

  1. Trough Concentration (Ctrough) of Trametinib When Administered Alone and in Combination With Dabrafenib [pre dose on Cycle 1 Day 15. The duration of 1 cycle was 28 days.]

    Pharmacokinetic (PK) parameters were calculated based on trametinib plasma concentrations by using non-compartmental methods. Ctrough is defined as the observed plasma concentration just prior to the beginning of, or at the end, of a dosing interval.

  2. Maximum Observed Plasma Concentration (Cmax) of Trametinib When Administered Alone and in Combination With Dabrafenib [pre dose, 1, 2, 4, 7, 10 and 24 hours post trametinib dose on Cycle 1 Day 15 (part A and B) and pre dose, 0.5, 1, 2, 3, 4, 6 and 8 hours post trametinib dose on Cycle 1 Day 15 (part C and D). The duration of 1 cycle was 28 days.]

    Pharmacokinetic (PK) parameters were calculated based on trametinib plasma concentrations by using non-compartmental methods. Cmax is defined as the maximum (peak) observed plasma concentration following a dose.

  3. Time to Reach Maximum Plasma Concentration (Tmax) of Trametinib When Administered Alone and in Combination With Dabrafenib [pre dose, 1, 2, 4, 7, 10 and 24 hours post trametinib dose on Cycle 1 Day 15 (part A and B) and pre dose, 0.5, 1, 2, 3, 4, 6 and 8 hours post trametinib dose on Cycle 1 Day 15 (part C and D). The duration of 1 cycle was 28 days.]

    Pharmacokinetic (PK) parameters were calculated based on trametinib plasma concentrations by using non-compartmental methods. Tmax is defined as the time to reach maximum (peak) plasma concentration following a dose.

  4. Area Under the Plasma Concentration-time Curve From Time Zero to the Time of Last Quantifiable Concentration (AUClast) of Trametinib When Administered Alone and in Combination With Dabrafenib [pre dose, 1, 2, 4, 7, 10 and 24 hours post trametinib dose on Cycle 1 Day 15 (part A and B) and pre dose, 0.5, 1, 2, 3, 4, 6 and 8 hours post trametinib dose on Cycle 1 Day 15 (part C and D). The duration of 1 cycle was 28 days.]

    Pharmacokinetic (PK) parameters were calculated based on trametinib plasma concentrations by using non-compartmental methods. The linear trapezoidal method was used for area under the curve calculation.

  5. Area Under the Plasma Concentration-time Curve From Time Zero to the End of the Dosing Interval Tau at Steady-state (AUCtau) of Trametinib When Administered Alone and in Combination With Dabrafenib [pre dose, 1, 2, 4, 7, 10 and 24 hours post trametinib dose on Cycle 1 Day 15 (part A and B) and pre dose, 0.5, 1, 2, 3, 4, 6 and 8 hours post trametinib dose on Cycle 1 Day 15 (part C and D). The duration of 1 cycle was 28 days.]

    Pharmacokinetic (PK) parameters were calculated based on trametinib plasma concentrations by using non-compartmental methods. The linear trapezoidal method was used for area under the curve calculation. The duration of the dosing interval (tau) was 24 hours for trametinib.

  6. Apparent Plasma Clearance (CL/F) of Trametinib When Administered Alone and in Combination With Dabrafenib [pre dose, 1, 2, 4, 7, 10 and 24 hours post trametinib dose on Cycle 1 Day 15 (part A and B) and pre dose, 0.5, 1, 2, 3, 4, 6 and 8 hours post trametinib dose on Cycle 1 Day 15 (part C and D). The duration of 1 cycle was 28 days.]

    Pharmacokinetic (PK) parameters were calculated based on trametinib plasma concentrations by using non-compartmental methods. Apparent plasma clearance (CL/F) values were calculated as Dose/AUCtau.

  7. Average Steady State Plasma Concentration (Cavg) of Trametinib When Administered in Combination With Dabrafenib [pre dose, 0.5, 1, 2, 3, 4, 6 and 8 hours post trametinib dose on Cycle 1 Day 15. The duration of 1 cycle was 28 days.]

    Pharmacokinetic (PK) parameters were calculated based on trametinib plasma concentrations by using non-compartmental methods. The average steady state plasma concentration (Cavg) of trametinib was calculated as the ratio of area under the curve (AUC)/tau, where tau = 24 h for trametinib.

  8. Incidence of Treatment Emergent Adverse Events in Subjects Treated With Trametinib in Combination With Dabrafenib [From the day of the first dose of the combination up to 30 days after the last dose, up to maximum duration of 53 months]

    Incidence of treatment emergent adverse events is defined as number of participants with adverse events (AEs) and serious adverse events (SAEs), including changes from baseline in vital signs and laboratory results qualifying and reported as AEs. The number of participants in each category is reported in the table.

  9. Best Overall Response (BOR) Based on RECIST v1.1, RANO and Dombi Criteria and as Per Investigator Assessment [From the day of the first dose of any study drug up to the last dose, up to maximum duration of 63 months]

    Response evaluations were assessed using Response Evaluation Criteria in Solid Tumors v1.1 (RECIST v1.1) for subjects with solid tumors except neuroblastomas, primary central nervous system tumors (gliomas) or plexiform neurofibromas (PNs). Response evaluations for subjects with neuroblastomas could have included: measureable disease (by CT/MRI alone) assessed according to RECIST v1.1, evaluable disease assessed for meta-iodobenzylguanidine (MIBG) response, and biochemical (urine HVA/VMA) with bone marrow involvement assessed by Hematoxylin and Eosin staining of bilateral bone marrow biopsies and aspirates. Response evaluations for glioma subjects was assessed using Response Assessment in Neuro Oncology (RANO) criteria with solid tumors through MRI scans. Response evaluations of PNs were assessed using volumetric determination and Dombi criteria through MRI scans. The number of participants in each response category is reported in the table.

  10. Objective Response Rate (ORR) Based on RECIST v1.1, RANO and Dombi Criteria and as Per Investigator Assessment [From the day of the first dose of any study drug up to the last dose, up to maximum duration of 63 months]

    Objective response rate (ORR) was defined as the percentage of subjects with best overall response rate (BOR) with confirmation of complete response (CR) or partial response (PR) according to criteria for a specific disease type, among subjects with disease assessment at baseline. BOR for each subject was determined from the sequence of overall responses according to the rules for RECIST v1.1, RANO and Dombi criteria. ORR was calculated based on the investigator assessment of tumor response data and was based on confirmed responses.

  11. Clinical Benefit Rate (CBR) Based on RECIST v1.1, RANO and Dombi Criteria and as Per Investigator Assessment [From the day of the first dose of any study drug up to the last dose, up to maximum duration of 63 months]

    Clinical Benefit Rate (CBR) was defined as the percentage of subjects with best overall response rate (BOR) with confirmation of complete response (CR), partial response (PR) or stable disease (SD) according to criteria for a specific disease type, among subjects with disease assessment at baseline. BOR for each subject was determined from the sequence of overall responses according to the rules for RECIST v1.1, RANO and Dombi criteria. ORR was calculated based on the investigator assessment of tumor response data and was based on confirmed responses.

  12. Apparent Clearance (CL/F) of Trametinib Estimated With a PopPK Model [pre dose, 1, 2, 4, 7, 10 and 24 hours post trametinib dose on Cycle 1 Day 15 (part A and B) and pre dose, 0.5, 1, 2, 3, 4, 6 and 8 hours post trametinib dose on Cycle 1 Day 15 (part C and D). The duration of 1 cycle was 28 days.]

    The population pharmacokinetic (PopPK) model of trametinib can be described using a two-compartment model with dual sequential 1st order absorption (Ka1, Ka2) and 1st order elimination. Apparent clearance (CL/F) of trametinib estimated with the PopPK model is summarized in this record.

  13. Apparent Central Volume (Vc/F) of Trametinib Estimated With a PopPK Model [pre dose, 1, 2, 4, 7, 10 and 24 hours post trametinib dose on Cycle 1 Day 15 (part A and B) and pre dose, 0.5, 1, 2, 3, 4, 6 and 8 hours post trametinib dose on Cycle 1 Day 15 (part C and D). The duration of 1 cycle was 28 days.]

    The population pharmacokinetic (PopPK) model of trametinib can be described using a two-compartment model with dual sequential 1st order absorption (Ka1, Ka2) and 1st order elimination. Apparent central volume (Vc/F) of trametinib estimated with the PopPK model is summarized in this record.

  14. Absorption Rate Constants (Ka1 and Ka2) of Trametinib Estimated With a PopPK Model [pre dose, 1, 2, 4, 7, 10 and 24 hours post trametinib dose on Cycle 1 Day 15 (part A and B) and pre dose, 0.5, 1, 2, 3, 4, 6 and 8 hours post trametinib dose on Cycle 1 Day 15 (part C and D). The duration of 1 cycle was 28 days.]

    The population pharmacokinetic (PopPK) model of trametinib can be described using a two-compartment model with dual sequential 1st order absorption (Ka1, Ka2) and 1st order elimination. The absorption rate constants (Ka1 and Ka2) estimated with the PopPK model are summarized in this record.

  15. Significant Covariates Estimated With a PopPK Model [pre dose, 1, 2, 4, 7, 10 and 24 hours post trametinib dose on Cycle 1 Day 15 (part A and B) and pre dose, 0.5, 1, 2, 3, 4, 6 and 8 hours post trametinib dose on Cycle 1 Day 15 (part C and D). The duration of 1 cycle was 28 days.]

    The population pharmacokinetic (PopPK) model of trametinib can be described using a two-compartment model with dual sequential 1st order absorption (Ka1, Ka2) and 1st order elimination. Sex and weight are significant covariates on apparent clearance (CL/F), and weight is also a significant covariate on apparent intercompartmental clearance (Q/F). Use of dabrafenib, yes or no, is a covariate on the relative bioavailability of trametinib, reflecting the effect of dabrafenib on the PK of trametinib. The estimates of these covariates (effect of weight on CL/F, effect of sex on CL/F, effect of weight on Q/F, effect of combination with dabrafenib on relative bioavailability F1) calculated with the PopPK model are summarized in this record.

  16. Trough Concentration (Ctrough) of Dabrafenib When Administered in Combination With Trametinib [pre dose on Cycle 1 Day 15. The duration of 1 cycle was 28 days.]

    Pharmacokinetic (PK) parameters were calculated based on dabrafenib plasma concentrations by using non-compartmental methods. Ctrough is defined as the observed plasma concentration just prior to the beginning of, or at the end, of a dosing interval.

  17. Maximum Observed Plasma Concentration (Cmax) of Dabrafenib When Administered in Combination With Trametinib [pre dose, 0.5, 1, 2, 3, 4, 6 and 8 hours post dabrafenib dose on Cycle 1 Day 15. The duration of 1 cycle was 28 days.]

    Pharmacokinetic (PK) parameters were calculated based on dabrafenib plasma concentrations by using non-compartmental methods. Cmax is defined as the maximum (peak) observed plasma concentration following a dose.

  18. Time to Reach Maximum Plasma Concentration (Tmax) of Dabrafenib When Administered in Combination With Trametinib [pre dose, 0.5, 1, 2, 3, 4, 6 and 8 hours post dabrafenib dose on Cycle 1 Day 15. The duration of 1 cycle was 28 days.]

    Pharmacokinetic (PK) parameters were calculated based on dabrafenib plasma concentrations by using non-compartmental methods. Tmax is defined as the time to reach maximum (peak) plasma concentration following a dose.

  19. Area Under the Plasma Concentration-time Curve From Time Zero to the Time of Last Quantifiable Concentration (AUClast) of Dabrafenib When Administered in Combination With Trametinib [pre dose, 0.5, 1, 2, 3, 4, 6 and 8 hours post dabrafenib dose on Cycle 1 Day 15. The duration of 1 cycle was 28 days.]

    Pharmacokinetic (PK) parameters were calculated based on dabrafenib plasma concentrations by using non-compartmental methods. The linear trapezoidal method was used for area under the curve calculation.

  20. Area Under the Plasma Concentration-time Curve From Time Zero to the End of the Dosing Interval Tau at Steady-state (AUCtau) of Dabrafenib When Administered in Combination With Trametinib [pre dose, 0.5, 1, 2, 3, 4, 6 and 8 hours post dabrafenib dose on Cycle 1 Day 15. The duration of 1 cycle was 28 days.]

    Pharmacokinetic (PK) parameters were calculated based on dabrafenib plasma concentrations by using non-compartmental methods. The linear trapezoidal method was used for area under the curve calculation. The duration of the dosing interval (tau) was 12 hours for dabrafenib.

  21. Apparent Plasma Clearance (CL/F) of Dabrafenib When Administered in Combination With Trametinib [pre dose, 0.5, 1, 2, 3, 4, 6 and 8 hours post dabrafenib dose on Cycle 1 Day 15. The duration of 1 cycle was 28 days.]

    Pharmacokinetic (PK) parameters were calculated based on dabrafenib plasma concentrations by using non-compartmental methods. Apparent plasma clearance (CL/F) values were calculated as Dose/AUCtau.

  22. Average Steady State Plasma Concentration (Cavg) of Dabrafenib When Administered in Combination With Trametinib [pre dose, 0.5, 1, 2, 3, 4, 6 and 8 hours post dabrafenib dose on Cycle 1 Day 15. The duration of 1 cycle was 28 days.]

    Pharmacokinetic (PK) parameters were calculated based on dabrafenib plasma concentrations by using non-compartmental methods. The average steady state plasma concentration (Cavg) of dabrafenib was calculated as the ratio of area under the curve (AUC)/tau, where tau = 12 h for dabrafenib.

  23. Palatability of Trametinib Oral Solution in Pediatric Subjects Assessed by Palatability Questionnaire [After the first dose of trametinib oral solution and no later than Day 8 (±3 days)]

    For subjects ≥ 12 years of age who received the trametinib oral solution, the subject completed a form to evaluate the various properties of the solution (e.g., bitterness, sweetness, appearance, texture and overall taste). For subjects < 12 years of age who received the solution, their caregiver (e.g. parent or guardian) evaluated the solution with the child based on verbal and non-verbal feedback. The questionnaire was completed after the first dose of study drug and no later than Day 8 (±3 days). Subjects completed a form for each drug separately if enrolled in Parts C and D.

  24. Palatability of Dabrafenib Oral Suspension in Pediatric Subjects Assessed by Palatability Questionnaire [After the first dose of dabrafenib oral suspension and no later than Day 8 (±3 days)]

    For subjects ≥ 12 years of age who received the dabrafenib suspension, the subject completed a form to evaluate the various properties of the suspension (e.g., bitterness, sweetness, appearance, texture and overall taste). For subjects < 12 years of age who received the suspension, their caregiver (e.g. parent or guardian) evaluated the suspension with the child based on verbal and non-verbal feedback. The questionnaire was completed after the first dose of study drug and no later than Day 8 (±3 days). Subjects completed a form for each drug separately if enrolled in Parts C and D.

Eligibility Criteria

Criteria

Ages Eligible for Study:
1 Month to 17 Years
Sexes Eligible for Study:
All
Accepts Healthy Volunteers:
No
Inclusion Criteria:
  • General Eligibility Criteria (All Parts)

  • Written informed consent - a signed informed consent and/or assent (as age appropriate) for study participation including PK sampling will be obtained according to institutional guidelines.

  • Male or female between one month and <18 years of age (inclusive) at the time of signing the informed consent form (Part C and Part D between 12 months and <18 years of age, inclusive).

  • Must have a disease that is relapsed/refractory to all potentially curative standard treatment regimens or must have a current disease for which there is no known curative therapy, or therapy proven to prolong survival with an acceptable quality of life.

  • Prior therapy: The subject's disease (i.e. cancer, neurofibromatosis type 1 [NF-1] with plexiform neurofibroma [PN], or Langerhans cell histocytosis [LCH]) must have relapsed after or failed to respond to frontline curative therapy or there must not be other potentially curative treatment options available. Curative therapy may include surgery, radiation therapy, chemotherapy, or any combination of these modalities. All subjects must have recovered to grade <=1 from the acute toxic effects of all prior chemotherapy, immunotherapy, or radiotherapy prior to enrollment. Prior therapy includes; myelosuppressive chemotherapy, differentiating agents/ biologic response modifiers (small molecules, antibodies, viral therapies) (anti-cancer agent), non-myelosuppressive anticancer agents, investigational agent, radiation therapy, stem cell transplantation or infusion, number of prior treatment regimens, colony stimulating factors, corticosteroids.

  • Performance score of >=50% according to the Karnofsky/Lansky performance status scale.

  • Females of child-bearing potential must be willing to practice acceptable methods of birth control. Additionally, females of childbearing potential must have a negative serum pregnancy test within 7 days prior to start of study drugs, throughout treatment period and for 4 months after last dose of study drugs.

  • Must have adequate organ function as defined by the following values: renal function - 24 hr creatinine clearance (revised Schwartz formula), or radioisotope glomerular filtration rate (GFR) >=60 milliliter (mL) per minute per 1.73 meter square (mL/min/1.73m^2); or a serum creatinine <=upper limit of normal (ULN) for age and gender; liver functions as bilirubin (sum of conjugated + unconjugated) <=1.5 x ULN for age, alanine aminotransferase (ALT) <=2.5 x ULN; for the purposes of enrollment and toxicity monitoring the ULN for ALT will be 45 unit per liter (U/L); cardiac function - corrected QT (QTcB) interval <480 milliseconds (msec), left ventricular ejection fraction (LVEF) >=lower limit of normal (LLN) by ECHO.

  • Able to swallow and retain enterally (per oral [PO] or nasogastric or gastric tube) administered medication and does not have any clinically significant gastrointestinal abnormalities that may alter absorption such as malabsorption syndrome or major resection of the stomach or bowels.

  • Adequate Blood Pressure Control defined as: Blood pressure <= the 95th percentile for age, height, and gender.

  • French subjects: In France, a subject will be eligible for inclusion in this study only if either affiliated to or a beneficiary of a social security category.

  • Specific Eligibility Criteria, Part A

  • Subjects must meet general eligibility criteria.

  • For the initial dose escalation to identify the maximum tolerable or PK target dose, age between 2 years and <18 years (inclusive) at the time of signing the informed consent form. Children < 2 years of age will be enrolled once the age specific expansion cohorts are open.

  • Histologically confirmed solid tumors, which may include but are not limited to rhabdomyosarcoma and other soft tissue sarcomas, Ewing sarcoma family of tumors, osteosarcoma, neuroblastoma, Wilms' tumor, hepatic tumors, germ cell tumors, primary brain tumors, NF-1 associated PF and LCH. In subjects with brain stem gliomas the requirement for histological confirmation can be waived if a biopsy was not performed. For plexiform neurofibromas, histologic confirmation of tumor is not necessary in the presence of consistent clinical and radiological findings, but should be considered if malignant degeneration of a PN is clinically suspected.

  • Measurable or evaluable tumors. Subjects with neuroblastoma that is only detectable by Meta-iodobenzylguanidine (MIBG) scan are eligible. Subjects with neuroblastoma that is only detected by bone marrow aspirate/biopsy or elevated homovanillic acid / vanillylmandelic acid (HVA/VMA) are not eligible.

  • Adequate bone marrow function defined as absolute neutrophil count (ANC)

=1000/microliter, hemoglobin >=8.0 gram per deciliter (g/dL) (may receive red blood cell transfusions), platelets >=75,000/ microliter (transfusion independent, defined as not receiving platelet transfusions within a 7 day period prior to enrollment).

  • Specific Eligibility Criteria, Part B

  • Subjects must meet general eligibility criteria. The specific eligibility criteria listed here will apply to subjects enrolling to different cohorts of Part B.

  • Tumor tissue (archived or fresh) is required and must be available to be shipped to GSK or site specific laboratory.

  • Solid tumor cohort (B1) specific criteria

  • B1: Refractory or relapsed neuroblastoma

  • B2: Recurrent or unresectable low grade gliomas with BRAF tandem duplication with fusion

  • B3: Neurofibromatosis Type -1 associated plexiform neurofibromas (NF-1 with PN) that are unresectable and medically significant.

  • B4: BRAF V600 mutant tumors.

  • Specific Eligibility Criteria, Part C - Subjects must meet general eligibility criteria.

  • Tumors that have been documented by CLIA or equivalent certified laboratory test to harbor BRAF V600 mutation at diagnosis or relapse

  • Measurable or evaluable disease

  • Adequate bone marrow function

  • Specific Eligibility Criteria, Part D - Subjects must meet general eligibility criteria

  • Measurable or evaluable disease

  • Recurrent or refractory BRAFV600 mutant LGG or LCH tumors

  • Adequate bone marrow function

Exclusion Criteria:
  • Lactating or pregnant female.

  • History of another malignancy including resected non-melanomatous skin cancer.

  • Subjects with NF-1 associated optic pathway tumors are excluded if they are actively receiving therapy for the optic pathway tumor or do not meet criteria for PN or malignant solid tumor.

  • Subjects with a history of NF-1 related cerebral vascular anomaly (such as Moyamoya).

  • Subjects with NF-1 actively receiving therapy for the optic pathway tumor.

  • Subjects with NF-1 and only PN lesions that cannot be evaluated by volumetric analysis (only applicable to Part B).

  • Any serious and/or unstable pre-existing medical, psychiatric disorder or other conditions that could interfere with subject's safety, obtaining informed consent or compliance to the study procedures.

  • Any prohibited medication(s), currently used or expected to be required.

  • Any medications for treatment of left ventricular systolic dysfunction.

  • Part B, Part C and Part D only: Previous treatment with dabrafenib or any BRAF inhibitor, trametinib or another MEK inhibitor, or and Extracellular signal-regulated kinase inhibitor (exception: prior treatment with sorafenib is permitted). Patients who have received prior dabrafenib or another BRAF inhibitor may enrol into Part B4. Patients who have had prior dabrafenib or BRAF inhibitor therapy may enroll in Part C or Part D if they have had prior benefit to dabrafenib or BRAF inhibitor monotherapy, as determined by the investigator.

  • Administration of an investigational study treatment within 30 days preceding the first dose of study treatment(s) in this study.

  • Have a known immediate or delayed hypersensitivity reaction or idiosyncrasy to drugs chemically related to study treatment or excipients that contraindicate their participation.

  • Current active liver or biliary disease (with the exception of Gilbert's syndrome or asymptomatic gallstones, or liver metastases).

  • History of hepatic sinusoid obstructive syndrome (venoocculsive disease) within the prior 3 months.

  • History of heparin-induced thrombocytopenia.

  • History of interstitial lung disease or pneumonitis.

  • History of or current evidence of retinal vein occlusion (RVO).

  • For subjects with solid tumors that are not primary central nervous system (CNS) tumors or NF-1 associated plexiform neurofibromas subjects with symptomatic or untreated leptomeningeal or brain metastases or spinal cord compression are excluded. NOTE: Subjects previously treated for these conditions that have had stable CNS disease (verified with consecutive imaging studies) for >3 months, are asymptomatic and are not currently taking corticosteroids, or are on stable dose or decreasing of corticosteroids for at least 7 days prior to enrolment are permitted.

  • A history of known Hepatitis B Virus (HBV), or Hepatitis C Virus (HCV) infection. Subjects with laboratory evidence of cleared HBV and HCV infection may be enrolled.

  • Unresolved toxicity of National Cancer Institute Common Terminology Criteria for Adverse Events, version 4.0 (NCI CTCAE v4.0) Grade 2 or higher from previous anti-cancer therapy, except alopecia.

  • Presence of active gastrointestinal (GI) disease or other condition that will interfere significantly with the absorption of drugs.

  • A history or evidence of cardiovascular risk including: a QT interval corrected for heart rate using the Bazett's formula (QTcB) >=480 msec; a history or evidence of current clinically significant uncontrolled arrhythmias (clarification: Subjects with atrial fibrillation controlled for >30 days prior to dosing are eligible); a history of acute coronary syndromes (including myocardial infarction or unstable angina), coronary angioplasty, or stenting within 6 months prior to randomization; a history or evidence of current >=Class II congestive heart failure as defined by the New York Heart Association (NYHA) guidelines; subjects with intra-cardiac defibrillators; abnormal cardiac valve morphology (>=grade 2) documented by echocardiogram (subjects with grade 1 abnormalities [i.e., mild regurgitation/stenosis] can be entered on study). Subjects with moderate valvular thickening should not be entered on study. Subjects with prosthetic valves can be considered eligible provided they meet the criteria as stated above; Treatment refractory hypertension defined as a blood pressure of systolic >140 millimeter of mercury (mmHg) and/or diastolic >90 mmHg (or above 95th age-specific percentile listed in protocol), which cannot be controlled by anti-hypertensive therapy.

Contacts and Locations

Locations

Site City State Country Postal Code
1 Novartis Investigative Site Phoenix Arizona United States 85016-7710
2 Novartis Investigative Site San Francisco California United States
3 Novartis Investigative Site Washington District of Columbia United States 20010
4 Novartis Investigative Site Baltimore Maryland United States 21287
5 Novartis Investigative Site Boston Massachusetts United States 02115
6 Novartis Investigative Site Minneapolis Minnesota United States 55455
7 Novartis Investigative Site New York New York United States 10065
8 Novartis Investigative Site Cincinnati Ohio United States 45229
9 Novartis Investigative Site Philadelphia Pennsylvania United States 19104
10 Novartis Investigative Site Memphis Tennessee United States 38105-3678
11 Novartis Investigative Site Westmead New South Wales Australia 2145
12 Novartis Investigative Site Toronto Ontario Canada M5G 1X8
13 Novartis Investigative Site Paris Cedex 05 France 75248
14 Novartis Investigative Site Villejuif Cedex France 94805
15 Novartis Investigative Site Sutton Surrey United Kingdom SM2 5PT
16 Novartis Investigative Site London United Kingdom WC1N 3JH

Sponsors and Collaborators

  • Novartis Pharmaceuticals

Investigators

  • Study Director: Novartis Pharmaceuticals, Novartis Pharmaceuticals

Study Documents (Full-Text)

More Information

Publications

None provided.
Responsible Party:
Novartis Pharmaceuticals
ClinicalTrials.gov Identifier:
NCT02124772
Other Study ID Numbers:
  • 116540
  • 2013-003596-35
  • CTMT212X2101
First Posted:
Apr 28, 2014
Last Update Posted:
Jul 14, 2021
Last Verified:
Jun 1, 2021
Individual Participant Data (IPD) Sharing Statement:
Yes
Plan to Share IPD:
Yes
Studies a U.S. FDA-regulated Drug Product:
Yes
Studies a U.S. FDA-regulated Device Product:
No
Keywords provided by Novartis Pharmaceuticals
Additional relevant MeSH terms:

Study Results

Participant Flow

Recruitment Details Participants took part in 16 investigative sites in 5 countries.
Pre-assignment Detail The participants were screened within 14 days prior to enrollment. After screening, the treatment period started on Cycle 1 Day 1.
Arm/Group Title Part A - TMT 0.0125 mg/kg/Day Part A - TMT 0.025 mg/kg/Day Part A - TMT 0.032 mg/kg/Day Part A - TMT 0.04 mg/kg/Day Part B - Neuroblastoma Part B - LGG Fusion Part B - NF-1 With PN Part B - BRAF V600 Mutant Solid Tumor Part C - TMT 0.025 mg/kg/Day + 50% DRB RP2D Part C - TMT 0.025 mg/kg/Day + 100% DRB RP2D Part C - TMT 0.032 mg/kg/Day + 100% DRB RP2D Part D - LGG Part D - LCH
Arm/Group Description Participants treated with trametinib 0.0125 mg/kg/day Participants treated with trametinib 0.025 mg/kg/day Participants under 6 years of age treated with trametinib 0.032 mg/kg/day Participants treated with trametinib 0.04 mg/kg/day Participants with refractory or relapsed neuroblastoma treated with trametinib 0.025 mg/kg/day Participants with refractory or relapsed neuroblastoma treated with trametinib 0.025 mg/kg/day Participants with neurofibromatosis Type -1 associated plexiform neurofibromas (NF-1 with PN) treated with trametinib 0.025 mg/kg/day Participants with BRAF V600 mutant solid tumors treated with trametinib 0.025 mg/kg/day Participants treated with a combination therapy of trametinib (0.025 mg/kg/day) plus 50% of the recommended phase II dose (RP2D) of dabrafenib monotherapy (2.63 mg/kg/day for <12 years old subjects and 2.25 mg/kg/day for ≥12 years old subjects) Participants treated with a combination therapy of trametinib (0.025 mg/kg/day) plus 100% of the recommended phase II dose (RP2D) of dabrafenib monotherapy (5.25 mg/kg/day for <12 years old subjects and 4.5 mg/kg/day for ≥12 years old subjects) Participants under 6 years of age treated with a combination therapy of trametinib (0.032 mg/kg/day) with 100% of the recommended phase II dose (RP2D) of dabrafenib monotherapy (5.25 mg/kg/day) Participants with low grade glioma (LGG) treated with a combination therapy of trametinib (0.032 mg/kg/day for < 6 years old subjects and 0.025 mg/kg/day for ≥ 6 years old subjects) plus 100% of the recommended phase II dose (RP2D) of dabrafenib monotherapy (5.25 mg/kg/day for <12 years old subjects and 4.5 mg/kg/day for ≥12 years old subjects) Participants with Langerhans cell histiocytosis (LCH) treated with a combination therapy of trametinib (0.032 mg/kg/day for < 6 years old subjects and 0.025 mg/kg/day for ≥ 6 years old subjects) plus 100% of the recommended phase II dose (RP2D) of dabrafenib monotherapy (5.25 mg/kg/day for <12 years old subjects and 4.5 mg/kg/day for ≥12 years old subjects)
Period Title: Overall Study
STARTED 3 19 12 16 11 10 10 10 3 9 6 20 10
COMPLETED 0 5 6 3 2 2 2 1 2 2 4 14 8
NOT COMPLETED 3 14 6 13 9 8 8 9 1 7 2 6 2

Baseline Characteristics

Arm/Group Title Part A - TMT 0.0125 mg/kg/Day Part A - TMT 0.025 mg/kg/Day Part A - TMT 0.032 mg/kg/Day Part A - TMT 0.04 mg/kg/Day Part B - Neuroblastoma Part B - LGG Fusion Part B - NF-1 With PN Part B - BRAF V600 Mutant Solid Tumor Part C - TMT 0.025 mg/kg/Day + 50% DRB RP2D Part C - TMT 0.025 mg/kg/Day + 100% DRB RP2D Part C - TMT 0.032 mg/kg/Day + 100% DRB RP2D Part D - LGG Part D - LCH Total
Arm/Group Description Participants treated with trametinib 0.0125 mg/kg/day Participants treated with trametinib 0.025 mg/kg/day Participants under 6 years of age treated with trametinib 0.032 mg/kg/day Participants treated with trametinib 0.04 mg/kg/day Participants with refractory or relapsed neuroblastoma treated with trametinib 0.025 mg/kg/day Participants with refractory or relapsed neuroblastoma treated with trametinib 0.025 mg/kg/day Participants with neurofibromatosis Type -1 associated plexiform neurofibromas (NF-1 with PN) treated with trametinib 0.025 mg/kg/day Participants with BRAF V600 mutant solid tumors treated with trametinib 0.025 mg/kg/day Participants treated with a combination therapy of trametinib (0.025 mg/kg/day) plus 50% of the recommended phase II dose (RP2D) of dabrafenib monotherapy (2.63 mg/kg/day for <12 years old subjects and 2.25 mg/kg/day for ≥12 years old subjects) Participants treated with a combination therapy of trametinib (0.025 mg/kg/day) plus 100% of the recommended phase II dose (RP2D) of dabrafenib monotherapy (5.25 mg/kg/day for <12 years old subjects and 4.5 mg/kg/day for ≥12 years old subjects) Participants under 6 years of age treated with a combination therapy of trametinib (0.032 mg/kg/day) with 100% of the recommended phase II dose (RP2D) of dabrafenib monotherapy (5.25 mg/kg/day) Participants with low grade glioma (LGG) treated with a combination therapy of trametinib (0.032 mg/kg/day for < 6 years old subjects and 0.025 mg/kg/day for ≥ 6 years old subjects) plus 100% of the recommended phase II dose (RP2D) of dabrafenib monotherapy (5.25 mg/kg/day for <12 years old subjects and 4.5 mg/kg/day for ≥12 years old subjects) Participants with Langerhans cell histiocytosis (LCH) treated with a combination therapy of trametinib (0.032 mg/kg/day for < 6 years old subjects and 0.025 mg/kg/day for ≥ 6 years old subjects) plus 100% of the recommended phase II dose (RP2D) of dabrafenib monotherapy (5.25 mg/kg/day for <12 years old subjects and 4.5 mg/kg/day for ≥12 years old subjects) Total of all reporting groups
Overall Participants 3 19 12 16 11 10 10 10 3 9 6 20 10 139
Age, Customized (Count of Participants)
< 2 years
0
0%
4
21.1%
1
8.3%
2
12.5%
1
9.1%
0
0%
1
10%
0
0%
0
0%
0
0%
1
16.7%
0
0%
0
0%
10
7.2%
2 - <6 years
1
33.3%
5
26.3%
11
91.7%
0
0%
3
27.3%
4
40%
4
40%
5
50%
0
0%
2
22.2%
5
83.3%
2
10%
6
60%
48
34.5%
6 - <12 years
1
33.3%
4
21.1%
0
0%
9
56.3%
5
45.5%
5
50%
3
30%
1
10%
1
33.3%
2
22.2%
0
0%
9
45%
3
30%
43
30.9%
≥ 12 years
1
33.3%
6
31.6%
0
0%
5
31.3%
2
18.2%
1
10%
2
20%
4
40%
2
66.7%
5
55.6%
0
0%
9
45%
1
10%
38
27.3%
Sex: Female, Male (Count of Participants)
Female
1
33.3%
7
36.8%
6
50%
7
43.8%
6
54.5%
5
50%
5
50%
5
50%
0
0%
6
66.7%
4
66.7%
10
50%
2
20%
64
46%
Male
2
66.7%
12
63.2%
6
50%
9
56.3%
5
45.5%
5
50%
5
50%
5
50%
3
100%
3
33.3%
2
33.3%
10
50%
8
80%
75
54%
Race (NIH/OMB) (Count of Participants)
American Indian or Alaska Native
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
10%
1
0.7%
Asian
0
0%
1
5.3%
0
0%
1
6.3%
0
0%
0
0%
0
0%
2
20%
1
33.3%
2
22.2%
0
0%
0
0%
1
10%
8
5.8%
Native Hawaiian or Other Pacific Islander
0
0%
0
0%
0
0%
0
0%
0
0%
0
0%
0
0%
0
0%
0
0%
0
0%
0
0%
0
0%
0
0%
0
0%
Black or African American
0
0%
2
10.5%
0
0%
1
6.3%
2
18.2%
2
20%
1
10%
0
0%
0
0%
1
11.1%
0
0%
0
0%
0
0%
9
6.5%
White
3
100%
16
84.2%
7
58.3%
14
87.5%
9
81.8%
6
60%
7
70%
5
50%
2
66.7%
6
66.7%
4
66.7%
16
80%
3
30%
98
70.5%
More than one race
0
0%
0
0%
0
0%
0
0%
0
0%
0
0%
1
10%
0
0%
0
0%
0
0%
0
0%
0
0%
1
10%
2
1.4%
Unknown or Not Reported
0
0%
0
0%
5
41.7%
0
0%
0
0%
2
20%
1
10%
3
30%
0
0%
0
0%
2
33.3%
4
20%
4
40%
21
15.1%

Outcome Measures

1. Primary Outcome
Title Incidence of Treatment Emergent Adverse Events in Subjects Treated With Trametinib Monotherapy
Description Incidence of treatment emergent adverse events is defined as number of participants with adverse events (AEs) and serious adverse events (SAEs), including changes from baseline in vital signs and laboratory results qualifying and reported as AEs. The number of participants in each category is reported in the table.
Time Frame From the day of the first dose of trametinib up to 30 days after the last dose, up to maximum duration of 64 months

Outcome Measure Data

Analysis Population Description
All subjects who received at least one dose of trametinib in Part A and B
Arm/Group Title Part A - TMT 0.0125 mg/kg/Day Part A - TMT 0.025 mg/kg/Day Part A - TMT 0.032 mg/kg/Day Part A - TMT 0.04 mg/kg/Day Part B - Neuroblastoma Part B - LGG Fusion Part B - NF-1 With PN Part B - BRAF V600 Mutant Solid Tumor
Arm/Group Description Participants treated with trametinib 0.0125 mg/kg/day Participants treated with trametinib 0.025 mg/kg/day Participants under 6 years of age treated with trametinib 0.032 mg/kg/day Participants treated with trametinib 0.04 mg/kg/day Participants with refractory or relapsed neuroblastoma treated with trametinib 0.025 mg/kg/day Participants with refractory or relapsed neuroblastoma treated with trametinib 0.025 mg/kg/day Participants with neurofibromatosis Type -1 associated plexiform neurofibromas (NF-1 with PN) treated with trametinib 0.025 mg/kg/day Participants with BRAF V600 mutant solid tumors treated with trametinib 0.025 mg/kg/day
Measure Participants 3 19 12 16 11 10 10 10
AEs
3
100%
19
100%
12
100%
16
100%
11
100%
10
100%
10
100%
10
100%
Treatment-related AEs
3
100%
19
100%
12
100%
16
100%
10
90.9%
10
100%
10
100%
10
100%
SAEs
1
33.3%
8
42.1%
3
25%
11
68.8%
6
54.5%
6
60%
6
60%
5
50%
Treatment-related SAEs
0
0%
5
26.3%
1
8.3%
6
37.5%
1
9.1%
2
20%
2
20%
3
30%
Fatal SAEs
0
0%
0
0%
0
0%
0
0%
0
0%
0
0%
0
0%
0
0%
AEs leading to discontinuation
1
33.3%
4
21.1%
1
8.3%
6
37.5%
4
36.4%
1
10%
1
10%
5
50%
AEs requiring dose interruptions
0
0%
12
63.2%
6
50%
14
87.5%
3
27.3%
8
80%
5
50%
8
80%
AEs requiring dose reductions
0
0%
9
47.4%
5
41.7%
9
56.3%
2
18.2%
4
40%
3
30%
7
70%
AEs requiring dose reductions or interruptions
0
0%
13
68.4%
7
58.3%
14
87.5%
3
27.3%
8
80%
6
60%
9
90%
2. Primary Outcome
Title Average Steady State Plasma Concentration (Cavg) of Trametinib When Administered Alone (Monotherapy)
Description Pharmacokinetic (PK) parameters were calculated based on trametinib plasma concentrations by using non-compartmental methods. The average steady state plasma concentration (Cavg) of trametinib was calculated as the ratio of area under the curve (AUC)/tau, where tau = 24 h for trametinib.
Time Frame pre dose, 1, 2, 4, 7, 10 and 24 hours post trametinib dose on Cycle 1 Day 15. The duration of 1 cycle was 28 days.

Outcome Measure Data

Analysis Population Description
All subjects who received at least one dose of trametinib in Part A and B and provided an evaluable PK profile with a value for the outcome measure
Arm/Group Title Part A - TMT 0.0125 mg/kg/Day Part A - TMT 0.025 mg/kg/Day Part A - TMT 0.032 mg/kg/Day Part A - TMT 0.04 mg/kg/Day Part B - Neuroblastoma Part B - LGG Fusion Part B - NF-1 With PN Part B - BRAF V600 Mutant Solid Tumor Part B - All Tumor Types TMT 0.025 mg/kg/Day
Arm/Group Description Participants treated with trametinib 0.0125 mg/kg/day Participants treated with trametinib 0.025 mg/kg/day Participants under 6 years of age treated with trametinib 0.032 mg/kg/day Participants treated with trametinib 0.04 mg/kg/day Participants with refractory or relapsed neuroblastoma treated with trametinib 0.025 mg/kg/day Participants with refractory or relapsed neuroblastoma treated with trametinib 0.025 mg/kg/day Participants with neurofibromatosis Type -1 associated plexiform neurofibromas (NF-1 with PN) treated with trametinib 0.025 mg/kg/day Participants with BRAF V600 mutant solid tumors treated with trametinib 0.025 mg/kg/day Participants (all tumor types in Part B) treated with trametinib 0.025 mg/kg/day
Measure Participants 3 18 9 15 9 10 10 9 38
Geometric Mean (Geometric Coefficient of Variation) [ng/mL]
5.76
(24.8)
13.9
(27.1)
15.2
(16.9)
21.3
(20.7)
15.1
(36.0)
13.2
(40.4)
13.5
(25.1)
15.8
(42.8)
14.3
(35.8)
3. Secondary Outcome
Title Trough Concentration (Ctrough) of Trametinib When Administered Alone and in Combination With Dabrafenib
Description Pharmacokinetic (PK) parameters were calculated based on trametinib plasma concentrations by using non-compartmental methods. Ctrough is defined as the observed plasma concentration just prior to the beginning of, or at the end, of a dosing interval.
Time Frame pre dose on Cycle 1 Day 15. The duration of 1 cycle was 28 days.

