A Phase Ib/IIb, Open-label, Multi-center, Study of Oral Panobinostat Administered With 5-Azacitidine (in Adult Patients With Myelodysplastic Syndromes (MDS), Chronic Myelomonocytic Leukemia (CMML), or Acute Myeloid Leukemia (AML).

• Sponsor: Novartis Pharmaceuticals (Industry)
• Overall Status: Completed
• CT.gov ID: NCT00946647
• Collaborator: (none)
• Enrollment: 113
• Locations: 38
• Arms: 2
• Actual Duration (Months): 112.9
• Patients Per Site: 3
• Patients Per Site Per Month: 0

Study Details

Study Description

Brief Summary

The purpose of this randomized, two-arm, open-label expansion phase study was to collect preliminary efficacy data of panobinostat at the recommended phase II dose (RPIID) level in combination with azacytidine (5-Aza) versus an active control arm 5-Aza alone. This randomized phase II part also allowed collecting safety data of panobinostat in combination with 5-Aza in comparison to single-agent 5-aza.

Condition or Disease	Intervention/Treatment	Phase
Myelodysplastic Syndromes; Chronic Myelomonocytic Leukemia; Acute Myeloid Leukemia	Drug: Panobinostat (LBH589); Drug: 5-Azacytidine	Phase 1/Phase 2

Detailed Description

The primary objective of the phase lb portion of this study was to determine the maximum tolerated dose (MTD )and/or recommended phase ll dose (RPIID) of oral panobinostat in combination with a fixed dose of 5-Aza in adult patients with International Prognostic Scoring System intermediate-2 (IPSS INT-2) or high risk myelodysplastic syndrome (MDS), Chronic myelomonocytic leukemia (CMML), or Acute myelogenous leukemia (AML).

The primary objective of the phase llb portion of this study was to assess preliminary efficacy of treatment with the panobinostat and 5-Aza combination at the RPIID relative to treatment with single agent 5-Aza through the assessment of composite CR (complete response (CR) or CRi or bone marrow CR).

In the phase lb phase of the study, the patients received escalating oral doses of panobinostat commencing in Cycle 1. The starting dose for panobinostat was 20 mg/day administered orally commencing on Day 3. Each treatment cycle consisted of 28 days (4 weeks). In each cycle, panobinostat was administered twice in Week 1 (Day 3, Day 5), thrice in Week 2 (Day 8, Day 10, and Day 12) and once in Week 3 (Day 15), with no dosing in Week 4. Successive cohorts of patients received escalating doses of panobinostat until the MTD/RPIID was determined. The dose of 5-Aza was fixed at 75 mg/m2/day for 7 days in Week 1 of each cycle.

After the MTD/RPIID was determined, enrollment in the Phase Ib part was closed and the Phase IIb part of the study commenced. Ongoing patients from the Phase Ib part continued their treatment at the assigned dose level according to the regimen and schedule for the Phase Ib part.

Once the RPIID was defined in Phase Ib, additional 80 patients were to be enrolled into the Phase IIb part of the study and randomly assigned in a 1:1 ratio receiving the RPIID of panobinostat plus 5-Aza (investigational arm) or single agent 5-Aza (active control arm). The treatment schedule for the investigational arm was the same as that for the Phase Ib. Single agent 5-Aza (active control arm) was administered according to the locally approved label (75mg/m2 daily for 7 days). Patients continued treatment until disease progression, unacceptable toxicity or consent withdrawal, whichever came first.

Study Design

• Study Type: Interventional
• Actual Enrollment: 113 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: None (Open Label)
• Masking Description: Treatment was assigned sequentially for the initial dose escalation part (phase Ib): If a dose was safe, the next cohort started with the next dose level. Randomization applies only for the phase IIb part.
• Primary Purpose: Treatment
• Official Title: A Phase Ib/IIb, Open-label, Multi-center, Study of Oral Panobinostat (LBH589) Administered With 5-Azacitidine (in Adult Patients With Myelodysplastic Syndromes (MDS), Chronic Myelomonocytic Leukemia (CMML), or Acute Myeloid Leukemia (AML).
• Actual Study Start Date: Dec 2, 2009
• Actual Primary Completion Date: Apr 29, 2019
• Actual Study Completion Date: Apr 29, 2019