Outcome Measure Data

Analysis Population Description
All subjects who received at least one dose of trametinib in Part A, B, C and D and provided an evaluable PK profile with a value for the outcome measure
Arm/Group Title Part A - TMT 0.0125 mg/kg/Day Part A - TMT 0.025 mg/kg/Day Part A - TMT 0.032 mg/kg/Day Part A - TMT 0.04 mg/kg/Day Part B - Neuroblastoma Part B - LGG Fusion Part B - NF-1 With PN Part B - BRAF V600 Mutant Solid Tumor Part B - All Tumor Types TMT 0.025 mg/kg/Day Part C - TMT 0.025 mg/kg/Day + 50% DRB RP2D Part C - TMT 0.025 mg/kg/Day + 100% DRB RP2D Part C - TMT 0.032 mg/kg/Day + 100% DRB RP2D Part D - LGG Part D - LCH Part D - All Tumor Types TMT 0.032 mg/kg/Day + 100% DRB RP2D Part D - All Tumor Types TMT 0.025 mg/kg/Day + 100% DRB RP2D
Arm/Group Description Participants treated with trametinib 0.0125 mg/kg/day Participants treated with trametinib 0.025 mg/kg/day Participants under 6 years of age treated with trametinib 0.032 mg/kg/day Participants treated with trametinib 0.04 mg/kg/day Participants with refractory or relapsed neuroblastoma treated with trametinib 0.025 mg/kg/day Participants with recurrent or unresectable low grade glioma (LGG) with BRAF tandem duplication with fusion treated with trametinib 0.025 mg/kg/day Participants with neurofibromatosis Type -1 associated plexiform neurofibromas (NF-1 with PN) treated with trametinib 0.025 mg/kg/day Participants with BRAF V600 mutant solid tumors treated with trametinib 0.025 mg/kg/day Participants (all tumor types in Part B) treated with trametinib 0.025 mg/kg/day Participants treated with a combination therapy of trametinib (0.025 mg/kg/day) plus 50% of the recommended phase II dose (RP2D) of dabrafenib monotherapy (2.63 mg/kg/day for <12 years old subjects and 2.25 mg/kg/day for ≥12 years old subjects) Participants treated with a combination therapy of trametinib (0.025 mg/kg/day) plus 100% of the recommended phase II dose (RP2D) of dabrafenib monotherapy (5.25 mg/kg/day for <12 years old subjects and 4.5 mg/kg/day for ≥12 years old subjects) Participants under 6 years of age treated with a combination therapy of trametinib (0.032 mg/kg/day) with 100% of the recommended phase II dose (RP2D) of dabrafenib monotherapy (5.25 mg/kg/day) Participants with low grade glioma (LGG) treated with a combination therapy of trametinib (0.032 mg/kg/day for < 6 years old subjects and 0.025 mg/kg/day for ≥ 6 years old subjects) plus 100% of the recommended phase II dose (RP2D) of dabrafenib monotherapy (5.25 mg/kg/day for <12 years old subjects and 4.5 mg/kg/day for ≥12 years old subjects) Participants with Langerhans cell histiocytosis (LCH) treated with a combination therapy of trametinib (0.032 mg/kg/day for < 6 years old subjects and 0.025 mg/kg/day for ≥ 6 years old subjects) plus 100% of the recommended phase II dose (RP2D) of dabrafenib monotherapy (5.25 mg/kg/day for <12 years old subjects and 4.5 mg/kg/day for ≥12 years old subjects) Participants under 6 years of age (all tumor types in Part D) treated with a combination therapy of trametinib (0.032 mg/kg/day) with 100% of the recommended phase II dose (RP2D) of dabrafenib monotherapy (5.25 mg/kg/day) Participants (all tumor types in Part D) treated with a combination therapy of trametinib (0.025 mg/kg/day) plus 100% of the recommended phase II dose (RP2D) of dabrafenib monotherapy (5.25 mg/kg/day for <12 years old subjects and 4.5 mg/kg/day for ≥12 years old subjects)
Measure Participants 3 19 9 15 9 10 10 9 38 1 1 6 20 6 5 21
Geometric Mean (Geometric Coefficient of Variation) [ng/mL]
4.37
(30.6)
11.1
(44.0)
10.2
(19.4)
15.6
(30.1)
10.7
(43.3)
9.45
(53.6)
9.25
(29.0)
11.3
(50.3)
10.1
(43.6)
8.31
10.2
3.86
(34.9)
8.60
(42.2)
3.74
(66.3)
3.05
(50.7)
8.68
(38.6)
4. Secondary Outcome
Title Maximum Observed Plasma Concentration (Cmax) of Trametinib When Administered Alone and in Combination With Dabrafenib
Description Pharmacokinetic (PK) parameters were calculated based on trametinib plasma concentrations by using non-compartmental methods. Cmax is defined as the maximum (peak) observed plasma concentration following a dose.
Time Frame pre dose, 1, 2, 4, 7, 10 and 24 hours post trametinib dose on Cycle 1 Day 15 (part A and B) and pre dose, 0.5, 1, 2, 3, 4, 6 and 8 hours post trametinib dose on Cycle 1 Day 15 (part C and D). The duration of 1 cycle was 28 days.

Outcome Measure Data

Analysis Population Description
All subjects who received at least one dose of trametinib in Part A, B, C and D and provided an evaluable PK profile with a value for the outcome measure
Arm/Group Title Part A - TMT 0.0125 mg/kg/Day Part A - TMT 0.025 mg/kg/Day Part A - TMT 0.032 mg/kg/Day Part A - TMT 0.04 mg/kg/Day Part B - Neuroblastoma Part B - LGG Fusion Part B - NF-1 With PN Part B - BRAF V600 Mutant Solid Tumor Part B - All Tumor Types TMT 0.025 mg/kg/Day Part C - TMT 0.025 mg/kg/Day + 50% DRB RP2D Part C - TMT 0.025 mg/kg/Day + 100% DRB RP2D Part C - TMT 0.032 mg/kg/Day + 100% DRB RP2D Part D - LGG Part D - LCH Part D - All Tumor Types TMT 0.032 mg/kg/Day + 100% DRB RP2D Part D - All Tumor Types TMT 0.025 mg/kg/Day + 100% DRB RP2D
Arm/Group Description Participants treated with trametinib 0.0125 mg/kg/day Participants treated with trametinib 0.025 mg/kg/day Participants under 6 years of age treated with trametinib 0.032 mg/kg/day Participants treated with trametinib 0.04 mg/kg/day Participants with refractory or relapsed neuroblastoma treated with trametinib 0.025 mg/kg/day Participants with recurrent or unresectable low grade glioma (LGG) with BRAF tandem duplication with fusion treated with trametinib 0.025 mg/kg/day Participants with neurofibromatosis Type -1 associated plexiform neurofibromas (NF-1 with PN) treated with trametinib 0.025 mg/kg/day Participants with BRAF V600 mutant solid tumors treated with trametinib 0.025 mg/kg/day Participants (all tumor types in Part B) treated with trametinib 0.025 mg/kg/day Participants treated with a combination therapy of trametinib (0.025 mg/kg/day) plus 50% of the recommended phase II dose (RP2D) of dabrafenib monotherapy (2.63 mg/kg/day for <12 years old subjects and 2.25 mg/kg/day for ≥12 years old subjects) Participants treated with a combination therapy of trametinib (0.025 mg/kg/day) plus 100% of the recommended phase II dose (RP2D) of dabrafenib monotherapy (5.25 mg/kg/day for <12 years old subjects and 4.5 mg/kg/day for ≥12 years old subjects) Participants under 6 years of age treated with a combination therapy of trametinib (0.032 mg/kg/day) with 100% of the recommended phase II dose (RP2D) of dabrafenib monotherapy (5.25 mg/kg/day) Participants with low grade glioma (LGG) treated with a combination therapy of trametinib (0.032 mg/kg/day for < 6 years old subjects and 0.025 mg/kg/day for ≥ 6 years old subjects) plus 100% of the recommended phase II dose (RP2D) of dabrafenib monotherapy (5.25 mg/kg/day for <12 years old subjects and 4.5 mg/kg/day for ≥12 years old subjects) Participants with Langerhans cell histiocytosis (LCH) treated with a combination therapy of trametinib (0.032 mg/kg/day for < 6 years old subjects and 0.025 mg/kg/day for ≥ 6 years old subjects) plus 100% of the recommended phase II dose (RP2D) of dabrafenib monotherapy (5.25 mg/kg/day for <12 years old subjects and 4.5 mg/kg/day for ≥12 years old subjects) Participants under 6 years of age (all tumor types in Part D) treated with a combination therapy of trametinib (0.032 mg/kg/day) with 100% of the recommended phase II dose (RP2D) of dabrafenib monotherapy (5.25 mg/kg/day) Participants (all tumor types in Part D) treated with a combination therapy of trametinib (0.025 mg/kg/day) plus 100% of the recommended phase II dose (RP2D) of dabrafenib monotherapy (5.25 mg/kg/day for <12 years old subjects and 4.5 mg/kg/day for ≥12 years old subjects)
Measure Participants 3 18 9 16 9 10 10 9 38 1 1 6 20 6 5 21
Geometric Mean (Geometric Coefficient of Variation) [ng/mL]
9.61
(32.9)
21.1
(33.3)
26.1
(16.8)
32.6
(28.9)
26.6
(39.6)
22.1
(41.9)
21.6
(26.1)
27.5
(31.6)
24.2
(35.6)
26.0
24.5
23.7
(36.3)
22.9
(29.2)
15.6
(52.5)
25.9
(35.8)
20.0
(38.1)
5. Secondary Outcome
Title Time to Reach Maximum Plasma Concentration (Tmax) of Trametinib When Administered Alone and in Combination With Dabrafenib
Description Pharmacokinetic (PK) parameters were calculated based on trametinib plasma concentrations by using non-compartmental methods. Tmax is defined as the time to reach maximum (peak) plasma concentration following a dose.
Time Frame pre dose, 1, 2, 4, 7, 10 and 24 hours post trametinib dose on Cycle 1 Day 15 (part A and B) and pre dose, 0.5, 1, 2, 3, 4, 6 and 8 hours post trametinib dose on Cycle 1 Day 15 (part C and D). The duration of 1 cycle was 28 days.

Outcome Measure Data

Analysis Population Description
All subjects who received at least one dose of trametinib in Part A, B, C and D and provided an evaluable PK profile with a value for the outcome measure
Arm/Group Title Part A - TMT 0.0125 mg/kg/Day Part A - TMT 0.025 mg/kg/Day Part A - TMT 0.032 mg/kg/Day Part A - TMT 0.04 mg/kg/Day Part B - Neuroblastoma Part B - LGG Fusion Part B - NF-1 With PN Part B - BRAF V600 Mutant Solid Tumor Part B - All Tumor Types TMT 0.025 mg/kg/Day Part C - TMT 0.025 mg/kg/Day + 50% DRB RP2D Part C - TMT 0.025 mg/kg/Day + 100% DRB RP2D Part C - TMT 0.032 mg/kg/Day + 100% DRB RP2D Part D - LGG Part D - LCH Part D - All Tumor Types TMT 0.032 mg/kg/Day + 100% DRB RP2D Part D - All Tumor Types TMT 0.025 mg/kg/Day + 100% DRB RP2D
Arm/Group Description Participants treated with trametinib 0.0125 mg/kg/day Participants treated with trametinib 0.025 mg/kg/day Participants under 6 years of age treated with trametinib 0.032 mg/kg/day Participants treated with trametinib 0.04 mg/kg/day Participants with refractory or relapsed neuroblastoma treated with trametinib 0.025 mg/kg/day Participants with recurrent or unresectable low grade glioma (LGG) with BRAF tandem duplication with fusion treated with trametinib 0.025 mg/kg/day Participants with neurofibromatosis Type -1 associated plexiform neurofibromas (NF-1 with PN) treated with trametinib 0.025 mg/kg/day Participants with BRAF V600 mutant solid tumors treated with trametinib 0.025 mg/kg/day Participants (all tumor types in Part B) treated with trametinib 0.025 mg/kg/day Participants treated with a combination therapy of trametinib (0.025 mg/kg/day) plus 50% of the recommended phase II dose (RP2D) of dabrafenib monotherapy (2.63 mg/kg/day for <12 years old subjects and 2.25 mg/kg/day for ≥12 years old subjects) Participants treated with a combination therapy of trametinib (0.025 mg/kg/day) plus 100% of the recommended phase II dose (RP2D) of dabrafenib monotherapy (5.25 mg/kg/day for <12 years old subjects and 4.5 mg/kg/day for ≥12 years old subjects) Participants under 6 years of age treated with a combination therapy of trametinib (0.032 mg/kg/day) with 100% of the recommended phase II dose (RP2D) of dabrafenib monotherapy (5.25 mg/kg/day) Participants with low grade glioma (LGG) treated with a combination therapy of trametinib (0.032 mg/kg/day for < 6 years old subjects and 0.025 mg/kg/day for ≥ 6 years old subjects) plus 100% of the recommended phase II dose (RP2D) of dabrafenib monotherapy (5.25 mg/kg/day for <12 years old subjects and 4.5 mg/kg/day for ≥12 years old subjects) Participants with Langerhans cell histiocytosis (LCH) treated with a combination therapy of trametinib (0.032 mg/kg/day for < 6 years old subjects and 0.025 mg/kg/day for ≥ 6 years old subjects) plus 100% of the recommended phase II dose (RP2D) of dabrafenib monotherapy (5.25 mg/kg/day for <12 years old subjects and 4.5 mg/kg/day for ≥12 years old subjects) Participants under 6 years of age (all tumor types in Part D) treated with a combination therapy of trametinib (0.032 mg/kg/day) with 100% of the recommended phase II dose (RP2D) of dabrafenib monotherapy (5.25 mg/kg/day) Participants (all tumor types in Part D) treated with a combination therapy of trametinib (0.025 mg/kg/day) plus 100% of the recommended phase II dose (RP2D) of dabrafenib monotherapy (5.25 mg/kg/day for <12 years old subjects and 4.5 mg/kg/day for ≥12 years old subjects)
Measure Participants 3 19 9 16 9 10 10 9 38 1 1 6 20 6 5 21
Median (Full Range) [hours]
1.00
2.00
1.00
2.00
1.00
1.50
1.00
1.00
1.00
1.00
1.00
1.50
2.00
1.00
1.00
2.00
6. Secondary Outcome
Title Area Under the Plasma Concentration-time Curve From Time Zero to the Time of Last Quantifiable Concentration (AUClast) of Trametinib When Administered Alone and in Combination With Dabrafenib
Description Pharmacokinetic (PK) parameters were calculated based on trametinib plasma concentrations by using non-compartmental methods. The linear trapezoidal method was used for area under the curve calculation.
Time Frame pre dose, 1, 2, 4, 7, 10 and 24 hours post trametinib dose on Cycle 1 Day 15 (part A and B) and pre dose, 0.5, 1, 2, 3, 4, 6 and 8 hours post trametinib dose on Cycle 1 Day 15 (part C and D). The duration of 1 cycle was 28 days.

Outcome Measure Data

Analysis Population Description
All subjects who received at least one dose of trametinib in Part A, B, C and D and provided an evaluable PK profile with a value for the outcome measure
Arm/Group Title Part A - TMT 0.0125 mg/kg/Day Part A - TMT 0.025 mg/kg/Day Part A - TMT 0.032 mg/kg/Day Part A - TMT 0.04 mg/kg/Day Part B - Neuroblastoma Part B - LGG Fusion Part B - NF-1 With PN Part B - BRAF V600 Mutant Solid Tumor Part B - All Tumor Types TMT 0.025 mg/kg/Day Part C - TMT 0.025 mg/kg/Day + 50% DRB RP2D Part C - TMT 0.025 mg/kg/Day + 100% DRB RP2D Part C - TMT 0.032 mg/kg/Day + 100% DRB RP2D Part D - LGG Part D - LCH Part D - All Tumor Types TMT 0.032 mg/kg/Day + 100% DRB RP2D Part D - All Tumor Types TMT 0.025 mg/kg/Day + 100% DRB RP2D
Arm/Group Description Participants treated with trametinib 0.0125 mg/kg/day Participants treated with trametinib 0.025 mg/kg/day Participants under 6 years of age treated with trametinib 0.032 mg/kg/day Participants treated with trametinib 0.04 mg/kg/day Participants with refractory or relapsed neuroblastoma treated with trametinib 0.025 mg/kg/day Participants with recurrent or unresectable low grade glioma (LGG) with BRAF tandem duplication with fusion treated with trametinib 0.025 mg/kg/day Participants with neurofibromatosis Type -1 associated plexiform neurofibromas (NF-1 with PN) treated with trametinib 0.025 mg/kg/day Participants with BRAF V600 mutant solid tumors treated with trametinib 0.025 mg/kg/day Participants (all tumor types in Part B) treated with trametinib 0.025 mg/kg/day Participants treated with a combination therapy of trametinib (0.025 mg/kg/day) plus 50% of the recommended phase II dose (RP2D) of dabrafenib monotherapy (2.63 mg/kg/day for <12 years old subjects and 2.25 mg/kg/day for ≥12 years old subjects) Participants treated with a combination therapy of trametinib (0.025 mg/kg/day) plus 100% of the recommended phase II dose (RP2D) of dabrafenib monotherapy (5.25 mg/kg/day for <12 years old subjects and 4.5 mg/kg/day for ≥12 years old subjects) Participants under 6 years of age treated with a combination therapy of trametinib (0.032 mg/kg/day) with 100% of the recommended phase II dose (RP2D) of dabrafenib monotherapy (5.25 mg/kg/day) Participants with low grade glioma (LGG) treated with a combination therapy of trametinib (0.032 mg/kg/day for < 6 years old subjects and 0.025 mg/kg/day for ≥ 6 years old subjects) plus 100% of the recommended phase II dose (RP2D) of dabrafenib monotherapy (5.25 mg/kg/day for <12 years old subjects and 4.5 mg/kg/day for ≥12 years old subjects) Participants with Langerhans cell histiocytosis (LCH) treated with a combination therapy of trametinib (0.032 mg/kg/day for < 6 years old subjects and 0.025 mg/kg/day for ≥ 6 years old subjects) plus 100% of the recommended phase II dose (RP2D) of dabrafenib monotherapy (5.25 mg/kg/day for <12 years old subjects and 4.5 mg/kg/day for ≥12 years old subjects) Participants under 6 years of age (all tumor types in Part D) treated with a combination therapy of trametinib (0.032 mg/kg/day) with 100% of the recommended phase II dose (RP2D) of dabrafenib monotherapy (5.25 mg/kg/day) Participants (all tumor types in Part D) treated with a combination therapy of trametinib (0.025 mg/kg/day) plus 100% of the recommended phase II dose (RP2D) of dabrafenib monotherapy (5.25 mg/kg/day for <12 years old subjects and 4.5 mg/kg/day for ≥12 years old subjects)
Measure Participants 3 19 9 16 9 10 10 9 38 1 1 6 20 6 5 21
Geometric Mean (Geometric Coefficient of Variation) [hours*ng/mL]
138
(24.8)
341
(28.3)
364
(16.9)
413
(76.2)
362
(36.0)
316
(40.4)
304
(36.9)
379
(42.8)
337
(38.6)
290
331
122
(29.0)
270
(35.8)
118
(53.4)
126
(30.7)
255
(49.2)
7. Secondary Outcome
Title Area Under the Plasma Concentration-time Curve From Time Zero to the End of the Dosing Interval Tau at Steady-state (AUCtau) of Trametinib When Administered Alone and in Combination With Dabrafenib
Description Pharmacokinetic (PK) parameters were calculated based on trametinib plasma concentrations by using non-compartmental methods. The linear trapezoidal method was used for area under the curve calculation. The duration of the dosing interval (tau) was 24 hours for trametinib.
Time Frame pre dose, 1, 2, 4, 7, 10 and 24 hours post trametinib dose on Cycle 1 Day 15 (part A and B) and pre dose, 0.5, 1, 2, 3, 4, 6 and 8 hours post trametinib dose on Cycle 1 Day 15 (part C and D). The duration of 1 cycle was 28 days.

Outcome Measure Data

Analysis Population Description
All subjects who received at least one dose of trametinib in Part A, B, C and D and provided an evaluable PK profile with a value for the outcome measure
Arm/Group Title Part A - TMT 0.0125 mg/kg/Day Part A - TMT 0.025 mg/kg/Day Part A - TMT 0.032 mg/kg/Day Part A - TMT 0.04 mg/kg/Day Part B - Neuroblastoma Part B - LGG Fusion Part B - NF-1 With PN Part B - BRAF V600 Mutant Solid Tumor Part B - All Tumor Types TMT 0.025 mg/kg/Day Part C - TMT 0.025 mg/kg/Day + 50% DRB RP2D Part C - TMT 0.025 mg/kg/Day + 100% DRB RP2D Part C - TMT 0.032 mg/kg/Day + 100% DRB RP2D Part D - LGG Part D - LCH Part D - All Tumor Types TMT 0.032 mg/kg/Day + 100% DRB RP2D Part D - All Tumor Types TMT 0.025 mg/kg/Day + 100% DRB RP2D
Arm/Group Description Participants treated with trametinib 0.0125 mg/kg/day Participants treated with trametinib 0.025 mg/kg/day Participants under 6 years of age treated with trametinib 0.032 mg/kg/day Participants treated with trametinib 0.04 mg/kg/day Participants with refractory or relapsed neuroblastoma treated with trametinib 0.025 mg/kg/day Participants with recurrent or unresectable low grade glioma (LGG) with BRAF tandem duplication with fusion treated with trametinib 0.025 mg/kg/day Participants with neurofibromatosis Type -1 associated plexiform neurofibromas (NF-1 with PN) treated with trametinib 0.025 mg/kg/day Participants with BRAF V600 mutant solid tumors treated with trametinib 0.025 mg/kg/day Participants (all tumor types in Part B) treated with trametinib 0.025 mg/kg/day Participants treated with a combination therapy of trametinib (0.025 mg/kg/day) plus 50% of the recommended phase II dose (RP2D) of dabrafenib monotherapy (2.63 mg/kg/day for <12 years old subjects and 2.25 mg/kg/day for ≥12 years old subjects) Participants treated with a combination therapy of trametinib (0.025 mg/kg/day) plus 100% of the recommended phase II dose (RP2D) of dabrafenib monotherapy (5.25 mg/kg/day for <12 years old subjects and 4.5 mg/kg/day for ≥12 years old subjects) Participants under 6 years of age treated with a combination therapy of trametinib (0.032 mg/kg/day) with 100% of the recommended phase II dose (RP2D) of dabrafenib monotherapy (5.25 mg/kg/day) Participants with low grade glioma (LGG) treated with a combination therapy of trametinib (0.032 mg/kg/day for < 6 years old subjects and 0.025 mg/kg/day for ≥ 6 years old subjects) plus 100% of the recommended phase II dose (RP2D) of dabrafenib monotherapy (5.25 mg/kg/day for <12 years old subjects and 4.5 mg/kg/day for ≥12 years old subjects) Participants with Langerhans cell histiocytosis (LCH) treated with a combination therapy of trametinib (0.032 mg/kg/day for < 6 years old subjects and 0.025 mg/kg/day for ≥ 6 years old subjects) plus 100% of the recommended phase II dose (RP2D) of dabrafenib monotherapy (5.25 mg/kg/day for <12 years old subjects and 4.5 mg/kg/day for ≥12 years old subjects) Participants under 6 years of age (all tumor types in Part D) treated with a combination therapy of trametinib (0.032 mg/kg/day) with 100% of the recommended phase II dose (RP2D) of dabrafenib monotherapy (5.25 mg/kg/day) Participants (all tumor types in Part D) treated with a combination therapy of trametinib (0.025 mg/kg/day) plus 100% of the recommended phase II dose (RP2D) of dabrafenib monotherapy (5.25 mg/kg/day for <12 years old subjects and 4.5 mg/kg/day for ≥12 years old subjects)
Measure Participants 3 18 9 15 9 10 10 9 38 1 1 6 20 6 5 21
Geometric Mean (Geometric Coefficient of Variation) [hours*ng/mL]
138
(24.8)
334
(27.1)
364
(16.9)
511
(20.7)
362
(36.0)
316
(40.4)
323
(25.1)
379
(42.8)
343
(35.8)
290
331
236
(28.4)
308
(20.0)
186
(23.7)
228
(33.1)
286
(28.4)
8. Secondary Outcome
Title Apparent Plasma Clearance (CL/F) of Trametinib When Administered Alone and in Combination With Dabrafenib
Description Pharmacokinetic (PK) parameters were calculated based on trametinib plasma concentrations by using non-compartmental methods. Apparent plasma clearance (CL/F) values were calculated as Dose/AUCtau.
Time Frame pre dose, 1, 2, 4, 7, 10 and 24 hours post trametinib dose on Cycle 1 Day 15 (part A and B) and pre dose, 0.5, 1, 2, 3, 4, 6 and 8 hours post trametinib dose on Cycle 1 Day 15 (part C and D). The duration of 1 cycle was 28 days.

Outcome Measure Data

Analysis Population Description
All subjects who received at least one dose of trametinib in Part A, B, C and D and provided an evaluable PK profile with a value for the outcome measure
Arm/Group Title Part A - TMT 0.0125 mg/kg/Day Part A - TMT 0.025 mg/kg/Day Part A - TMT 0.032 mg/kg/Day Part A - TMT 0.04 mg/kg/Day Part B - Neuroblastoma Part B - LGG Fusion Part B - NF-1 With PN Part B - BRAF V600 Mutant Solid Tumor Part B - All Tumor Types TMT 0.025 mg/kg/Day Part C - TMT 0.025 mg/kg/Day + 50% DRB RP2D Part C - TMT 0.025 mg/kg/Day + 100% DRB RP2D Part C - TMT 0.032 mg/kg/Day + 100% DRB RP2D Part D - LGG Part D - LCH Part D - All Tumor Types TMT 0.032 mg/kg/Day + 100% DRB RP2D Part D - All Tumor Types TMT 0.025 mg/kg/Day + 100% DRB RP2D
Arm/Group Description Participants treated with trametinib 0.0125 mg/kg/day Participants treated with trametinib 0.025 mg/kg/day Participants under 6 years of age treated with trametinib 0.032 mg/kg/day Participants treated with trametinib 0.04 mg/kg/day Participants with refractory or relapsed neuroblastoma treated with trametinib 0.025 mg/kg/day Participants with recurrent or unresectable low grade glioma (LGG) with BRAF tandem duplication with fusion treated with trametinib 0.025 mg/kg/day Participants with neurofibromatosis Type -1 associated plexiform neurofibromas (NF-1 with PN) treated with trametinib 0.025 mg/kg/day Participants with BRAF V600 mutant solid tumors treated with trametinib 0.025 mg/kg/day Participants (all tumor types in Part B) treated with trametinib 0.025 mg/kg/day Participants treated with a combination therapy of trametinib (0.025 mg/kg/day) plus 50% of the recommended phase II dose (RP2D) of dabrafenib monotherapy (2.63 mg/kg/day for <12 years old subjects and 2.25 mg/kg/day for ≥12 years old subjects) Participants treated with a combination therapy of trametinib (0.025 mg/kg/day) plus 100% of the recommended phase II dose (RP2D) of dabrafenib monotherapy (5.25 mg/kg/day for <12 years old subjects and 4.5 mg/kg/day for ≥12 years old subjects) Participants under 6 years of age treated with a combination therapy of trametinib (0.032 mg/kg/day) with 100% of the recommended phase II dose (RP2D) of dabrafenib monotherapy (5.25 mg/kg/day) Participants with low grade glioma (LGG) treated with a combination therapy of trametinib (0.032 mg/kg/day for < 6 years old subjects and 0.025 mg/kg/day for ≥ 6 years old subjects) plus 100% of the recommended phase II dose (RP2D) of dabrafenib monotherapy (5.25 mg/kg/day for <12 years old subjects and 4.5 mg/kg/day for ≥12 years old subjects) Participants with Langerhans cell histiocytosis (LCH) treated with a combination therapy of trametinib (0.032 mg/kg/day for < 6 years old subjects and 0.025 mg/kg/day for ≥ 6 years old subjects) plus 100% of the recommended phase II dose (RP2D) of dabrafenib monotherapy (5.25 mg/kg/day for <12 years old subjects and 4.5 mg/kg/day for ≥12 years old subjects) Participants under 6 years of age (all tumor types in Part D) treated with a combination therapy of trametinib (0.032 mg/kg/day) with 100% of the recommended phase II dose (RP2D) of dabrafenib monotherapy (5.25 mg/kg/day) Participants (all tumor types in Part D) treated with a combination therapy of trametinib (0.025 mg/kg/day) plus 100% of the recommended phase II dose (RP2D) of dabrafenib monotherapy (5.25 mg/kg/day for <12 years old subjects and 4.5 mg/kg/day for ≥12 years old subjects)
Measure Participants 3 18 9 15 9 10 10 9 38 1 1 6 20 6 5 21
Geometric Mean (Geometric Coefficient of Variation) [mL/hour]
2750
(69.4)
1530
(64.5)
1240
(25.5)
2040
(71.5)
1710
(55.6)
1910
(47.8)
1590
(65.3)
1820
(42.6)
1750
(51.5)
2590
3770
2010
(38.5)
3540
(54.0)
3060
(44.9)
2180
(23.9)
3810
(49.6)
9. Secondary Outcome
Title Average Steady State Plasma Concentration (Cavg) of Trametinib When Administered in Combination With Dabrafenib
Description Pharmacokinetic (PK) parameters were calculated based on trametinib plasma concentrations by using non-compartmental methods. The average steady state plasma concentration (Cavg) of trametinib was calculated as the ratio of area under the curve (AUC)/tau, where tau = 24 h for trametinib.
Time Frame pre dose, 0.5, 1, 2, 3, 4, 6 and 8 hours post trametinib dose on Cycle 1 Day 15. The duration of 1 cycle was 28 days.

Outcome Measure Data

Analysis Population Description
All subjects who received at least one dose of trametinib in Part C and D and provided an evaluable PK profile with a value for the outcome measure
Arm/Group Title Part C - TMT 0.025 mg/kg/Day + 50% DRB RP2D Part C - TMT 0.025 mg/kg/Day + 100% DRB RP2D Part C - TMT 0.032 mg/kg/Day + 100% DRB RP2D Part D - LGG Part D - LCH Part D - All Tumor Types TMT 0.032 mg/kg/Day + 100% DRB RP2D Part D - All Tumor Types TMT 0.025 mg/kg/Day + 100% DRB RP2D
Arm/Group Description Participants treated with a combination therapy of trametinib (0.025 mg/kg/day) plus 50% of the recommended phase II dose (RP2D) of dabrafenib monotherapy (2.63 mg/kg/day for <12 years old subjects and 2.25 mg/kg/day for ≥12 years old subjects) Participants treated with a combination therapy of trametinib (0.025 mg/kg/day) plus 100% of the recommended phase II dose (RP2D) of dabrafenib monotherapy (5.25 mg/kg/day for <12 years old subjects and 4.5 mg/kg/day for ≥12 years old subjects) Participants under 6 years of age treated with a combination therapy of trametinib (0.032 mg/kg/day) with 100% of the recommended phase II dose (RP2D) of dabrafenib monotherapy (5.25 mg/kg/day) Participants with low grade glioma (LGG) treated with a combination therapy of trametinib (0.032 mg/kg/day for < 6 years old subjects and 0.025 mg/kg/day for ≥ 6 years old subjects) plus 100% of the recommended phase II dose (RP2D) of dabrafenib monotherapy (5.25 mg/kg/day for <12 years old subjects and 4.5 mg/kg/day for ≥12 years old subjects) Participants with Langerhans cell histiocytosis (LCH) treated with a combination therapy of trametinib (0.032 mg/kg/day for < 6 years old subjects and 0.025 mg/kg/day for ≥ 6 years old subjects) plus 100% of the recommended phase II dose (RP2D) of dabrafenib monotherapy (5.25 mg/kg/day for <12 years old subjects and 4.5 mg/kg/day for ≥12 years old subjects) Participants under 6 years of age (all tumor types in Part D) treated with a combination therapy of trametinib (0.032 mg/kg/day) with 100% of the recommended phase II dose (RP2D) of dabrafenib monotherapy (5.25 mg/kg/day) Participants (all tumor types in Part D) treated with a combination therapy of trametinib (0.025 mg/kg/day) plus 100% of the recommended phase II dose (RP2D) of dabrafenib monotherapy (5.25 mg/kg/day for <12 years old subjects and 4.5 mg/kg/day for ≥12 years old subjects)
Measure Participants 1 1 6 20 6 5 21
Geometric Mean (Geometric Coefficient of Variation) [ng/mL]
12.1
13.8
9.83
(28.4)
12.8
(20.0)
7.76
(23.7)
9.50
(33.1)
11.9
(28.4)
10. Secondary Outcome
Title Incidence of Treatment Emergent Adverse Events in Subjects Treated With Trametinib in Combination With Dabrafenib
Description Incidence of treatment emergent adverse events is defined as number of participants with adverse events (AEs) and serious adverse events (SAEs), including changes from baseline in vital signs and laboratory results qualifying and reported as AEs. The number of participants in each category is reported in the table.
Time Frame From the day of the first dose of the combination up to 30 days after the last dose, up to maximum duration of 53 months

Outcome Measure Data

Analysis Population Description
All subjects who received at least one dose of any component of the combination in Part C and Part D
Arm/Group Title Part C - TMT 0.025 mg/kg/Day + 50% DRB RP2D Part C - TMT 0.025 mg/kg/Day + 100% DRB RP2D Part C - TMT 0.032 mg/kg/Day + 100% DRB RP2D Part D - LGG Part D - LCH
Arm/Group Description Participants treated with a combination therapy of trametinib (0.025 mg/kg/day) plus 50% of the recommended phase II dose (RP2D) of dabrafenib monotherapy (2.63 mg/kg/day for <12 years old subjects and 2.25 mg/kg/day for ≥12 years old subjects) Participants treated with a combination therapy of trametinib (0.025 mg/kg/day) plus 100% of the recommended phase II dose (RP2D) of dabrafenib monotherapy (5.25 mg/kg/day for <12 years old subjects and 4.5 mg/kg/day for ≥12 years old subjects) Participants under 6 years of age treated with a combination therapy of trametinib (0.032 mg/kg/day) with 100% of the recommended phase II dose (RP2D) of dabrafenib monotherapy (5.25 mg/kg/day) Participants with low grade glioma (LGG) treated with a combination therapy of trametinib (0.032 mg/kg/day for < 6 years old subjects and 0.025 mg/kg/day for ≥ 6 years old subjects) plus 100% of the recommended phase II dose (RP2D) of dabrafenib monotherapy (5.25 mg/kg/day for <12 years old subjects and 4.5 mg/kg/day for ≥12 years old subjects) Participants with Langerhans cell histiocytosis (LCH) treated with a combination therapy of trametinib (0.032 mg/kg/day for < 6 years old subjects and 0.025 mg/kg/day for ≥ 6 years old subjects) plus 100% of the recommended phase II dose (RP2D) of dabrafenib monotherapy (5.25 mg/kg/day for <12 years old subjects and 4.5 mg/kg/day for ≥12 years old subjects)
Measure Participants 3 9 6 20 10
AEs
3
100%
9
47.4%
6
50%
20
125%
10
90.9%
Treatment-related AEs
3
100%
9
47.4%
6
50%
20
125%
10
90.9%
SAEs
1
33.3%
5
26.3%
2
16.7%
8
50%
6
54.5%
Treatment-related SAEs
0
0%
2
10.5%
1
8.3%
5
31.3%
3
27.3%
Fatal SAEs
0
0%
0
0%
0
0%
0
0%
0
0%
AEs leading to discontinuation
0
0%
3
15.8%
1
8.3%
5
31.3%
1
9.1%
AEs requiring dose interruptions
1
33.3%
6
31.6%
4
33.3%
16
100%
8
72.7%
AEs requiring dose reductions
1
33.3%
3
15.8%
1
8.3%
6
37.5%
1
9.1%
AEs requiring dose reductions or interruptions
1
33.3%
7
36.8%
4
33.3%
16
100%
8
72.7%
11. Secondary Outcome
Title Best Overall Response (BOR) Based on RECIST v1.1, RANO and Dombi Criteria and as Per Investigator Assessment
Description Response evaluations were assessed using Response Evaluation Criteria in Solid Tumors v1.1 (RECIST v1.1) for subjects with solid tumors except neuroblastomas, primary central nervous system tumors (gliomas) or plexiform neurofibromas (PNs). Response evaluations for subjects with neuroblastomas could have included: measureable disease (by CT/MRI alone) assessed according to RECIST v1.1, evaluable disease assessed for meta-iodobenzylguanidine (MIBG) response, and biochemical (urine HVA/VMA) with bone marrow involvement assessed by Hematoxylin and Eosin staining of bilateral bone marrow biopsies and aspirates. Response evaluations for glioma subjects was assessed using Response Assessment in Neuro Oncology (RANO) criteria with solid tumors through MRI scans. Response evaluations of PNs were assessed using volumetric determination and Dombi criteria through MRI scans. The number of participants in each response category is reported in the table.
Time Frame From the day of the first dose of any study drug up to the last dose, up to maximum duration of 63 months

Outcome Measure Data

Analysis Population Description
All subjects who received at least one dose of trametinib in Part A and Part B or at least one dose of any component of the combination in Part C and Part D
Arm/Group Title Part A - TMT 0.0125 mg/kg/Day Part A - TMT 0.025 mg/kg/Day Part A - TMT 0.032 mg/kg/Day Part A - TMT 0.04 mg/kg/Day Part B - Neuroblastoma Part B - LGG Fusion Part B - NF-1 With PN Part B - BRAF V600 Mutant Solid Tumor Part C - TMT 0.025 mg/kg/Day + 50% DRB RP2D Part C - TMT 0.025 mg/kg/Day + 100% DRB RP2D Part C - TMT 0.032 mg/kg/Day + 100% DRB RP2D Part D - LGG Part D - LCH
Arm/Group Description Participants treated with trametinib 0.0125 mg/kg/day Participants treated with trametinib 0.025 mg/kg/day Participants under 6 years of age treated with trametinib 0.032 mg/kg/day Participants treated with trametinib 0.04 mg/kg/day Participants with refractory or relapsed neuroblastoma treated with trametinib 0.025 mg/kg/day Participants with refractory or relapsed neuroblastoma treated with trametinib 0.025 mg/kg/day Participants with neurofibromatosis Type -1 associated plexiform neurofibromas (NF-1 with PN) treated with trametinib 0.025 mg/kg/day Participants with BRAF V600 mutant solid tumors treated with trametinib 0.025 mg/kg/day Participants treated with a combination therapy of trametinib (0.025 mg/kg/day) plus 50% of the recommended phase II dose (RP2D) of dabrafenib monotherapy (2.63 mg/kg/day for <12 years old subjects and 2.25 mg/kg/day for ≥12 years old subjects) Participants treated with a combination therapy of trametinib (0.025 mg/kg/day) plus 100% of the recommended phase II dose (RP2D) of dabrafenib monotherapy (5.25 mg/kg/day for <12 years old subjects and 4.5 mg/kg/day for ≥12 years old subjects) Participants under 6 years of age treated with a combination therapy of trametinib (0.032 mg/kg/day) with 100% of the recommended phase II dose (RP2D) of dabrafenib monotherapy (5.25 mg/kg/day) Participants with low grade glioma (LGG) treated with a combination therapy of trametinib (0.032 mg/kg/day for < 6 years old subjects and 0.025 mg/kg/day for ≥ 6 years old subjects) plus 100% of the recommended phase II dose (RP2D) of dabrafenib monotherapy (5.25 mg/kg/day for <12 years old subjects and 4.5 mg/kg/day for ≥12 years old subjects) Participants with Langerhans cell histiocytosis (LCH) treated with a combination therapy of trametinib (0.032 mg/kg/day for < 6 years old subjects and 0.025 mg/kg/day for ≥ 6 years old subjects) plus 100% of the recommended phase II dose (RP2D) of dabrafenib monotherapy (5.25 mg/kg/day for <12 years old subjects and 4.5 mg/kg/day for ≥12 years old subjects)
Measure Participants 3 19 12 16 11 10 10 10 3 9 6 20 10
Complete response (CR)
0
0%
0
0%
0
0%
0
0%
0
0%
0
0%
0
0%
0
0%
0
0%
0
0%
2
33.3%
2
10%
3
30%
Partial response (PR)
0
0%
1
5.3%
1
8.3%
0
0%
1
9.1%
3
30%
0
0%
5
50%
2
66.7%
3
33.3%
2
33.3%
9
45%
3
30%
Stable disease (SD)
1
33.3%
2
10.5%
3
25%
4
25%
1
9.1%
7
70%
8
80%
4
40%
1
33.3%
5
55.6%
1
16.7%
8
40%
3
30%
Progressive disease (PD)
0
0%
0
0%
2
16.7%
0
0%
5
45.5%
0
0%
0
0%
1
10%
0
0%
1
11.1%
0
0%
0
0%
0
0%
Non-CR/Non-PD
0
0%
0
0%
0
0%
0
0%
0
0%
0
0%
0
0%
0
0%
0
0%
0
0%
0
0%
0
0%
0
0%
Unknown
0
0%
0
0%
0
0%
2
12.5%
1
9.1%
0
0%
0
0%
0
0%
0
0%
0
0%
0
0%
1
5%
0
0%
Missing
2
66.7%
16
84.2%
6
50%
10
62.5%
3
27.3%
0
0%
2
20%
0
0%
0
0%
0
0%
1
16.7%
0
0%
1
10%
12. Secondary Outcome
Title Objective Response Rate (ORR) Based on RECIST v1.1, RANO and Dombi Criteria and as Per Investigator Assessment
Description Objective response rate (ORR) was defined as the percentage of subjects with best overall response rate (BOR) with confirmation of complete response (CR) or partial response (PR) according to criteria for a specific disease type, among subjects with disease assessment at baseline. BOR for each subject was determined from the sequence of overall responses according to the rules for RECIST v1.1, RANO and Dombi criteria. ORR was calculated based on the investigator assessment of tumor response data and was based on confirmed responses.
Time Frame From the day of the first dose of any study drug up to the last dose, up to maximum duration of 63 months

Outcome Measure Data

Analysis Population Description
All subjects who received at least one dose of trametinib in Part A and Part B or at least one dose of any component of the combination in Part C and Part D
Arm/Group Title Part A - TMT 0.0125 mg/kg/Day Part A - TMT 0.025 mg/kg/Day Part A - TMT 0.032 mg/kg/Day Part A - TMT 0.04 mg/kg/Day Part B - Neuroblastoma Part B - LGG Fusion Part B - NF-1 With PN Part B - BRAF V600 Mutant Solid Tumor Part C - TMT 0.025 mg/kg/Day + 50% DRB RP2D Part C - TMT 0.025 mg/kg/Day + 100% DRB RP2D Part C - TMT 0.032 mg/kg/Day + 100% DRB RP2D Part D - LGG Part D - LCH
Arm/Group Description Participants treated with trametinib 0.0125 mg/kg/day Participants treated with trametinib 0.025 mg/kg/day Participants under 6 years of age treated with trametinib 0.032 mg/kg/day Participants treated with trametinib 0.04 mg/kg/day Participants with refractory or relapsed neuroblastoma treated with trametinib 0.025 mg/kg/day Participants with refractory or relapsed neuroblastoma treated with trametinib 0.025 mg/kg/day Participants with neurofibromatosis Type -1 associated plexiform neurofibromas (NF-1 with PN) treated with trametinib 0.025 mg/kg/day Participants with BRAF V600 mutant solid tumors treated with trametinib 0.025 mg/kg/day Participants treated with a combination therapy of trametinib (0.025 mg/kg/day) plus 50% of the recommended phase II dose (RP2D) of dabrafenib monotherapy (2.63 mg/kg/day for <12 years old subjects and 2.25 mg/kg/day for ≥12 years old subjects) Participants treated with a combination therapy of trametinib (0.025 mg/kg/day) plus 100% of the recommended phase II dose (RP2D) of dabrafenib monotherapy (5.25 mg/kg/day for <12 years old subjects and 4.5 mg/kg/day for ≥12 years old subjects) Participants under 6 years of age treated with a combination therapy of trametinib (0.032 mg/kg/day) with 100% of the recommended phase II dose (RP2D) of dabrafenib monotherapy (5.25 mg/kg/day) Participants with low grade glioma (LGG) treated with a combination therapy of trametinib (0.032 mg/kg/day for < 6 years old subjects and 0.025 mg/kg/day for ≥ 6 years old subjects) plus 100% of the recommended phase II dose (RP2D) of dabrafenib monotherapy (5.25 mg/kg/day for <12 years old subjects and 4.5 mg/kg/day for ≥12 years old subjects) Participants with Langerhans cell histiocytosis (LCH) treated with a combination therapy of trametinib (0.032 mg/kg/day for < 6 years old subjects and 0.025 mg/kg/day for ≥ 6 years old subjects) plus 100% of the recommended phase II dose (RP2D) of dabrafenib monotherapy (5.25 mg/kg/day for <12 years old subjects and 4.5 mg/kg/day for ≥12 years old subjects)
Measure Participants 3 19 12 16 11 10 10 10 3 9 6 20 10
Number (95% Confidence Interval) [percentage of participants]
0
0%
5.3
27.9%
8.3
69.2%
0
0%
9.1
82.7%
30.0
300%
0
0%
50.0
500%
66.7
2223.3%
33.3
370%
66.7
1111.7%
55.0
275%
60.0
600%
13. Secondary Outcome
Title Clinical Benefit Rate (CBR) Based on RECIST v1.1, RANO and Dombi Criteria and as Per Investigator Assessment
Description Clinical Benefit Rate (CBR) was defined as the percentage of subjects with best overall response rate (BOR) with confirmation of complete response (CR), partial response (PR) or stable disease (SD) according to criteria for a specific disease type, among subjects with disease assessment at baseline. BOR for each subject was determined from the sequence of overall responses according to the rules for RECIST v1.1, RANO and Dombi criteria. ORR was calculated based on the investigator assessment of tumor response data and was based on confirmed responses.
Time Frame From the day of the first dose of any study drug up to the last dose, up to maximum duration of 63 months

Outcome Measure Data

Analysis Population Description
All subjects who received at least one dose of trametinib in Part A and Part B or at least one dose of any component of the combination in Part C and Part D
Arm/Group Title Part A - TMT 0.0125 mg/kg/Day Part A - TMT 0.025 mg/kg/Day Part A - TMT 0.032 mg/kg/Day Part A - TMT 0.04 mg/kg/Day Part B - Neuroblastoma Part B - LGG Fusion Part B - NF-1 With PN Part B - BRAF V600 Mutant Solid Tumor Part C - TMT 0.025 mg/kg/Day + 50% DRB RP2D Part C - TMT 0.025 mg/kg/Day + 100% DRB RP2D Part C - TMT 0.032 mg/kg/Day + 100% DRB RP2D Part D - LGG Part D - LCH
Arm/Group Description Participants treated with trametinib 0.0125 mg/kg/day Participants treated with trametinib 0.025 mg/kg/day Participants under 6 years of age treated with trametinib 0.032 mg/kg/day Participants treated with trametinib 0.04 mg/kg/day Participants with refractory or relapsed neuroblastoma treated with trametinib 0.025 mg/kg/day Participants with refractory or relapsed neuroblastoma treated with trametinib 0.025 mg/kg/day Participants with neurofibromatosis Type -1 associated plexiform neurofibromas (NF-1 with PN) treated with trametinib 0.025 mg/kg/day Participants with BRAF V600 mutant solid tumors treated with trametinib 0.025 mg/kg/day Participants treated with a combination therapy of trametinib (0.025 mg/kg/day) plus 50% of the recommended phase II dose (RP2D) of dabrafenib monotherapy (2.63 mg/kg/day for <12 years old subjects and 2.25 mg/kg/day for ≥12 years old subjects) Participants treated with a combination therapy of trametinib (0.025 mg/kg/day) plus 100% of the recommended phase II dose (RP2D) of dabrafenib monotherapy (5.25 mg/kg/day for <12 years old subjects and 4.5 mg/kg/day for ≥12 years old subjects) Participants under 6 years of age treated with a combination therapy of trametinib (0.032 mg/kg/day) with 100% of the recommended phase II dose (RP2D) of dabrafenib monotherapy (5.25 mg/kg/day) Participants with low grade glioma (LGG) treated with a combination therapy of trametinib (0.032 mg/kg/day for < 6 years old subjects and 0.025 mg/kg/day for ≥ 6 years old subjects) plus 100% of the recommended phase II dose (RP2D) of dabrafenib monotherapy (5.25 mg/kg/day for <12 years old subjects and 4.5 mg/kg/day for ≥12 years old subjects) Participants with Langerhans cell histiocytosis (LCH) treated with a combination therapy of trametinib (0.032 mg/kg/day for < 6 years old subjects and 0.025 mg/kg/day for ≥ 6 years old subjects) plus 100% of the recommended phase II dose (RP2D) of dabrafenib monotherapy (5.25 mg/kg/day for <12 years old subjects and 4.5 mg/kg/day for ≥12 years old subjects)
Measure Participants 3 19 12 16 11 10 10 10 3 9 6 20 10
Number (95% Confidence Interval) [percentage of participants]
33.3
1110%
15.8
83.2%
33.3
277.5%
25.0
156.3%
18.2
165.5%
100
1000%
80.0
800%
90.0
900%
100
3333.3%
88.9
987.8%
83.3
1388.3%
95.0
475%
90.0
900%
14. Secondary Outcome
Title Apparent Clearance (CL/F) of Trametinib Estimated With a PopPK Model
Description The population pharmacokinetic (PopPK) model of trametinib can be described using a two-compartment model with dual sequential 1st order absorption (Ka1, Ka2) and 1st order elimination. Apparent clearance (CL/F) of trametinib estimated with the PopPK model is summarized in this record.
Time Frame pre dose, 1, 2, 4, 7, 10 and 24 hours post trametinib dose on Cycle 1 Day 15 (part A and B) and pre dose, 0.5, 1, 2, 3, 4, 6 and 8 hours post trametinib dose on Cycle 1 Day 15 (part C and D). The duration of 1 cycle was 28 days.

Outcome Measure Data

Analysis Population Description
All subjects who received at least one dose of trametinib in Part A, B, C and D and provided an evaluable PK profile. All trametinib and dabrafenib concentration-time data were combined and included in a population PK analysis that examined the influence of demographics on the PK of study treatment.
Arm/Group Title Part A, B, C and D - All Participants With PK Data
Arm/Group Description Participants in the study (all doses and all tumor types) with available pharmacokinetic data
Measure Participants 133
Number [liters/hour]
5.07
15. Secondary Outcome
Title Apparent Central Volume (Vc/F) of Trametinib Estimated With a PopPK Model
Description The population pharmacokinetic (PopPK) model of trametinib can be described using a two-compartment model with dual sequential 1st order absorption (Ka1, Ka2) and 1st order elimination. Apparent central volume (Vc/F) of trametinib estimated with the PopPK model is summarized in this record.
Time Frame pre dose, 1, 2, 4, 7, 10 and 24 hours post trametinib dose on Cycle 1 Day 15 (part A and B) and pre dose, 0.5, 1, 2, 3, 4, 6 and 8 hours post trametinib dose on Cycle 1 Day 15 (part C and D). The duration of 1 cycle was 28 days.

Outcome Measure Data

Analysis Population Description
All subjects who received at least one dose of trametinib in Part A, B, C and D and provided an evaluable PK profile. All trametinib and dabrafenib concentration-time data were combined and included in a population PK analysis that examined the influence of demographics on the PK of study treatment.
Arm/Group Title Part A, B, C and D - All Participants With PK Data
Arm/Group Description Participants in the study (all doses and all tumor types) with available pharmacokinetic data
Measure Participants 133
Number [liters]
184
16. Secondary Outcome
Title Absorption Rate Constants (Ka1 and Ka2) of Trametinib Estimated With a PopPK Model
Description The population pharmacokinetic (PopPK) model of trametinib can be described using a two-compartment model with dual sequential 1st order absorption (Ka1, Ka2) and 1st order elimination. The absorption rate constants (Ka1 and Ka2) estimated with the PopPK model are summarized in this record.
Time Frame pre dose, 1, 2, 4, 7, 10 and 24 hours post trametinib dose on Cycle 1 Day 15 (part A and B) and pre dose, 0.5, 1, 2, 3, 4, 6 and 8 hours post trametinib dose on Cycle 1 Day 15 (part C and D). The duration of 1 cycle was 28 days.

Outcome Measure Data

Analysis Population Description
All subjects who received at least one dose of trametinib in Part A, B, C and D and provided an evaluable PK profile. All trametinib and dabrafenib concentration-time data were combined and included in a population PK analysis that examined the influence of demographics on the PK of study treatment.
Arm/Group Title Part A, B, C and D - All Participants With PK Data
Arm/Group Description Participants in the study (all doses and all tumor types) with available pharmacokinetic data
Measure Participants 133
Ka1
0.134
Ka2
1.55
17. Secondary Outcome
Title Significant Covariates Estimated With a PopPK Model
Description The population pharmacokinetic (PopPK) model of trametinib can be described using a two-compartment model with dual sequential 1st order absorption (Ka1, Ka2) and 1st order elimination. Sex and weight are significant covariates on apparent clearance (CL/F), and weight is also a significant covariate on apparent intercompartmental clearance (Q/F). Use of dabrafenib, yes or no, is a covariate on the relative bioavailability of trametinib, reflecting the effect of dabrafenib on the PK of trametinib. The estimates of these covariates (effect of weight on CL/F, effect of sex on CL/F, effect of weight on Q/F, effect of combination with dabrafenib on relative bioavailability F1) calculated with the PopPK model are summarized in this record.
Time Frame pre dose, 1, 2, 4, 7, 10 and 24 hours post trametinib dose on Cycle 1 Day 15 (part A and B) and pre dose, 0.5, 1, 2, 3, 4, 6 and 8 hours post trametinib dose on Cycle 1 Day 15 (part C and D). The duration of 1 cycle was 28 days.

Outcome Measure Data

Analysis Population Description
All subjects who received at least one dose of trametinib in Part A, B, C and D and provided an evaluable PK profile. All trametinib and dabrafenib concentration-time data were combined and included in a population PK analysis that examined the influence of demographics on the PK of study treatment.
Arm/Group Title Part A, B, C and D - All Participants With PK Data
Arm/Group Description Participants in the study (all doses and all tumor types) with available pharmacokinetic data
Measure Participants 133
Effect of weight on CL/F
0.788
Effect of sex on CL/F
1.24
Effect of weight on Q/F
0.679
Effect of combination with dabrafenib on relative bioavailability F1
0.876
18. Secondary Outcome
Title Trough Concentration (Ctrough) of Dabrafenib When Administered in Combination With Trametinib
Description Pharmacokinetic (PK) parameters were calculated based on dabrafenib plasma concentrations by using non-compartmental methods. Ctrough is defined as the observed plasma concentration just prior to the beginning of, or at the end, of a dosing interval.
Time Frame pre dose on Cycle 1 Day 15. The duration of 1 cycle was 28 days.

Outcome Measure Data

Analysis Population Description
All subjects who received at least one dose of dabrafenib in Part C and D and provided an evaluable PK profile with a value for the outcome measure
Arm/Group Title Part C - TMT 0.025 mg/kg/Day + 50% DRB RP2D Part C - TMT 0.025 mg/kg/Day + 100% DRB RP2D Part C - TMT 0.032 mg/kg/Day + 100% DRB RP2D Part D - LGG Part D - LCH Part D - All Tumor Types TMT 0.032 mg/kg/Day + 100% DRB RP2D Part D - All Tumor Types TMT 0.025 mg/kg/Day + 100% DRB RP2D
Arm/Group Description Participants treated with a combination therapy of trametinib (0.025 mg/kg/day) plus 50% of the recommended phase II dose (RP2D) of dabrafenib monotherapy (2.63 mg/kg/day for <12 years old subjects and 2.25 mg/kg/day for ≥12 years old subjects) Participants treated with a combination therapy of trametinib (0.025 mg/kg/day) plus 100% of the recommended phase II dose (RP2D) of dabrafenib monotherapy (5.25 mg/kg/day for <12 years old subjects and 4.5 mg/kg/day for ≥12 years old subjects) Participants under 6 years of age treated with a combination therapy of trametinib (0.032 mg/kg/day) with 100% of the recommended phase II dose (RP2D) of dabrafenib monotherapy (5.25 mg/kg/day) Participants with low grade glioma (LGG) treated with a combination therapy of trametinib (0.032 mg/kg/day for < 6 years old subjects and 0.025 mg/kg/day for ≥ 6 years old subjects) plus 100% of the recommended phase II dose (RP2D) of dabrafenib monotherapy (5.25 mg/kg/day for <12 years old subjects and 4.5 mg/kg/day for ≥12 years old subjects) Participants with Langerhans cell histiocytosis (LCH) treated with a combination therapy of trametinib (0.032 mg/kg/day for < 6 years old subjects and 0.025 mg/kg/day for ≥ 6 years old subjects) plus 100% of the recommended phase II dose (RP2D) of dabrafenib monotherapy (5.25 mg/kg/day for <12 years old subjects and 4.5 mg/kg/day for ≥12 years old subjects) Participants under 6 years of age (all tumor types in Part D) treated with a combination therapy of trametinib (0.032 mg/kg/day) with 100% of the recommended phase II dose (RP2D) of dabrafenib monotherapy (5.25 mg/kg/day) Participants (all tumor types in Part D) treated with a combination therapy of trametinib (0.025 mg/kg/day) plus 100% of the recommended phase II dose (RP2D) of dabrafenib monotherapy (5.25 mg/kg/day for <12 years old subjects and 4.5 mg/kg/day for ≥12 years old subjects)
Measure Participants 3 7 6 19 8 6 21
Geometric Mean (Geometric Coefficient of Variation) [ng/mL]
88.9
(99.6)
28.6
(203.5)
8.10
(159.6)
38.2
(130.9)
11.8
(869.4)
5.36
(429.6)
42.7
(137.4)
19. Secondary Outcome
Title Maximum Observed Plasma Concentration (Cmax) of Dabrafenib When Administered in Combination With Trametinib
Description Pharmacokinetic (PK) parameters were calculated based on dabrafenib plasma concentrations by using non-compartmental methods. Cmax is defined as the maximum (peak) observed plasma concentration following a dose.
Time Frame pre dose, 0.5, 1, 2, 3, 4, 6 and 8 hours post dabrafenib dose on Cycle 1 Day 15. The duration of 1 cycle was 28 days.

Outcome Measure Data

Analysis Population Description
All subjects who received at least one dose of dabrafenib in Part C and D and provided an evaluable PK profile with a value for the outcome measure
Arm/Group Title Part C - TMT 0.025 mg/kg/Day + 50% DRB RP2D Part C - TMT 0.025 mg/kg/Day + 100% DRB RP2D Part C - TMT 0.032 mg/kg/Day + 100% DRB RP2D Part D - LGG Part D - LCH Part D - All Tumor Types TMT 0.032 mg/kg/Day + 100% DRB RP2D Part D - All Tumor Types TMT 0.025 mg/kg/Day + 100% DRB RP2D
Arm/Group Description Participants treated with a combination therapy of trametinib (0.025 mg/kg/day) plus 50% of the recommended phase II dose (RP2D) of dabrafenib monotherapy (2.63 mg/kg/day for <12 years old subjects and 2.25 mg/kg/day for ≥12 years old subjects) Participants treated with a combination therapy of trametinib (0.025 mg/kg/day) plus 100% of the recommended phase II dose (RP2D) of dabrafenib monotherapy (5.25 mg/kg/day for <12 years old subjects and 4.5 mg/kg/day for ≥12 years old subjects) Participants under 6 years of age treated with a combination therapy of trametinib (0.032 mg/kg/day) with 100% of the recommended phase II dose (RP2D) of dabrafenib monotherapy (5.25 mg/kg/day) Participants with low grade glioma (LGG) treated with a combination therapy of trametinib (0.032 mg/kg/day for < 6 years old subjects and 0.025 mg/kg/day for ≥ 6 years old subjects) plus 100% of the recommended phase II dose (RP2D) of dabrafenib monotherapy (5.25 mg/kg/day for <12 years old subjects and 4.5 mg/kg/day for ≥12 years old subjects) Participants with Langerhans cell histiocytosis (LCH) treated with a combination therapy of trametinib (0.032 mg/kg/day for < 6 years old subjects and 0.025 mg/kg/day for ≥ 6 years old subjects) plus 100% of the recommended phase II dose (RP2D) of dabrafenib monotherapy (5.25 mg/kg/day for <12 years old subjects and 4.5 mg/kg/day for ≥12 years old subjects) Participants under 6 years of age (all tumor types in Part D) treated with a combination therapy of trametinib (0.032 mg/kg/day) with 100% of the recommended phase II dose (RP2D) of dabrafenib monotherapy (5.25 mg/kg/day) Participants (all tumor types in Part D) treated with a combination therapy of trametinib (0.025 mg/kg/day) plus 100% of the recommended phase II dose (RP2D) of dabrafenib monotherapy (5.25 mg/kg/day for <12 years old subjects and 4.5 mg/kg/day for ≥12 years old subjects)
Measure Participants 3 7 6 19 8 6 21
Geometric Mean (Geometric Coefficient of Variation) [ng/mL]
630
(235.2)
1560
(35.3)
1440
(43.3)
1360
(55.6)
1490
(88.1)
1840
(35.2)
1290
(68.7)
20. Secondary Outcome
Title Time to Reach Maximum Plasma Concentration (Tmax) of Dabrafenib When Administered in Combination With Trametinib
Description Pharmacokinetic (PK) parameters were calculated based on dabrafenib plasma concentrations by using non-compartmental methods. Tmax is defined as the time to reach maximum (peak) plasma concentration following a dose.
Time Frame pre dose, 0.5, 1, 2, 3, 4, 6 and 8 hours post dabrafenib dose on Cycle 1 Day 15. The duration of 1 cycle was 28 days.

Outcome Measure Data

Analysis Population Description
All subjects who received at least one dose of dabrafenib in Part C and D and provided an evaluable PK profile with a value for the outcome measure
Arm/Group Title Part C - TMT 0.025 mg/kg/Day + 50% DRB RP2D Part C - TMT 0.025 mg/kg/Day + 100% DRB RP2D Part C - TMT 0.032 mg/kg/Day + 100% DRB RP2D Part D - LGG Part D - LCH Part D - All Tumor Types TMT 0.032 mg/kg/Day + 100% DRB RP2D Part D - All Tumor Types TMT 0.025 mg/kg/Day + 100% DRB RP2D
Arm/Group Description Participants treated with a combination therapy of trametinib (0.025 mg/kg/day) plus 50% of the recommended phase II dose (RP2D) of dabrafenib monotherapy (2.63 mg/kg/day for <12 years old subjects and 2.25 mg/kg/day for ≥12 years old subjects) Participants treated with a combination therapy of trametinib (0.025 mg/kg/day) plus 100% of the recommended phase II dose (RP2D) of dabrafenib monotherapy (5.25 mg/kg/day for <12 years old subjects and 4.5 mg/kg/day for ≥12 years old subjects) Participants under 6 years of age treated with a combination therapy of trametinib (0.032 mg/kg/day) with 100% of the recommended phase II dose (RP2D) of dabrafenib monotherapy (5.25 mg/kg/day) Participants with low grade glioma (LGG) treated with a combination therapy of trametinib (0.032 mg/kg/day for < 6 years old subjects and 0.025 mg/kg/day for ≥ 6 years old subjects) plus 100% of the recommended phase II dose (RP2D) of dabrafenib monotherapy (5.25 mg/kg/day for <12 years old subjects and 4.5 mg/kg/day for ≥12 years old subjects) Participants with Langerhans cell histiocytosis (LCH) treated with a combination therapy of trametinib (0.032 mg/kg/day for < 6 years old subjects and 0.025 mg/kg/day for ≥ 6 years old subjects) plus 100% of the recommended phase II dose (RP2D) of dabrafenib monotherapy (5.25 mg/kg/day for <12 years old subjects and 4.5 mg/kg/day for ≥12 years old subjects) Participants under 6 years of age (all tumor types in Part D) treated with a combination therapy of trametinib (0.032 mg/kg/day) with 100% of the recommended phase II dose (RP2D) of dabrafenib monotherapy (5.25 mg/kg/day) Participants (all tumor types in Part D) treated with a combination therapy of trametinib (0.025 mg/kg/day) plus 100% of the recommended phase II dose (RP2D) of dabrafenib monotherapy (5.25 mg/kg/day for <12 years old subjects and 4.5 mg/kg/day for ≥12 years old subjects)
Measure Participants 3 7 6 19 8 6 21
Median (Full Range) [hours]
2.00
1.00
2.00
2.00
1.00
1.00
2.00
21. Secondary Outcome
Title Area Under the Plasma Concentration-time Curve From Time Zero to the Time of Last Quantifiable Concentration (AUClast) of Dabrafenib When Administered in Combination With Trametinib
Description Pharmacokinetic (PK) parameters were calculated based on dabrafenib plasma concentrations by using non-compartmental methods. The linear trapezoidal method was used for area under the curve calculation.
Time Frame pre dose, 0.5, 1, 2, 3, 4, 6 and 8 hours post dabrafenib dose on Cycle 1 Day 15. The duration of 1 cycle was 28 days.

Outcome Measure Data

Analysis Population Description
All subjects who received at least one dose of dabrafenib in Part C and D and provided an evaluable PK profile with a value for the outcome measure
Arm/Group Title Part C - TMT 0.025 mg/kg/Day + 50% DRB RP2D Part C - TMT 0.025 mg/kg/Day + 100% DRB RP2D Part C - TMT 0.032 mg/kg/Day + 100% DRB RP2D Part D - LGG Part D - LCH Part D - All Tumor Types TMT 0.032 mg/kg/Day + 100% DRB RP2D Part D - All Tumor Types TMT 0.025 mg/kg/Day + 100% DRB RP2D
Arm/Group Description Participants treated with a combination therapy of trametinib (0.025 mg/kg/day) plus 50% of the recommended phase II dose (RP2D) of dabrafenib monotherapy (2.63 mg/kg/day for <12 years old subjects and 2.25 mg/kg/day for ≥12 years old subjects) Participants treated with a combination therapy of trametinib (0.025 mg/kg/day) plus 100% of the recommended phase II dose (RP2D) of dabrafenib monotherapy (5.25 mg/kg/day for <12 years old subjects and 4.5 mg/kg/day for ≥12 years old subjects) Participants under 6 years of age treated with a combination therapy of trametinib (0.032 mg/kg/day) with 100% of the recommended phase II dose (RP2D) of dabrafenib monotherapy (5.25 mg/kg/day) Participants with low grade glioma (LGG) treated with a combination therapy of trametinib (0.032 mg/kg/day for < 6 years old subjects and 0.025 mg/kg/day for ≥ 6 years old subjects) plus 100% of the recommended phase II dose (RP2D) of dabrafenib monotherapy (5.25 mg/kg/day for <12 years old subjects and 4.5 mg/kg/day for ≥12 years old subjects) Participants with Langerhans cell histiocytosis (LCH) treated with a combination therapy of trametinib (0.032 mg/kg/day for < 6 years old subjects and 0.025 mg/kg/day for ≥ 6 years old subjects) plus 100% of the recommended phase II dose (RP2D) of dabrafenib monotherapy (5.25 mg/kg/day for <12 years old subjects and 4.5 mg/kg/day for ≥12 years old subjects) Participants under 6 years of age (all tumor types in Part D) treated with a combination therapy of trametinib (0.032 mg/kg/day) with 100% of the recommended phase II dose (RP2D) of dabrafenib monotherapy (5.25 mg/kg/day) Participants (all tumor types in Part D) treated with a combination therapy of trametinib (0.025 mg/kg/day) plus 100% of the recommended phase II dose (RP2D) of dabrafenib monotherapy (5.25 mg/kg/day for <12 years old subjects and 4.5 mg/kg/day for ≥12 years old subjects)
Measure Participants 3 7 6 19 8 6 21
Geometric Mean (Geometric Coefficient of Variation) [hours*ng/mL]
2560
(157.1)
4160
(24.6)
3910
(48.8)
4030
(46.4)
3800
(35.4)
3990
(28.3)
3950
(46.9)
22. Secondary Outcome
Title Area Under the Plasma Concentration-time Curve From Time Zero to the End of the Dosing Interval Tau at Steady-state (AUCtau) of Dabrafenib When Administered in Combination With Trametinib
Description Pharmacokinetic (PK) parameters were calculated based on dabrafenib plasma concentrations by using non-compartmental methods. The linear trapezoidal method was used for area under the curve calculation. The duration of the dosing interval (tau) was 12 hours for dabrafenib.
Time Frame pre dose, 0.5, 1, 2, 3, 4, 6 and 8 hours post dabrafenib dose on Cycle 1 Day 15. The duration of 1 cycle was 28 days.

Outcome Measure Data

Analysis Population Description
All subjects who received at least one dose of dabrafenib in Part C and D and provided an evaluable PK profile with a value for the outcome measure
Arm/Group Title Part C - TMT 0.025 mg/kg/Day + 50% DRB RP2D Part C - TMT 0.025 mg/kg/Day + 100% DRB RP2D Part C - TMT 0.032 mg/kg/Day + 100% DRB RP2D Part D - LGG Part D - LCH Part D - All Tumor Types TMT 0.032 mg/kg/Day + 100% DRB RP2D Part D - All Tumor Types TMT 0.025 mg/kg/Day + 100% DRB RP2D
Arm/Group Description Participants treated with a combination therapy of trametinib (0.025 mg/kg/day) plus 50% of the recommended phase II dose (RP2D) of dabrafenib monotherapy (2.63 mg/kg/day for <12 years old subjects and 2.25 mg/kg/day for ≥12 years old subjects) Participants treated with a combination therapy of trametinib (0.025 mg/kg/day) plus 100% of the recommended phase II dose (RP2D) of dabrafenib monotherapy (5.25 mg/kg/day for <12 years old subjects and 4.5 mg/kg/day for ≥12 years old subjects) Participants under 6 years of age treated with a combination therapy of trametinib (0.032 mg/kg/day) with 100% of the recommended phase II dose (RP2D) of dabrafenib monotherapy (5.25 mg/kg/day) Participants with low grade glioma (LGG) treated with a combination therapy of trametinib (0.032 mg/kg/day for < 6 years old subjects and 0.025 mg/kg/day for ≥ 6 years old subjects) plus 100% of the recommended phase II dose (RP2D) of dabrafenib monotherapy (5.25 mg/kg/day for <12 years old subjects and 4.5 mg/kg/day for ≥12 years old subjects) Participants with Langerhans cell histiocytosis (LCH) treated with a combination therapy of trametinib (0.032 mg/kg/day for < 6 years old subjects and 0.025 mg/kg/day for ≥ 6 years old subjects) plus 100% of the recommended phase II dose (RP2D) of dabrafenib monotherapy (5.25 mg/kg/day for <12 years old subjects and 4.5 mg/kg/day for ≥12 years old subjects) Participants under 6 years of age (all tumor types in Part D) treated with a combination therapy of trametinib (0.032 mg/kg/day) with 100% of the recommended phase II dose (RP2D) of dabrafenib monotherapy (5.25 mg/kg/day) Participants (all tumor types in Part D) treated with a combination therapy of trametinib (0.025 mg/kg/day) plus 100% of the recommended phase II dose (RP2D) of dabrafenib monotherapy (5.25 mg/kg/day for <12 years old subjects and 4.5 mg/kg/day for ≥12 years old subjects)
Measure Participants 3 7 6 19 8 6 21
Geometric Mean (Geometric Coefficient of Variation) [hours*ng/mL]
2870
(116.6)
4160
(24.6)
4040
(47.9)
4070
(46.7)
3910
(37.4)
4150
(30.2)
3990
(47.3)
23. Secondary Outcome
Title Apparent Plasma Clearance (CL/F) of Dabrafenib When Administered in Combination With Trametinib
Description Pharmacokinetic (PK) parameters were calculated based on dabrafenib plasma concentrations by using non-compartmental methods. Apparent plasma clearance (CL/F) values were calculated as Dose/AUCtau.
Time Frame pre dose, 0.5, 1, 2, 3, 4, 6 and 8 hours post dabrafenib dose on Cycle 1 Day 15. The duration of 1 cycle was 28 days.

Outcome Measure Data

Analysis Population Description
All subjects who received at least one dose of dabrafenib in Part C and D and provided an evaluable PK profile with a value for the outcome measure
Arm/Group Title Part C - TMT 0.025 mg/kg/Day + 50% DRB RP2D Part C - TMT 0.025 mg/kg/Day + 100% DRB RP2D Part C - TMT 0.032 mg/kg/Day + 100% DRB RP2D Part D - LGG Part D - LCH Part D - All Tumor Types TMT 0.032 mg/kg/Day + 100% DRB RP2D Part D - All Tumor Types TMT 0.025 mg/kg/Day + 100% DRB RP2D
Arm/Group Description Participants treated with a combination therapy of trametinib (0.025 mg/kg/day) plus 50% of the recommended phase II dose (RP2D) of dabrafenib monotherapy (2.63 mg/kg/day for <12 years old subjects and 2.25 mg/kg/day for ≥12 years old subjects) Participants treated with a combination therapy of trametinib (0.025 mg/kg/day) plus 100% of the recommended phase II dose (RP2D) of dabrafenib monotherapy (5.25 mg/kg/day for <12 years old subjects and 4.5 mg/kg/day for ≥12 years old subjects) Participants under 6 years of age treated with a combination therapy of trametinib (0.032 mg/kg/day) with 100% of the recommended phase II dose (RP2D) of dabrafenib monotherapy (5.25 mg/kg/day) Participants with low grade glioma (LGG) treated with a combination therapy of trametinib (0.032 mg/kg/day for < 6 years old subjects and 0.025 mg/kg/day for ≥ 6 years old subjects) plus 100% of the recommended phase II dose (RP2D) of dabrafenib monotherapy (5.25 mg/kg/day for <12 years old subjects and 4.5 mg/kg/day for ≥12 years old subjects) Participants with Langerhans cell histiocytosis (LCH) treated with a combination therapy of trametinib (0.032 mg/kg/day for < 6 years old subjects and 0.025 mg/kg/day for ≥ 6 years old subjects) plus 100% of the recommended phase II dose (RP2D) of dabrafenib monotherapy (5.25 mg/kg/day for <12 years old subjects and 4.5 mg/kg/day for ≥12 years old subjects) Participants under 6 years of age (all tumor types in Part D) treated with a combination therapy of trametinib (0.032 mg/kg/day) with 100% of the recommended phase II dose (RP2D) of dabrafenib monotherapy (5.25 mg/kg/day) Participants (all tumor types in Part D) treated with a combination therapy of trametinib (0.025 mg/kg/day) plus 100% of the recommended phase II dose (RP2D) of dabrafenib monotherapy (5.25 mg/kg/day for <12 years old subjects and 4.5 mg/kg/day for ≥12 years old subjects)
Measure Participants 3 7 6 19 8 6 21
Geometric Mean (Geometric Coefficient of Variation) [mL/hour]
22900
(191.2)
20400
(45.4)
10100
(67.0)
25400
(70.5)
12500
(63.0)
10200
(41.6)
25100
(69.3)
24. Secondary Outcome
Title Average Steady State Plasma Concentration (Cavg) of Dabrafenib When Administered in Combination With Trametinib
Description Pharmacokinetic (PK) parameters were calculated based on dabrafenib plasma concentrations by using non-compartmental methods. The average steady state plasma concentration (Cavg) of dabrafenib was calculated as the ratio of area under the curve (AUC)/tau, where tau = 12 h for dabrafenib.
Time Frame pre dose, 0.5, 1, 2, 3, 4, 6 and 8 hours post dabrafenib dose on Cycle 1 Day 15. The duration of 1 cycle was 28 days.

Outcome Measure Data

Analysis Population Description
All subjects who received at least one dose of dabrafenib in Part C and D and provided an evaluable PK profile with a value for the outcome measure
Arm/Group Title Part C - TMT 0.025 mg/kg/Day + 50% DRB RP2D Part C - TMT 0.025 mg/kg/Day + 100% DRB RP2D Part C - TMT 0.032 mg/kg/Day + 100% DRB RP2D Part D - LGG Part D - LCH Part D - All Tumor Types TMT 0.032 mg/kg/Day + 100% DRB RP2D Part D - All Tumor Types TMT 0.025 mg/kg/Day + 100% DRB RP2D
Arm/Group Description Participants treated with a combination therapy of trametinib (0.025 mg/kg/day) plus 50% of the recommended phase II dose (RP2D) of dabrafenib monotherapy (2.63 mg/kg/day for <12 years old subjects and 2.25 mg/kg/day for ≥12 years old subjects) Participants treated with a combination therapy of trametinib (0.025 mg/kg/day) plus 100% of the recommended phase II dose (RP2D) of dabrafenib monotherapy (5.25 mg/kg/day for <12 years old subjects and 4.5 mg/kg/day for ≥12 years old subjects) Participants under 6 years of age treated with a combination therapy of trametinib (0.032 mg/kg/day) with 100% of the recommended phase II dose (RP2D) of dabrafenib monotherapy (5.25 mg/kg/day) Participants with low grade glioma (LGG) treated with a combination therapy of trametinib (0.032 mg/kg/day for < 6 years old subjects and 0.025 mg/kg/day for ≥ 6 years old subjects) plus 100% of the recommended phase II dose (RP2D) of dabrafenib monotherapy (5.25 mg/kg/day for <12 years old subjects and 4.5 mg/kg/day for ≥12 years old subjects) Participants with Langerhans cell histiocytosis (LCH) treated with a combination therapy of trametinib (0.032 mg/kg/day for < 6 years old subjects and 0.025 mg/kg/day for ≥ 6 years old subjects) plus 100% of the recommended phase II dose (RP2D) of dabrafenib monotherapy (5.25 mg/kg/day for <12 years old subjects and 4.5 mg/kg/day for ≥12 years old subjects) Participants under 6 years of age (all tumor types in Part D) treated with a combination therapy of trametinib (0.032 mg/kg/day) with 100% of the recommended phase II dose (RP2D) of dabrafenib monotherapy (5.25 mg/kg/day) Participants (all tumor types in Part D) treated with a combination therapy of trametinib (0.025 mg/kg/day) plus 100% of the recommended phase II dose (RP2D) of dabrafenib monotherapy (5.25 mg/kg/day for <12 years old subjects and 4.5 mg/kg/day for ≥12 years old subjects)
Measure Participants 3 7 6 19 8 6 21
Geometric Mean (Geometric Coefficient of Variation) [ng/mL]
239
(116.6)
347
(24.6)
337
(47.9)
339
(46.7)
326
(37.4)
346
(30.2)
332
(47.3)
25. Secondary Outcome
Title Palatability of Trametinib Oral Solution in Pediatric Subjects Assessed by Palatability Questionnaire
Description For subjects ≥ 12 years of age who received the trametinib oral solution, the subject completed a form to evaluate the various properties of the solution (e.g., bitterness, sweetness, appearance, texture and overall taste). For subjects < 12 years of age who received the solution, their caregiver (e.g. parent or guardian) evaluated the solution with the child based on verbal and non-verbal feedback. The questionnaire was completed after the first dose of study drug and no later than Day 8 (±3 days). Subjects completed a form for each drug separately if enrolled in Parts C and D.
Time Frame After the first dose of trametinib oral solution and no later than Day 8 (±3 days)

Outcome Measure Data

Analysis Population Description
All subjects who received at least one dose of trametinib oral solution and filled in the palatability questionnaire. All palatability questionnaire results were combined and reported based on drug dose to better determine the acceptability and palatability of the formulation.
Arm/Group Title TMT 0.0125 mg/kg/Day TMT 0.025 mg/kg/Day TMT 0.032 mg/kg/Day TMT 0.04 mg/kg/Day
Arm/Group Description Participants treated with trametinib oral solution at a dose level of 0.0125 mg/kg/day Participants treated with trametinib oral solution at a dose level of 0.025 mg/kg/day Participants treated with trametinib oral solution at a dose level of 0.032 mg/kg/day Participants treated with trametinib oral solution at a dose level of 0.04 mg/kg/day
Measure Participants 2 29 21 4
Yes
0
0%
1
5.3%
1
8.3%
0
0%
No
2
66.7%
26
136.8%
19
158.3%
4
25%
missing
0
0%
2
10.5%
1
8.3%
0
0%
Yes
0
0%
0
0%
2
16.7%
0
0%
No
2
66.7%
29
152.6%
18
150%
4
25%
missing
0
0%
0
0%
1
8.3%
0
0%
Yes
0
0%
5
26.3%
5
41.7%
1
6.3%
No
2
66.7%
24
126.3%
15
125%
3
18.8%
missing
0
0%
0
0%
1
8.3%
0
0%
Yes
2
66.7%
8
42.1%
6
50%
2
12.5%
No
0
0%
16
84.2%
13
108.3%
1
6.3%
missing
0
0%
5
26.3%
2
16.7%
1
6.3%
Yes
0
0%
6
31.6%
7
58.3%
1
6.3%
No
2
66.7%
19
100%
13
108.3%
3
18.8%
missing
0
0%
4
21.1%
1
8.3%
0
0%
Yes
0
0%
7
36.8%
6
50%
1
6.3%
No
2
66.7%
18
94.7%
14
116.7%
3
18.8%
missing
0
0%
4
21.1%
1
8.3%
0
0%
Yes
0
0%
3
15.8%
0
0%
0
0%
No
0
0%
2
10.5%
1
8.3%
0
0%
missing
2
66.7%
24
126.3%
20
166.7%
4
25%
Yes
0
0%
2
10.5%
1
8.3%
0
0%
No
0
0%
3
15.8%
0
0%
0
0%
missing
2
66.7%
24
126.3%
20
166.7%
4
25%
Yes
0
0%
2
10.5%
0
0%
0
0%
No
0
0%
3
15.8%
1
8.3%
0
0%
missing
2
66.7%
24
126.3%
20
166.7%
4
25%
Yes
0
0%
1
5.3%
0
0%
0
0%
No
0
0%
4
21.1%
1
8.3%
0
0%
missing
2
66.7%
24
126.3%
20
166.7%
4
25%
Yes
0
0%
1
5.3%
0
0%
0
0%
No
0
0%
5
26.3%
1
8.3%
0
0%
missing
2
66.7%
23
121.1%
20
166.7%
4
25%
26. Secondary Outcome
Title Palatability of Dabrafenib Oral Suspension in Pediatric Subjects Assessed by Palatability Questionnaire
Description For subjects ≥ 12 years of age who received the dabrafenib suspension, the subject completed a form to evaluate the various properties of the suspension (e.g., bitterness, sweetness, appearance, texture and overall taste). For subjects < 12 years of age who received the suspension, their caregiver (e.g. parent or guardian) evaluated the suspension with the child based on verbal and non-verbal feedback. The questionnaire was completed after the first dose of study drug and no later than Day 8 (±3 days). Subjects completed a form for each drug separately if enrolled in Parts C and D.
Time Frame After the first dose of dabrafenib oral suspension and no later than Day 8 (±3 days)