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Panobinostat + 5-Azacytidine In phase I: Panobinostat : Escalating doses starting with 20 mg delivered orally at Day 3, Day 5, Day 8, Day 10, Day 12, Day 15. In phase II: Panobinostat : Rapid Phase II doses at 30 mg delivered orally at Day 3, Day 5, Day 8, Day 10, Day 12, Day 15. In both phases, dose of 5-Azacytidine was 75 mg/m^2, subcutaneously Daily for Day 1 to Day 7.	Drug: Panobinostat (LBH589); Panobinostat was supplied by Novartis as immediate-release hard gelatin capsules in strengths of 5 mg, 10 mg, and 20 mg packaged in high density polyethylene bottles.; Drug: 5-Azacytidine
Active Comparator: 5-Azacytidine The dose of 5-Aza was fixed at 75 mg/m2/day for 7 days in Week 1 of each cycle. 5-Aza was sourced locally, except in 4 countries (Hungary, Switzerland, UK, and Spain, for which a central purchase was used by Novartis. Dose of 5-Azacytidine : 75 mg/m^2 subcutaneously daily from Day 1 to Day 7.	Drug: 5-Azacytidine

Outcome Measures

Primary Outcome Measures

1. Number of Participants With Dose Limiting Toxicity (DLT) (Phase lb) [within the first 28 days (cycle 1)]

   Dose limiting toxicity (DLT) was defined as a toxicity requiring treatment withdrawal and included the following: Non-hematologic toxicity qualifying for DLT and Hematologic toxicity qualifying for DLT

2. Number of Dose Limiting Toxicity (DLT) (Phase lb) [within the first 28 days (cycle 1)]

   Dose limiting toxicity (DLT) was defined as a toxicity requiring treatment withdrawal and included the following: Non-hematologic toxicity qualifying for DLT and Hematologic toxicity qualifying for DLT

3. Composite Complete Response (Phase Llb) [48 months]

   Composite complete response is defined as complete response (CR), Complete response with incomplete blood count recovery (CRi) or bone marrow complete response (BM-CR) as defined by the International Working Group (IWG) response criteria.

Secondary Outcome Measures

1. Clinical Response Other Than Composite Clinical Response for Myeloid Dysplastic Syndromes(MDS)/Chronic Myelomonocytic Leukemia (CMML) Patients Per Investigator (Phase Llb) [48 months]

   This is the best overall response as measured by Clinical response. Clinical response is defined as having complete remission (CR), bone marrow complete remission (BM-CR), partial remission or hematologic improvement (HI) as defined by the International Working Group (IWG) response criteria.

2. Clinical Response Other Than Composite Clinical Response for Acute Myelogenous Leukemia (AML) Patients Per Investigator (Phase Llb) [48 months]

   This is the best overall response as measured by Clinical response. Clinical response is defined as having complete remission (CR), complete remission with incomplete blood count recovery (CRi) or partial remission as defined by the International Working Group (IWG) response criteria.

3. Overall Response Rate (ORR) Assessed by Best Overall Response: Participants With MDS/CMML Per Investigator (Phase Llb) [48 months]

   Best overall response as measured by complete remission (CR) or bone marrow CR (BM-CR) or partial remission (PR) or hematologic improvement (HI). Overall response patients achieved other than the composite CR by individual response category: CR, CRi, mCR or PR as defined by the International Working Group (IWG) response criteria.

4. Overall Response Rate (ORR) Assessed by Best Overall Response: Participants With AML Per Investigator (Phase Llb) [48 months]

   Best overall response as measured by complete remission (CR) or complete response with incomplete blood count recovery (CRi) or partial remission (PR). Overall response patients achieved other than the composite CR by individual response category: CR, CRi or PR.