Outcome Measure Data

Analysis Population Description
All subjects who received at least one dose of dabrafenib oral suspension and filled in the palatability questionnaire. All palatability questionnaire results were combined and reported based on drug dose to better determine the acceptability and palatability of the formulation. There were no results available for participants who received 50% of the RP2D of dabrafenib monotherapy in combination with trametinib because the participants did not fill in the questionnaire.
Arm/Group Title TMT 0.025 mg/kg/Day + 50% DRB RP2D TMT 0.025 mg/kg/Day + 100% DRB RP2D TMT 0.032 mg/kg/Day + 100% DRB RP2D
Arm/Group Description Participants treated with a combination therapy of trametinib (0.025 mg/kg/day) plus 50% of the RP2D of dabrafenib monotherapy (oral suspension formulation) Participants treated with a combination therapy of trametinib (0.025 mg/kg/day) plus 100% of the RP2D of dabrafenib monotherapy (oral suspension formulation) Participants treated with a combination therapy of trametinib (0.032 mg/kg/day) plus 100% of the RP2D of dabrafenib monotherapy (oral suspension formulation)
Measure Participants 0 4 6
Yes
0
0%
1
5.3%
No
4
133.3%
5
26.3%
missing
0
0%
0
0%
Yes
0
0%
1
5.3%
No
4
133.3%
5
26.3%
missing
0
0%
0
0%
Yes
0
0%
1
5.3%
No
4
133.3%
5
26.3%
missing
0
0%
0
0%
Yes
0
0%
4
21.1%
No
1
33.3%
2
10.5%
missing
3
100%
0
0%
Yes
0
0%
2
10.5%
No
1
33.3%
4
21.1%
missing
3
100%
0
0%
Yes
0
0%
4
21.1%
No
1
33.3%
2
10.5%
missing
3
100%
0
0%
Yes
1
33.3%
0
0%
No
2
66.7%
0
0%
missing
1
33.3%
6
31.6%
Yes
0
0%
0
0%
No
3
100%
0
0%
missing
1
33.3%
6
31.6%
Yes
2
66.7%
0
0%
No
1
33.3%
0
0%
missing
1
33.3%
6
31.6%
Yes
1
33.3%
0
0%
No
2
66.7%
0
0%
missing
1
33.3%
6
31.6%
Yes
0
0%
0
0%
No
3
100%
0
0%
missing
1
33.3%
6
31.6%