5. Hematologic Improvement (HI) for Myeloid Dysplastic Syndromes(MDS)/Chronic Myelomonocytic Leukemia (CMML) Patients Per Investigator (Phase Llb) [48 months]

   Hematologic response consists of Erythroid response (HI-E), Platelet response (HI-P) and Neutrophil response (HI-N). HI-E: Hgb increase by ≥ 1.5 g/dL over pretreatment & relevant reduction of units of RBC transfusions by an absolute number of at least 4 units of PRBCs/8 weeks compared with the pretreatment transfusion number in the previous 8 weeks. Only RBC transfusions given for a Hgb of ≤ 9.0 g/dL pretreatment will count in the RBC transfusion response evaluation. HI-P: Absolute increase of ≥ 30 x 109/L over pretreatment or patients starting with ≥ 20 x 109/L platelets OR increase from <20 x 109/L at pretreatment to > 20 x 109/L and by at least 100%. HI-N: At least 100% increase and an absolute increase > 0.5 x 109/L over pretreatment value.

6. 1-year Survival Rate (Phase Llb) [12 months]

   Overall survival was defined as the time from date of randomization to date of death due to any cause. If a patient was not known to have died, survival was censored at the date of last contact. Patients not known to have died were censored for 'Lost to follow-up' if the time between their last contact date and the analysis cut-off date was longer than 3 months and 2 weeks (104 days) during the first year after study evaluation completion, and longer than 6 months and 2 weeks (194 days), thereafter. The 1-year survival rate was obtained from the Kaplan-Meier analysis of overall survival, and its variance was estimated by Greenwood's formula.

7. Time to Progression (TTP) (Phase Llb) [48 months]

   Time to progression (TTP) was defined as the time from the date of randomization to the date of the first documented PD per investigator's assessment or death due to study indication. Time to progression was analyzed by the Kaplan Meier method. Based on the Guidelines for Implementation of international working group (IWG) response criteria in AML, MDS and CMML according to Cheson 2003 and 2006.

Eligibility Criteria

Criteria

• Ages Eligible for Study: 18 Years and Older
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Inclusion Criteria:

Phase l:

• Patients with cytopathologically confirmed diagnosis of AML according to WHO criteria, excluding acute promyelocytic leukemia who are eligible for Vidaza treatment

• ECOG performance status greater less than or equal to 2

Phase ll:

• Adult patients (age ≥ 18 years) who were candidates for treatment with 5-Aza and present with one of the following:

• intermediate-2 or high-risk myelodysplastic syndromes according to the International Prognostic Scoring System (IPSS). OR

• AML with multilineage dysplasia and maximum of 30% blasts (former RAEB-T according to FAB) OR

• chronic myelomonocytic leukemia (CMML)

• Patients must have had the following laboratory values unless elevations are considered due to MDS or leukemia: AST/SGOT and/or ALT/SGPT ≤ 2.5 x ULN; serum creatinine ≤ 1.5 x ULN; serum bilirubin (total and direct) ≤ 2 x ULN; electrolyte panel within normal ranges (WNL) for the institution.

Exclusion Criteria:

Phase l:

• Prior treatment with deacetylase inhibitors

• Concurrent therapy with any other investigational agent

Phase ll:

• Planned hematopoietic stem-cell transplantation (HSCT)

• Patients with therapy-related MDS

• Patients with therapy-related AML and/or relapsed/refractory AML

• Patients with impaired cardiac function including any of the following:

• Complete left bundle branch block or use of a permanent cardiac pacemaker, congenital long QT syndrome, history or presence of ventricular tachyarrhythmia, clinically significant resting bradycardia (<50 beats per minute), QTcF > 460 ms on screening ECG, or right bundle branch block + left anterior hemiblock (bifascicular block)

• Presence of unstable atrial fibrillation (ventricular response rate >100 bpm). Patients with stable atrial fibrillation are eligible provided they do not meet the other cardiac exclusion criteria

• Previous history of angina pectoris or acute MI within 6 months

• Screening LVEF <45% by echocardiography or MUGA

• Other clinically significant heart disease (e.g. uncontrolled hypertension or history of poor compliance with an antihypertensive regimen).

• Any of concurrent severe and/or uncontrolled medical conditions which could compromise participation in the study. For example:

• Uncontrolled diabetes

• Active or uncontrolled infection

• Uncontrolled hypothyroidism

• Acute or chronic liver or renal disease

• Patient had evidence of clinically significant mucosal or internal bleeding

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Georgia Health Sciences University Dept. of MCG	Augusta	Georgia	United States	30912
2	Goshen Center for Cancer Care IU Cancer Center	Indianapolis	Indiana	United States	46202
3	University of Kansas Hospital and Medical Center SC - Univ KS	Kansas City	Kansas	United States	66160
4	Dana Farber Cancer Institute Beth Israel Deaconess Med Ctr	Boston	Massachusetts	United States	02215
5	Memorial Sloan Kettering Sloan Kettering 2	New York	New York	United States	10017
6	Cleveland Clinic Foundation Cleve Clinic	Cleveland	Ohio	United States	44195
7	Medical University of South Carolina -Hollings Cancer Center MUSC	Charleston	South Carolina	United States	29425
8	University of Texas MD Anderson Cancer Center Dept of MD Anderson (16)	Houston	Texas	United States	77030
9	Novartis Investigative Site	Innsbruck		Austria	A-6020
10	Novartis Investigative Site	Vienna		Austria	A-1100
11	Novartis Investigative Site	Brugge		Belgium	8000
12	Novartis Investigative Site	Yvoir		Belgium	5530
13	Novartis Investigative Site	Edmonton	Alberta	Canada	T6G 2B7
14	Novartis Investigative Site	Toronto	Ontario	Canada	M5G 2M9
15	Novartis Investigative Site	Bobigny Cedex		France	93009
16	Novartis Investigative Site	Frankfurt		Germany	60590
17	Novartis Investigative Site	Freiburg		Germany	79106
18	Novartis Investigative Site	Budapest		Hungary	1097
19	Novartis Investigative Site	Debrecen		Hungary	4032
20	Novartis Investigative Site	Kaposvar		Hungary	7400
21	Novartis Investigative Site	Szeged		Hungary	H 6725
22	Novartis Investigative Site	Firenze	FI	Italy	50134
23	Novartis Investigative Site	Reggio Calabria	RC	Italy	89124
24	Novartis Investigative Site	Roma	RM	Italy	00161
25	Novartis Investigative Site	Seoul	Korea	Korea, Republic of	05505
26	Novartis Investigative Site	Seoul		Korea, Republic of	06351
27	Novartis Investigative Site	Malaga	Andalucia	Spain	29010
28	Novartis Investigative Site	Barcelona	Catalunya	Spain	08035
29	Novartis Investigative Site	Madrid		Spain	28006
30	Novartis Investigative Site	Gothenburg		Sweden	413 45
31	Novartis Investigative Site	Stockholm		Sweden	SE-118 83
32	Novartis Investigative Site	Basel		Switzerland	4031
33	Novartis Investigative Site	Geneve		Switzerland	1205
34	Novartis Investigative Site	St. Gallen		Switzerland	9007
35	Novartis Investigative Site	Bangkok		Thailand	10330
36	Novartis Investigative Site	Bangkok		Thailand	10700
37	Novartis Investigative Site	London		United Kingdom	EC1A 7BE
38	Novartis Investigative Site	Wolverhampton		United Kingdom	WV10 0QP

Sponsors and Collaborators

• Novartis Pharmaceuticals

Investigators

• Study Director: Novartis Pharmaceuticals, Novartis Pharmaceuticals

Study Documents (Full-Text)

• Statistical Analysis Plan - Oct 29, 2014
• Study Protocol - Nov 18, 2016

More Information

Publications

None provided.