Adverse Events

Time Frame From the day of the first dose of any study drug up to 30 days after the last dose, up to maximum duration of 64 months.
Adverse Event Reporting Description Any sign or symptom that occurs during the study treatment plus the 30 days post treatment.
Arm/Group Title Part A - TMT 0.0125 mg/kg/Day Part A - TMT 0.025 mg/kg/Day Part A - TMT 0.032 mg/kg/Day Part A - TMT 0.04 mg/kg/Day Part B - Neuroblastoma Part B - LGG Fusion Part B - NF-1 With PN Part B - BRAF V600 Mutant Solid Tumor Part C - TMT 0.025 mg/kg/Day + 50% DRB RP2D Part C - TMT 0.025 mg/kg/Day + 100% DRB RP2D Part C - TMT 0.032 mg/kg/Day + 100% DRB RP2D Part D - LGG Part D - LCH
Arm/Group Description Participants treated with trametinib 0.0125 mg/kg/day Participants treated with trametinib 0.025 mg/kg/day Participants under 6 years of age treated with trametinib 0.032 mg/kg/day Participants treated with trametinib 0.04 mg/kg/day Participants with refractory or relapsed neuroblastoma treated with trametinib 0.025 mg/kg/day Participants with recurrent or unresectable low grade glioma (LGG) with BRAF tandem duplication with fusion treated with trametinib 0.025 mg/kg/day Participants with neurofibromatosis Type -1 associated plexiform neurofibromas (NF-1 with PN) treated with trametinib 0.025 mg/kg/day Participants with BRAF V600 mutant solid tumors treated with trametinib 0.025 mg/kg/day Participants treated with a combination therapy of trametinib (0.025 mg/kg/day) plus 50% of the recommended phase II dose (RP2D) of dabrafenib monotherapy (2.63 mg/kg/day for <12 years old subjects and 2.25 mg/kg/day for ≥12 years old subjects) Participants treated with a combination therapy of trametinib (0.025 mg/kg/day) plus 100% of the recommended phase II dose (RP2D) of dabrafenib monotherapy (5.25 mg/kg/day for <12 years old subjects and 4.5 mg/kg/day for ≥12 years old subjects) Participants under 6 years of age treated with a combination therapy of trametinib (0.032 mg/kg/day) with 100% of the recommended phase II dose (RP2D) of dabrafenib monotherapy (5.25 mg/kg/day) Participants with low grade glioma (LGG) treated with a combination therapy of trametinib (0.032 mg/kg/day for < 6 years old subjects and 0.025 mg/kg/day for ≥ 6 years old subjects) plus 100% of the recommended phase II dose (RP2D) of dabrafenib monotherapy (5.25 mg/kg/day for <12 years old subjects and 4.5 mg/kg/day for ≥12 years old subjects) Participants with Langerhans cell histiocytosis (LCH) treated with a combination therapy of trametinib (0.032 mg/kg/day for < 6 years old subjects and 0.025 mg/kg/day for ≥ 6 years old subjects) plus 100% of the recommended phase II dose (RP2D) of dabrafenib monotherapy (5.25 mg/kg/day for <12 years old subjects and 4.5 mg/kg/day for ≥12 years old subjects)
All Cause Mortality
Part A - TMT 0.0125 mg/kg/Day Part A - TMT 0.025 mg/kg/Day Part A - TMT 0.032 mg/kg/Day Part A - TMT 0.04 mg/kg/Day Part B - Neuroblastoma Part B - LGG Fusion Part B - NF-1 With PN Part B - BRAF V600 Mutant Solid Tumor Part C - TMT 0.025 mg/kg/Day + 50% DRB RP2D Part C - TMT 0.025 mg/kg/Day + 100% DRB RP2D Part C - TMT 0.032 mg/kg/Day + 100% DRB RP2D Part D - LGG Part D - LCH
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 0/3 (0%) 0/19 (0%) 0/12 (0%) 0/16 (0%) 0/11 (0%) 0/10 (0%) 0/10 (0%) 0/10 (0%) 0/3 (0%) 0/9 (0%) 0/6 (0%) 0/20 (0%) 0/10 (0%)
Serious Adverse Events
Part A - TMT 0.0125 mg/kg/Day Part A - TMT 0.025 mg/kg/Day Part A - TMT 0.032 mg/kg/Day Part A - TMT 0.04 mg/kg/Day Part B - Neuroblastoma Part B - LGG Fusion Part B - NF-1 With PN Part B - BRAF V600 Mutant Solid Tumor Part C - TMT 0.025 mg/kg/Day + 50% DRB RP2D Part C - TMT 0.025 mg/kg/Day + 100% DRB RP2D Part C - TMT 0.032 mg/kg/Day + 100% DRB RP2D Part D - LGG Part D - LCH
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 1/3 (33.3%) 8/19 (42.1%) 3/12 (25%) 11/16 (68.8%) 6/11 (54.5%) 6/10 (60%) 6/10 (60%) 5/10 (50%) 1/3 (33.3%) 5/9 (55.6%) 2/6 (33.3%) 8/20 (40%) 6/10 (60%)
Blood and lymphatic system disorders
Neutropenia 0/3 (0%) 0/19 (0%) 0/12 (0%) 0/16 (0%) 0/11 (0%) 0/10 (0%) 0/10 (0%) 0/10 (0%) 0/3 (0%) 0/9 (0%) 0/6 (0%) 1/20 (5%) 0/10 (0%)
Cardiac disorders
Bradycardia 0/3 (0%) 0/19 (0%) 0/12 (0%) 1/16 (6.3%) 0/11 (0%) 0/10 (0%) 0/10 (0%) 0/10 (0%) 0/3 (0%) 0/9 (0%) 0/6 (0%) 0/20 (0%) 0/10 (0%)
Tachycardia 1/3 (33.3%) 0/19 (0%) 0/12 (0%) 0/16 (0%) 0/11 (0%) 0/10 (0%) 0/10 (0%) 0/10 (0%) 0/3 (0%) 0/9 (0%) 0/6 (0%) 0/20 (0%) 1/10 (10%)
Endocrine disorders
Adrenal insufficiency 0/3 (0%) 1/19 (5.3%) 0/12 (0%) 0/16 (0%) 0/11 (0%) 0/10 (0%) 0/10 (0%) 0/10 (0%) 0/3 (0%) 0/9 (0%) 0/6 (0%) 0/20 (0%) 0/10 (0%)
Gastrointestinal disorders
Abdominal pain 0/3 (0%) 0/19 (0%) 0/12 (0%) 0/16 (0%) 0/11 (0%) 1/10 (10%) 0/10 (0%) 0/10 (0%) 0/3 (0%) 0/9 (0%) 0/6 (0%) 0/20 (0%) 0/10 (0%)
Anal haemorrhage 0/3 (0%) 0/19 (0%) 0/12 (0%) 0/16 (0%) 0/11 (0%) 1/10 (10%) 0/10 (0%) 0/10 (0%) 0/3 (0%) 0/9 (0%) 0/6 (0%) 0/20 (0%) 0/10 (0%)
Diarrhoea 0/3 (0%) 0/19 (0%) 0/12 (0%) 0/16 (0%) 0/11 (0%) 1/10 (10%) 0/10 (0%) 0/10 (0%) 0/3 (0%) 0/9 (0%) 0/6 (0%) 0/20 (0%) 0/10 (0%)
Nausea 0/3 (0%) 0/19 (0%) 0/12 (0%) 0/16 (0%) 0/11 (0%) 0/10 (0%) 0/10 (0%) 0/10 (0%) 0/3 (0%) 1/9 (11.1%) 0/6 (0%) 0/20 (0%) 0/10 (0%)
Pancreatitis 0/3 (0%) 0/19 (0%) 0/12 (0%) 1/16 (6.3%) 0/11 (0%) 0/10 (0%) 0/10 (0%) 0/10 (0%) 0/3 (0%) 0/9 (0%) 0/6 (0%) 0/20 (0%) 0/10 (0%)
Vomiting 0/3 (0%) 1/19 (5.3%) 1/12 (8.3%) 1/16 (6.3%) 0/11 (0%) 1/10 (10%) 0/10 (0%) 1/10 (10%) 0/3 (0%) 2/9 (22.2%) 0/6 (0%) 0/20 (0%) 0/10 (0%)
General disorders
Fatigue 0/3 (0%) 0/19 (0%) 0/12 (0%) 0/16 (0%) 1/11 (9.1%) 0/10 (0%) 0/10 (0%) 0/10 (0%) 0/3 (0%) 0/9 (0%) 0/6 (0%) 0/20 (0%) 0/10 (0%)
Hypothermia 0/3 (0%) 0/19 (0%) 0/12 (0%) 0/16 (0%) 0/11 (0%) 1/10 (10%) 0/10 (0%) 0/10 (0%) 0/3 (0%) 0/9 (0%) 0/6 (0%) 0/20 (0%) 0/10 (0%)
Influenza like illness 0/3 (0%) 0/19 (0%) 0/12 (0%) 1/16 (6.3%) 0/11 (0%) 0/10 (0%) 0/10 (0%) 0/10 (0%) 0/3 (0%) 0/9 (0%) 0/6 (0%) 0/20 (0%) 0/10 (0%)
Mucosal inflammation 0/3 (0%) 0/19 (0%) 0/12 (0%) 1/16 (6.3%) 0/11 (0%) 0/10 (0%) 0/10 (0%) 0/10 (0%) 0/3 (0%) 0/9 (0%) 0/6 (0%) 0/20 (0%) 0/10 (0%)
Oedema peripheral 0/3 (0%) 1/19 (5.3%) 0/12 (0%) 0/16 (0%) 0/11 (0%) 0/10 (0%) 0/10 (0%) 0/10 (0%) 0/3 (0%) 0/9 (0%) 0/6 (0%) 0/20 (0%) 0/10 (0%)
Pyrexia 0/3 (0%) 2/19 (10.5%) 1/12 (8.3%) 1/16 (6.3%) 2/11 (18.2%) 0/10 (0%) 2/10 (20%) 2/10 (20%) 0/3 (0%) 3/9 (33.3%) 1/6 (16.7%) 4/20 (20%) 4/10 (40%)
Infections and infestations
Adenovirus infection 0/3 (0%) 0/19 (0%) 0/12 (0%) 0/16 (0%) 0/11 (0%) 0/10 (0%) 0/10 (0%) 0/10 (0%) 0/3 (0%) 0/9 (0%) 0/6 (0%) 0/20 (0%) 1/10 (10%)
Arthritis infective 0/3 (0%) 0/19 (0%) 0/12 (0%) 1/16 (6.3%) 0/11 (0%) 0/10 (0%) 0/10 (0%) 0/10 (0%) 0/3 (0%) 0/9 (0%) 0/6 (0%) 0/20 (0%) 0/10 (0%)
Bronchiolitis 0/3 (0%) 1/19 (5.3%) 0/12 (0%) 0/16 (0%) 0/11 (0%) 0/10 (0%) 0/10 (0%) 0/10 (0%) 0/3 (0%) 0/9 (0%) 0/6 (0%) 0/20 (0%) 0/10 (0%)
Cellulitis 0/3 (0%) 1/19 (5.3%) 0/12 (0%) 0/16 (0%) 1/11 (9.1%) 0/10 (0%) 0/10 (0%) 0/10 (0%) 0/3 (0%) 0/9 (0%) 0/6 (0%) 0/20 (0%) 0/10 (0%)
Device related infection 0/3 (0%) 0/19 (0%) 0/12 (0%) 1/16 (6.3%) 0/11 (0%) 1/10 (10%) 0/10 (0%) 2/10 (20%) 0/3 (0%) 0/9 (0%) 0/6 (0%) 0/20 (0%) 0/10 (0%)
Enterobacter infection 0/3 (0%) 0/19 (0%) 0/12 (0%) 0/16 (0%) 1/11 (9.1%) 0/10 (0%) 0/10 (0%) 0/10 (0%) 0/3 (0%) 0/9 (0%) 0/6 (0%) 0/20 (0%) 0/10 (0%)
Enterococcal bacteraemia 0/3 (0%) 1/19 (5.3%) 0/12 (0%) 0/16 (0%) 0/11 (0%) 0/10 (0%) 0/10 (0%) 0/10 (0%) 0/3 (0%) 0/9 (0%) 0/6 (0%) 0/20 (0%) 0/10 (0%)
Escherichia infection 0/3 (0%) 0/19 (0%) 0/12 (0%) 1/16 (6.3%) 0/11 (0%) 0/10 (0%) 0/10 (0%) 0/10 (0%) 0/3 (0%) 0/9 (0%) 0/6 (0%) 0/20 (0%) 0/10 (0%)
Gastroenteritis 0/3 (0%) 2/19 (10.5%) 0/12 (0%) 0/16 (0%) 0/11 (0%) 0/10 (0%) 0/10 (0%) 1/10 (10%) 0/3 (0%) 0/9 (0%) 0/6 (0%) 0/20 (0%) 0/10 (0%)
Influenza 0/3 (0%) 0/19 (0%) 0/12 (0%) 0/16 (0%) 0/11 (0%) 0/10 (0%) 0/10 (0%) 1/10 (10%) 0/3 (0%) 0/9 (0%) 0/6 (0%) 0/20 (0%) 0/10 (0%)
Lymphangitis 0/3 (0%) 0/19 (0%) 0/12 (0%) 0/16 (0%) 0/11 (0%) 1/10 (10%) 0/10 (0%) 0/10 (0%) 0/3 (0%) 0/9 (0%) 0/6 (0%) 0/20 (0%) 0/10 (0%)
Medical device site infection 0/3 (0%) 1/19 (5.3%) 0/12 (0%) 0/16 (0%) 0/11 (0%) 0/10 (0%) 0/10 (0%) 0/10 (0%) 0/3 (0%) 0/9 (0%) 0/6 (0%) 0/20 (0%) 0/10 (0%)
Osteomyelitis 0/3 (0%) 1/19 (5.3%) 0/12 (0%) 0/16 (0%) 0/11 (0%) 0/10 (0%) 0/10 (0%) 0/10 (0%) 0/3 (0%) 0/9 (0%) 0/6 (0%) 0/20 (0%) 0/10 (0%)
Paronychia 0/3 (0%) 0/19 (0%) 0/12 (0%) 0/16 (0%) 0/11 (0%) 0/10 (0%) 1/10 (10%) 0/10 (0%) 0/3 (0%) 0/9 (0%) 0/6 (0%) 0/20 (0%) 0/10 (0%)
Parotitis 0/3 (0%) 0/19 (0%) 0/12 (0%) 0/16 (0%) 0/11 (0%) 0/10 (0%) 0/10 (0%) 0/10 (0%) 0/3 (0%) 0/9 (0%) 0/6 (0%) 0/20 (0%) 1/10 (10%)
Pelvic abscess 0/3 (0%) 0/19 (0%) 0/12 (0%) 1/16 (6.3%) 0/11 (0%) 0/10 (0%) 0/10 (0%) 0/10 (0%) 0/3 (0%) 0/9 (0%) 0/6 (0%) 0/20 (0%) 0/10 (0%)
Pharyngitis 0/3 (0%) 0/19 (0%) 0/12 (0%) 0/16 (0%) 0/11 (0%) 0/10 (0%) 0/10 (0%) 1/10 (10%) 0/3 (0%) 0/9 (0%) 0/6 (0%) 0/20 (0%) 0/10 (0%)
Pharyngitis streptococcal 0/3 (0%) 0/19 (0%) 0/12 (0%) 0/16 (0%) 0/11 (0%) 0/10 (0%) 0/10 (0%) 0/10 (0%) 0/3 (0%) 0/9 (0%) 0/6 (0%) 0/20 (0%) 1/10 (10%)
Pneumonia 0/3 (0%) 2/19 (10.5%) 1/12 (8.3%) 0/16 (0%) 1/11 (9.1%) 1/10 (10%) 0/10 (0%) 0/10 (0%) 0/3 (0%) 0/9 (0%) 0/6 (0%) 0/20 (0%) 0/10 (0%)
Pyelonephritis 0/3 (0%) 1/19 (5.3%) 0/12 (0%) 0/16 (0%) 0/11 (0%) 0/10 (0%) 0/10 (0%) 0/10 (0%) 0/3 (0%) 0/9 (0%) 0/6 (0%) 0/20 (0%) 0/10 (0%)
Rotavirus infection 0/3 (0%) 1/19 (5.3%) 0/12 (0%) 0/16 (0%) 0/11 (0%) 0/10 (0%) 0/10 (0%) 0/10 (0%) 0/3 (0%) 0/9 (0%) 0/6 (0%) 0/20 (0%) 0/10 (0%)
Sepsis 0/3 (0%) 0/19 (0%) 0/12 (0%) 0/16 (0%) 0/11 (0%) 0/10 (0%) 0/10 (0%) 1/10 (10%) 0/3 (0%) 0/9 (0%) 0/6 (0%) 0/20 (0%) 0/10 (0%)
Skin infection 0/3 (0%) 1/19 (5.3%) 0/12 (0%) 1/16 (6.3%) 0/11 (0%) 0/10 (0%) 0/10 (0%) 0/10 (0%) 0/3 (0%) 0/9 (0%) 0/6 (0%) 0/20 (0%) 0/10 (0%)
Tonsillitis 0/3 (0%) 1/19 (5.3%) 0/12 (0%) 0/16 (0%) 0/11 (0%) 0/10 (0%) 0/10 (0%) 0/10 (0%) 0/3 (0%) 0/9 (0%) 0/6 (0%) 1/20 (5%) 0/10 (0%)
Upper respiratory tract infection 0/3 (0%) 1/19 (5.3%) 0/12 (0%) 0/16 (0%) 0/11 (0%) 0/10 (0%) 1/10 (10%) 1/10 (10%) 0/3 (0%) 0/9 (0%) 1/6 (16.7%) 0/20 (0%) 1/10 (10%)
Varicella 0/3 (0%) 0/19 (0%) 0/12 (0%) 0/16 (0%) 0/11 (0%) 1/10 (10%) 1/10 (10%) 0/10 (0%) 0/3 (0%) 0/9 (0%) 1/6 (16.7%) 0/20 (0%) 0/10 (0%)
Vascular device infection 0/3 (0%) 0/19 (0%) 0/12 (0%) 0/16 (0%) 0/11 (0%) 1/10 (10%) 0/10 (0%) 0/10 (0%) 0/3 (0%) 0/9 (0%) 0/6 (0%) 0/20 (0%) 0/10 (0%)
Viral infection 0/3 (0%) 2/19 (10.5%) 0/12 (0%) 1/16 (6.3%) 0/11 (0%) 0/10 (0%) 0/10 (0%) 0/10 (0%) 0/3 (0%) 0/9 (0%) 0/6 (0%) 0/20 (0%) 0/10 (0%)
Injury, poisoning and procedural complications
Accidental overdose 0/3 (0%) 0/19 (0%) 0/12 (0%) 0/16 (0%) 0/11 (0%) 0/10 (0%) 1/10 (10%) 0/10 (0%) 0/3 (0%) 0/9 (0%) 0/6 (0%) 0/20 (0%) 0/10 (0%)
Femur fracture 0/3 (0%) 0/19 (0%) 0/12 (0%) 1/16 (6.3%) 0/11 (0%) 0/10 (0%) 0/10 (0%) 0/10 (0%) 0/3 (0%) 0/9 (0%) 0/6 (0%) 0/20 (0%) 0/10 (0%)
Foot fracture 0/3 (0%) 1/19 (5.3%) 0/12 (0%) 0/16 (0%) 0/11 (0%) 0/10 (0%) 0/10 (0%) 0/10 (0%) 0/3 (0%) 0/9 (0%) 0/6 (0%) 0/20 (0%) 0/10 (0%)
Hip fracture 0/3 (0%) 0/19 (0%) 0/12 (0%) 1/16 (6.3%) 0/11 (0%) 0/10 (0%) 0/10 (0%) 0/10 (0%) 0/3 (0%) 0/9 (0%) 0/6 (0%) 0/20 (0%) 0/10 (0%)
Upper limb fracture 0/3 (0%) 0/19 (0%) 0/12 (0%) 0/16 (0%) 0/11 (0%) 0/10 (0%) 0/10 (0%) 0/10 (0%) 0/3 (0%) 1/9 (11.1%) 0/6 (0%) 0/20 (0%) 0/10 (0%)
Vascular access complication 0/3 (0%) 0/19 (0%) 0/12 (0%) 0/16 (0%) 0/11 (0%) 1/10 (10%) 0/10 (0%) 0/10 (0%) 0/3 (0%) 0/9 (0%) 0/6 (0%) 0/20 (0%) 0/10 (0%)
Wound secretion 0/3 (0%) 0/19 (0%) 0/12 (0%) 0/16 (0%) 1/11 (9.1%) 0/10 (0%) 0/10 (0%) 0/10 (0%) 0/3 (0%) 0/9 (0%) 0/6 (0%) 0/20 (0%) 0/10 (0%)
Investigations
Alanine aminotransferase increased 0/3 (0%) 0/19 (0%) 0/12 (0%) 0/16 (0%) 1/11 (9.1%) 0/10 (0%) 0/10 (0%) 0/10 (0%) 0/3 (0%) 0/9 (0%) 0/6 (0%) 0/20 (0%) 1/10 (10%)
Aspartate aminotransferase increased 0/3 (0%) 0/19 (0%) 0/12 (0%) 0/16 (0%) 1/11 (9.1%) 0/10 (0%) 0/10 (0%) 0/10 (0%) 0/3 (0%) 0/9 (0%) 0/6 (0%) 0/20 (0%) 1/10 (10%)
Blood alkaline phosphatase increased 0/3 (0%) 1/19 (5.3%) 0/12 (0%) 0/16 (0%) 0/11 (0%) 0/10 (0%) 0/10 (0%) 0/10 (0%) 0/3 (0%) 0/9 (0%) 0/6 (0%) 0/20 (0%) 0/10 (0%)
Blood bilirubin increased 0/3 (0%) 0/19 (0%) 0/12 (0%) 0/16 (0%) 1/11 (9.1%) 0/10 (0%) 0/10 (0%) 0/10 (0%) 0/3 (0%) 0/9 (0%) 0/6 (0%) 0/20 (0%) 0/10 (0%)
Blood culture positive 0/3 (0%) 1/19 (5.3%) 0/12 (0%) 0/16 (0%) 0/11 (0%) 1/10 (10%) 0/10 (0%) 0/10 (0%) 0/3 (0%) 0/9 (0%) 0/6 (0%) 0/20 (0%) 0/10 (0%)
C-reactive protein increased 0/3 (0%) 0/19 (0%) 0/12 (0%) 0/16 (0%) 0/11 (0%) 0/10 (0%) 0/10 (0%) 0/10 (0%) 0/3 (0%) 1/9 (11.1%) 0/6 (0%) 0/20 (0%) 0/10 (0%)
Ejection fraction decreased 0/3 (0%) 0/19 (0%) 0/12 (0%) 0/16 (0%) 0/11 (0%) 0/10 (0%) 0/10 (0%) 0/10 (0%) 0/3 (0%) 2/9 (22.2%) 0/6 (0%) 1/20 (5%) 0/10 (0%)
Weight decreased 0/3 (0%) 0/19 (0%) 0/12 (0%) 0/16 (0%) 0/11 (0%) 0/10 (0%) 0/10 (0%) 0/10 (0%) 0/3 (0%) 0/9 (0%) 0/6 (0%) 1/20 (5%) 0/10 (0%)
White blood cell count decreased 0/3 (0%) 0/19 (0%) 0/12 (0%) 0/16 (0%) 0/11 (0%) 0/10 (0%) 0/10 (0%) 0/10 (0%) 0/3 (0%) 0/9 (0%) 0/6 (0%) 1/20 (5%) 0/10 (0%)
Metabolism and nutrition disorders
Decreased appetite 0/3 (0%) 0/19 (0%) 0/12 (0%) 0/16 (0%) 1/11 (9.1%) 0/10 (0%) 0/10 (0%) 0/10 (0%) 0/3 (0%) 0/9 (0%) 0/6 (0%) 0/20 (0%) 0/10 (0%)
Dehydration 0/3 (0%) 0/19 (0%) 0/12 (0%) 0/16 (0%) 0/11 (0%) 0/10 (0%) 0/10 (0%) 0/10 (0%) 0/3 (0%) 1/9 (11.1%) 1/6 (16.7%) 0/20 (0%) 0/10 (0%)
Hyperglycaemia 0/3 (0%) 0/19 (0%) 0/12 (0%) 0/16 (0%) 0/11 (0%) 0/10 (0%) 0/10 (0%) 0/10 (0%) 0/3 (0%) 0/9 (0%) 0/6 (0%) 1/20 (5%) 0/10 (0%)
Hypernatraemia 0/3 (0%) 1/19 (5.3%) 0/12 (0%) 1/16 (6.3%) 0/11 (0%) 0/10 (0%) 0/10 (0%) 0/10 (0%) 0/3 (0%) 0/9 (0%) 0/6 (0%) 0/20 (0%) 0/10 (0%)
Hyponatraemia 0/3 (0%) 1/19 (5.3%) 0/12 (0%) 1/16 (6.3%) 0/11 (0%) 0/10 (0%) 0/10 (0%) 1/10 (10%) 0/3 (0%) 0/9 (0%) 0/6 (0%) 0/20 (0%) 0/10 (0%)
Musculoskeletal and connective tissue disorders
Back pain 0/3 (0%) 0/19 (0%) 0/12 (0%) 0/16 (0%) 0/11 (0%) 0/10 (0%) 0/10 (0%) 0/10 (0%) 0/3 (0%) 0/9 (0%) 0/6 (0%) 1/20 (5%) 0/10 (0%)
Kyphosis 0/3 (0%) 0/19 (0%) 0/12 (0%) 0/16 (0%) 1/11 (9.1%) 0/10 (0%) 0/10 (0%) 0/10 (0%) 0/3 (0%) 0/9 (0%) 0/6 (0%) 0/20 (0%) 0/10 (0%)
Muscular weakness 0/3 (0%) 0/19 (0%) 0/12 (0%) 0/16 (0%) 0/11 (0%) 0/10 (0%) 0/10 (0%) 1/10 (10%) 0/3 (0%) 0/9 (0%) 0/6 (0%) 0/20 (0%) 0/10 (0%)
Pain in extremity 0/3 (0%) 0/19 (0%) 0/12 (0%) 1/16 (6.3%) 0/11 (0%) 0/10 (0%) 0/10 (0%) 0/10 (0%) 0/3 (0%) 0/9 (0%) 0/6 (0%) 0/20 (0%) 0/10 (0%)
Spinal instability 0/3 (0%) 0/19 (0%) 0/12 (0%) 0/16 (0%) 1/11 (9.1%) 0/10 (0%) 0/10 (0%) 0/10 (0%) 0/3 (0%) 0/9 (0%) 0/6 (0%) 0/20 (0%) 0/10 (0%)
Nervous system disorders
Ataxia 0/3 (0%) 0/19 (0%) 0/12 (0%) 0/16 (0%) 1/11 (9.1%) 0/10 (0%) 0/10 (0%) 0/10 (0%) 0/3 (0%) 1/9 (11.1%) 0/6 (0%) 0/20 (0%) 0/10 (0%)
Balance disorder 0/3 (0%) 0/19 (0%) 0/12 (0%) 0/16 (0%) 0/11 (0%) 0/10 (0%) 0/10 (0%) 0/10 (0%) 0/3 (0%) 1/9 (11.1%) 0/6 (0%) 0/20 (0%) 0/10 (0%)
Brain oedema 0/3 (0%) 0/19 (0%) 0/12 (0%) 0/16 (0%) 0/11 (0%) 0/10 (0%) 0/10 (0%) 0/10 (0%) 1/3 (33.3%) 0/9 (0%) 0/6 (0%) 0/20 (0%) 0/10 (0%)
Depressed level of consciousness 0/3 (0%) 0/19 (0%) 0/12 (0%) 0/16 (0%) 0/11 (0%) 0/10 (0%) 0/10 (0%) 1/10 (10%) 0/3 (0%) 0/9 (0%) 0/6 (0%) 0/20 (0%) 0/10 (0%)
Dysarthria 0/3 (0%) 0/19 (0%) 0/12 (0%) 0/16 (0%) 0/11 (0%) 0/10 (0%) 0/10 (0%) 0/10 (0%) 0/3 (0%) 1/9 (11.1%) 0/6 (0%) 0/20 (0%) 0/10 (0%)
Encephalopathy 0/3 (0%) 0/19 (0%) 0/12 (0%) 0/16 (0%) 0/11 (0%) 0/10 (0%) 0/10 (0%) 1/10 (10%) 0/3 (0%) 0/9 (0%) 0/6 (0%) 0/20 (0%) 0/10 (0%)
Epilepsy 0/3 (0%) 0/19 (0%) 0/12 (0%) 1/16 (6.3%) 0/11 (0%) 0/10 (0%) 0/10 (0%) 0/10 (0%) 0/3 (0%) 0/9 (0%) 0/6 (0%) 0/20 (0%) 0/10 (0%)
Headache 0/3 (0%) 0/19 (0%) 0/12 (0%) 0/16 (0%) 0/11 (0%) 1/10 (10%) 0/10 (0%) 0/10 (0%) 0/3 (0%) 0/9 (0%) 0/6 (0%) 0/20 (0%) 0/10 (0%)
Hydrocephalus 0/3 (0%) 1/19 (5.3%) 0/12 (0%) 0/16 (0%) 0/11 (0%) 0/10 (0%) 0/10 (0%) 1/10 (10%) 0/3 (0%) 0/9 (0%) 0/6 (0%) 0/20 (0%) 0/10 (0%)
Intracranial pressure increased 0/3 (0%) 0/19 (0%) 0/12 (0%) 0/16 (0%) 0/11 (0%) 0/10 (0%) 0/10 (0%) 1/10 (10%) 0/3 (0%) 0/9 (0%) 0/6 (0%) 0/20 (0%) 0/10 (0%)
Posterior reversible encephalopathy syndrome 0/3 (0%) 0/19 (0%) 0/12 (0%) 0/16 (0%) 0/11 (0%) 0/10 (0%) 0/10 (0%) 0/10 (0%) 0/3 (0%) 0/9 (0%) 0/6 (0%) 1/20 (5%) 0/10 (0%)
Pyramidal tract syndrome 0/3 (0%) 0/19 (0%) 0/12 (0%) 0/16 (0%) 0/11 (0%) 0/10 (0%) 0/10 (0%) 1/10 (10%) 0/3 (0%) 0/9 (0%) 0/6 (0%) 0/20 (0%) 0/10 (0%)
Seizure 0/3 (0%) 0/19 (0%) 0/12 (0%) 3/16 (18.8%) 0/11 (0%) 0/10 (0%) 0/10 (0%) 1/10 (10%) 0/3 (0%) 0/9 (0%) 0/6 (0%) 1/20 (5%) 0/10 (0%)
Syncope 0/3 (0%) 0/19 (0%) 0/12 (0%) 0/16 (0%) 0/11 (0%) 0/10 (0%) 1/10 (10%) 0/10 (0%) 0/3 (0%) 0/9 (0%) 0/6 (0%) 0/20 (0%) 0/10 (0%)
Psychiatric disorders
Restlessness 0/3 (0%) 0/19 (0%) 0/12 (0%) 0/16 (0%) 0/11 (0%) 0/10 (0%) 0/10 (0%) 0/10 (0%) 0/3 (0%) 0/9 (0%) 0/6 (0%) 1/20 (5%) 0/10 (0%)
Renal and urinary disorders
Haematuria 0/3 (0%) 0/19 (0%) 0/12 (0%) 0/16 (0%) 0/11 (0%) 1/10 (10%) 0/10 (0%) 0/10 (0%) 0/3 (0%) 0/9 (0%) 0/6 (0%) 0/20 (0%) 0/10 (0%)
Respiratory, thoracic and mediastinal disorders
Aspiration 0/3 (0%) 0/19 (0%) 0/12 (0%) 0/16 (0%) 1/11 (9.1%) 0/10 (0%) 1/10 (10%) 0/10 (0%) 0/3 (0%) 0/9 (0%) 0/6 (0%) 0/20 (0%) 0/10 (0%)
Cough 0/3 (0%) 0/19 (0%) 0/12 (0%) 0/16 (0%) 0/11 (0%) 0/10 (0%) 0/10 (0%) 1/10 (10%) 0/3 (0%) 0/9 (0%) 1/6 (16.7%) 0/20 (0%) 0/10 (0%)
Hypoxia 0/3 (0%) 1/19 (5.3%) 0/12 (0%) 1/16 (6.3%) 0/11 (0%) 0/10 (0%) 0/10 (0%) 0/10 (0%) 0/3 (0%) 0/9 (0%) 0/6 (0%) 0/20 (0%) 0/10 (0%)
Lung disorder 0/3 (0%) 0/19 (0%) 0/12 (0%) 0/16 (0%) 0/11 (0%) 0/10 (0%) 0/10 (0%) 0/10 (0%) 0/3 (0%) 0/9 (0%) 0/6 (0%) 1/20 (5%) 0/10 (0%)
Pneumonitis 0/3 (0%) 0/19 (0%) 0/12 (0%) 0/16 (0%) 0/11 (0%) 0/10 (0%) 0/10 (0%) 1/10 (10%) 0/3 (0%) 0/9 (0%) 0/6 (0%) 0/20 (0%) 0/10 (0%)
Respiratory distress 0/3 (0%) 0/19 (0%) 0/12 (0%) 0/16 (0%) 0/11 (0%) 0/10 (0%) 0/10 (0%) 0/10 (0%) 0/3 (0%) 0/9 (0%) 0/6 (0%) 1/20 (5%) 0/10 (0%)
Tonsillar hypertrophy 0/3 (0%) 1/19 (5.3%) 0/12 (0%) 0/16 (0%) 0/11 (0%) 0/10 (0%) 0/10 (0%) 0/10 (0%) 0/3 (0%) 0/9 (0%) 0/6 (0%) 0/20 (0%) 0/10 (0%)
Skin and subcutaneous tissue disorders
Rash 0/3 (0%) 1/19 (5.3%) 0/12 (0%) 0/16 (0%) 0/11 (0%) 0/10 (0%) 0/10 (0%) 0/10 (0%) 0/3 (0%) 0/9 (0%) 0/6 (0%) 0/20 (0%) 0/10 (0%)
Surgical and medical procedures
Gastrointestinal tube insertion 0/3 (0%) 0/19 (0%) 1/12 (8.3%) 0/16 (0%) 0/11 (0%) 0/10 (0%) 0/10 (0%) 0/10 (0%) 0/3 (0%) 0/9 (0%) 0/6 (0%) 0/20 (0%) 0/10 (0%)
Vascular disorders
Hypertension 0/3 (0%) 0/19 (0%) 0/12 (0%) 0/16 (0%) 0/11 (0%) 0/10 (0%) 0/10 (0%) 0/10 (0%) 0/3 (0%) 0/9 (0%) 0/6 (0%) 1/20 (5%) 0/10 (0%)
Hypotension 0/3 (0%) 0/19 (0%) 0/12 (0%) 1/16 (6.3%) 0/11 (0%) 1/10 (10%) 0/10 (0%) 0/10 (0%) 0/3 (0%) 0/9 (0%) 0/6 (0%) 1/20 (5%) 1/10 (10%)
Other (Not Including Serious) Adverse Events
Part A - TMT 0.0125 mg/kg/Day Part A - TMT 0.025 mg/kg/Day Part A - TMT 0.032 mg/kg/Day Part A - TMT 0.04 mg/kg/Day Part B - Neuroblastoma Part B - LGG Fusion Part B - NF-1 With PN Part B - BRAF V600 Mutant Solid Tumor Part C - TMT 0.025 mg/kg/Day + 50% DRB RP2D Part C - TMT 0.025 mg/kg/Day + 100% DRB RP2D Part C - TMT 0.032 mg/kg/Day + 100% DRB RP2D Part D - LGG Part D - LCH
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 3/3 (100%) 19/19 (100%) 12/12 (100%) 16/16 (100%) 11/11 (100%) 10/10 (100%) 10/10 (100%) 10/10 (100%) 3/3 (100%) 9/9 (100%) 6/6 (100%) 20/20 (100%) 10/10 (100%)
Blood and lymphatic system disorders
Anaemia 0/3 (0%) 9/19 (47.4%) 6/12 (50%) 7/16 (43.8%) 6/11 (54.5%) 3/10 (30%) 4/10 (40%) 5/10 (50%) 0/3 (0%) 4/9 (44.4%) 1/6 (16.7%) 4/20 (20%) 2/10 (20%)
Bone marrow oedema 0/3 (0%) 0/19 (0%) 1/12 (8.3%) 0/16 (0%) 0/11 (0%) 0/10 (0%) 0/10 (0%) 0/10 (0%) 0/3 (0%) 0/9 (0%) 0/6 (0%) 0/20 (0%) 0/10 (0%)
Eosinophilia 0/3 (0%) 0/19 (0%) 1/12 (8.3%) 0/16 (0%) 0/11 (0%) 0/10 (0%) 0/10 (0%) 0/10 (0%) 0/3 (0%) 0/9 (0%) 0/6 (0%) 0/20 (0%) 0/10 (0%)
Febrile neutropenia 0/3 (0%) 0/19 (0%) 0/12 (0%) 0/16 (0%) 0/11 (0%) 0/10 (0%) 0/10 (0%) 0/10 (0%) 0/3 (0%) 1/9 (11.1%) 0/6 (0%) 0/20 (0%) 0/10 (0%)
Hypochromasia 0/3 (0%) 1/19 (5.3%) 0/12 (0%) 0/16 (0%) 0/11 (0%) 0/10 (0%) 0/10 (0%) 0/10 (0%) 0/3 (0%) 0/9 (0%) 0/6 (0%) 0/20 (0%) 0/10 (0%)
Leukocytosis 0/3 (0%) 0/19 (0%) 1/12 (8.3%) 0/16 (0%) 0/11 (0%) 0/10 (0%) 0/10 (0%) 0/10 (0%) 0/3 (0%) 0/9 (0%) 0/6 (0%) 0/20 (0%) 0/10 (0%)
Leukopenia 0/3 (0%) 0/19 (0%) 0/12 (0%) 0/16 (0%) 0/11 (0%) 0/10 (0%) 0/10 (0%) 1/10 (10%) 0/3 (0%) 0/9 (0%) 0/6 (0%) 0/20 (0%) 0/10 (0%)
Lymphadenitis 0/3 (0%) 1/19 (5.3%) 0/12 (0%) 0/16 (0%) 0/11 (0%) 0/10 (0%) 0/10 (0%) 0/10 (0%) 0/3 (0%) 0/9 (0%) 0/6 (0%) 0/20 (0%) 0/10 (0%)
Lymphadenopathy 0/3 (0%) 1/19 (5.3%) 0/12 (0%) 1/16 (6.3%) 1/11 (9.1%) 0/10 (0%) 0/10 (0%) 0/10 (0%) 0/3 (0%) 1/9 (11.1%) 0/6 (0%) 0/20 (0%) 0/10 (0%)
Lymphopenia 0/3 (0%) 0/19 (0%) 0/12 (0%) 0/16 (0%) 1/11 (9.1%) 0/10 (0%) 0/10 (0%) 0/10 (0%) 0/3 (0%) 0/9 (0%) 1/6 (16.7%) 0/20 (0%) 0/10 (0%)
Neutropenia 0/3 (0%) 0/19 (0%) 0/12 (0%) 1/16 (6.3%) 1/11 (9.1%) 0/10 (0%) 0/10 (0%) 1/10 (10%) 0/3 (0%) 0/9 (0%) 0/6 (0%) 3/20 (15%) 0/10 (0%)
Thrombocytopenia 1/3 (33.3%) 0/19 (0%) 0/12 (0%) 0/16 (0%) 1/11 (9.1%) 1/10 (10%) 0/10 (0%) 0/10 (0%) 0/3 (0%) 0/9 (0%) 0/6 (0%) 0/20 (0%) 0/10 (0%)
Thrombocytosis 0/3 (0%) 0/19 (0%) 0/12 (0%) 0/16 (0%) 0/11 (0%) 0/10 (0%) 0/10 (0%) 1/10 (10%) 0/3 (0%) 0/9 (0%) 0/6 (0%) 0/20 (0%) 0/10 (0%)
Cardiac disorders
Angina pectoris 0/3 (0%) 0/19 (0%) 0/12 (0%) 1/16 (6.3%) 0/11 (0%) 0/10 (0%) 0/10 (0%) 0/10 (0%) 0/3 (0%) 0/9 (0%) 0/6 (0%) 0/20 (0%) 0/10 (0%)
Atrioventricular block first degree 0/3 (0%) 0/19 (0%) 0/12 (0%) 0/16 (0%) 0/11 (0%) 0/10 (0%) 0/10 (0%) 0/10 (0%) 0/3 (0%) 1/9 (11.1%) 0/6 (0%) 0/20 (0%) 0/10 (0%)
Bradycardia 0/3 (0%) 0/19 (0%) 0/12 (0%) 0/16 (0%) 0/11 (0%) 0/10 (0%) 0/10 (0%) 0/10 (0%) 0/3 (0%) 0/9 (0%) 0/6 (0%) 0/20 (0%) 1/10 (10%)
Cardiac disorder 0/3 (0%) 0/19 (0%) 0/12 (0%) 0/16 (0%) 0/11 (0%) 1/10 (10%) 0/10 (0%) 0/10 (0%) 0/3 (0%) 0/9 (0%) 0/6 (0%) 0/20 (0%) 0/10 (0%)
Mitral valve disease 0/3 (0%) 0/19 (0%) 2/12 (16.7%) 0/16 (0%) 0/11 (0%) 0/10 (0%) 0/10 (0%) 0/10 (0%) 1/3 (33.3%) 0/9 (0%) 0/6 (0%) 0/20 (0%) 0/10 (0%)
Palpitations 0/3 (0%) 1/19 (5.3%) 0/12 (0%) 0/16 (0%) 0/11 (0%) 0/10 (0%) 0/10 (0%) 0/10 (0%) 0/3 (0%) 0/9 (0%) 0/6 (0%) 0/20 (0%) 0/10 (0%)
Sinus bradycardia 0/3 (0%) 0/19 (0%) 1/12 (8.3%) 0/16 (0%) 0/11 (0%) 0/10 (0%) 0/10 (0%) 0/10 (0%) 0/3 (0%) 1/9 (11.1%) 0/6 (0%) 2/20 (10%) 0/10 (0%)
Sinus tachycardia 0/3 (0%) 5/19 (26.3%) 1/12 (8.3%) 2/16 (12.5%) 2/11 (18.2%) 1/10 (10%) 0/10 (0%) 1/10 (10%) 0/3 (0%) 3/9 (33.3%) 0/6 (0%) 2/20 (10%) 1/10 (10%)
Systolic dysfunction 0/3 (0%) 0/19 (0%) 0/12 (0%) 0/16 (0%) 0/11 (0%) 1/10 (10%) 0/10 (0%) 0/10 (0%) 0/3 (0%) 0/9 (0%) 0/6 (0%) 0/20 (0%) 0/10 (0%)
Tachycardia 0/3 (0%) 0/19 (0%) 1/12 (8.3%) 1/16 (6.3%) 0/11 (0%) 0/10 (0%) 0/10 (0%) 0/10 (0%) 0/3 (0%) 2/9 (22.2%) 0/6 (0%) 1/20 (5%) 1/10 (10%)
Tricuspid valve disease 0/3 (0%) 0/19 (0%) 1/12 (8.3%) 0/16 (0%) 0/11 (0%) 0/10 (0%) 0/10 (0%) 0/10 (0%) 0/3 (0%) 0/9 (0%) 0/6 (0%) 0/20 (0%) 0/10 (0%)
Congenital, familial and genetic disorders
Phimosis 0/3 (0%) 0/19 (0%) 1/12 (8.3%) 0/16 (0%) 0/11 (0%) 0/10 (0%) 0/10 (0%) 0/10 (0%) 0/3 (0%) 0/9 (0%) 0/6 (0%) 0/20 (0%) 0/10 (0%)
Ear and labyrinth disorders
Deafness unilateral 0/3 (0%) 1/19 (5.3%) 0/12 (0%) 0/16 (0%) 0/11 (0%) 0/10 (0%) 0/10 (0%) 0/10 (0%) 0/3 (0%) 0/9 (0%) 0/6 (0%) 0/20 (0%) 0/10 (0%)
Ear pain 1/3 (33.3%) 2/19 (10.5%) 2/12 (16.7%) 0/16 (0%) 1/11 (9.1%) 1/10 (10%) 0/10 (0%) 0/10 (0%) 0/3 (0%) 0/9 (0%) 0/6 (0%) 0/20 (0%) 0/10 (0%)
External ear inflammation 0/3 (0%) 0/19 (0%) 0/12 (0%) 1/16 (6.3%) 1/11 (9.1%) 0/10 (0%) 0/10 (0%) 0/10 (0%) 0/3 (0%) 0/9 (0%) 0/6 (0%) 0/20 (0%) 0/10 (0%)
External ear pain 0/3 (0%) 0/19 (0%) 0/12 (0%) 1/16 (6.3%) 0/11 (0%) 0/10 (0%) 0/10 (0%) 0/10 (0%) 0/3 (0%) 0/9 (0%) 0/6 (0%) 0/20 (0%) 0/10 (0%)
Hypoacusis 0/3 (0%) 0/19 (0%) 0/12 (0%) 1/16 (6.3%) 0/11 (0%) 0/10 (0%) 0/10 (0%) 0/10 (0%) 0/3 (0%) 0/9 (0%) 0/6 (0%) 0/20 (0%) 0/10 (0%)
Middle ear inflammation 0/3 (0%) 0/19 (0%) 0/12 (0%) 0/16 (0%) 1/11 (9.1%) 0/10 (0%) 0/10 (0%) 0/10 (0%) 0/3 (0%) 0/9 (0%) 0/6 (0%) 0/20 (0%) 0/10 (0%)
Otorrhoea 0/3 (0%) 1/19 (5.3%) 0/12 (0%) 0/16 (0%) 0/11 (0%) 0/10 (0%) 0/10 (0%) 0/10 (0%) 0/3 (0%) 0/9 (0%) 0/6 (0%) 0/20 (0%) 0/10 (0%)
Tympanic membrane perforation 0/3 (0%) 0/19 (0%) 0/12 (0%) 0/16 (0%) 0/11 (0%) 0/10 (0%) 0/10 (0%) 0/10 (0%) 0/3 (0%) 0/9 (0%) 0/6 (0%) 1/20 (5%) 1/10 (10%)
Vertigo 0/3 (0%) 1/19 (5.3%) 0/12 (0%) 0/16 (0%) 0/11 (0%) 0/10 (0%) 0/10 (0%) 0/10 (0%) 0/3 (0%) 0/9 (0%) 0/6 (0%) 0/20 (0%) 0/10 (0%)
Endocrine disorders
Adrenal insufficiency 0/3 (0%) 1/19 (5.3%) 0/12 (0%) 0/16 (0%) 0/11 (0%) 0/10 (0%) 0/10 (0%) 0/10 (0%) 0/3 (0%) 0/9 (0%) 0/6 (0%) 0/20 (0%) 0/10 (0%)
Adrenocorticotropic hormone deficiency 0/3 (0%) 0/19 (0%) 0/12 (0%) 0/16 (0%) 0/11 (0%) 0/10 (0%) 0/10 (0%) 0/10 (0%) 0/3 (0%) 1/9 (11.1%) 0/6 (0%) 0/20 (0%) 0/10 (0%)
Growth hormone deficiency 0/3 (0%) 0/19 (0%) 0/12 (0%) 0/16 (0%) 0/11 (0%) 0/10 (0%) 0/10 (0%) 0/10 (0%) 0/3 (0%) 1/9 (11.1%) 0/6 (0%) 0/20 (0%) 0/10 (0%)
Hypogonadism 0/3 (0%) 0/19 (0%) 0/12 (0%) 0/16 (0%) 0/11 (0%) 0/10 (0%) 0/10 (0%) 0/10 (0%) 1/3 (33.3%) 0/9 (0%) 0/6 (0%) 0/20 (0%) 0/10 (0%)
Hypothyroidism 0/3 (0%) 0/19 (0%) 0/12 (0%) 0/16 (0%) 0/11 (0%) 0/10 (0%) 0/10 (0%) 0/10 (0%) 0/3 (0%) 1/9 (11.1%) 0/6 (0%) 0/20 (0%) 0/10 (0%)
Precocious puberty 0/3 (0%) 0/19 (0%) 0/12 (0%) 0/16 (0%) 0/11 (0%) 1/10 (10%) 0/10 (0%) 0/10 (0%) 0/3 (0%) 0/9 (0%) 1/6 (16.7%) 0/20 (0%) 0/10 (0%)
Eye disorders
Amblyopia 0/3 (0%) 2/19 (10.5%) 0/12 (0%) 0/16 (0%) 0/11 (0%) 0/10 (0%) 0/10 (0%) 0/10 (0%) 0/3 (0%) 0/9 (0%) 0/6 (0%) 0/20 (0%) 0/10 (0%)
Astigmatism 0/3 (0%) 1/19 (5.3%) 1/12 (8.3%) 0/16 (0%) 0/11 (0%) 0/10 (0%) 0/10 (0%) 0/10 (0%) 0/3 (0%) 0/9 (0%) 0/6 (0%) 0/20 (0%) 0/10 (0%)
Bell's phenomenon 0/3 (0%) 1/19 (5.3%) 0/12 (0%) 0/16 (0%) 0/11 (0%) 0/10 (0%) 0/10 (0%) 0/10 (0%) 0/3 (0%) 0/9 (0%) 0/6 (0%) 0/20 (0%) 0/10 (0%)
Blepharitis 0/3 (0%) 1/19 (5.3%) 2/12 (16.7%) 3/16 (18.8%) 0/11 (0%) 1/10 (10%) 0/10 (0%) 0/10 (0%) 0/3 (0%) 1/9 (11.1%) 0/6 (0%) 0/20 (0%) 0/10 (0%)
Blindness 0/3 (0%) 1/19 (5.3%) 0/12 (0%) 0/16 (0%) 0/11 (0%) 0/10 (0%) 0/10 (0%) 0/10 (0%) 0/3 (0%) 0/9 (0%) 0/6 (0%) 0/20 (0%) 0/10 (0%)
Cataract 0/3 (0%) 0/19 (0%) 0/12 (0%) 1/16 (6.3%) 0/11 (0%) 0/10 (0%) 0/10 (0%) 0/10 (0%) 0/3 (0%) 0/9 (0%) 0/6 (0%) 0/20 (0%) 0/10 (0%)
Dry eye 1/3 (33.3%) 0/19 (0%) 1/12 (8.3%) 0/16 (0%) 0/11 (0%) 1/10 (10%) 0/10 (0%) 1/10 (10%) 0/3 (0%) 0/9 (0%) 0/6 (0%) 0/20 (0%) 0/10 (0%)
Dyschromatopsia 0/3 (0%) 0/19 (0%) 0/12 (0%) 0/16 (0%) 0/11 (0%) 1/10 (10%) 0/10 (0%) 0/10 (0%) 0/3 (0%) 0/9 (0%) 0/6 (0%) 0/20 (0%) 0/10 (0%)
Erythema of eyelid 0/3 (0%) 0/19 (0%) 0/12 (0%) 0/16 (0%) 0/11 (0%) 1/10 (10%) 0/10 (0%) 0/10 (0%) 0/3 (0%) 0/9 (0%) 0/6 (0%) 0/20 (0%) 0/10 (0%)
Eye discharge 0/3 (0%) 1/19 (5.3%) 0/12 (0%) 3/16 (18.8%) 0/11 (0%) 1/10 (10%) 0/10 (0%) 0/10 (0%) 0/3 (0%) 0/9 (0%) 0/6 (0%) 0/20 (0%) 0/10 (0%)
Eye haemorrhage 0/3 (0%) 0/19 (0%) 0/12 (0%) 1/16 (6.3%) 0/11 (0%) 0/10 (0%) 0/10 (0%) 0/10 (0%) 0/3 (0%) 0/9 (0%) 0/6 (0%) 0/20 (0%) 0/10 (0%)
Eye pain 0/3 (0%) 2/19 (10.5%) 0/12 (0%) 0/16 (0%) 0/11 (0%) 0/10 (0%) 0/10 (0%) 0/10 (0%) 0/3 (0%) 1/9 (11.1%) 0/6 (0%) 0/20 (0%) 1/10 (10%)
Eye pruritus 0/3 (0%) 0/19 (0%) 0/12 (0%) 0/16 (0%) 0/11 (0%) 0/10 (0%) 0/10 (0%) 0/10 (0%) 0/3 (0%) 2/9 (22.2%) 0/6 (0%) 0/20 (0%) 0/10 (0%)
Eye swelling 0/3 (0%) 0/19 (0%) 2/12 (16.7%) 0/16 (0%) 1/11 (9.1%) 0/10 (0%) 0/10 (0%) 0/10 (0%) 0/3 (0%) 0/9 (0%) 0/6 (0%) 0/20 (0%) 0/10 (0%)
Eyelid margin crusting 0/3 (0%) 0/19 (0%) 0/12 (0%) 1/16 (6.3%) 0/11 (0%) 0/10 (0%) 0/10 (0%) 0/10 (0%) 0/3 (0%) 0/9 (0%) 0/6 (0%) 0/20 (0%) 0/10 (0%)
Gaze palsy 0/3 (0%) 0/19 (0%) 0/12 (0%) 1/16 (6.3%) 0/11 (0%) 0/10 (0%) 0/10 (0%) 0/10 (0%) 0/3 (0%) 0/9 (0%) 0/6 (0%) 0/20 (0%) 0/10 (0%)
Heterophoria 0/3 (0%) 0/19 (0%) 0/12 (0%) 0/16 (0%) 0/11 (0%) 0/10 (0%) 0/10 (0%) 1/10 (10%) 0/3 (0%) 0/9 (0%) 0/6 (0%) 1/20 (5%) 0/10 (0%)
Hypermetropia 0/3 (0%) 0/19 (0%) 0/12 (0%) 0/16 (0%) 0/11 (0%) 0/10 (0%) 1/10 (10%) 0/10 (0%) 0/3 (0%) 0/9 (0%) 0/6 (0%) 0/20 (0%) 0/10 (0%)
Iridocyclitis 0/3 (0%) 0/19 (0%) 0/12 (0%) 0/16 (0%) 0/11 (0%) 0/10 (0%) 0/10 (0%) 0/10 (0%) 0/3 (0%) 1/9 (11.1%) 0/6 (0%) 0/20 (0%) 1/10 (10%)
Keratitis 0/3 (0%) 0/19 (0%) 1/12 (8.3%) 0/16 (0%) 0/11 (0%) 0/10 (0%) 0/10 (0%) 0/10 (0%) 0/3 (0%) 0/9 (0%) 0/6 (0%) 0/20 (0%) 0/10 (0%)
Lacrimation increased 1/3 (33.3%) 1/19 (5.3%) 1/12 (8.3%) 0/16 (0%) 0/11 (0%) 0/10 (0%) 0/10 (0%) 0/10 (0%) 0/3 (0%) 0/9 (0%) 0/6 (0%) 0/20 (0%) 0/10 (0%)
Mydriasis 0/3 (0%) 0/19 (0%) 0/12 (0%) 0/16 (0%) 0/11 (0%) 0/10 (0%) 0/10 (0%) 0/10 (0%) 0/3 (0%) 1/9 (11.1%) 0/6 (0%) 0/20 (0%) 0/10 (0%)
Ocular hyperaemia 0/3 (0%) 0/19 (0%) 0/12 (0%) 0/16 (0%) 0/11 (0%) 0/10 (0%) 0/10 (0%) 0/10 (0%) 0/3 (0%) 1/9 (11.1%) 0/6 (0%) 0/20 (0%) 2/10 (20%)
Ocular hypertension 0/3 (0%) 0/19 (0%) 0/12 (0%) 0/16 (0%) 1/11 (9.1%) 0/10 (0%) 0/10 (0%) 0/10 (0%) 0/3 (0%) 0/9 (0%) 0/6 (0%) 0/20 (0%) 0/10 (0%)
Optic disc disorder 0/3 (0%) 0/19 (0%) 0/12 (0%) 1/16 (6.3%) 0/11 (0%) 0/10 (0%) 0/10 (0%) 0/10 (0%) 0/3 (0%) 0/9 (0%) 0/6 (0%) 0/20 (0%) 0/10 (0%)
Optic disc haemorrhage 0/3 (0%) 1/19 (5.3%) 0/12 (0%) 0/16 (0%) 0/11 (0%) 0/10 (0%) 0/10 (0%) 0/10 (0%) 0/3 (0%) 0/9 (0%) 0/6 (0%) 0/20 (0%) 0/10 (0%)
Optic nerve disorder 0/3 (0%) 0/19 (0%) 1/12 (8.3%) 1/16 (6.3%) 0/11 (0%) 0/10 (0%) 0/10 (0%) 0/10 (0%) 0/3 (0%) 0/9 (0%) 0/6 (0%) 0/20 (0%) 0/10 (0%)
Periorbital oedema 0/3 (0%) 0/19 (0%) 0/12 (0%) 1/16 (6.3%) 0/11 (0%) 0/10 (0%) 0/10 (0%) 0/10 (0%) 0/3 (0%) 0/9 (0%) 0/6 (0%) 0/20 (0%) 1/10 (10%)
Photophobia 0/3 (0%) 0/19 (0%) 0/12 (0%) 0/16 (0%) 0/11 (0%) 0/10 (0%) 0/10 (0%) 0/10 (0%) 0/3 (0%) 0/9 (0%) 0/6 (0%) 0/20 (0%) 1/10 (10%)
Pupillary reflex impaired 0/3 (0%) 0/19 (0%) 0/12 (0%) 1/16 (6.3%) 0/11 (0%) 0/10 (0%) 0/10 (0%) 0/10 (0%) 0/3 (0%) 0/9 (0%) 0/6 (0%) 0/20 (0%) 0/10 (0%)
Retinopathy 0/3 (0%) 0/19 (0%) 0/12 (0%) 0/16 (0%) 0/11 (0%) 1/10 (10%) 0/10 (0%) 0/10 (0%) 0/3 (0%) 0/9 (0%) 0/6 (0%) 0/20 (0%) 0/10 (0%)
Strabismus 0/3 (0%) 0/19 (0%) 0/12 (0%) 1/16 (6.3%) 0/11 (0%) 0/10 (0%) 0/10 (0%) 0/10 (0%) 0/3 (0%) 0/9 (0%) 0/6 (0%) 0/20 (0%) 0/10 (0%)
Trichomegaly 0/3 (0%) 0/19 (0%) 1/12 (8.3%) 0/16 (0%) 0/11 (0%) 0/10 (0%) 0/10 (0%) 0/10 (0%) 0/3 (0%) 0/9 (0%) 0/6 (0%) 0/20 (0%) 0/10 (0%)
Uveitis 0/3 (0%) 0/19 (0%) 0/12 (0%) 0/16 (0%) 0/11 (0%) 0/10 (0%) 0/10 (0%) 0/10 (0%) 1/3 (33.3%) 0/9 (0%) 0/6 (0%) 0/20 (0%) 0/10 (0%)
Vision blurred 0/3 (0%) 0/19 (0%) 0/12 (0%) 0/16 (0%) 0/11 (0%) 0/10 (0%) 2/10 (20%) 1/10 (10%) 1/3 (33.3%) 1/9 (11.1%) 0/6 (0%) 1/20 (5%) 0/10 (0%)
Visual acuity reduced 0/3 (0%) 0/19 (0%) 0/12 (0%) 1/16 (6.3%) 0/11 (0%) 0/10 (0%) 0/10 (0%) 0/10 (0%) 0/3 (0%) 1/9 (11.1%) 1/6 (16.7%) 0/20 (0%) 0/10 (0%)
Visual impairment 0/3 (0%) 0/19 (0%) 1/12 (8.3%) 0/16 (0%) 0/11 (0%) 1/10 (10%) 0/10 (0%) 0/10 (0%) 0/3 (0%) 1/9 (11.1%) 0/6 (0%) 0/20 (0%) 0/10 (0%)
Vitreous floaters 0/3 (0%) 0/19 (0%) 0/12 (0%) 1/16 (6.3%) 0/11 (0%) 0/10 (0%) 0/10 (0%) 0/10 (0%) 0/3 (0%) 0/9 (0%) 0/6 (0%) 0/20 (0%) 0/10 (0%)
Gastrointestinal disorders
Abdominal discomfort 0/3 (0%) 1/19 (5.3%) 0/12 (0%) 0/16 (0%) 0/11 (0%) 0/10 (0%) 0/10 (0%) 0/10 (0%) 0/3 (0%) 0/9 (0%) 0/6 (0%) 0/20 (0%) 0/10 (0%)
Abdominal distension 0/3 (0%) 0/19 (0%) 0/12 (0%) 0/16 (0%) 0/11 (0%) 0/10 (0%) 0/10 (0%) 0/10 (0%) 0/3 (0%) 1/9 (11.1%) 0/6 (0%) 0/20 (0%) 1/10 (10%)
Abdominal mass 0/3 (0%) 0/19 (0%) 0/12 (0%) 0/16 (0%) 1/11 (9.1%) 0/10 (0%) 0/10 (0%) 0/10 (0%) 0/3 (0%) 0/9 (0%) 0/6 (0%) 0/20 (0%) 0/10 (0%)
Abdominal pain 0/3 (0%) 8/19 (42.1%) 7/12 (58.3%) 5/16 (31.3%) 1/11 (9.1%) 5/10 (50%) 1/10 (10%) 2/10 (20%) 0/3 (0%) 3/9 (33.3%) 2/6 (33.3%) 6/20 (30%) 4/10 (40%)
Abdominal pain lower 0/3 (0%) 0/19 (0%) 0/12 (0%) 0/16 (0%) 1/11 (9.1%) 0/10 (0%) 0/10 (0%) 0/10 (0%) 0/3 (0%) 0/9 (0%) 0/6 (0%) 0/20 (0%) 0/10 (0%)
Abdominal pain upper 1/3 (33.3%) 5/19 (26.3%) 2/12 (16.7%) 2/16 (12.5%) 1/11 (9.1%) 0/10 (0%) 0/10 (0%) 0/10 (0%) 0/3 (0%) 0/9 (0%) 0/6 (0%) 1/20 (5%) 0/10 (0%)
Anal fissure 0/3 (0%) 1/19 (5.3%) 1/12 (8.3%) 0/16 (0%) 0/11 (0%) 0/10 (0%) 0/10 (0%) 0/10 (0%) 0/3 (0%) 0/9 (0%) 0/6 (0%) 0/20 (0%) 0/10 (0%)
Anal incontinence 0/3 (0%) 0/19 (0%) 0/12 (0%) 1/16 (6.3%) 1/11 (9.1%) 0/10 (0%) 0/10 (0%) 0/10 (0%) 0/3 (0%) 0/9 (0%) 0/6 (0%) 0/20 (0%) 0/10 (0%)
Anal inflammation 0/3 (0%) 1/19 (5.3%) 0/12 (0%) 0/16 (0%) 0/11 (0%) 0/10 (0%) 0/10 (0%) 0/10 (0%) 0/3 (0%) 0/9 (0%) 0/6 (0%) 0/20 (0%) 0/10 (0%)
Anal rash 0/3 (0%) 0/19 (0%) 0/12 (0%) 0/16 (0%) 0/11 (0%) 0/10 (0%) 0/10 (0%) 0/10 (0%) 0/3 (0%) 0/9 (0%) 0/6 (0%) 0/20 (0%) 1/10 (10%)
Angular cheilitis 0/3 (0%) 4/19 (21.1%) 1/12 (8.3%) 2/16 (12.5%) 0/11 (0%) 1/10 (10%) 0/10 (0%) 3/10 (30%) 0/3 (0%) 1/9 (11.1%) 0/6 (0%) 2/20 (10%) 1/10 (10%)
Aphthous ulcer 0/3 (0%) 1/19 (5.3%) 0/12 (0%) 0/16 (0%) 0/11 (0%) 0/10 (0%) 0/10 (0%) 1/10 (10%) 0/3 (0%) 0/9 (0%) 0/6 (0%) 0/20 (0%) 0/10 (0%)
Chapped lips 0/3 (0%) 1/19 (5.3%) 1/12 (8.3%) 0/16 (0%) 0/11 (0%) 0/10 (0%) 0/10 (0%) 0/10 (0%) 0/3 (0%) 0/9 (0%) 0/6 (0%) 0/20 (0%) 0/10 (0%)
Cheilitis 0/3 (0%) 1/19 (5.3%) 3/12 (25%) 6/16 (37.5%) 0/11 (0%) 0/10 (0%) 2/10 (20%) 1/10 (10%) 0/3 (0%) 1/9 (11.1%) 0/6 (0%) 2/20 (10%) 0/10 (0%)
Constipation 1/3 (33.3%) 8/19 (42.1%) 6/12 (50%) 3/16 (18.8%) 4/11 (36.4%) 5/10 (50%) 2/10 (20%) 6/10 (60%) 1/3 (33.3%) 2/9 (22.2%) 1/6 (16.7%) 5/20 (25%) 2/10 (20%)
Dental caries 0/3 (0%) 1/19 (5.3%) 1/12 (8.3%) 1/16 (6.3%) 0/11 (0%) 0/10 (0%) 0/10 (0%) 0/10 (0%) 0/3 (0%) 0/9 (0%) 1/6 (16.7%) 0/20 (0%) 0/10 (0%)
Diarrhoea 1/3 (33.3%) 17/19 (89.5%) 10/12 (83.3%) 9/16 (56.3%) 6/11 (54.5%) 6/10 (60%) 5/10 (50%) 6/10 (60%) 2/3 (66.7%) 3/9 (33.3%) 3/6 (50%) 7/20 (35%) 5/10 (50%)
Dry mouth 0/3 (0%) 1/19 (5.3%) 0/12 (0%) 0/16 (0%) 0/11 (0%) 0/10 (0%) 0/10 (0%) 0/10 (0%) 0/3 (0%) 0/9 (0%) 0/6 (0%) 0/20 (0%) 0/10 (0%)
Dyspepsia 0/3 (0%) 1/19 (5.3%) 0/12 (0%) 0/16 (0%) 0/11 (0%) 0/10 (0%) 0/10 (0%) 1/10 (10%) 0/3 (0%) 0/9 (0%) 0/6 (0%) 0/20 (0%) 0/10 (0%)
Dysphagia 0/3 (0%) 1/19 (5.3%) 1/12 (8.3%) 0/16 (0%) 1/11 (9.1%) 0/10 (0%) 0/10 (0%) 0/10 (0%) 0/3 (0%) 0/9 (0%) 0/6 (0%) 1/20 (5%) 0/10 (0%)
Flatulence 0/3 (0%) 0/19 (0%) 0/12 (0%) 0/16 (0%) 0/11 (0%) 0/10 (0%) 0/10 (0%) 0/10 (0%) 0/3 (0%) 0/9 (0%) 0/6 (0%) 0/20 (0%) 1/10 (10%)
Gastrooesophageal reflux disease 0/3 (0%) 2/19 (10.5%) 1/12 (8.3%) 0/16 (0%) 0/11 (0%) 0/10 (0%) 0/10 (0%) 1/10 (10%) 0/3 (0%) 2/9 (22.2%) 0/6 (0%) 2/20 (10%) 0/10 (0%)
Gingival bleeding 0/3 (0%) 0/19 (0%) 0/12 (0%) 1/16 (6.3%) 0/11 (0%) 0/10 (0%) 0/10 (0%) 0/10 (0%) 0/3 (0%) 0/9 (0%) 0/6 (0%) 0/20 (0%) 0/10 (0%)
Gingival erythema 0/3 (0%) 0/19 (0%) 0/12 (0%) 0/16 (0%) 0/11 (0%) 1/10 (10%) 0/10 (0%) 0/10 (0%) 0/3 (0%) 0/9 (0%) 0/6 (0%) 0/20 (0%) 0/10 (0%)
Gingival hypertrophy 0/3 (0%) 0/19 (0%) 0/12 (0%) 1/16 (6.3%) 0/11 (0%) 0/10 (0%) 0/10 (0%) 0/10 (0%) 0/3 (0%) 0/9 (0%) 0/6 (0%) 0/20 (0%) 0/10 (0%)
Gingival oedema 0/3 (0%) 1/19 (5.3%) 0/12 (0%) 0/16 (0%) 0/11 (0%) 0/10 (0%) 0/10 (0%) 0/10 (0%) 0/3 (0%) 0/9 (0%) 0/6 (0%) 0/20 (0%) 0/10 (0%)
Gingival swelling 0/3 (0%) 0/19 (0%) 0/12 (0%) 0/16 (0%) 0/11 (0%) 1/10 (10%) 0/10 (0%) 0/10 (0%) 0/3 (0%) 0/9 (0%) 0/6 (0%) 0/20 (0%) 0/10 (0%)
Haematemesis 0/3 (0%) 0/19 (0%) 0/12 (0%) 0/16 (0%) 1/11 (9.1%) 0/10 (0%) 0/10 (0%) 0/10 (0%) 0/3 (0%) 0/9 (0%) 0/6 (0%) 0/20 (0%) 0/10 (0%)
Haematochezia 0/3 (0%) 1/19 (5.3%) 2/12 (16.7%) 0/16 (0%) 0/11 (0%) 0/10 (0%) 0/10 (0%) 0/10 (0%) 0/3 (0%) 0/9 (0%) 0/6 (0%) 0/20 (0%) 0/10 (0%)
Lip blister 0/3 (0%) 1/19 (5.3%) 0/12 (0%) 0/16 (0%) 0/11 (0%) 0/10 (0%) 0/10 (0%) 0/10 (0%) 0/3 (0%) 0/9 (0%) 0/6 (0%) 0/20 (0%) 0/10 (0%)
Lip dry 0/3 (0%) 3/19 (15.8%) 2/12 (16.7%) 0/16 (0%) 0/11 (0%) 3/10 (30%) 0/10 (0%) 2/10 (20%) 0/3 (0%) 1/9 (11.1%) 0/6 (0%) 1/20 (5%) 0/10 (0%)
Lip haemorrhage 0/3 (0%) 0/19 (0%) 0/12 (0%) 1/16 (6.3%) 1/11 (9.1%) 0/10 (0%) 0/10 (0%) 0/10 (0%) 0/3 (0%) 0/9 (0%) 0/6 (0%) 0/20 (0%) 0/10 (0%)
Lip swelling 0/3 (0%) 0/19 (0%) 0/12 (0%) 0/16 (0%) 1/11 (9.1%) 0/10 (0%) 0/10 (0%) 0/10 (0%) 0/3 (0%) 0/9 (0%) 0/6 (0%) 0/20 (0%) 0/10 (0%)
Mouth haemorrhage 0/3 (0%) 0/19 (0%) 0/12 (0%) 1/16 (6.3%) 0/11 (0%) 0/10 (0%) 0/10 (0%) 0/10 (0%) 0/3 (0%) 0/9 (0%) 0/6 (0%) 0/20 (0%) 0/10 (0%)
Mouth ulceration 0/3 (0%) 3/19 (15.8%) 0/12 (0%) 0/16 (0%) 0/11 (0%) 1/10 (10%) 1/10 (10%) 1/10 (10%) 0/3 (0%) 0/9 (0%) 0/6 (0%) 0/20 (0%) 0/10 (0%)
Mucous stools 0/3 (0%) 0/19 (0%) 1/12 (8.3%) 0/16 (0%) 0/11 (0%) 0/10 (0%) 0/10 (0%) 0/10 (0%) 0/3 (0%) 0/9 (0%) 0/6 (0%) 0/20 (0%) 0/10 (0%)
Nausea 0/3 (0%) 6/19 (31.6%) 1/12 (8.3%) 4/16 (25%) 3/11 (27.3%) 2/10 (20%) 3/10 (30%) 3/10 (30%) 0/3 (0%) 4/9 (44.4%) 1/6 (16.7%) 8/20 (40%) 3/10 (30%)
Odynophagia 0/3 (0%) 3/19 (15.8%) 1/12 (8.3%) 1/16 (6.3%) 0/11 (0%) 0/10 (0%) 0/10 (0%) 0/10 (0%) 0/3 (0%) 0/9 (0%) 0/6 (0%) 1/20 (5%) 0/10 (0%)
Oral disorder 0/3 (0%) 0/19 (0%) 0/12 (0%) 0/16 (0%) 1/11 (9.1%) 0/10 (0%) 0/10 (0%) 0/10 (0%) 0/3 (0%) 0/9 (0%) 1/6 (16.7%) 0/20 (0%) 0/10 (0%)
Oral dysaesthesia 0/3 (0%) 0/19 (0%) 0/12 (0%) 1/16 (6.3%) 0/11 (0%) 0/10 (0%) 0/10 (0%) 0/10 (0%) 0/3 (0%) 0/9 (0%) 0/6 (0%) 0/20 (0%) 0/10 (0%)
Oral pain 0/3 (0%) 2/19 (10.5%) 0/12 (0%) 0/16 (0%) 0/11 (0%) 0/10 (0%) 0/10 (0%) 0/10 (0%) 0/3 (0%) 0/9 (0%) 0/6 (0%) 0/20 (0%) 1/10 (10%)
Proctalgia 0/3 (0%) 1/19 (5.3%) 0/12 (0%) 0/16 (0%) 0/11 (0%) 0/10 (0%) 0/10 (0%) 0/10 (0%) 0/3 (0%) 0/9 (0%) 0/6 (0%) 0/20 (0%) 0/10 (0%)
Rectal haemorrhage 0/3 (0%) 0/19 (0%) 0/12 (0%) 0/16 (0%) 0/11 (0%) 0/10 (0%) 0/10 (0%) 0/10 (0%) 0/3 (0%) 0/9 (0%) 0/6 (0%) 0/20 (0%) 1/10 (10%)
Stomatitis 0/3 (0%) 3/19 (15.8%) 3/12 (25%) 2/16 (12.5%) 1/11 (9.1%) 4/10 (40%) 3/10 (30%) 2/10 (20%) 0/3 (0%) 2/9 (22.2%) 0/6 (0%) 1/20 (5%) 0/10 (0%)
Teething 0/3 (0%) 1/19 (5.3%) 0/12 (0%) 0/16 (0%) 0/11 (0%) 0/10 (0%) 0/10 (0%) 0/10 (0%) 0/3 (0%) 0/9 (0%) 0/6 (0%) 0/20 (0%) 0/10 (0%)
Tooth discolouration 0/3 (0%) 0/19 (0%) 0/12 (0%) 0/16 (0%) 0/11 (0%) 0/10 (0%) 1/10 (10%) 0/10 (0%) 0/3 (0%) 0/9 (0%) 0/6 (0%) 0/20 (0%) 0/10 (0%)
Toothache 0/3 (0%) 1/19 (5.3%) 1/12 (8.3%) 0/16 (0%) 0/11 (0%) 0/10 (0%) 0/10 (0%) 0/10 (0%) 0/3 (0%) 0/9 (0%) 0/6 (0%) 1/20 (5%) 0/10 (0%)
Vomiting 1/3 (33.3%) 13/19 (68.4%) 9/12 (75%) 6/16 (37.5%) 3/11 (27.3%) 3/10 (30%) 3/10 (30%) 6/10 (60%) 1/3 (33.3%) 4/9 (44.4%) 4/6 (66.7%) 9/20 (45%) 7/10 (70%)
General disorders
Asthenia 0/3 (0%) 4/19 (21.1%) 0/12 (0%) 4/16 (25%) 0/11 (0%) 1/10 (10%) 1/10 (10%) 1/10 (10%) 0/3 (0%) 1/9 (11.1%) 0/6 (0%) 1/20 (5%) 0/10 (0%)
Catheter site hypersensitivity 0/3 (0%) 1/19 (5.3%) 0/12 (0%) 0/16 (0%) 0/11 (0%) 0/10 (0%) 0/10 (0%) 0/10 (0%) 0/3 (0%) 0/9 (0%) 0/6 (0%) 0/20 (0%) 0/10 (0%)
Catheter site pain 0/3 (0%) 0/19 (0%) 0/12 (0%) 0/16 (0%) 0/11 (0%) 0/10 (0%) 1/10 (10%) 0/10 (0%) 0/3 (0%) 0/9 (0%) 0/6 (0%) 0/20 (0%) 0/10 (0%)
Catheter site rash 0/3 (0%) 0/19 (0%) 0/12 (0%) 0/16 (0%) 1/11 (9.1%) 0/10 (0%) 0/10 (0%) 0/10 (0%) 0/3 (0%) 0/9 (0%) 0/6 (0%) 0/20 (0%) 0/10 (0%)
Chest discomfort 0/3 (0%) 0/19 (0%) 0/12 (0%) 0/16 (0%) 0/11 (0%) 0/10 (0%) 0/10 (0%) 1/10 (10%) 0/3 (0%) 0/9 (0%) 0/6 (0%) 0/20 (0%) 0/10 (0%)
Chest pain 0/3 (0%) 1/19 (5.3%) 0/12 (0%) 0/16 (0%) 0/11 (0%) 0/10 (0%) 0/10 (0%) 0/10 (0%) 0/3 (0%) 0/9 (0%) 0/6 (0%) 1/20 (5%) 0/10 (0%)
Chills 0/3 (0%) 2/19 (10.5%) 1/12 (8.3%) 0/16 (0%) 0/11 (0%) 1/10 (10%) 0/10 (0%) 1/10 (10%) 0/3 (0%) 3/9 (33.3%) 0/6 (0%) 3/20 (15%) 0/10 (0%)
Cyst 0/3 (0%) 0/19 (0%) 0/12 (0%) 0/16 (0%) 0/11 (0%) 0/10 (0%) 0/10 (0%) 1/10 (10%) 0/3 (0%) 0/9 (0%) 0/6 (0%) 0/20 (0%) 0/10 (0%)
Face oedema 0/3 (0%) 2/19 (10.5%) 1/12 (8.3%) 1/16 (6.3%) 0/11 (0%) 0/10 (0%) 0/10 (0%) 0/10 (0%) 0/3 (0%) 0/9 (0%) 0/6 (0%) 0/20 (0%) 0/10 (0%)
Fatigue 1/3 (33.3%) 10/19 (52.6%) 9/12 (75%) 4/16 (25%) 1/11 (9.1%) 1/10 (10%) 0/10 (0%) 6/10 (60%) 2/3 (66.7%) 4/9 (44.4%) 1/6 (16.7%) 9/20 (45%) 4/10 (40%)
Feeling cold 0/3 (0%) 1/19 (5.3%) 0/12 (0%) 0/16 (0%) 0/11 (0%) 1/10 (10%) 0/10 (0%) 0/10 (0%) 1/3 (33.3%) 0/9 (0%) 0/6 (0%) 0/20 (0%) 0/10 (0%)
Gait disturbance 0/3 (0%) 2/19 (10.5%) 0/12 (0%) 1/16 (6.3%) 0/11 (0%) 1/10 (10%) 0/10 (0%) 1/10 (10%) 0/3 (0%) 0/9 (0%) 0/6 (0%) 1/20 (5%) 0/10 (0%)
Granuloma 0/3 (0%) 1/19 (5.3%) 0/12 (0%) 0/16 (0%) 0/11 (0%) 0/10 (0%) 0/10 (0%) 0/10 (0%) 0/3 (0%) 0/9 (0%) 0/6 (0%) 0/20 (0%) 0/10 (0%)
Hypothermia 0/3 (0%) 0/19 (0%) 0/12 (0%) 1/16 (6.3%) 0/11 (0%) 0/10 (0%) 0/10 (0%) 0/10 (0%) 0/3 (0%) 0/9 (0%) 0/6 (0%) 1/20 (5%) 0/10 (0%)
Influenza like illness 0/3 (0%) 1/19 (5.3%) 2/12 (16.7%) 1/16 (6.3%) 0/11 (0%) 1/10 (10%) 0/10 (0%) 1/10 (10%) 1/3 (33.3%) 1/9 (11.1%) 2/6 (33.3%) 2/20 (10%) 3/10 (30%)
Localised oedema 0/3 (0%) 1/19 (5.3%) 0/12 (0%) 0/16 (0%) 0/11 (0%) 0/10 (0%) 0/10 (0%) 0/10 (0%) 0/3 (0%) 0/9 (0%) 0/6 (0%) 1/20 (5%) 0/10 (0%)
Malaise 0/3 (0%) 0/19 (0%) 0/12 (0%) 1/16 (6.3%) 0/11 (0%) 0/10 (0%) 0/10 (0%) 0/10 (0%) 0/3 (0%) 0/9 (0%) 0/6 (0%) 2/20 (10%) 0/10 (0%)
Mucosal inflammation 0/3 (0%) 4/19 (21.1%) 1/12 (8.3%) 1/16 (6.3%) 0/11 (0%) 1/10 (10%) 1/10 (10%) 3/10 (30%) 1/3 (33.3%) 0/9 (0%) 0/6 (0%) 1/20 (5%) 0/10 (0%)
Non-cardiac chest pain 0/3 (0%) 2/19 (10.5%) 0/12 (0%) 0/16 (0%) 1/11 (9.1%) 0/10 (0%) 0/10 (0%) 0/10 (0%) 0/3 (0%) 0/9 (0%) 0/6 (0%) 0/20 (0%) 0/10 (0%)
Oedema peripheral 0/3 (0%) 4/19 (21.1%) 0/12 (0%) 1/16 (6.3%) 0/11 (0%) 0/10 (0%) 0/10 (0%) 2/10 (20%) 0/3 (0%) 0/9 (0%) 0/6 (0%) 3/20 (15%) 1/10 (10%)
Pain 0/3 (0%) 3/19 (15.8%) 1/12 (8.3%) 0/16 (0%) 0/11 (0%) 0/10 (0%) 2/10 (20%) 0/10 (0%) 0/3 (0%) 1/9 (11.1%) 0/6 (0%) 0/20 (0%) 0/10 (0%)
Peripheral swelling 0/3 (0%) 2/19 (10.5%) 1/12 (8.3%) 0/16 (0%) 0/11 (0%) 0/10 (0%) 0/10 (0%) 0/10 (0%) 0/3 (0%) 0/9 (0%) 0/6 (0%) 0/20 (0%) 0/10 (0%)
Pyrexia 1/3 (33.3%) 11/19 (57.9%) 8/12 (66.7%) 10/16 (62.5%) 5/11 (45.5%) 5/10 (50%) 6/10 (60%) 4/10 (40%) 0/3 (0%) 7/9 (77.8%) 4/6 (66.7%) 15/20 (75%) 8/10 (80%)
Swelling face 0/3 (0%) 0/19 (0%) 0/12 (0%) 0/16 (0%) 0/11 (0%) 0/10 (0%) 0/10 (0%) 0/10 (0%) 0/3 (0%) 0/9 (0%) 0/6 (0%) 0/20 (0%) 1/10 (10%)
Ulcer 0/3 (0%) 0/19 (0%) 0/12 (0%) 0/16 (0%) 0/11 (0%) 1/10 (10%) 0/10 (0%) 0/10 (0%) 0/3 (0%) 0/9 (0%) 0/6 (0%) 0/20 (0%) 0/10 (0%)
Xerosis 0/3 (0%) 4/19 (21.1%) 2/12 (16.7%) 2/16 (12.5%) 1/11 (9.1%) 2/10 (20%) 1/10 (10%) 3/10 (30%) 0/3 (0%) 0/9 (0%) 0/6 (0%) 0/20 (0%) 0/10 (0%)
Hepatobiliary disorders
Jaundice 0/3 (0%) 0/19 (0%) 0/12 (0%) 0/16 (0%) 1/11 (9.1%) 0/10 (0%) 0/10 (0%) 0/10 (0%) 0/3 (0%) 0/9 (0%) 0/6 (0%) 0/20 (0%) 0/10 (0%)
Ocular icterus 0/3 (0%) 0/19 (0%) 0/12 (0%) 0/16 (0%) 1/11 (9.1%) 0/10 (0%) 0/10 (0%) 0/10 (0%) 0/3 (0%) 0/9 (0%) 0/6 (0%) 0/20 (0%) 0/10 (0%)
Immune system disorders
Allergy to arthropod sting 0/3 (0%) 0/19 (0%) 0/12 (0%) 0/16 (0%) 0/11 (0%) 0/10 (0%) 0/10 (0%) 1/10 (10%) 0/3 (0%) 0/9 (0%) 0/6 (0%) 0/20 (0%) 0/10 (0%)
Hypersensitivity 0/3 (0%) 0/19 (0%) 0/12 (0%) 0/16 (0%) 1/11 (9.1%) 0/10 (0%) 0/10 (0%) 1/10 (10%) 0/3 (0%) 0/9 (0%) 0/6 (0%) 2/20 (10%) 0/10 (0%)
Infections and infestations
Beta haemolytic streptococcal infection 0/3 (0%) 1/19 (5.3%) 0/12 (0%) 0/16 (0%) 0/11 (0%) 0/10 (0%) 0/10 (0%) 0/10 (0%) 0/3 (0%) 0/9 (0%) 0/6 (0%) 0/20 (0%) 0/10 (0%)
Bronchitis 0/3 (0%) 1/19 (5.3%) 0/12 (0%) 0/16 (0%) 0/11 (0%) 0/10 (0%) 0/10 (0%) 0/10 (0%) 0/3 (0%) 0/9 (0%) 0/6 (0%) 0/20 (0%) 0/10 (0%)
COVID-19 0/3 (0%) 0/19 (0%) 0/12 (0%) 0/16 (0%) 0/11 (0%) 0/10 (0%) 0/10 (0%) 0/10 (0%) 0/3 (0%) 0/9 (0%) 0/6 (0%) 0/20 (0%) 1/10 (10%)
Candida infection 0/3 (0%) 0/19 (0%) 0/12 (0%) 0/16 (0%) 0/11 (0%) 1/10 (10%) 0/10 (0%) 0/10 (0%) 0/3 (0%) 0/9 (0%) 0/6 (0%) 1/20 (5%) 0/10 (0%)
Cellulitis 0/3 (0%) 0/19 (0%) 0/12 (0%) 1/16 (6.3%) 0/11 (0%) 0/10 (0%) 0/10 (0%) 0/10 (0%) 0/3 (0%) 0/9 (0%) 1/6 (16.7%) 0/20 (0%) 1/10 (10%)
Conjunctivitis 0/3 (0%) 2/19 (10.5%) 1/12 (8.3%) 4/16 (25%) 1/11 (9.1%) 1/10 (10%) 1/10 (10%) 0/10 (0%) 0/3 (0%) 0/9 (0%) 1/6 (16.7%) 1/20 (5%) 1/10 (10%)
Coronavirus infection 0/3 (0%) 0/19 (0%) 0/12 (0%) 0/16 (0%) 1/11 (9.1%) 0/10 (0%) 0/10 (0%) 0/10 (0%) 0/3 (0%) 0/9 (0%) 0/6 (0%) 0/20 (0%) 0/10 (0%)
Coxsackie viral infection 0/3 (0%) 0/19 (0%) 1/12 (8.3%) 0/16 (0%) 0/11 (0%) 0/10 (0%) 0/10 (0%) 0/10 (0%) 0/3 (0%) 0/9 (0%) 0/6 (0%) 0/20 (0%) 0/10 (0%)
Device related infection 0/3 (0%) 1/19 (5.3%) 0/12 (0%) 0/16 (0%) 0/11 (0%) 0/10 (0%) 0/10 (0%) 1/10 (10%) 0/3 (0%) 0/9 (0%) 1/6 (16.7%) 0/20 (0%) 0/10 (0%)
Ear infection 0/3 (0%) 2/19 (10.5%) 2/12 (16.7%) 1/16 (6.3%) 1/11 (9.1%) 1/10 (10%) 1/10 (10%) 0/10 (0%) 0/3 (0%) 1/9 (11.1%) 0/6 (0%) 1/20 (5%) 0/10 (0%)
Enterocolitis infectious 0/3 (0%) 0/19 (0%) 0/12 (0%) 0/16 (0%) 1/11 (9.1%) 0/10 (0%) 0/10 (0%) 0/10 (0%) 0/3 (0%) 0/9 (0%) 0/6 (0%) 0/20 (0%) 0/10 (0%)
Enterovirus infection 0/3 (0%) 0/19 (0%) 0/12 (0%) 0/16 (0%) 0/11 (0%) 0/10 (0%) 0/10 (0%) 0/10 (0%) 0/3 (0%) 0/9 (0%) 0/6 (0%) 0/20 (0%) 1/10 (10%)
Epstein-Barr virus infection 0/3 (0%) 0/19 (0%) 0/12 (0%) 0/16 (0%) 0/11 (0%) 0/10 (0%) 0/10 (0%) 0/10 (0%) 0/3 (0%) 0/9 (0%) 0/6 (0%) 0/20 (0%) 1/10 (10%)
Escherichia urinary tract infection 0/3 (0%) 0/19 (0%) 0/12 (0%) 0/16 (0%) 0/11 (0%) 0/10 (0%) 0/10 (0%) 0/10 (0%) 0/3 (0%) 1/9 (11.1%) 0/6 (0%) 0/20 (0%) 0/10 (0%)
Eye infection 0/3 (0%) 1/19 (5.3%) 1/12 (8.3%) 1/16 (6.3%) 0/11 (0%) 0/10 (0%) 0/10 (0%) 0/10 (0%) 0/3 (0%) 0/9 (0%) 0/6 (0%) 0/20 (0%) 0/10 (0%)
Folliculitis 0/3 (0%) 6/19 (31.6%) 3/12 (25%) 4/16 (25%) 0/11 (0%) 0/10 (0%) 2/10 (20%) 2/10 (20%) 0/3 (0%) 0/9 (0%) 0/6 (0%) 0/20 (0%) 1/10 (10%)
Fungal infection 0/3 (0%) 0/19 (0%) 0/12 (0%) 0/16 (0%) 0/11 (0%) 0/10 (0%) 0/10 (0%) 2/10 (20%) 0/3 (0%) 0/9 (0%) 0/6 (0%) 1/20 (5%) 0/10 (0%)
Fungal skin infection 0/3 (0%) 1/19 (5.3%) 0/12 (0%) 0/16 (0%) 0/11 (0%) 1/10 (10%) 0/10 (0%) 0/10 (0%) 0/3 (0%) 0/9 (0%) 0/6 (0%) 0/20 (0%) 0/10 (0%)
Furuncle 0/3 (0%) 0/19 (0%) 0/12 (0%) 1/16 (6.3%) 0/11 (0%) 0/10 (0%) 1/10 (10%) 0/10 (0%) 0/3 (0%) 0/9 (0%) 0/6 (0%) 0/20 (0%) 0/10 (0%)
Gastroenteritis 0/3 (0%) 3/19 (15.8%) 0/12 (0%) 2/16 (12.5%) 0/11 (0%) 1/10 (10%) 1/10 (10%) 1/10 (10%) 0/3 (0%) 0/9 (0%) 0/6 (0%) 1/20 (5%) 0/10 (0%)
Gastroenteritis bacterial 0/3 (0%) 0/19 (0%) 1/12 (8.3%) 0/16 (0%) 0/11 (0%) 0/10 (0%) 0/10 (0%) 0/10 (0%) 0/3 (0%) 0/9 (0%) 0/6 (0%) 0/20 (0%) 0/10 (0%)
Gastroenteritis viral 0/3 (0%) 1/19 (5.3%) 0/12 (0%) 0/16 (0%) 0/11 (0%) 0/10 (0%) 0/10 (0%) 1/10 (10%) 0/3 (0%) 2/9 (22.2%) 0/6 (0%) 0/20 (0%) 0/10 (0%)
Gastrointestinal infection 0/3 (0%) 0/19 (0%) 0/12 (0%) 0/16 (0%) 0/11 (0%) 1/10 (10%) 0/10 (0%) 0/10 (0%) 0/3 (0%) 0/9 (0%) 0/6 (0%) 0/20 (0%) 0/10 (0%)
Gingivitis 0/3 (0%) 1/19 (5.3%) 0/12 (0%) 0/16 (0%) 0/11 (0%) 0/10 (0%) 0/10 (0%) 0/10 (0%) 0/3 (0%) 0/9 (0%) 0/6 (0%) 1/20 (5%) 0/10 (0%)
Herpes dermatitis 0/3 (0%) 0/19 (0%) 0/12 (0%) 0/16 (0%) 0/11 (0%) 1/10 (10%) 0/10 (0%) 0/10 (0%) 0/3 (0%) 0/9 (0%) 0/6 (0%) 0/20 (0%) 0/10 (0%)
Herpes simplex 0/3 (0%) 0/19 (0%) 0/12 (0%) 0/16 (0%) 0/11 (0%) 0/10 (0%) 0/10 (0%) 1/10 (10%) 0/3 (0%) 0/9 (0%) 0/6 (0%) 0/20 (0%) 0/10 (0%)
Herpes virus infection 0/3 (0%) 0/19 (0%) 0/12 (0%) 0/16 (0%) 0/11 (0%) 0/10 (0%) 1/10 (10%) 0/10 (0%) 0/3 (0%) 0/9 (0%) 0/6 (0%) 0/20 (0%) 0/10 (0%)
Herpes zoster 0/3 (0%) 0/19 (0%) 0/12 (0%) 0/16 (0%) 1/11 (9.1%) 1/10 (10%) 0/10 (0%) 0/10 (0%) 0/3 (0%) 0/9 (0%) 0/6 (0%) 0/20 (0%) 0/10 (0%)
Hordeolum 0/3 (0%) 3/19 (15.8%) 0/12 (0%) 1/16 (6.3%) 0/11 (0%) 0/10 (0%) 0/10 (0%) 1/10 (10%) 1/3 (33.3%) 0/9 (0%) 0/6 (0%) 0/20 (0%) 1/10 (10%)
Impetigo 0/3 (0%) 0/19 (0%) 1/12 (8.3%) 0/16 (0%) 0/11 (0%) 1/10 (10%) 0/10 (0%) 0/10 (0%) 0/3 (0%) 0/9 (0%) 0/6 (0%) 0/20 (0%) 0/10 (0%)
Infected bite 0/3 (0%) 0/19 (0%) 0/12 (0%) 0/16 (0%) 0/11 (0%) 0/10 (0%) 0/10 (0%) 1/10 (10%) 0/3 (0%) 0/9 (0%) 0/6 (0%) 0/20 (0%) 0/10 (0%)
Infected skin ulcer 0/3 (0%) 0/19 (0%) 0/12 (0%) 0/16 (0%) 0/11 (0%) 1/10 (10%) 0/10 (0%) 0/10 (0%) 0/3 (0%) 0/9 (0%) 0/6 (0%) 0/20 (0%) 0/10 (0%)
Infection 0/3 (0%) 1/19 (5.3%) 1/12 (8.3%) 0/16 (0%) 0/11 (0%) 0/10 (0%) 0/10 (0%) 0/10 (0%) 0/3 (0%) 0/9 (0%) 0/6 (0%) 0/20 (0%) 1/10 (10%)
Influenza 0/3 (0%) 0/19 (0%) 2/12 (16.7%) 0/16 (0%) 0/11 (0%) 2/10 (20%) 0/10 (0%) 0/10 (0%) 0/3 (0%) 0/9 (0%) 0/6 (0%) 0/20 (0%) 0/10 (0%)
Laryngitis 0/3 (0%) 0/19 (0%) 0/12 (0%) 0/16 (0%) 0/11 (0%) 0/10 (0%) 0/10 (0%) 1/10 (10%) 0/3 (0%) 0/9 (0%) 0/6 (0%) 0/20 (0%) 0/10 (0%)
Localised infection 0/3 (0%) 1/19 (5.3%) 0/12 (0%) 0/16 (0%) 1/11 (9.1%) 1/10 (10%) 0/10 (0%) 0/10 (0%) 1/3 (33.3%) 0/9 (0%) 0/6 (0%) 0/20 (0%) 0/10 (0%)
Lower respiratory tract infection 0/3 (0%) 0/19 (0%) 0/12 (0%) 0/16 (0%) 0/11 (0%) 0/10 (0%) 0/10 (0%) 0/10 (0%) 0/3 (0%) 0/9 (0%) 1/6 (16.7%) 0/20 (0%) 0/10 (0%)
Lymph gland infection 0/3 (0%) 0/19 (0%) 0/12 (0%) 0/16 (0%) 0/11 (0%) 0/10 (0%) 0/10 (0%) 0/10 (0%) 1/3 (33.3%) 0/9 (0%) 0/6 (0%) 0/20 (0%) 1/10 (10%)
Mucosal infection 0/3 (0%) 0/19 (0%) 1/12 (8.3%) 0/16 (0%) 0/11 (0%) 0/10 (0%) 0/10 (0%) 0/10 (0%) 0/3 (0%) 0/9 (0%) 0/6 (0%) 1/20 (5%) 1/10 (10%)
Nail infection 0/3 (0%) 0/19 (0%) 0/12 (0%) 1/16 (6.3%) 1/11 (9.1%) 0/10 (0%) 0/10 (0%) 0/10 (0%) 0/3 (0%) 0/9 (0%) 0/6 (0%) 0/20 (0%) 0/10 (0%)
Nasal vestibulitis 0/3 (0%) 0/19 (0%) 1/12 (8.3%) 0/16 (0%) 0/11 (0%) 0/10 (0%) 0/10 (0%) 0/10 (0%) 0/3 (0%) 0/9 (0%) 0/6 (0%) 0/20 (0%) 0/10 (0%)
Nasopharyngitis 0/3 (0%) 0/19 (0%) 0/12 (0%) 0/16 (0%) 0/11 (0%) 0/10 (0%) 2/10 (20%) 0/10 (0%) 0/3 (0%) 0/9 (0%) 1/6 (16.7%) 3/20 (15%) 0/10 (0%)
Onychomycosis 0/3 (0%) 0/19 (0%) 0/12 (0%) 0/16 (0%) 0/11 (0%) 0/10 (0%) 0/10 (0%) 1/10 (10%) 0/3 (0%) 0/9 (0%) 0/6 (0%) 0/20 (0%) 0/10 (0%)
Oral candidiasis 0/3 (0%) 1/19 (5.3%) 0/12 (0%) 0/16 (0%) 0/11 (0%) 1/10 (10%) 0/10 (0%) 0/10 (0%) 0/3 (0%) 0/9 (0%) 0/6 (0%) 0/20 (0%) 0/10 (0%)
Oral herpes 0/3 (0%) 1/19 (5.3%) 0/12 (0%) 0/16 (0%) 0/11 (0%) 0/10 (0%) 0/10 (0%) 0/10 (0%) 1/3 (33.3%) 0/9 (0%) 0/6 (0%) 0/20 (0%) 1/10 (10%)
Otitis externa 0/3 (0%) 0/19 (0%) 1/12 (8.3%) 0/16 (0%) 1/11 (9.1%) 0/10 (0%) 1/10 (10%) 0/10 (0%) 0/3 (0%) 0/9 (0%) 0/6 (0%) 0/20 (0%) 0/10 (0%)
Otitis media 0/3 (0%) 1/19 (5.3%) 3/12 (25%) 1/16 (6.3%) 1/11 (9.1%) 0/10 (0%) 0/10 (0%) 2/10 (20%) 0/3 (0%) 0/9 (0%) 0/6 (0%) 2/20 (10%) 2/10 (20%)
Otitis media acute 0/3 (0%) 0/19 (0%) 0/12 (0%) 0/16 (0%) 0/11 (0%) 0/10 (0%) 0/10 (0%) 0/10 (0%) 0/3 (0%) 0/9 (0%) 0/6 (0%) 1/20 (5%) 1/10 (10%)
Paronychia 0/3 (0%) 16/19 (84.2%) 10/12 (83.3%) 12/16 (75%) 0/11 (0%) 4/10 (40%) 7/10 (70%) 7/10 (70%) 2/3 (66.7%) 1/9 (11.1%) 1/6 (16.7%) 6/20 (30%) 1/10 (10%)