• Responsible Party: Novartis Pharmaceuticals
• ClinicalTrials.gov Identifier: NCT00946647
• Other Study ID Numbers: CLBH589H2101; 2009-010548-32
• First Posted: Jul 27, 2009
• Last Update Posted: Aug 4, 2020
• Last Verified: Jul 1, 2020

• Individual Participant Data (IPD) Sharing Statement: Yes
• Plan to Share IPD: Yes
• Studies a U.S. FDA-regulated Drug Product: Yes
• Keywords provided by Novartis Pharmaceuticals: Myelodysplastic Syndromes; Chronic Myelomonocytic Leukemia; Acute Myeloid Leukemia; hypomethylating therapy; deacetylase inhibitor; MDS; CMML; AML
• Additional relevant MeSH terms: Leukemia; Leukemia, Myeloid; Leukemia, Myeloid, Acute; Preleukemia; Leukemia, Myelomonocytic, Acute; Leukemia, Myelomonocytic, Chronic; Leukemia, Myelomonocytic, Juvenile; Myelodysplastic Syndromes; Syndrome; Azacitidine; Panobinostat

Study Results

Participant Flow

Recruitment Details	In phase l a total of 31 patients were treated with escalating dose of PAN, 20 mg 30 mg & 40 mg. In phase ll a total of 82 patients were actually randomized with 40 patients assigned to PAN+5-Aza and 42 patients assigned to 5-Aza.
Pre-assignment Detail	For phase I, approximately 26 patients were planned to be enrolled in cohorts of at least three MTD evaluable patients per dose level. For phase ll, approximately 80 patients were planned to be enrolled, 40 patients per arm.

Arm/Group Title	PAN + 5-Aza 20 mg	PAN + 5-Aza 30 mg	PAN + 5-Aza 40 mg	Panobinostat + 5-Azacytidine	5-Azacytidine
Arm/Group Description	In this escalating phase, participants took panobinostat of 20 mg delivered orally at Day 3, Day 5, Day 8, Day 10, Day 12, Day 15 and a fixed dose of 5-Azacytidine (5-Aza) at 75 mg/m2/day for 7 days in Week 1 of each cycle.	In this escalating phase, participants took panobinostat of 30 mg delivered orally at Day 3, Day 5, Day 8, Day 10, Day 12, Day 15 and a fixed dose of 5-Azacytidine (5-Aza) at 75 mg/m2/day for 7 days in Week 1 of each cycle.	In this escalating phase, participants took panobinostat of 40 mg delivered orally at Day 3, Day 5, Day 8, Day 10, Day 12, Day 15 and a fixed dose of 5-Azacytidine (5-Aza) at 75 mg/m2/day for 7 days in Week 1 of each cycle	In phase II: Panobinostat : Rapid Phase II doses at 30 mg delivered orally at Day 3, Day 5, Day 8, Day 10, Day 12, Day 15. In both phases, dose of 5-Azacytidine was 75 mg/m^2, subcutaneously Daily for Day 1 to Day 7.	The dose of 5-Aza was fixed at 75 mg/m2/day for 7 days in Week 1 of each cycle. 5-Aza was sourced locally, except in 4 countries (Hungary, Switzerland, UK, and Spain, for which a central purchase was used by Novartis. Dose of 5-Azacytidine : 75 mg/m^2 subcutaneously daily from Day 1 to Day 7.
Period Title: Phase 1 Part
STARTED	6	18	7	0	0
COMPLETED	0	0	0	0	0
NOT COMPLETED	6	18	7	0	0
Period Title: Phase 1 Part
STARTED	0	0	0	40	42
Safety Set	0	0	0	38	42
COMPLETED	0	0	0	0	0
NOT COMPLETED	0	0	0	40	42