Parotitis 0/3 (0%) 0/19 (0%) 0/12 (0%) 0/16 (0%) 0/11 (0%) 0/10 (0%) 0/10 (0%) 0/10 (0%) 0/3 (0%) 0/9 (0%) 0/6 (0%) 0/20 (0%) 1/10 (10%)
Pharyngitis 0/3 (0%) 3/19 (15.8%) 1/12 (8.3%) 0/16 (0%) 0/11 (0%) 1/10 (10%) 0/10 (0%) 0/10 (0%) 1/3 (33.3%) 0/9 (0%) 0/6 (0%) 3/20 (15%) 0/10 (0%)
Pharyngitis streptococcal 0/3 (0%) 2/19 (10.5%) 1/12 (8.3%) 2/16 (12.5%) 1/11 (9.1%) 2/10 (20%) 0/10 (0%) 1/10 (10%) 0/3 (0%) 0/9 (0%) 0/6 (0%) 1/20 (5%) 0/10 (0%)
Pneumonia 0/3 (0%) 1/19 (5.3%) 2/12 (16.7%) 1/16 (6.3%) 1/11 (9.1%) 0/10 (0%) 0/10 (0%) 0/10 (0%) 0/3 (0%) 0/9 (0%) 0/6 (0%) 0/20 (0%) 0/10 (0%)
Post procedural infection 0/3 (0%) 0/19 (0%) 0/12 (0%) 1/16 (6.3%) 0/11 (0%) 0/10 (0%) 0/10 (0%) 0/10 (0%) 0/3 (0%) 0/9 (0%) 0/6 (0%) 0/20 (0%) 0/10 (0%)
Pustule 0/3 (0%) 0/19 (0%) 0/12 (0%) 0/16 (0%) 0/11 (0%) 1/10 (10%) 0/10 (0%) 0/10 (0%) 0/3 (0%) 0/9 (0%) 0/6 (0%) 1/20 (5%) 0/10 (0%)
Rash pustular 1/3 (33.3%) 5/19 (26.3%) 0/12 (0%) 3/16 (18.8%) 0/11 (0%) 1/10 (10%) 0/10 (0%) 0/10 (0%) 0/3 (0%) 1/9 (11.1%) 1/6 (16.7%) 1/20 (5%) 1/10 (10%)
Respiratory syncytial virus infection 0/3 (0%) 1/19 (5.3%) 1/12 (8.3%) 0/16 (0%) 0/11 (0%) 0/10 (0%) 0/10 (0%) 0/10 (0%) 0/3 (0%) 0/9 (0%) 0/6 (0%) 0/20 (0%) 0/10 (0%)
Respiratory tract infection 0/3 (0%) 0/19 (0%) 1/12 (8.3%) 1/16 (6.3%) 0/11 (0%) 0/10 (0%) 0/10 (0%) 0/10 (0%) 0/3 (0%) 0/9 (0%) 0/6 (0%) 0/20 (0%) 0/10 (0%)
Respiratory tract infection bacterial 0/3 (0%) 0/19 (0%) 1/12 (8.3%) 0/16 (0%) 0/11 (0%) 0/10 (0%) 0/10 (0%) 0/10 (0%) 0/3 (0%) 0/9 (0%) 0/6 (0%) 0/20 (0%) 0/10 (0%)
Rhinitis 0/3 (0%) 4/19 (21.1%) 0/12 (0%) 2/16 (12.5%) 0/11 (0%) 2/10 (20%) 3/10 (30%) 1/10 (10%) 0/3 (0%) 2/9 (22.2%) 0/6 (0%) 2/20 (10%) 0/10 (0%)
Rhinovirus infection 0/3 (0%) 0/19 (0%) 1/12 (8.3%) 0/16 (0%) 0/11 (0%) 0/10 (0%) 0/10 (0%) 0/10 (0%) 0/3 (0%) 0/9 (0%) 0/6 (0%) 0/20 (0%) 1/10 (10%)
Sinusitis 0/3 (0%) 0/19 (0%) 1/12 (8.3%) 1/16 (6.3%) 0/11 (0%) 0/10 (0%) 0/10 (0%) 1/10 (10%) 0/3 (0%) 1/9 (11.1%) 0/6 (0%) 1/20 (5%) 0/10 (0%)
Skin bacterial infection 0/3 (0%) 1/19 (5.3%) 0/12 (0%) 0/16 (0%) 0/11 (0%) 0/10 (0%) 0/10 (0%) 0/10 (0%) 0/3 (0%) 0/9 (0%) 0/6 (0%) 0/20 (0%) 0/10 (0%)
Skin candida 0/3 (0%) 0/19 (0%) 0/12 (0%) 0/16 (0%) 1/11 (9.1%) 0/10 (0%) 0/10 (0%) 0/10 (0%) 0/3 (0%) 0/9 (0%) 0/6 (0%) 0/20 (0%) 0/10 (0%)
Skin infection 0/3 (0%) 4/19 (21.1%) 2/12 (16.7%) 3/16 (18.8%) 2/11 (18.2%) 1/10 (10%) 0/10 (0%) 1/10 (10%) 0/3 (0%) 0/9 (0%) 1/6 (16.7%) 1/20 (5%) 0/10 (0%)
Staphylococcal infection 0/3 (0%) 1/19 (5.3%) 0/12 (0%) 0/16 (0%) 0/11 (0%) 1/10 (10%) 1/10 (10%) 0/10 (0%) 0/3 (0%) 0/9 (0%) 0/6 (0%) 0/20 (0%) 0/10 (0%)
Staphylococcal skin infection 0/3 (0%) 1/19 (5.3%) 1/12 (8.3%) 0/16 (0%) 0/11 (0%) 1/10 (10%) 0/10 (0%) 1/10 (10%) 0/3 (0%) 0/9 (0%) 0/6 (0%) 0/20 (0%) 0/10 (0%)
Stoma site infection 0/3 (0%) 0/19 (0%) 0/12 (0%) 0/16 (0%) 0/11 (0%) 0/10 (0%) 1/10 (10%) 1/10 (10%) 0/3 (0%) 0/9 (0%) 0/6 (0%) 0/20 (0%) 0/10 (0%)
Tinea capitis 0/3 (0%) 0/19 (0%) 0/12 (0%) 0/16 (0%) 0/11 (0%) 0/10 (0%) 1/10 (10%) 0/10 (0%) 0/3 (0%) 0/9 (0%) 0/6 (0%) 0/20 (0%) 0/10 (0%)
Tinea faciei 0/3 (0%) 0/19 (0%) 0/12 (0%) 0/16 (0%) 0/11 (0%) 0/10 (0%) 1/10 (10%) 0/10 (0%) 0/3 (0%) 0/9 (0%) 0/6 (0%) 0/20 (0%) 0/10 (0%)
Tinea infection 1/3 (33.3%) 0/19 (0%) 0/12 (0%) 1/16 (6.3%) 0/11 (0%) 0/10 (0%) 0/10 (0%) 0/10 (0%) 0/3 (0%) 0/9 (0%) 0/6 (0%) 0/20 (0%) 0/10 (0%)
Tinea pedis 0/3 (0%) 0/19 (0%) 1/12 (8.3%) 0/16 (0%) 0/11 (0%) 0/10 (0%) 0/10 (0%) 0/10 (0%) 0/3 (0%) 0/9 (0%) 0/6 (0%) 0/20 (0%) 0/10 (0%)
Tonsillitis 0/3 (0%) 3/19 (15.8%) 0/12 (0%) 1/16 (6.3%) 0/11 (0%) 0/10 (0%) 0/10 (0%) 0/10 (0%) 0/3 (0%) 0/9 (0%) 0/6 (0%) 1/20 (5%) 0/10 (0%)
Tooth infection 0/3 (0%) 0/19 (0%) 0/12 (0%) 0/16 (0%) 0/11 (0%) 0/10 (0%) 0/10 (0%) 1/10 (10%) 0/3 (0%) 0/9 (0%) 0/6 (0%) 0/20 (0%) 0/10 (0%)
Tracheitis 0/3 (0%) 1/19 (5.3%) 0/12 (0%) 0/16 (0%) 0/11 (0%) 0/10 (0%) 0/10 (0%) 0/10 (0%) 0/3 (0%) 0/9 (0%) 0/6 (0%) 0/20 (0%) 0/10 (0%)
Upper respiratory tract infection 0/3 (0%) 6/19 (31.6%) 3/12 (25%) 1/16 (6.3%) 0/11 (0%) 0/10 (0%) 3/10 (30%) 3/10 (30%) 0/3 (0%) 2/9 (22.2%) 1/6 (16.7%) 6/20 (30%) 4/10 (40%)
Urinary tract infection 0/3 (0%) 2/19 (10.5%) 1/12 (8.3%) 1/16 (6.3%) 1/11 (9.1%) 1/10 (10%) 1/10 (10%) 0/10 (0%) 0/3 (0%) 0/9 (0%) 0/6 (0%) 0/20 (0%) 0/10 (0%)
Varicella 0/3 (0%) 1/19 (5.3%) 0/12 (0%) 1/16 (6.3%) 0/11 (0%) 0/10 (0%) 0/10 (0%) 0/10 (0%) 0/3 (0%) 0/9 (0%) 0/6 (0%) 0/20 (0%) 0/10 (0%)
Viral infection 0/3 (0%) 4/19 (21.1%) 1/12 (8.3%) 1/16 (6.3%) 0/11 (0%) 0/10 (0%) 2/10 (20%) 0/10 (0%) 0/3 (0%) 1/9 (11.1%) 1/6 (16.7%) 1/20 (5%) 1/10 (10%)
Viral pharyngitis 0/3 (0%) 1/19 (5.3%) 0/12 (0%) 0/16 (0%) 1/11 (9.1%) 0/10 (0%) 0/10 (0%) 0/10 (0%) 0/3 (0%) 0/9 (0%) 0/6 (0%) 0/20 (0%) 0/10 (0%)
Viral rhinitis 0/3 (0%) 0/19 (0%) 0/12 (0%) 0/16 (0%) 0/11 (0%) 1/10 (10%) 0/10 (0%) 0/10 (0%) 0/3 (0%) 0/9 (0%) 0/6 (0%) 0/20 (0%) 0/10 (0%)
Viral upper respiratory tract infection 0/3 (0%) 0/19 (0%) 0/12 (0%) 0/16 (0%) 0/11 (0%) 0/10 (0%) 0/10 (0%) 0/10 (0%) 0/3 (0%) 0/9 (0%) 1/6 (16.7%) 0/20 (0%) 0/10 (0%)
Wound sepsis 0/3 (0%) 0/19 (0%) 0/12 (0%) 1/16 (6.3%) 0/11 (0%) 0/10 (0%) 0/10 (0%) 0/10 (0%) 0/3 (0%) 0/9 (0%) 0/6 (0%) 0/20 (0%) 0/10 (0%)
Injury, poisoning and procedural complications
Arthropod bite 0/3 (0%) 1/19 (5.3%) 0/12 (0%) 0/16 (0%) 1/11 (9.1%) 0/10 (0%) 0/10 (0%) 0/10 (0%) 1/3 (33.3%) 0/9 (0%) 0/6 (0%) 1/20 (5%) 0/10 (0%)
Contusion 0/3 (0%) 1/19 (5.3%) 0/12 (0%) 0/16 (0%) 2/11 (18.2%) 0/10 (0%) 0/10 (0%) 1/10 (10%) 0/3 (0%) 1/9 (11.1%) 1/6 (16.7%) 0/20 (0%) 0/10 (0%)
Fall 0/3 (0%) 1/19 (5.3%) 0/12 (0%) 1/16 (6.3%) 0/11 (0%) 1/10 (10%) 1/10 (10%) 1/10 (10%) 0/3 (0%) 1/9 (11.1%) 0/6 (0%) 1/20 (5%) 0/10 (0%)
Fracture 0/3 (0%) 1/19 (5.3%) 0/12 (0%) 0/16 (0%) 0/11 (0%) 0/10 (0%) 0/10 (0%) 0/10 (0%) 0/3 (0%) 0/9 (0%) 0/6 (0%) 1/20 (5%) 1/10 (10%)
Gastrostomy tube site complication 0/3 (0%) 2/19 (10.5%) 0/12 (0%) 0/16 (0%) 0/11 (0%) 0/10 (0%) 0/10 (0%) 0/10 (0%) 0/3 (0%) 0/9 (0%) 0/6 (0%) 0/20 (0%) 0/10 (0%)
Hand fracture 0/3 (0%) 0/19 (0%) 1/12 (8.3%) 1/16 (6.3%) 0/11 (0%) 2/10 (20%) 0/10 (0%) 0/10 (0%) 0/3 (0%) 0/9 (0%) 0/6 (0%) 0/20 (0%) 0/10 (0%)
Head injury 0/3 (0%) 0/19 (0%) 0/12 (0%) 0/16 (0%) 0/11 (0%) 1/10 (10%) 1/10 (10%) 0/10 (0%) 0/3 (0%) 0/9 (0%) 0/6 (0%) 0/20 (0%) 0/10 (0%)
Incision site pruritus 0/3 (0%) 1/19 (5.3%) 0/12 (0%) 0/16 (0%) 0/11 (0%) 0/10 (0%) 0/10 (0%) 0/10 (0%) 0/3 (0%) 0/9 (0%) 0/6 (0%) 0/20 (0%) 0/10 (0%)
Limb injury 0/3 (0%) 1/19 (5.3%) 1/12 (8.3%) 2/16 (12.5%) 0/11 (0%) 1/10 (10%) 0/10 (0%) 0/10 (0%) 0/3 (0%) 0/9 (0%) 0/6 (0%) 0/20 (0%) 0/10 (0%)
Muscle strain 0/3 (0%) 1/19 (5.3%) 0/12 (0%) 0/16 (0%) 0/11 (0%) 0/10 (0%) 0/10 (0%) 0/10 (0%) 0/3 (0%) 0/9 (0%) 0/6 (0%) 0/20 (0%) 0/10 (0%)
Nasal injury 0/3 (0%) 0/19 (0%) 0/12 (0%) 0/16 (0%) 0/11 (0%) 0/10 (0%) 0/10 (0%) 1/10 (10%) 0/3 (0%) 0/9 (0%) 0/6 (0%) 0/20 (0%) 0/10 (0%)
Overdose 0/3 (0%) 0/19 (0%) 0/12 (0%) 0/16 (0%) 0/11 (0%) 0/10 (0%) 1/10 (10%) 0/10 (0%) 0/3 (0%) 0/9 (0%) 0/6 (0%) 0/20 (0%) 0/10 (0%)
Procedural pain 0/3 (0%) 0/19 (0%) 0/12 (0%) 0/16 (0%) 0/11 (0%) 0/10 (0%) 0/10 (0%) 0/10 (0%) 1/3 (33.3%) 0/9 (0%) 0/6 (0%) 0/20 (0%) 0/10 (0%)
Procedural vomiting 0/3 (0%) 0/19 (0%) 1/12 (8.3%) 0/16 (0%) 0/11 (0%) 0/10 (0%) 0/10 (0%) 0/10 (0%) 0/3 (0%) 0/9 (0%) 0/6 (0%) 0/20 (0%) 0/10 (0%)
Radius fracture 0/3 (0%) 0/19 (0%) 0/12 (0%) 0/16 (0%) 0/11 (0%) 0/10 (0%) 0/10 (0%) 1/10 (10%) 0/3 (0%) 0/9 (0%) 0/6 (0%) 0/20 (0%) 0/10 (0%)
Scar 0/3 (0%) 0/19 (0%) 0/12 (0%) 1/16 (6.3%) 0/11 (0%) 0/10 (0%) 0/10 (0%) 0/10 (0%) 0/3 (0%) 0/9 (0%) 0/6 (0%) 0/20 (0%) 0/10 (0%)
Scratch 0/3 (0%) 0/19 (0%) 1/12 (8.3%) 0/16 (0%) 0/11 (0%) 0/10 (0%) 0/10 (0%) 0/10 (0%) 0/3 (0%) 0/9 (0%) 0/6 (0%) 0/20 (0%) 0/10 (0%)
Skin abrasion 1/3 (33.3%) 2/19 (10.5%) 3/12 (25%) 0/16 (0%) 1/11 (9.1%) 0/10 (0%) 0/10 (0%) 1/10 (10%) 0/3 (0%) 0/9 (0%) 0/6 (0%) 1/20 (5%) 0/10 (0%)
Skin laceration 0/3 (0%) 0/19 (0%) 0/12 (0%) 0/16 (0%) 1/11 (9.1%) 0/10 (0%) 1/10 (10%) 0/10 (0%) 0/3 (0%) 0/9 (0%) 0/6 (0%) 1/20 (5%) 0/10 (0%)
Stoma site hypergranulation 0/3 (0%) 0/19 (0%) 0/12 (0%) 0/16 (0%) 0/11 (0%) 0/10 (0%) 1/10 (10%) 0/10 (0%) 0/3 (0%) 0/9 (0%) 0/6 (0%) 0/20 (0%) 0/10 (0%)
Stoma site pain 0/3 (0%) 1/19 (5.3%) 0/12 (0%) 0/16 (0%) 0/11 (0%) 0/10 (0%) 0/10 (0%) 0/10 (0%) 0/3 (0%) 0/9 (0%) 0/6 (0%) 0/20 (0%) 0/10 (0%)
Sunburn 0/3 (0%) 1/19 (5.3%) 0/12 (0%) 1/16 (6.3%) 0/11 (0%) 0/10 (0%) 1/10 (10%) 0/10 (0%) 0/3 (0%) 0/9 (0%) 0/6 (0%) 0/20 (0%) 0/10 (0%)
Thermal burn 0/3 (0%) 1/19 (5.3%) 0/12 (0%) 0/16 (0%) 0/11 (0%) 0/10 (0%) 1/10 (10%) 0/10 (0%) 0/3 (0%) 0/9 (0%) 0/6 (0%) 0/20 (0%) 0/10 (0%)
Tongue injury 0/3 (0%) 0/19 (0%) 0/12 (0%) 0/16 (0%) 0/11 (0%) 0/10 (0%) 0/10 (0%) 1/10 (10%) 0/3 (0%) 0/9 (0%) 0/6 (0%) 0/20 (0%) 0/10 (0%)
Upper limb fracture 0/3 (0%) 1/19 (5.3%) 0/12 (0%) 0/16 (0%) 0/11 (0%) 0/10 (0%) 0/10 (0%) 0/10 (0%) 0/3 (0%) 0/9 (0%) 0/6 (0%) 1/20 (5%) 0/10 (0%)
Venomous sting 0/3 (0%) 0/19 (0%) 0/12 (0%) 0/16 (0%) 0/11 (0%) 0/10 (0%) 1/10 (10%) 0/10 (0%) 0/3 (0%) 0/9 (0%) 0/6 (0%) 0/20 (0%) 0/10 (0%)
Wrist fracture 0/3 (0%) 0/19 (0%) 1/12 (8.3%) 1/16 (6.3%) 0/11 (0%) 0/10 (0%) 0/10 (0%) 0/10 (0%) 0/3 (0%) 0/9 (0%) 0/6 (0%) 0/20 (0%) 0/10 (0%)
Investigations
Activated partial thromboplastin time prolonged 0/3 (0%) 1/19 (5.3%) 0/12 (0%) 0/16 (0%) 1/11 (9.1%) 0/10 (0%) 0/10 (0%) 0/10 (0%) 0/3 (0%) 0/9 (0%) 0/6 (0%) 0/20 (0%) 0/10 (0%)
Alanine aminotransferase increased 0/3 (0%) 3/19 (15.8%) 1/12 (8.3%) 5/16 (31.3%) 2/11 (18.2%) 2/10 (20%) 0/10 (0%) 0/10 (0%) 1/3 (33.3%) 1/9 (11.1%) 1/6 (16.7%) 3/20 (15%) 0/10 (0%)
Albumin urine present 0/3 (0%) 0/19 (0%) 1/12 (8.3%) 0/16 (0%) 0/11 (0%) 0/10 (0%) 0/10 (0%) 0/10 (0%) 0/3 (0%) 0/9 (0%) 0/6 (0%) 0/20 (0%) 0/10 (0%)
Anion gap decreased 0/3 (0%) 0/19 (0%) 1/12 (8.3%) 0/16 (0%) 0/11 (0%) 0/10 (0%) 0/10 (0%) 0/10 (0%) 0/3 (0%) 0/9 (0%) 0/6 (0%) 0/20 (0%) 0/10 (0%)
Aspartate aminotransferase increased 1/3 (33.3%) 8/19 (42.1%) 4/12 (33.3%) 7/16 (43.8%) 3/11 (27.3%) 1/10 (10%) 1/10 (10%) 6/10 (60%) 1/3 (33.3%) 3/9 (33.3%) 3/6 (50%) 5/20 (25%) 1/10 (10%)
Bacterial test positive 0/3 (0%) 0/19 (0%) 1/12 (8.3%) 0/16 (0%) 0/11 (0%) 0/10 (0%) 0/10 (0%) 1/10 (10%) 0/3 (0%) 0/9 (0%) 0/6 (0%) 0/20 (0%) 0/10 (0%)
Blood albumin decreased 0/3 (0%) 0/19 (0%) 0/12 (0%) 0/16 (0%) 0/11 (0%) 0/10 (0%) 0/10 (0%) 1/10 (10%) 0/3 (0%) 0/9 (0%) 0/6 (0%) 0/20 (0%) 0/10 (0%)
Blood alkaline phosphatase increased 0/3 (0%) 5/19 (26.3%) 0/12 (0%) 2/16 (12.5%) 2/11 (18.2%) 0/10 (0%) 0/10 (0%) 1/10 (10%) 0/3 (0%) 2/9 (22.2%) 2/6 (33.3%) 2/20 (10%) 1/10 (10%)
Blood bicarbonate decreased 0/3 (0%) 0/19 (0%) 1/12 (8.3%) 0/16 (0%) 0/11 (0%) 0/10 (0%) 0/10 (0%) 0/10 (0%) 0/3 (0%) 0/9 (0%) 0/6 (0%) 0/20 (0%) 0/10 (0%)
Blood bicarbonate increased 0/3 (0%) 0/19 (0%) 0/12 (0%) 0/16 (0%) 0/11 (0%) 0/10 (0%) 0/10 (0%) 0/10 (0%) 0/3 (0%) 0/9 (0%) 0/6 (0%) 0/20 (0%) 1/10 (10%)
Blood chloride increased 0/3 (0%) 0/19 (0%) 1/12 (8.3%) 0/16 (0%) 0/11 (0%) 0/10 (0%) 0/10 (0%) 0/10 (0%) 0/3 (0%) 0/9 (0%) 0/6 (0%) 1/20 (5%) 0/10 (0%)
Blood creatine phosphokinase increased 0/3 (0%) 0/19 (0%) 0/12 (0%) 0/16 (0%) 1/11 (9.1%) 0/10 (0%) 0/10 (0%) 0/10 (0%) 0/3 (0%) 0/9 (0%) 0/6 (0%) 0/20 (0%) 0/10 (0%)
Blood creatinine increased 0/3 (0%) 3/19 (15.8%) 1/12 (8.3%) 2/16 (12.5%) 5/11 (45.5%) 1/10 (10%) 0/10 (0%) 1/10 (10%) 0/3 (0%) 2/9 (22.2%) 2/6 (33.3%) 0/20 (0%) 2/10 (20%)
Blood glucose increased 0/3 (0%) 0/19 (0%) 0/12 (0%) 0/16 (0%) 0/11 (0%) 0/10 (0%) 0/10 (0%) 0/10 (0%) 0/3 (0%) 0/9 (0%) 0/6 (0%) 0/20 (0%) 1/10 (10%)
Blood urea decreased 0/3 (0%) 0/19 (0%) 0/12 (0%) 1/16 (6.3%) 0/11 (0%) 0/10 (0%) 0/10 (0%) 0/10 (0%) 0/3 (0%) 0/9 (0%) 0/6 (0%) 0/20 (0%) 0/10 (0%)
Blood urea increased 1/3 (33.3%) 1/19 (5.3%) 0/12 (0%) 0/16 (0%) 0/11 (0%) 0/10 (0%) 0/10 (0%) 0/10 (0%) 0/3 (0%) 0/9 (0%) 0/6 (0%) 1/20 (5%) 0/10 (0%)
Body temperature fluctuation 0/3 (0%) 0/19 (0%) 0/12 (0%) 1/16 (6.3%) 0/11 (0%) 0/10 (0%) 0/10 (0%) 0/10 (0%) 0/3 (0%) 0/9 (0%) 0/6 (0%) 0/20 (0%) 0/10 (0%)
Ejection fraction decreased 0/3 (0%) 0/19 (0%) 1/12 (8.3%) 1/16 (6.3%) 0/11 (0%) 1/10 (10%) 0/10 (0%) 3/10 (30%) 0/3 (0%) 0/9 (0%) 0/6 (0%) 0/20 (0%) 0/10 (0%)
Electrocardiogram QT prolonged 0/3 (0%) 0/19 (0%) 0/12 (0%) 0/16 (0%) 1/11 (9.1%) 0/10 (0%) 0/10 (0%) 0/10 (0%) 0/3 (0%) 1/9 (11.1%) 0/6 (0%) 0/20 (0%) 0/10 (0%)
Electrocardiogram ST-T segment abnormal 0/3 (0%) 1/19 (5.3%) 0/12 (0%) 0/16 (0%) 0/11 (0%) 0/10 (0%) 0/10 (0%) 0/10 (0%) 0/3 (0%) 0/9 (0%) 0/6 (0%) 0/20 (0%) 0/10 (0%)
Electrocardiogram T wave amplitude decreased 0/3 (0%) 1/19 (5.3%) 0/12 (0%) 0/16 (0%) 0/11 (0%) 0/10 (0%) 0/10 (0%) 0/10 (0%) 0/3 (0%) 0/9 (0%) 0/6 (0%) 0/20 (0%) 0/10 (0%)
End-tidal CO2 decreased 0/3 (0%) 1/19 (5.3%) 0/12 (0%) 0/16 (0%) 0/11 (0%) 0/10 (0%) 0/10 (0%) 0/10 (0%) 0/3 (0%) 0/9 (0%) 0/6 (0%) 0/20 (0%) 0/10 (0%)
Gamma-glutamyltransferase increased 0/3 (0%) 2/19 (10.5%) 0/12 (0%) 2/16 (12.5%) 1/11 (9.1%) 0/10 (0%) 0/10 (0%) 2/10 (20%) 1/3 (33.3%) 2/9 (22.2%) 2/6 (33.3%) 3/20 (15%) 1/10 (10%)
Grip strength decreased 0/3 (0%) 0/19 (0%) 1/12 (8.3%) 0/16 (0%) 0/11 (0%) 0/10 (0%) 0/10 (0%) 0/10 (0%) 0/3 (0%) 0/9 (0%) 0/6 (0%) 0/20 (0%) 0/10 (0%)
Haematocrit increased 0/3 (0%) 0/19 (0%) 1/12 (8.3%) 0/16 (0%) 0/11 (0%) 0/10 (0%) 0/10 (0%) 0/10 (0%) 0/3 (0%) 0/9 (0%) 0/6 (0%) 0/20 (0%) 0/10 (0%)
Haemoglobin decreased 0/3 (0%) 0/19 (0%) 0/12 (0%) 0/16 (0%) 0/11 (0%) 0/10 (0%) 0/10 (0%) 1/10 (10%) 0/3 (0%) 0/9 (0%) 0/6 (0%) 0/20 (0%) 0/10 (0%)
Haemoglobin increased 0/3 (0%) 0/19 (0%) 1/12 (8.3%) 0/16 (0%) 0/11 (0%) 0/10 (0%) 0/10 (0%) 0/10 (0%) 0/3 (0%) 0/9 (0%) 0/6 (0%) 2/20 (10%) 0/10 (0%)
Lung diffusion test decreased 0/3 (0%) 0/19 (0%) 0/12 (0%) 0/16 (0%) 0/11 (0%) 0/10 (0%) 0/10 (0%) 0/10 (0%) 0/3 (0%) 0/9 (0%) 0/6 (0%) 0/20 (0%) 1/10 (10%)
Lymphocyte count decreased 0/3 (0%) 2/19 (10.5%) 2/12 (16.7%) 1/16 (6.3%) 2/11 (18.2%) 0/10 (0%) 0/10 (0%) 2/10 (20%) 0/3 (0%) 2/9 (22.2%) 0/6 (0%) 1/20 (5%) 1/10 (10%)
Lymphocyte count increased 0/3 (0%) 3/19 (15.8%) 0/12 (0%) 0/16 (0%) 0/11 (0%) 0/10 (0%) 0/10 (0%) 0/10 (0%) 0/3 (0%) 0/9 (0%) 0/6 (0%) 0/20 (0%) 0/10 (0%)
Lymphocyte percentage decreased 0/3 (0%) 0/19 (0%) 1/12 (8.3%) 0/16 (0%) 0/11 (0%) 0/10 (0%) 0/10 (0%) 0/10 (0%) 0/3 (0%) 0/9 (0%) 0/6 (0%) 0/20 (0%) 0/10 (0%)
Neutrophil count decreased 0/3 (0%) 0/19 (0%) 1/12 (8.3%) 2/16 (12.5%) 2/11 (18.2%) 1/10 (10%) 0/10 (0%) 0/10 (0%) 0/3 (0%) 3/9 (33.3%) 0/6 (0%) 3/20 (15%) 5/10 (50%)
Neutrophil percentage increased 0/3 (0%) 0/19 (0%) 1/12 (8.3%) 0/16 (0%) 0/11 (0%) 0/10 (0%) 0/10 (0%) 0/10 (0%) 0/3 (0%) 0/9 (0%) 0/6 (0%) 0/20 (0%) 0/10 (0%)
Nitrite urine present 0/3 (0%) 0/19 (0%) 0/12 (0%) 0/16 (0%) 0/11 (0%) 0/10 (0%) 0/10 (0%) 0/10 (0%) 0/3 (0%) 0/9 (0%) 1/6 (16.7%) 0/20 (0%) 0/10 (0%)
Platelet count decreased 0/3 (0%) 1/19 (5.3%) 0/12 (0%) 2/16 (12.5%) 2/11 (18.2%) 1/10 (10%) 0/10 (0%) 1/10 (10%) 0/3 (0%) 1/9 (11.1%) 0/6 (0%) 1/20 (5%) 1/10 (10%)
Protein total decreased 1/3 (33.3%) 1/19 (5.3%) 2/12 (16.7%) 0/16 (0%) 0/11 (0%) 0/10 (0%) 0/10 (0%) 0/10 (0%) 0/3 (0%) 0/9 (0%) 0/6 (0%) 0/20 (0%) 0/10 (0%)
Protein urine 0/3 (0%) 0/19 (0%) 0/12 (0%) 0/16 (0%) 0/11 (0%) 0/10 (0%) 1/10 (10%) 0/10 (0%) 0/3 (0%) 0/9 (0%) 0/6 (0%) 0/20 (0%) 0/10 (0%)
Red blood cell count decreased 0/3 (0%) 0/19 (0%) 1/12 (8.3%) 0/16 (0%) 0/11 (0%) 0/10 (0%) 0/10 (0%) 0/10 (0%) 0/3 (0%) 0/9 (0%) 0/6 (0%) 1/20 (5%) 0/10 (0%)
Red blood cells urine 0/3 (0%) 0/19 (0%) 1/12 (8.3%) 0/16 (0%) 0/11 (0%) 0/10 (0%) 0/10 (0%) 0/10 (0%) 0/3 (0%) 0/9 (0%) 0/6 (0%) 0/20 (0%) 0/10 (0%)
Red blood cells urine positive 0/3 (0%) 0/19 (0%) 1/12 (8.3%) 0/16 (0%) 0/11 (0%) 0/10 (0%) 0/10 (0%) 0/10 (0%) 0/3 (0%) 0/9 (0%) 0/6 (0%) 0/20 (0%) 0/10 (0%)
Specific gravity urine increased 0/3 (0%) 0/19 (0%) 1/12 (8.3%) 0/16 (0%) 0/11 (0%) 0/10 (0%) 0/10 (0%) 0/10 (0%) 0/3 (0%) 0/9 (0%) 1/6 (16.7%) 0/20 (0%) 0/10 (0%)
Staphylococcus test positive 0/3 (0%) 0/19 (0%) 0/12 (0%) 0/16 (0%) 1/11 (9.1%) 1/10 (10%) 0/10 (0%) 0/10 (0%) 0/3 (0%) 0/9 (0%) 0/6 (0%) 0/20 (0%) 0/10 (0%)
Urine ketone body present 0/3 (0%) 0/19 (0%) 1/12 (8.3%) 1/16 (6.3%) 0/11 (0%) 0/10 (0%) 0/10 (0%) 0/10 (0%) 0/3 (0%) 0/9 (0%) 1/6 (16.7%) 0/20 (0%) 0/10 (0%)
Urine leukocyte esterase positive 0/3 (0%) 0/19 (0%) 1/12 (8.3%) 0/16 (0%) 0/11 (0%) 0/10 (0%) 0/10 (0%) 0/10 (0%) 0/3 (0%) 0/9 (0%) 1/6 (16.7%) 0/20 (0%) 0/10 (0%)
Urine output decreased 0/3 (0%) 0/19 (0%) 0/12 (0%) 0/16 (0%) 0/11 (0%) 0/10 (0%) 0/10 (0%) 1/10 (10%) 0/3 (0%) 0/9 (0%) 0/6 (0%) 0/20 (0%) 0/10 (0%)
Weight decreased 0/3 (0%) 2/19 (10.5%) 1/12 (8.3%) 1/16 (6.3%) 1/11 (9.1%) 1/10 (10%) 0/10 (0%) 0/10 (0%) 1/3 (33.3%) 0/9 (0%) 0/6 (0%) 0/20 (0%) 0/10 (0%)
Weight increased 0/3 (0%) 5/19 (26.3%) 3/12 (25%) 0/16 (0%) 2/11 (18.2%) 3/10 (30%) 0/10 (0%) 1/10 (10%) 1/3 (33.3%) 1/9 (11.1%) 2/6 (33.3%) 5/20 (25%) 1/10 (10%)
White blood cell count decreased 0/3 (0%) 2/19 (10.5%) 3/12 (25%) 4/16 (25%) 3/11 (27.3%) 1/10 (10%) 0/10 (0%) 0/10 (0%) 0/3 (0%) 2/9 (22.2%) 0/6 (0%) 3/20 (15%) 1/10 (10%)
White blood cell count increased 0/3 (0%) 0/19 (0%) 0/12 (0%) 0/16 (0%) 0/11 (0%) 0/10 (0%) 1/10 (10%) 0/10 (0%) 0/3 (0%) 0/9 (0%) 0/6 (0%) 1/20 (5%) 0/10 (0%)
White blood cells urine positive 0/3 (0%) 0/19 (0%) 1/12 (8.3%) 0/16 (0%) 0/11 (0%) 0/10 (0%) 0/10 (0%) 1/10 (10%) 0/3 (0%) 0/9 (0%) 0/6 (0%) 0/20 (0%) 0/10 (0%)
pH urine increased 0/3 (0%) 0/19 (0%) 1/12 (8.3%) 0/16 (0%) 0/11 (0%) 0/10 (0%) 0/10 (0%) 0/10 (0%) 0/3 (0%) 0/9 (0%) 0/6 (0%) 1/20 (5%) 0/10 (0%)
Metabolism and nutrition disorders
Alkalosis 0/3 (0%) 0/19 (0%) 0/12 (0%) 0/16 (0%) 0/11 (0%) 0/10 (0%) 0/10 (0%) 0/10 (0%) 0/3 (0%) 1/9 (11.1%) 0/6 (0%) 0/20 (0%) 0/10 (0%)
Decreased appetite 2/3 (66.7%) 11/19 (57.9%) 4/12 (33.3%) 5/16 (31.3%) 1/11 (9.1%) 3/10 (30%) 2/10 (20%) 3/10 (30%) 0/3 (0%) 1/9 (11.1%) 0/6 (0%) 4/20 (20%) 0/10 (0%)
Dehydration 0/3 (0%) 1/19 (5.3%) 2/12 (16.7%) 1/16 (6.3%) 0/11 (0%) 1/10 (10%) 0/10 (0%) 0/10 (0%) 0/3 (0%) 0/9 (0%) 0/6 (0%) 1/20 (5%) 0/10 (0%)
Hyperchloraemia 0/3 (0%) 0/19 (0%) 1/12 (8.3%) 0/16 (0%) 0/11 (0%) 1/10 (10%) 0/10 (0%) 0/10 (0%) 0/3 (0%) 1/9 (11.1%) 0/6 (0%) 0/20 (0%) 0/10 (0%)
Hyperglycaemia 0/3 (0%) 4/19 (21.1%) 3/12 (25%) 4/16 (25%) 3/11 (27.3%) 2/10 (20%) 1/10 (10%) 2/10 (20%) 0/3 (0%) 3/9 (33.3%) 0/6 (0%) 4/20 (20%) 1/10 (10%)
Hyperkalaemia 0/3 (0%) 1/19 (5.3%) 1/12 (8.3%) 2/16 (12.5%) 1/11 (9.1%) 0/10 (0%) 0/10 (0%) 1/10 (10%) 0/3 (0%) 0/9 (0%) 0/6 (0%) 1/20 (5%) 0/10 (0%)
Hypermagnesaemia 0/3 (0%) 1/19 (5.3%) 0/12 (0%) 1/16 (6.3%) 0/11 (0%) 0/10 (0%) 0/10 (0%) 1/10 (10%) 0/3 (0%) 2/9 (22.2%) 0/6 (0%) 1/20 (5%) 0/10 (0%)
Hypernatraemia 0/3 (0%) 5/19 (26.3%) 1/12 (8.3%) 2/16 (12.5%) 1/11 (9.1%) 1/10 (10%) 0/10 (0%) 3/10 (30%) 0/3 (0%) 2/9 (22.2%) 1/6 (16.7%) 2/20 (10%) 0/10 (0%)
Hyperphosphataemia 0/3 (0%) 2/19 (10.5%) 0/12 (0%) 0/16 (0%) 0/11 (0%) 0/10 (0%) 0/10 (0%) 0/10 (0%) 0/3 (0%) 0/9 (0%) 0/6 (0%) 0/20 (0%) 0/10 (0%)
Hypoalbuminaemia 1/3 (33.3%) 5/19 (26.3%) 6/12 (50%) 4/16 (25%) 4/11 (36.4%) 3/10 (30%) 1/10 (10%) 3/10 (30%) 0/3 (0%) 4/9 (44.4%) 2/6 (33.3%) 3/20 (15%) 2/10 (20%)
Hypocalcaemia 0/3 (0%) 3/19 (15.8%) 5/12 (41.7%) 3/16 (18.8%) 2/11 (18.2%) 1/10 (10%) 1/10 (10%) 2/10 (20%) 0/3 (0%) 4/9 (44.4%) 0/6 (0%) 2/20 (10%) 0/10 (0%)
Hypochloraemia 0/3 (0%) 0/19 (0%) 0/12 (0%) 1/16 (6.3%) 0/11 (0%) 0/10 (0%) 0/10 (0%) 0/10 (0%) 0/3 (0%) 0/9 (0%) 0/6 (0%) 0/20 (0%) 0/10 (0%)
Hypoglycaemia 0/3 (0%) 4/19 (21.1%) 2/12 (16.7%) 4/16 (25%) 1/11 (9.1%) 0/10 (0%) 1/10 (10%) 1/10 (10%) 0/3 (0%) 3/9 (33.3%) 1/6 (16.7%) 0/20 (0%) 0/10 (0%)
Hypokalaemia 0/3 (0%) 2/19 (10.5%) 1/12 (8.3%) 1/16 (6.3%) 2/11 (18.2%) 1/10 (10%) 0/10 (0%) 2/10 (20%) 0/3 (0%) 2/9 (22.2%) 0/6 (0%) 1/20 (5%) 0/10 (0%)
Hypomagnesaemia 0/3 (0%) 0/19 (0%) 1/12 (8.3%) 0/16 (0%) 2/11 (18.2%) 0/10 (0%) 0/10 (0%) 1/10 (10%) 0/3 (0%) 2/9 (22.2%) 1/6 (16.7%) 4/20 (20%) 1/10 (10%)
Hyponatraemia 0/3 (0%) 2/19 (10.5%) 1/12 (8.3%) 1/16 (6.3%) 3/11 (27.3%) 1/10 (10%) 0/10 (0%) 1/10 (10%) 0/3 (0%) 0/9 (0%) 0/6 (0%) 0/20 (0%) 1/10 (10%)
Hypophagia 0/3 (0%) 0/19 (0%) 0/12 (0%) 0/16 (0%) 1/11 (9.1%) 0/10 (0%) 0/10 (0%) 0/10 (0%) 0/3 (0%) 0/9 (0%) 0/6 (0%) 1/20 (5%) 0/10 (0%)
Hypophosphataemia 0/3 (0%) 2/19 (10.5%) 1/12 (8.3%) 1/16 (6.3%) 3/11 (27.3%) 1/10 (10%) 0/10 (0%) 2/10 (20%) 0/3 (0%) 1/9 (11.1%) 1/6 (16.7%) 3/20 (15%) 2/10 (20%)
Hypoproteinaemia 0/3 (0%) 0/19 (0%) 0/12 (0%) 1/16 (6.3%) 0/11 (0%) 0/10 (0%) 0/10 (0%) 1/10 (10%) 0/3 (0%) 0/9 (0%) 0/6 (0%) 1/20 (5%) 0/10 (0%)
Obesity 0/3 (0%) 0/19 (0%) 0/12 (0%) 0/16 (0%) 0/11 (0%) 1/10 (10%) 0/10 (0%) 0/10 (0%) 0/3 (0%) 0/9 (0%) 0/6 (0%) 0/20 (0%) 0/10 (0%)
Salt craving 0/3 (0%) 0/19 (0%) 0/12 (0%) 1/16 (6.3%) 0/11 (0%) 0/10 (0%) 0/10 (0%) 0/10 (0%) 0/3 (0%) 0/9 (0%) 0/6 (0%) 0/20 (0%) 0/10 (0%)
Vitamin D deficiency 0/3 (0%) 1/19 (5.3%) 0/12 (0%) 0/16 (0%) 0/11 (0%) 0/10 (0%) 0/10 (0%) 0/10 (0%) 0/3 (0%) 1/9 (11.1%) 0/6 (0%) 0/20 (0%) 0/10 (0%)
Musculoskeletal and connective tissue disorders
Arthralgia 0/3 (0%) 5/19 (26.3%) 2/12 (16.7%) 3/16 (18.8%) 1/11 (9.1%) 2/10 (20%) 0/10 (0%) 1/10 (10%) 1/3 (33.3%) 4/9 (44.4%) 0/6 (0%) 4/20 (20%) 0/10 (0%)
Back pain 0/3 (0%) 3/19 (15.8%) 2/12 (16.7%) 4/16 (25%) 1/11 (9.1%) 0/10 (0%) 1/10 (10%) 1/10 (10%) 0/3 (0%) 1/9 (11.1%) 0/6 (0%) 1/20 (5%) 0/10 (0%)
Bone pain 0/3 (0%) 0/19 (0%) 0/12 (0%) 0/16 (0%) 1/11 (9.1%) 0/10 (0%) 0/10 (0%) 0/10 (0%) 0/3 (0%) 0/9 (0%) 0/6 (0%) 1/20 (5%) 0/10 (0%)
Costochondritis 0/3 (0%) 0/19 (0%) 1/12 (8.3%) 0/16 (0%) 0/11 (0%) 0/10 (0%) 0/10 (0%) 0/10 (0%) 0/3 (0%) 0/9 (0%) 0/6 (0%) 1/20 (5%) 0/10 (0%)
Flank pain 0/3 (0%) 1/19 (5.3%) 0/12 (0%) 0/16 (0%) 0/11 (0%) 0/10 (0%) 0/10 (0%) 0/10 (0%) 0/3 (0%) 0/9 (0%) 0/6 (0%) 0/20 (0%) 0/10 (0%)
Foot deformity 0/3 (0%) 0/19 (0%) 0/12 (0%) 0/16 (0%) 0/11 (0%) 1/10 (10%) 0/10 (0%) 0/10 (0%) 0/3 (0%) 0/9 (0%) 0/6 (0%) 0/20 (0%) 0/10 (0%)
Groin pain 0/3 (0%) 0/19 (0%) 0/12 (0%) 0/16 (0%) 0/11 (0%) 1/10 (10%) 0/10 (0%) 0/10 (0%) 0/3 (0%) 0/9 (0%) 0/6 (0%) 0/20 (0%) 0/10 (0%)
Joint range of motion decreased 0/3 (0%) 1/19 (5.3%) 0/12 (0%) 0/16 (0%) 0/11 (0%) 0/10 (0%) 0/10 (0%) 0/10 (0%) 0/3 (0%) 0/9 (0%) 0/6 (0%) 0/20 (0%) 0/10 (0%)
Joint swelling 0/3 (0%) 1/19 (5.3%) 0/12 (0%) 0/16 (0%) 0/11 (0%) 0/10 (0%) 0/10 (0%) 0/10 (0%) 0/3 (0%) 0/9 (0%) 0/6 (0%) 0/20 (0%) 0/10 (0%)
Kyphosis 0/3 (0%) 0/19 (0%) 0/12 (0%) 2/16 (12.5%) 0/11 (0%) 0/10 (0%) 0/10 (0%) 0/10 (0%) 0/3 (0%) 0/9 (0%) 0/6 (0%) 0/20 (0%) 0/10 (0%)
Muscle atrophy 0/3 (0%) 1/19 (5.3%) 0/12 (0%) 0/16 (0%) 0/11 (0%) 0/10 (0%) 0/10 (0%) 0/10 (0%) 0/3 (0%) 0/9 (0%) 0/6 (0%) 0/20 (0%) 0/10 (0%)
Muscle spasms 0/3 (0%) 2/19 (10.5%) 0/12 (0%) 0/16 (0%) 0/11 (0%) 1/10 (10%) 0/10 (0%) 1/10 (10%) 0/3 (0%) 0/9 (0%) 0/6 (0%) 1/20 (5%) 0/10 (0%)
Muscle swelling 0/3 (0%) 1/19 (5.3%) 0/12 (0%) 0/16 (0%) 0/11 (0%) 0/10 (0%) 0/10 (0%) 0/10 (0%) 0/3 (0%) 0/9 (0%) 0/6 (0%) 0/20 (0%) 0/10 (0%)
Muscular weakness 0/3 (0%) 1/19 (5.3%) 1/12 (8.3%) 1/16 (6.3%) 0/11 (0%) 1/10 (10%) 0/10 (0%) 0/10 (0%) 0/3 (0%) 2/9 (22.2%) 0/6 (0%) 0/20 (0%) 0/10 (0%)
Musculoskeletal deformity 0/3 (0%) 0/19 (0%) 0/12 (0%) 1/16 (6.3%) 0/11 (0%) 0/10 (0%) 0/10 (0%) 0/10 (0%) 0/3 (0%) 0/9 (0%) 0/6 (0%) 0/20 (0%) 0/10 (0%)
Musculoskeletal pain 0/3 (0%) 0/19 (0%) 0/12 (0%) 0/16 (0%) 0/11 (0%) 0/10 (0%) 0/10 (0%) 0/10 (0%) 0/3 (0%) 0/9 (0%) 0/6 (0%) 0/20 (0%) 1/10 (10%)
Myalgia 0/3 (0%) 0/19 (0%) 1/12 (8.3%) 0/16 (0%) 0/11 (0%) 0/10 (0%) 0/10 (0%) 1/10 (10%) 1/3 (33.3%) 2/9 (22.2%) 0/6 (0%) 1/20 (5%) 1/10 (10%)
Neck pain 0/3 (0%) 3/19 (15.8%) 2/12 (16.7%) 1/16 (6.3%) 0/11 (0%) 0/10 (0%) 1/10 (10%) 0/10 (0%) 0/3 (0%) 0/9 (0%) 0/6 (0%) 2/20 (10%) 0/10 (0%)
Osteoporosis 0/3 (0%) 0/19 (0%) 1/12 (8.3%) 0/16 (0%) 0/11 (0%) 0/10 (0%) 0/10 (0%) 0/10 (0%) 0/3 (0%) 0/9 (0%) 0/6 (0%) 0/20 (0%) 0/10 (0%)
Pain in extremity 0/3 (0%) 7/19 (36.8%) 3/12 (25%) 3/16 (18.8%) 2/11 (18.2%) 0/10 (0%) 1/10 (10%) 2/10 (20%) 0/3 (0%) 1/9 (11.1%) 0/6 (0%) 3/20 (15%) 4/10 (40%)
Scoliosis 0/3 (0%) 1/19 (5.3%) 0/12 (0%) 0/16 (0%) 0/11 (0%) 0/10 (0%) 0/10 (0%) 0/10 (0%) 0/3 (0%) 0/9 (0%) 0/6 (0%) 0/20 (0%) 0/10 (0%)
Spinal deformity 0/3 (0%) 0/19 (0%) 1/12 (8.3%) 0/16 (0%) 0/11 (0%) 0/10 (0%) 0/10 (0%) 0/10 (0%) 0/3 (0%) 0/9 (0%) 0/6 (0%) 0/20 (0%) 0/10 (0%)
Spinal pain 0/3 (0%) 0/19 (0%) 0/12 (0%) 0/16 (0%) 0/11 (0%) 0/10 (0%) 1/10 (10%) 0/10 (0%) 0/3 (0%) 0/9 (0%) 0/6 (0%) 0/20 (0%) 0/10 (0%)
Tendonitis 0/3 (0%) 0/19 (0%) 0/12 (0%) 1/16 (6.3%) 0/11 (0%) 0/10 (0%) 0/10 (0%) 0/10 (0%) 0/3 (0%) 0/9 (0%) 0/6 (0%) 0/20 (0%) 0/10 (0%)
Toe walking 0/3 (0%) 0/19 (0%) 0/12 (0%) 1/16 (6.3%) 0/11 (0%) 0/10 (0%) 0/10 (0%) 0/10 (0%) 0/3 (0%) 0/9 (0%) 0/6 (0%) 0/20 (0%) 0/10 (0%)
Trismus 0/3 (0%) 1/19 (5.3%) 0/12 (0%) 0/16 (0%) 0/11 (0%) 0/10 (0%) 0/10 (0%) 0/10 (0%) 0/3 (0%) 0/9 (0%) 0/6 (0%) 0/20 (0%) 0/10 (0%)
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Melanocytic naevus 0/3 (0%) 1/19 (5.3%) 0/12 (0%) 2/16 (12.5%) 0/11 (0%) 0/10 (0%) 0/10 (0%) 0/10 (0%) 0/3 (0%) 1/9 (11.1%) 0/6 (0%) 1/20 (5%) 0/10 (0%)
Neoplasm progression 0/3 (0%) 0/19 (0%) 0/12 (0%) 0/16 (0%) 1/11 (9.1%) 0/10 (0%) 0/10 (0%) 0/10 (0%) 0/3 (0%) 0/9 (0%) 0/6 (0%) 0/20 (0%) 0/10 (0%)
Skin papilloma 0/3 (0%) 1/19 (5.3%) 0/12 (0%) 0/16 (0%) 0/11 (0%) 0/10 (0%) 0/10 (0%) 0/10 (0%) 0/3 (0%) 0/9 (0%) 0/6 (0%) 2/20 (10%) 1/10 (10%)
Tumour pain 0/3 (0%) 0/19 (0%) 0/12 (0%) 0/16 (0%) 0/11 (0%) 0/10 (0%) 1/10 (10%) 0/10 (0%) 0/3 (0%) 0/9 (0%) 0/6 (0%) 0/20 (0%) 0/10 (0%)
Nervous system disorders
Allodynia 0/3 (0%) 0/19 (0%) 0/12 (0%) 1/16 (6.3%) 0/11 (0%) 0/10 (0%) 0/10 (0%) 0/10 (0%) 0/3 (0%) 0/9 (0%) 0/6 (0%) 0/20 (0%) 0/10 (0%)
Aphasia 0/3 (0%) 0/19 (0%) 0/12 (0%) 0/16 (0%) 1/11 (9.1%) 0/10 (0%) 0/10 (0%) 0/10 (0%) 0/3 (0%) 1/9 (11.1%) 0/6 (0%) 0/20 (0%) 0/10 (0%)
Ataxia 0/3 (0%) 1/19 (5.3%) 0/12 (0%) 0/16 (0%) 0/11 (0%) 0/10 (0%) 0/10 (0%) 0/10 (0%) 0/3 (0%) 0/9 (0%) 0/6 (0%) 0/20 (0%) 0/10 (0%)
Aura 0/3 (0%) 0/19 (0%) 0/12 (0%) 0/16 (0%) 0/11 (0%) 0/10 (0%) 0/10 (0%) 1/10 (10%) 0/3 (0%) 0/9 (0%) 0/6 (0%) 0/20 (0%) 0/10 (0%)
Depressed level of consciousness 0/3 (0%) 0/19 (0%) 0/12 (0%) 1/16 (6.3%) 0/11 (0%) 0/10 (0%) 0/10 (0%) 0/10 (0%) 0/3 (0%) 0/9 (0%) 0/6 (0%) 0/20 (0%) 0/10 (0%)
Disturbance in attention 0/3 (0%) 1/19 (5.3%) 1/12 (8.3%) 0/16 (0%) 0/11 (0%) 0/10 (0%) 0/10 (0%) 0/10 (0%) 0/3 (0%) 0/9 (0%) 0/6 (0%) 0/20 (0%) 0/10 (0%)
Dizziness 0/3 (0%) 2/19 (10.5%) 0/12 (0%) 1/16 (6.3%) 0/11 (0%) 0/10 (0%) 1/10 (10%) 2/10 (20%) 0/3 (0%) 3/9 (33.3%) 0/6 (0%) 4/20 (20%) 1/10 (10%)
Dysarthria 0/3 (0%) 1/19 (5.3%) 0/12 (0%) 0/16 (0%) 0/11 (0%) 0/10 (0%) 0/10 (0%) 0/10 (0%) 0/3 (0%) 0/9 (0%) 0/6 (0%) 1/20 (5%) 0/10 (0%)
Dysgeusia 0/3 (0%) 0/19 (0%) 0/12 (0%) 0/16 (0%) 0/11 (0%) 0/10 (0%) 0/10 (0%) 1/10 (10%) 0/3 (0%) 0/9 (0%) 0/6 (0%) 0/20 (0%) 0/10 (0%)
Dyskinesia 0/3 (0%) 0/19 (0%) 0/12 (0%) 0/16 (0%) 0/11 (0%) 0/10 (0%) 0/10 (0%) 0/10 (0%) 0/3 (0%) 1/9 (11.1%) 0/6 (0%) 0/20 (0%) 0/10 (0%)
Facial paralysis 0/3 (0%) 1/19 (5.3%) 0/12 (0%) 0/16 (0%) 0/11 (0%) 0/10 (0%) 0/10 (0%) 0/10 (0%) 0/3 (0%) 0/9 (0%) 0/6 (0%) 0/20 (0%) 0/10 (0%)
Headache 1/3 (33.3%) 11/19 (57.9%) 3/12 (25%) 5/16 (31.3%) 1/11 (9.1%) 4/10 (40%) 4/10 (40%) 3/10 (30%) 1/3 (33.3%) 4/9 (44.4%) 1/6 (16.7%) 9/20 (45%) 2/10 (20%)
Horner's syndrome 0/3 (0%) 1/19 (5.3%) 0/12 (0%) 0/16 (0%) 0/11 (0%) 0/10 (0%) 0/10 (0%) 0/10 (0%) 0/3 (0%) 0/9 (0%) 0/6 (0%) 0/20 (0%) 0/10 (0%)
Hydrocephalus 0/3 (0%) 0/19 (0%) 0/12 (0%) 0/16 (0%) 0/11 (0%) 0/10 (0%) 0/10 (0%) 1/10 (10%) 0/3 (0%) 0/9 (0%) 0/6 (0%) 0/20 (0%) 0/10 (0%)
Hypoaesthesia 0/3 (0%) 0/19 (0%) 0/12 (0%) 1/16 (6.3%) 0/11 (0%) 0/10 (0%) 1/10 (10%) 0/10 (0%) 0/3 (0%) 0/9 (0%) 0/6 (0%) 0/20 (0%) 0/10 (0%)
Lethargy 0/3 (0%) 2/19 (10.5%) 0/12 (0%) 1/16 (6.3%) 2/11 (18.2%) 0/10 (0%) 0/10 (0%) 2/10 (20%) 0/3 (0%) 1/9 (11.1%) 0/6 (0%) 1/20 (5%) 1/10 (10%)
Memory impairment 0/3 (0%) 0/19 (0%) 0/12 (0%) 0/16 (0%) 0/11 (0%) 0/10 (0%) 0/10 (0%) 0/10 (0%) 0/3 (0%) 0/9 (0%) 0/6 (0%) 2/20 (10%) 0/10 (0%)
Movement disorder 0/3 (0%) 0/19 (0%) 0/12 (0%) 0/16 (0%) 0/11 (0%) 0/10 (0%) 0/10 (0%) 1/10 (10%) 0/3 (0%) 0/9 (0%) 0/6 (0%) 0/20 (0%) 0/10 (0%)
Muscle spasticity 0/3 (0%) 0/19 (0%) 0/12 (0%) 0/16 (0%) 0/11 (0%) 0/10 (0%) 0/10 (0%) 1/10 (10%) 0/3 (0%) 0/9 (0%) 0/6 (0%) 0/20 (0%) 0/10 (0%)
Nystagmus 0/3 (0%) 0/19 (0%) 0/12 (0%) 1/16 (6.3%) 0/11 (0%) 0/10 (0%) 1/10 (10%) 0/10 (0%) 0/3 (0%) 0/9 (0%) 0/6 (0%) 0/20 (0%) 0/10 (0%)
Paraesthesia 0/3 (0%) 0/19 (0%) 0/12 (0%) 0/16 (0%) 0/11 (0%) 0/10 (0%) 0/10 (0%) 0/10 (0%) 0/3 (0%) 3/9 (33.3%) 0/6 (0%) 1/20 (5%) 0/10 (0%)
Peripheral sensory neuropathy 0/3 (0%) 1/19 (5.3%) 0/12 (0%) 0/16 (0%) 0/11 (0%) 0/10 (0%) 0/10 (0%) 0/10 (0%) 0/3 (0%) 0/9 (0%) 0/6 (0%) 0/20 (0%) 0/10 (0%)
Sciatica 0/3 (0%) 0/19 (0%) 0/12 (0%) 1/16 (6.3%) 0/11 (0%) 0/10 (0%) 0/10 (0%) 0/10 (0%) 0/3 (0%) 0/9 (0%) 0/6 (0%) 0/20 (0%) 0/10 (0%)
Seizure 0/3 (0%) 0/19 (0%) 1/12 (8.3%) 1/16 (6.3%) 0/11 (0%) 2/10 (20%) 0/10 (0%) 2/10 (20%) 0/3 (0%) 1/9 (11.1%) 1/6 (16.7%) 1/20 (5%) 0/10 (0%)
Somnolence 0/3 (0%) 1/19 (5.3%) 0/12 (0%) 0/16 (0%) 1/11 (9.1%) 0/10 (0%) 0/10 (0%) 0/10 (0%) 0/3 (0%) 0/9 (0%) 0/6 (0%) 0/20 (0%) 0/10 (0%)
Syncope 0/3 (0%) 0/19 (0%) 0/12 (0%) 0/16 (0%) 0/11 (0%) 1/10 (10%) 0/10 (0%) 0/10 (0%) 0/3 (0%) 0/9 (0%) 0/6 (0%) 0/20 (0%) 0/10 (0%)
Tremor 0/3 (0%) 0/19 (0%) 0/12 (0%) 0/16 (0%) 0/11 (0%) 0/10 (0%) 0/10 (0%) 1/10 (10%) 0/3 (0%) 0/9 (0%) 0/6 (0%) 0/20 (0%) 0/10 (0%)
Visual field defect 0/3 (0%) 1/19 (5.3%) 0/12 (0%) 0/16 (0%) 0/11 (0%) 0/10 (0%) 0/10 (0%) 0/10 (0%) 0/3 (0%) 0/9 (0%) 0/6 (0%) 1/20 (5%) 0/10 (0%)
Psychiatric disorders
Abnormal behaviour 0/3 (0%) 0/19 (0%) 0/12 (0%) 0/16 (0%) 0/11 (0%) 1/10 (10%) 0/10 (0%) 0/10 (0%) 0/3 (0%) 0/9 (0%) 0/6 (0%) 0/20 (0%) 0/10 (0%)
Agitation 0/3 (0%) 1/19 (5.3%) 1/12 (8.3%) 1/16 (6.3%) 1/11 (9.1%) 1/10 (10%) 0/10 (0%) 0/10 (0%) 0/3 (0%) 0/9 (0%) 0/6 (0%) 1/20 (5%) 0/10 (0%)
Anxiety 0/3 (0%) 2/19 (10.5%) 1/12 (8.3%) 1/16 (6.3%) 0/11 (0%) 1/10 (10%) 1/10 (10%) 1/10 (10%) 0/3 (0%) 0/9 (0%) 0/6 (0%) 2/20 (10%) 0/10 (0%)
Attention deficit hyperactivity disorder 0/3 (0%) 0/19 (0%) 0/12 (0%) 0/16 (0%) 0/11 (0%) 1/10 (10%) 0/10 (0%) 0/10 (0%) 0/3 (0%) 0/9 (0%) 0/6 (0%) 0/20 (0%) 0/10 (0%)
Confusional state 0/3 (0%) 0/19 (0%) 1/12 (8.3%) 0/16 (0%) 1/11 (9.1%) 0/10 (0%) 0/10 (0%) 0/10 (0%) 0/3 (0%) 0/9 (0%) 0/6 (0%) 0/20 (0%) 1/10 (10%)
Delirium 0/3 (0%) 0/19 (0%) 0/12 (0%) 0/16 (0%) 0/11 (0%) 0/10 (0%) 0/10 (0%) 0/10 (0%) 0/3 (0%) 1/9 (11.1%) 0/6 (0%) 0/20 (0%) 0/10 (0%)
Depression 0/3 (0%) 0/19 (0%) 1/12 (8.3%) 0/16 (0%) 0/11 (0%) 1/10 (10%) 1/10 (10%) 0/10 (0%) 0/3 (0%) 0/9 (0%) 0/6 (0%) 1/20 (5%) 0/10 (0%)
Dyssomnia 0/3 (0%) 1/19 (5.3%) 0/12 (0%) 0/16 (0%) 0/11 (0%) 0/10 (0%) 0/10 (0%) 0/10 (0%) 0/3 (0%) 0/9 (0%) 0/6 (0%) 0/20 (0%) 0/10 (0%)
Enuresis 0/3 (0%) 0/19 (0%) 1/12 (8.3%) 0/16 (0%) 0/11 (0%) 0/10 (0%) 0/10 (0%) 0/10 (0%) 0/3 (0%) 0/9 (0%) 0/6 (0%) 0/20 (0%) 0/10 (0%)
Initial insomnia 0/3 (0%) 0/19 (0%) 0/12 (0%) 0/16 (0%) 0/11 (0%) 0/10 (0%) 1/10 (10%) 0/10 (0%) 0/3 (0%) 0/9 (0%) 0/6 (0%) 0/20 (0%) 0/10 (0%)
Insomnia 0/3 (0%) 4/19 (21.1%) 1/12 (8.3%) 0/16 (0%) 0/11 (0%) 0/10 (0%) 2/10 (20%) 0/10 (0%) 0/3 (0%) 1/9 (11.1%) 0/6 (0%) 0/20 (0%) 2/10 (20%)
Irritability 0/3 (0%) 2/19 (10.5%) 1/12 (8.3%) 1/16 (6.3%) 1/11 (9.1%) 0/10 (0%) 0/10 (0%) 1/10 (10%) 0/3 (0%) 0/9 (0%) 0/6 (0%) 0/20 (0%) 0/10 (0%)
Mood altered 0/3 (0%) 0/19 (0%) 0/12 (0%) 0/16 (0%) 0/11 (0%) 0/10 (0%) 1/10 (10%) 0/10 (0%) 0/3 (0%) 0/9 (0%) 0/6 (0%) 1/20 (5%) 0/10 (0%)
Obsessive-compulsive disorder 0/3 (0%) 0/19 (0%) 0/12 (0%) 0/16 (0%) 0/11 (0%) 0/10 (0%) 1/10 (10%) 0/10 (0%) 0/3 (0%) 0/9 (0%) 0/6 (0%) 0/20 (0%) 0/10 (0%)
Restlessness 0/3 (0%) 0/19 (0%) 0/12 (0%) 0/16 (0%) 0/11 (0%) 0/10 (0%) 0/10 (0%) 0/10 (0%) 0/3 (0%) 0/9 (0%) 0/6 (0%) 0/20 (0%) 1/10 (10%)
Renal and urinary disorders
Albuminuria 0/3 (0%) 0/19 (0%) 0/12 (0%) 1/16 (6.3%) 0/11 (0%) 0/10 (0%) 0/10 (0%) 0/10 (0%) 0/3 (0%) 0/9 (0%) 0/6 (0%) 0/20 (0%) 0/10 (0%)
Crystalluria 0/3 (0%) 0/19 (0%) 1/12 (8.3%) 0/16 (0%) 0/11 (0%) 0/10 (0%) 0/10 (0%) 0/10 (0%) 0/3 (0%) 0/9 (0%) 0/6 (0%) 0/20 (0%) 0/10 (0%)
Cystitis noninfective 0/3 (0%) 0/19 (0%) 0/12 (0%) 0/16 (0%) 0/11 (0%) 0/10 (0%) 0/10 (0%) 0/10 (0%) 0/3 (0%) 0/9 (0%) 0/6 (0%) 0/20 (0%) 1/10 (10%)
Dysuria 0/3 (0%) 1/19 (5.3%) 0/12 (0%) 0/16 (0%) 1/11 (9.1%) 1/10 (10%) 0/10 (0%) 0/10 (0%) 0/3 (0%) 1/9 (11.1%) 0/6 (0%) 2/20 (10%) 0/10 (0%)
Glycosuria 0/3 (0%) 0/19 (0%) 0/12 (0%) 0/16 (0%) 0/11 (0%) 0/10 (0%) 0/10 (0%) 1/10 (10%) 0/3 (0%) 0/9 (0%) 0/6 (0%) 1/20 (5%) 0/10 (0%)
Haematuria 0/3 (0%) 4/19 (21.1%) 1/12 (8.3%) 0/16 (0%) 2/11 (18.2%) 1/10 (10%) 0/10 (0%) 2/10 (20%) 0/3 (0%) 4/9 (44.4%) 0/6 (0%) 1/20 (5%) 0/10 (0%)
Pollakiuria 0/3 (0%) 0/19 (0%) 0/12 (0%) 0/16 (0%) 1/11 (9.1%) 0/10 (0%) 0/10 (0%) 0/10 (0%) 0/3 (0%) 0/9 (0%) 0/6 (0%) 0/20 (0%) 0/10 (0%)
Proteinuria 0/3 (0%) 4/19 (21.1%) 3/12 (25%) 2/16 (12.5%) 3/11 (27.3%) 2/10 (20%) 0/10 (0%) 3/10 (30%) 0/3 (0%) 3/9 (33.3%) 2/6 (33.3%) 1/20 (5%) 0/10 (0%)
Urethritis noninfective 0/3 (0%) 0/19 (0%) 0/12 (0%) 1/16 (6.3%) 0/11 (0%) 0/10 (0%) 0/10 (0%) 0/10 (0%) 0/3 (0%) 0/9 (0%) 0/6 (0%) 0/20 (0%) 0/10 (0%)
Urinary incontinence 1/3 (33.3%) 1/19 (5.3%) 0/12 (0%) 0/16 (0%) 0/11 (0%) 0/10 (0%) 0/10 (0%) 0/10 (0%) 0/3 (0%) 0/9 (0%) 0/6 (0%) 0/20 (0%) 0/10 (0%)
Urinary retention 0/3 (0%) 0/19 (0%) 0/12 (0%) 0/16 (0%) 1/11 (9.1%) 0/10 (0%) 0/10 (0%) 0/10 (0%) 0/3 (0%) 0/9 (0%) 0/6 (0%) 0/20 (0%) 0/10 (0%)
Urine abnormality 0/3 (0%) 0/19 (0%) 1/12 (8.3%) 1/16 (6.3%) 0/11 (0%) 0/10 (0%) 0/10 (0%) 0/10 (0%) 0/3 (0%) 0/9 (0%) 0/6 (0%) 0/20 (0%) 0/10 (0%)
Reproductive system and breast disorders
Menstruation irregular 0/3 (0%) 0/19 (0%) 0/12 (0%) 0/16 (0%) 0/11 (0%) 0/10 (0%) 0/10 (0%) 0/10 (0%) 0/3 (0%) 1/9 (11.1%) 0/6 (0%) 0/20 (0%) 0/10 (0%)
Perineal rash 0/3 (0%) 0/19 (0%) 0/12 (0%) 0/16 (0%) 0/11 (0%) 0/10 (0%) 0/10 (0%) 1/10 (10%) 0/3 (0%) 0/9 (0%) 0/6 (0%) 0/20 (0%) 0/10 (0%)
Vulvovaginal discomfort 0/3 (0%) 0/19 (0%) 1/12 (8.3%) 0/16 (0%) 0/11 (0%) 0/10 (0%) 0/10 (0%) 0/10 (0%) 0/3 (0%) 0/9 (0%) 0/6 (0%) 0/20 (0%) 0/10 (0%)
Vulvovaginal pain 0/3 (0%) 1/19 (5.3%) 0/12 (0%) 0/16 (0%) 0/11 (0%) 0/10 (0%) 0/10 (0%) 0/10 (0%) 0/3 (0%) 0/9 (0%) 0/6 (0%) 0/20 (0%) 0/10 (0%)
Vulvovaginal pruritus 0/3 (0%) 0/19 (0%) 0/12 (0%) 0/16 (0%) 0/11 (0%) 0/10 (0%) 0/10 (0%) 2/10 (20%) 0/3 (0%) 0/9 (0%) 0/6 (0%) 0/20 (0%) 0/10 (0%)
Respiratory, thoracic and mediastinal disorders
Apnoea 0/3 (0%) 1/19 (5.3%) 0/12 (0%) 1/16 (6.3%) 0/11 (0%) 0/10 (0%) 0/10 (0%) 1/10 (10%) 0/3 (0%) 0/9 (0%) 0/6 (0%) 1/20 (5%) 0/10 (0%)
Aspiration 0/3 (0%) 0/19 (0%) 0/12 (0%) 0/16 (0%) 1/11 (9.1%) 0/10 (0%) 0/10 (0%) 0/10 (0%) 0/3 (0%) 0/9 (0%) 0/6 (0%) 0/20 (0%) 0/10 (0%)
Cough 1/3 (33.3%) 7/19 (36.8%) 6/12 (50%) 4/16 (25%) 2/11 (18.2%) 4/10 (40%) 5/10 (50%) 4/10 (40%) 1/3 (33.3%) 4/9 (44.4%) 1/6 (16.7%) 8/20 (40%) 6/10 (60%)
Dysphonia 0/3 (0%) 0/19 (0%) 0/12 (0%) 1/16 (6.3%) 0/11 (0%) 0/10 (0%) 0/10 (0%) 0/10 (0%) 0/3 (0%) 0/9 (0%) 0/6 (0%) 0/20 (0%) 0/10 (0%)
Dyspnoea 0/3 (0%) 1/19 (5.3%) 0/12 (0%) 0/16 (0%) 0/11 (0%) 0/10 (0%) 0/10 (0%) 1/10 (10%) 0/3 (0%) 1/9 (11.1%) 0/6 (0%) 1/20 (5%) 1/10 (10%)
Dyspnoea exertional 0/3 (0%) 0/19 (0%) 0/12 (0%) 0/16 (0%) 0/11 (0%) 1/10 (10%) 0/10 (0%) 0/10 (0%) 0/3 (0%) 0/9 (0%) 0/6 (0%) 0/20 (0%) 0/10 (0%)
Epistaxis 1/3 (33.3%) 9/19 (47.4%) 4/12 (33.3%) 8/16 (50%) 2/11 (18.2%) 2/10 (20%) 1/10 (10%) 2/10 (20%) 1/3 (33.3%) 2/9 (22.2%) 0/6 (0%) 2/20 (10%) 3/10 (30%)
Hypoxia 0/3 (0%) 1/19 (5.3%) 0/12 (0%) 0/16 (0%) 0/11 (0%) 0/10 (0%) 0/10 (0%) 1/10 (10%) 0/3 (0%) 0/9 (0%) 0/6 (0%) 0/20 (0%) 0/10 (0%)
Laryngeal inflammation 0/3 (0%) 0/19 (0%) 0/12 (0%) 0/16 (0%) 0/11 (0%) 1/10 (10%) 0/10 (0%) 0/10 (0%) 0/3 (0%) 0/9 (0%) 0/6 (0%) 1/20 (5%) 0/10 (0%)
Nasal congestion 0/3 (0%) 2/19 (10.5%) 1/12 (8.3%) 1/16 (6.3%) 1/11 (9.1%) 0/10 (0%) 3/10 (30%) 1/10 (10%) 0/3 (0%) 2/9 (22.2%) 1/6 (16.7%) 5/20 (25%) 3/10 (30%)
Nasal inflammation 0/3 (0%) 0/19 (0%) 0/12 (0%) 0/16 (0%) 0/11 (0%) 1/10 (10%) 0/10 (0%) 0/10 (0%) 0/3 (0%) 0/9 (0%) 0/6 (0%) 0/20 (0%) 0/10 (0%)
Nasal odour 0/3 (0%) 1/19 (5.3%) 0/12 (0%) 0/16 (0%) 0/11 (0%) 0/10 (0%) 0/10 (0%) 0/10 (0%) 0/3 (0%) 0/9 (0%) 0/6 (0%) 0/20 (0%) 0/10 (0%)
Oropharyngeal pain 0/3 (0%) 4/19 (21.1%) 1/12 (8.3%) 2/16 (12.5%) 0/11 (0%) 1/10 (10%) 1/10 (10%) 3/10 (30%) 1/3 (33.3%) 3/9 (33.3%) 0/6 (0%) 3/20 (15%) 2/10 (20%)
Pharyngeal swelling 0/3 (0%) 1/19 (5.3%) 0/12 (0%) 0/16 (0%) 0/11 (0%) 0/10 (0%) 0/10 (0%) 0/10 (0%) 0/3 (0%) 0/9 (0%) 0/6 (0%) 0/20 (0%) 0/10 (0%)
Pleural effusion 0/3 (0%) 0/19 (0%) 0/12 (0%) 0/16 (0%) 1/11 (9.1%) 0/10 (0%) 0/10 (0%) 0/10 (0%) 0/3 (0%) 0/9 (0%) 0/6 (0%) 0/20 (0%) 0/10 (0%)
Productive cough 0/3 (0%) 1/19 (5.3%) 0/12 (0%) 0/16 (0%) 1/11 (9.1%) 0/10 (0%) 0/10 (0%) 2/10 (20%) 0/3 (0%) 0/9 (0%) 0/6 (0%) 0/20 (0%) 0/10 (0%)
Respiratory disorder 0/3 (0%) 1/19 (5.3%) 0/12 (0%) 0/16 (0%) 0/11 (0%) 1/10 (10%) 0/10 (0%) 0/10 (0%) 0/3 (0%) 0/9 (0%) 0/6 (0%) 0/20 (0%) 0/10 (0%)
Respiratory tract congestion 0/3 (0%) 2/19 (10.5%) 0/12 (0%) 1/16 (6.3%) 0/11 (0%) 0/10 (0%) 0/10 (0%) 0/10 (0%) 0/3 (0%) 2/9 (22.2%) 0/6 (0%) 0/20 (0%) 0/10 (0%)
Rhinitis allergic 0/3 (0%) 2/19 (10.5%) 0/12 (0%) 0/16 (0%) 0/11 (0%) 0/10 (0%) 1/10 (10%) 1/10 (10%) 0/3 (0%) 0/9 (0%) 0/6 (0%) 1/20 (5%) 0/10 (0%)
Rhinorrhoea 0/3 (0%) 2/19 (10.5%) 4/12 (33.3%) 1/16 (6.3%) 1/11 (9.1%) 2/10 (20%) 1/10 (10%) 1/10 (10%) 0/3 (0%) 3/9 (33.3%) 0/6 (0%) 0/20 (0%) 1/10 (10%)
Sinus congestion 0/3 (0%) 1/19 (5.3%) 0/12 (0%) 0/16 (0%) 0/11 (0%) 0/10 (0%) 0/10 (0%) 0/10 (0%) 0/3 (0%) 0/9 (0%) 0/6 (0%) 0/20 (0%) 0/10 (0%)
Sleep apnoea syndrome 0/3 (0%) 1/19 (5.3%) 0/12 (0%) 0/16 (0%) 0/11 (0%) 1/10 (10%) 1/10 (10%) 1/10 (10%) 0/3 (0%) 0/9 (0%) 0/6 (0%) 1/20 (5%) 0/10 (0%)
Sneezing 0/3 (0%) 0/19 (0%) 0/12 (0%) 0/16 (0%) 1/11 (9.1%) 0/10 (0%) 0/10 (0%) 0/10 (0%) 0/3 (0%) 1/9 (11.1%) 0/6 (0%) 0/20 (0%) 0/10 (0%)
Snoring 0/3 (0%) 0/19 (0%) 0/12 (0%) 0/16 (0%) 0/11 (0%) 0/10 (0%) 0/10 (0%) 1/10 (10%) 0/3 (0%) 0/9 (0%) 0/6 (0%) 1/20 (5%) 0/10 (0%)
Tachypnoea 0/3 (0%) 3/19 (15.8%) 1/12 (8.3%) 2/16 (12.5%) 1/11 (9.1%) 1/10 (10%) 0/10 (0%) 2/10 (20%) 0/3 (0%) 3/9 (33.3%) 0/6 (0%) 0/20 (0%) 1/10 (10%)
Throat irritation 0/3 (0%) 0/19 (0%) 0/12 (0%) 1/16 (6.3%) 0/11 (0%) 0/10 (0%) 0/10 (0%) 0/10 (0%) 0/3 (0%) 0/9 (0%) 0/6 (0%) 0/20 (0%) 0/10 (0%)
Tonsillar hypertrophy 0/3 (0%) 1/19 (5.3%) 0/12 (0%) 0/16 (0%) 0/11 (0%) 0/10 (0%) 0/10 (0%) 1/10 (10%) 0/3 (0%) 0/9 (0%) 0/6 (0%) 0/20 (0%) 0/10 (0%)
Wheezing 0/3 (0%) 1/19 (5.3%) 1/12 (8.3%) 0/16 (0%) 0/11 (0%) 0/10 (0%) 0/10 (0%) 1/10 (10%) 0/3 (0%) 0/9 (0%) 0/6 (0%) 0/20 (0%) 0/10 (0%)
Skin and subcutaneous tissue disorders
Acne 1/3 (33.3%) 3/19 (15.8%) 0/12 (0%) 0/16 (0%) 0/11 (0%) 1/10 (10%) 0/10 (0%) 0/10 (0%) 0/3 (0%) 0/9 (0%) 1/6 (16.7%) 3/20 (15%) 0/10 (0%)
Alopecia 0/3 (0%) 7/19 (36.8%) 4/12 (33.3%) 6/16 (37.5%) 1/11 (9.1%) 5/10 (50%) 4/10 (40%) 3/10 (30%) 0/3 (0%) 1/9 (11.1%) 1/6 (16.7%) 1/20 (5%) 1/10 (10%)
Blister 0/3 (0%) 1/19 (5.3%) 0/12 (0%) 0/16 (0%) 0/11 (0%) 1/10 (10%) 1/10 (10%) 0/10 (0%) 0/3 (0%) 0/9 (0%) 0/6 (0%) 0/20 (0%) 0/10 (0%)
Dermatitis 0/3 (0%) 2/19 (10.5%) 2/12 (16.7%) 0/16 (0%) 0/11 (0%) 0/10 (0%) 1/10 (10%) 1/10 (10%) 0/3 (0%) 1/9 (11.1%) 0/6 (0%) 0/20 (0%) 0/10 (0%)
Dermatitis acneiform 0/3 (0%) 6/19 (31.6%) 4/12 (33.3%) 10/16 (62.5%) 1/11 (9.1%) 4/10 (40%) 3/10 (30%) 4/10 (40%) 2/3 (66.7%) 4/9 (44.4%) 1/6 (16.7%) 8/20 (40%) 1/10 (10%)
Dermatitis atopic 0/3 (0%) 0/19 (0%) 0/12 (0%) 0/16 (0%) 1/11 (9.1%) 0/10 (0%) 0/10 (0%) 0/10 (0%) 0/3 (0%) 0/9 (0%) 0/6 (0%) 0/20 (0%) 0/10 (0%)
Dermatitis contact 0/3 (0%) 0/19 (0%) 0/12 (0%) 0/16 (0%) 1/11 (9.1%) 0/10 (0%) 0/10 (0%) 0/10 (0%) 0/3 (0%) 0/9 (0%) 0/6 (0%) 0/20 (0%) 0/10 (0%)
Dermatitis diaper 0/3 (0%) 2/19 (10.5%) 1/12 (8.3%) 0/16 (0%) 0/11 (0%) 0/10 (0%) 1/10 (10%) 1/10 (10%) 0/3 (0%) 0/9 (0%) 0/6 (0%) 0/20 (0%) 0/10 (0%)
Dermatosis 0/3 (0%) 0/19 (0%) 0/12 (0%) 0/16 (0%) 0/11 (0%) 0/10 (0%) 0/10 (0%) 1/10 (10%) 0/3 (0%) 0/9 (0%) 0/6 (0%) 0/20 (0%) 0/10 (0%)
Dry skin 1/3 (33.3%) 12/19 (63.2%) 10/12 (83.3%) 6/16 (37.5%) 4/11 (36.4%) 7/10 (70%) 5/10 (50%) 6/10 (60%) 2/3 (66.7%) 5/9 (55.6%) 3/6 (50%) 8/20 (40%) 5/10 (50%)
Eczema 1/3 (33.3%) 8/19 (42.1%) 5/12 (41.7%) 9/16 (56.3%) 2/11 (18.2%) 5/10 (50%) 1/10 (10%) 1/10 (10%) 1/3 (33.3%) 0/9 (0%) 0/6 (0%) 3/20 (15%) 2/10 (20%)
Eczema asteatotic 0/3 (0%) 1/19 (5.3%) 0/12 (0%) 0/16 (0%) 0/11 (0%) 0/10 (0%) 1/10 (10%) 0/10 (0%) 0/3 (0%) 0/9 (0%) 0/6 (0%) 0/20 (0%) 0/10 (0%)
Eczema nummular 0/3 (0%) 1/19 (5.3%) 0/12 (0%) 1/16 (6.3%) 0/11 (0%) 0/10 (0%) 0/10 (0%) 0/10 (0%) 0/3 (0%) 0/9 (0%) 0/6 (0%) 0/20 (0%) 0/10 (0%)
Erythema 0/3 (0%) 5/19 (26.3%) 1/12 (8.3%) 5/16 (31.3%) 2/11 (18.2%) 0/10 (0%) 0/10 (0%) 3/10 (30%) 0/3 (0%) 1/9 (11.1%) 0/6 (0%) 2/20 (10%) 1/10 (10%)
Erythema multiforme 0/3 (0%) 0/19 (0%) 0/12 (0%) 0/16 (0%) 0/11 (0%) 0/10 (0%) 2/10 (20%) 0/10 (0%) 0/3 (0%) 0/9 (0%) 0/6 (0%) 0/20 (0%) 0/10 (0%)
Erythema nodosum 0/3 (0%) 0/19 (0%) 0/12 (0%) 0/16 (0%) 0/11 (0%) 0/10 (0%) 0/10 (0%) 0/10 (0%) 0/3 (0%) 0/9 (0%) 0/6 (0%) 2/20 (10%) 1/10 (10%)
Hair colour changes 0/3 (0%) 3/19 (15.8%) 3/12 (25%) 1/16 (6.3%) 1/11 (9.1%) 2/10 (20%) 0/10 (0%) 2/10 (20%) 0/3 (0%) 1/9 (11.1%) 0/6 (0%) 0/20 (0%) 0/10 (0%)
Hair texture abnormal 0/3 (0%) 0/19 (0%) 0/12 (0%) 1/16 (6.3%) 0/11 (0%) 1/10 (10%) 0/10 (0%) 0/10 (0%) 0/3 (0%) 1/9 (11.1%) 1/6 (16.7%) 1/20 (5%) 0/10 (0%)
Hand dermatitis 0/3 (0%) 0/19 (0%) 0/12 (0%) 0/16 (0%) 0/11 (0%) 0/10 (0%) 1/10 (10%) 0/10 (0%) 0/3 (0%) 1/9 (11.1%) 0/6 (0%) 0/20 (0%) 0/10 (0%)
Hyperkeratosis 0/3 (0%) 0/19 (0%) 0/12 (0%) 2/16 (12.5%) 0/11 (0%) 0/10 (0%) 0/10 (0%) 0/10 (0%) 0/3 (0%) 2/9 (22.2%) 0/6 (0%) 1/20 (5%) 2/10 (20%)
Hypertrichosis 0/3 (0%) 1/19 (5.3%) 1/12 (8.3%) 0/16 (0%) 0/11 (0%) 0/10 (0%) 0/10 (0%) 0/10 (0%) 0/3 (0%) 0/9 (0%) 0/6 (0%) 1/20 (5%) 0/10 (0%)
Ingrowing nail 0/3 (0%) 1/19 (5.3%) 0/12 (0%) 0/16 (0%) 0/11 (0%) 0/10 (0%) 0/10 (0%) 1/10 (10%) 0/3 (0%) 0/9 (0%) 0/6 (0%) 0/20 (0%) 0/10 (0%)
Intertrigo 0/3 (0%) 0/19 (0%) 0/12 (0%) 0/16 (0%) 0/11 (0%) 0/10 (0%) 0/10 (0%) 1/10 (10%) 0/3 (0%) 0/9 (0%) 0/6 (0%) 0/20 (0%) 0/10 (0%)
Keratosis pilaris 0/3 (0%) 0/19 (0%) 0/12 (0%) 1/16 (6.3%) 0/11 (0%) 1/10 (10%) 0/10 (0%) 0/10 (0%) 0/3 (0%) 0/9 (0%) 0/6 (0%) 0/20 (0%) 0/10 (0%)
Livedo reticularis 0/3 (0%) 0/19 (0%) 1/12 (8.3%) 0/16 (0%) 0/11 (0%) 0/10 (0%) 0/10 (0%) 0/10 (0%) 0/3 (0%) 0/9 (0%) 0/6 (0%) 0/20 (0%) 0/10 (0%)
Macule 0/3 (0%) 0/19 (0%) 0/12 (0%) 1/16 (6.3%) 0/11 (0%) 0/10 (0%) 0/10 (0%) 0/10 (0%) 0/3 (0%) 0/9 (0%) 0/6 (0%) 1/20 (5%) 0/10 (0%)
Nail discolouration 0/3 (0%) 0/19 (0%) 1/12 (8.3%) 0/16 (0%) 0/11 (0%) 0/10 (0%) 0/10 (0%) 0/10 (0%) 0/3 (0%) 0/9 (0%) 0/6 (0%) 0/20 (0%) 0/10 (0%)
Nail disorder 0/3 (0%) 0/19 (0%) 0/12 (0%) 0/16 (0%) 0/11 (0%) 0/10 (0%) 1/10 (10%) 1/10 (10%) 0/3 (0%) 0/9 (0%) 0/6 (0%) 0/20 (0%) 0/10 (0%)
Pain of skin 0/3 (0%) 2/19 (10.5%) 0/12 (0%) 0/16 (0%) 0/11 (0%) 0/10 (0%) 0/10 (0%) 0/10 (0%) 0/3 (0%) 0/9 (0%) 0/6 (0%) 1/20 (5%) 0/10 (0%)
Palmar erythema 0/3 (0%) 0/19 (0%) 0/12 (0%) 0/16 (0%) 0/11 (0%) 0/10 (0%) 0/10 (0%) 0/10 (0%) 0/3 (0%) 0/9 (0%) 1/6 (16.7%) 0/20 (0%) 0/10 (0%)
Palmar-plantar erythrodysaesthesia syndrome 0/3 (0%) 0/19 (0%) 0/12 (0%) 0/16 (0%) 0/11 (0%) 1/10 (10%) 0/10 (0%) 0/10 (0%) 0/3 (0%) 0/9 (0%) 0/6 (0%) 1/20 (5%) 0/10 (0%)
Panniculitis 0/3 (0%) 0/19 (0%) 0/12 (0%) 1/16 (6.3%) 0/11 (0%) 0/10 (0%) 0/10 (0%) 0/10 (0%) 1/3 (33.3%) 1/9 (11.1%) 1/6 (16.7%) 1/20 (5%) 1/10 (10%)
Papule 0/3 (0%) 2/19 (10.5%) 1/12 (8.3%) 0/16 (0%) 0/11 (0%) 0/10 (0%) 0/10 (0%) 0/10 (0%) 0/3 (0%) 0/9 (0%) 0/6 (0%) 2/20 (10%) 0/10 (0%)
Perioral dermatitis 0/3 (0%) 0/19 (0%) 0/12 (0%) 0/16 (0%) 0/11 (0%) 1/10 (10%) 0/10 (0%) 0/10 (0%) 0/3 (0%) 0/9 (0%) 0/6 (0%) 0/20 (0%) 0/10 (0%)
Petechiae 0/3 (0%) 1/19 (5.3%) 0/12 (0%) 0/16 (0%) 0/11 (0%) 0/10 (0%) 0/10 (0%) 0/10 (0%) 0/3 (0%) 1/9 (11.1%) 0/6 (0%) 0/20 (0%) 0/10 (0%)
Photosensitivity reaction 0/3 (0%) 0/19 (0%) 0/12 (0%) 0/16 (0%) 0/11 (0%) 0/10 (0%) 0/10 (0%) 0/10 (0%) 0/3 (0%) 1/9 (11.1%) 0/6 (0%) 1/20 (5%) 0/10 (0%)
Pigmentation disorder 0/3 (0%) 0/19 (0%) 0/12 (0%) 0/16 (0%) 0/11 (0%) 0/10 (0%) 1/10 (10%) 0/10 (0%) 1/3 (33.3%) 0/9 (0%) 0/6 (0%) 0/20 (0%) 0/10 (0%)
Plantar erythema 0/3 (0%) 0/19 (0%) 0/12 (0%) 0/16 (0%) 0/11 (0%) 0/10 (0%) 0/10 (0%) 0/10 (0%) 0/3 (0%) 0/9 (0%) 1/6 (16.7%) 0/20 (0%) 0/10 (0%)
Prurigo 0/3 (0%) 0/19 (0%) 0/12 (0%) 0/16 (0%) 0/11 (0%) 1/10 (10%) 0/10 (0%) 0/10 (0%) 0/3 (0%) 0/9 (0%) 0/6 (0%) 0/20 (0%) 0/10 (0%)
Pruritus 0/3 (0%) 5/19 (26.3%) 1/12 (8.3%) 4/16 (25%) 2/11 (18.2%) 1/10 (10%) 1/10 (10%) 3/10 (30%) 0/3 (0%) 2/9 (22.2%) 0/6 (0%) 3/20 (15%) 3/10 (30%)
Pseudofolliculitis 0/3 (0%) 0/19 (0%) 0/12 (0%) 0/16 (0%) 0/11 (0%) 0/10 (0%) 0/10 (0%) 1/10 (10%) 0/3 (0%) 0/9 (0%) 0/6 (0%) 0/20 (0%) 0/10 (0%)
Rash 1/3 (33.3%) 9/19 (47.4%) 5/12 (41.7%) 8/16 (50%) 4/11 (36.4%) 5/10 (50%) 6/10 (60%) 2/10 (20%) 3/3 (100%) 6/9 (66.7%) 2/6 (33.3%) 3/20 (15%) 2/10 (20%)
Rash erythematous 0/3 (0%) 3/19 (15.8%) 1/12 (8.3%) 2/16 (12.5%) 0/11 (0%) 0/10 (0%) 1/10 (10%) 2/10 (20%) 0/3 (0%) 0/9 (0%) 1/6 (16.7%) 3/20 (15%) 0/10 (0%)
Rash follicular 0/3 (0%) 0/19 (0%) 0/12 (0%) 0/16 (0%) 0/11 (0%) 1/10 (10%) 0/10 (0%) 0/10 (0%) 0/3 (0%) 0/9 (0%) 0/6 (0%) 1/20 (5%) 0/10 (0%)
Rash macular 0/3 (0%) 0/19 (0%) 1/12 (8.3%) 1/16 (6.3%) 1/11 (9.1%) 1/10 (10%) 0/10 (0%) 0/10 (0%) 0/3 (0%) 0/9 (0%) 1/6 (16.7%) 0/20 (0%) 1/10 (10%)
Rash maculo-papular 2/3 (66.7%) 3/19 (15.8%) 4/12 (33.3%) 4/16 (25%) 2/11 (18.2%) 4/10 (40%) 2/10 (20%) 3/10 (30%) 1/3 (33.3%) 0/9 (0%) 2/6 (33.3%) 6/20 (30%) 5/10 (50%)
Rash papular 0/3 (0%) 4/19 (21.1%) 3/12 (25%) 3/16 (18.8%) 0/11 (0%) 2/10 (20%) 0/10 (0%) 4/10 (40%) 0/3 (0%) 1/9 (11.1%) 0/6 (0%) 2/20 (10%) 1/10 (10%)
Rash pruritic 0/3 (0%) 1/19 (5.3%) 0/12 (0%) 0/16 (0%) 0/11 (0%) 0/10 (0%) 0/10 (0%) 0/10 (0%) 0/3 (0%) 0/9 (0%) 0/6 (0%) 0/20 (0%) 0/10 (0%)
Seborrhoea 0/3 (0%) 0/19 (0%) 0/12 (0%) 1/16 (6.3%) 0/11 (0%) 0/10 (0%) 0/10 (0%) 0/10 (0%) 0/3 (0%) 0/9 (0%) 0/6 (0%) 0/20 (0%) 0/10 (0%)
Seborrhoeic dermatitis 0/3 (0%) 0/19 (0%) 1/12 (8.3%) 1/16 (6.3%) 0/11 (0%) 0/10 (0%) 1/10 (10%) 2/10 (20%) 0/3 (0%) 0/9 (0%) 1/6 (16.7%) 1/20 (5%) 0/10 (0%)
Skin burning sensation 0/3 (0%) 0/19 (0%) 0/12 (0%) 0/16 (0%) 0/11 (0%) 1/10 (10%) 0/10 (0%) 0/10 (0%) 0/3 (0%) 0/9 (0%) 0/6 (0%) 0/20 (0%) 0/10 (0%)
Skin depigmentation 0/3 (0%) 0/19 (0%) 0/12 (0%) 0/16 (0%) 0/11 (0%) 0/10 (0%) 0/10 (0%) 1/10 (10%) 0/3 (0%) 0/9 (0%) 0/6 (0%) 1/20 (5%) 0/10 (0%)
Skin disorder 0/3 (0%) 1/19 (5.3%) 0/12 (0%) 0/16 (0%) 0/11 (0%) 0/10 (0%) 0/10 (0%) 1/10 (10%) 0/3 (0%) 0/9 (0%) 0/6 (0%) 0/20 (0%) 0/10 (0%)
Skin exfoliation 0/3 (0%) 2/19 (10.5%) 1/12 (8.3%) 2/16 (12.5%) 0/11 (0%) 0/10 (0%) 0/10 (0%) 0/10 (0%) 0/3 (0%) 0/9 (0%) 0/6 (0%) 1/20 (5%) 0/10 (0%)
Skin fissures 0/3 (0%) 1/19 (5.3%) 0/12 (0%) 2/16 (12.5%) 0/11 (0%) 1/10 (10%) 1/10 (10%) 3/10 (30%) 0/3 (0%) 0/9 (0%) 0/6 (0%) 0/20 (0%) 0/10 (0%)
Skin fragility 0/3 (0%) 0/19 (0%) 0/12 (0%) 0/16 (0%) 0/11 (0%) 0/10 (0%) 0/10 (0%) 0/10 (0%) 0/3 (0%) 0/9 (0%) 0/6 (0%) 0/20 (0%) 1/10 (10%)
Skin hyperpigmentation 0/3 (0%) 2/19 (10.5%) 0/12 (0%) 1/16 (6.3%) 0/11 (0%) 0/10 (0%) 0/10 (0%) 1/10 (10%) 0/3 (0%) 1/9 (11.1%) 0/6 (0%) 1/20 (5%) 0/10 (0%)
Skin hypopigmentation 0/3 (0%) 0/19 (0%) 0/12 (0%) 0/16 (0%) 0/11 (0%) 0/10 (0%) 2/10 (20%) 0/10 (0%) 0/3 (0%) 0/9 (0%) 0/6 (0%) 0/20 (0%) 1/10 (10%)
Skin lesion 1/3 (33.3%) 2/19 (10.5%) 3/12 (25%) 2/16 (12.5%) 0/11 (0%) 1/10 (10%) 1/10 (10%) 1/10 (10%) 0/3 (0%) 1/9 (11.1%) 0/6 (0%) 2/20 (10%) 0/10 (0%)
Skin mass 0/3 (0%) 1/19 (5.3%) 0/12 (0%) 0/16 (0%) 0/11 (0%) 0/10 (0%) 0/10 (0%) 0/10 (0%) 0/3 (0%) 0/9 (0%) 0/6 (0%) 1/20 (5%) 0/10 (0%)
Skin toxicity 0/3 (0%) 0/19 (0%) 0/12 (0%) 0/16 (0%) 0/11 (0%) 0/10 (0%) 1/10 (10%) 0/10 (0%) 0/3 (0%) 0/9 (0%) 0/6 (0%) 0/20 (0%) 0/10 (0%)
Skin ulcer 0/3 (0%) 2/19 (10.5%) 0/12 (0%) 4/16 (25%) 0/11 (0%) 0/10 (0%) 0/10 (0%) 1/10 (10%) 0/3 (0%) 1/9 (11.1%) 0/6 (0%) 0/20 (0%) 0/10 (0%)
Telangiectasia 0/3 (0%) 0/19 (0%) 0/12 (0%) 0/16 (0%) 0/11 (0%) 0/10 (0%) 0/10 (0%) 0/10 (0%) 0/3 (0%) 0/9 (0%) 0/6 (0%) 0/20 (0%) 1/10 (10%)
Urticaria 0/3 (0%) 1/19 (5.3%) 1/12 (8.3%) 1/16 (6.3%) 0/11 (0%) 0/10 (0%) 0/10 (0%) 1/10 (10%) 1/3 (33.3%) 0/9 (0%) 0/6 (0%) 3/20 (15%) 0/10 (0%)
Surgical and medical procedures
Central venous catheter removal 0/3 (0%) 0/19 (0%) 0/12 (0%) 0/16 (0%) 0/11 (0%) 0/10 (0%) 0/10 (0%) 0/10 (0%) 0/3 (0%) 0/9 (0%) 0/6 (0%) 1/20 (5%) 1/10 (10%)
Tonsillectomy 0/3 (0%) 0/19 (0%) 0/12 (0%) 0/16 (0%) 0/11 (0%) 0/10 (0%) 0/10 (0%) 0/10 (0%) 0/3 (0%) 0/9 (0%) 1/6 (16.7%) 0/20 (0%) 0/10 (0%)
Vascular disorders
Flushing 0/3 (0%) 2/19 (10.5%) 0/12 (0%) 0/16 (0%) 0/11 (0%) 0/10 (0%) 0/10 (0%) 0/10 (0%) 0/3 (0%) 1/9 (11.1%) 0/6 (0%) 2/20 (10%) 1/10 (10%)
Haematoma 0/3 (0%) 0/19 (0%) 0/12 (0%) 1/16 (6.3%) 0/11 (0%) 0/10 (0%) 0/10 (0%) 1/10 (10%) 0/3 (0%) 0/9 (0%) 0/6 (0%) 1/20 (5%) 0/10 (0%)
Hypertension 0/3 (0%) 0/19 (0%) 0/12 (0%) 1/16 (6.3%) 2/11 (18.2%) 0/10 (0%) 0/10 (0%) 1/10 (10%) 0/3 (0%) 0/9 (0%) 0/6 (0%) 0/20 (0%) 0/10 (0%)
Hypotension 0/3 (0%) 2/19 (10.5%) 3/12 (25%) 3/16 (18.8%) 0/11 (0%) 1/10 (10%) 1/10 (10%) 1/10 (10%) 0/3 (0%) 2/9 (22.2%) 0/6 (0%) 0/20 (0%) 1/10 (10%)
Lymphoedema 0/3 (0%) 0/19 (0%) 0/12 (0%) 0/16 (0%) 0/11 (0%) 0/10 (0%) 1/10 (10%) 1/10 (10%) 0/3 (0%) 0/9 (0%) 0/6 (0%) 0/20 (0%) 0/10 (0%)
Pallor 0/3 (0%) 1/19 (5.3%) 1/12 (8.3%) 0/16 (0%) 0/11 (0%) 1/10 (10%) 0/10 (0%) 0/10 (0%) 0/3 (0%) 1/9 (11.1%) 0/6 (0%) 0/20 (0%) 0/10 (0%)

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

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

The terms and conditions of Novartis' agreements with its investigators may vary. Novartis does not prohibit any investigator from publishing. Any publications from a single site are postponed until the publication of the pooled data (ie, data from all sites) in the clinical trial.

Results Point of Contact

Name/Title Study Director
Organization Novartis Pharmaceuticals
Phone 862-778-8300
Email Novartis.email@novartis.com
Responsible Party:
Novartis Pharmaceuticals
ClinicalTrials.gov Identifier:
NCT02124772
Other Study ID Numbers:
  • 116540
  • 2013-003596-35
  • CTMT212X2101
First Posted:
Apr 28, 2014
Last Update Posted:
Jul 14, 2021
Last Verified:
Jun 1, 2021