Baseline Characteristics

Arm/Group Title	PAN + 5-Aza 20 mg	PAN + 5-Aza 30 mg	PAN + 5-Aza 40 mg	Panobinostat + 5-Azacytidine	5-Azacytidine	Total
Arm/Group Description	In this escalating phase, participants took panobinostat of 20 mg delivered orally at Day 3, Day 5, Day 8, Day 10, Day 12, Day 15 and a fixed dose of 5-Azacytidine (5-Aza) at 75 mg/m2/day for 7 days in Week 1 of each cycle.	In this escalating phase, participants took panobinostat of 30 mg delivered orally at Day 3, Day 5, Day 8, Day 10, Day 12, Day 15 and a fixed dose of 5-Azacytidine (5-Aza) at 75 mg/m2/day for 7 days in Week 1 of each cycle.	In this escalating phase, participants took panobinostat of 40 mg delivered orally at Day 3, Day 5, Day 8, Day 10, Day 12, Day 15 and a fixed dose of 5-Azacytidine (5-Aza) at 75 mg/m2/day for 7 days in Week 1 of each cycle.	In phase II: Panobinostat : Rapid Phase II doses at 30 mg delivered orally at Day 3, Day 5, Day 8, Day 10, Day 12, Day 15. In both phases, dose of 5-Azacytidine was 75 mg/m^2, subcutaneously Daily for Day 1 to Day 7.	The dose of 5-Aza was fixed at 75 mg/m2/day for 7 days in Week 1 of each cycle. 5-Aza was sourced locally, except in 4 countries (Hungary, Switzerland, UK, and Spain, for which a central purchase was used by Novartis. Dose of 5-Azacytidine : 75 mg/m^2 subcutaneously daily from Day 1 to Day 7.	Total of all reporting groups
Overall Participants	6	18	7	40	42	113
Age, Customized (participants) [Number]
< 65	1 16.7%	5 27.8%	1 14.3%	14 35%	8 19%	29 25.7%
>= 65	5 83.3%	13 72.2%	6 85.7%	26 65%	34 81%	84 74.3%
Sex: Female, Male (Count of Participants)
Female	2 33.3%	10 55.6%	4 57.1%	11 27.5%	17 40.5%	44 38.9%
Male	4 66.7%	8 44.4%	3 42.9%	29 72.5%	25 59.5%	69 61.1%
Race/Ethnicity, Customized (participants) [Number]
Caucasian	5 83.3%	15 83.3%	6 85.7%	29 72.5%	36 85.7%	91 80.5%
Black	0 0%	0 0%	1 14.3%	1 2.5%	0 0%	2 1.8%
Asian	0 0%	0 0%	0 0%	7 17.5%	2 4.8%	9 8%
Other	1 16.7%	3 16.7%	0 0%	3 7.5%	4 9.5%	11 9.7%

Outcome Measures

1. Primary Outcome

Title	Number of Participants With Dose Limiting Toxicity (DLT) (Phase lb)
Description	Dose limiting toxicity (DLT) was defined as a toxicity requiring treatment withdrawal and included the following: Non-hematologic toxicity qualifying for DLT and Hematologic toxicity qualifying for DLT
Time Frame	within the first 28 days (cycle 1)

Outcome Measure Data

Analysis Population Description

Maximum Tolerated Dose (MTD) determining set: Consisted of all patients of the safety set who either received sufficient study treatment as defined in the minimum exposure criteria in Cycle 1 (patients had to have 100% of the planned dose of each compound), and had sufficient safety evaluations or discontinued due to DLT in Cycle 1.

Arm/Group Title	PAN + 5-Aza 20 mg	PAN + 5-Aza 30 mg	PAN + 5-Aza 40 mg
Arm/Group Description	In this escalating phase, participants took panobinostat of 20 mg delivered orally at Day 3, Day 5, Day 8, Day 10, Day 12, Day 15 and a fixed dose of 5-Azacytidine (5-Aza) at 75 mg/m2/day for 7 days in Week 1 of each cycle.	In this escalating phase, participants took panobinostat of 30 mg delivered orally at Day 3, Day 5, Day 8, Day 10, Day 12, Day 15 and a fixed dose of 5-Azacytidine (5-Aza) at 75 mg/m2/day for 7 days in Week 1 of each cycle.	In this escalating phase, participants took panobinostat of 40 mg delivered orally at Day 3, Day 5, Day 8, Day 10, Day 12, Day 15 and a fixed dose of 5-Azacytidine (5-Aza) at 75 mg/m2/day for 7 days in Week 1 of each cycle.
Measure Participants	5	14	7
Number [Participants]	1 16.7%	3 16.7%	2 28.6%

2. Primary Outcome

Title	Number of Dose Limiting Toxicity (DLT) (Phase lb)
Description	Dose limiting toxicity (DLT) was defined as a toxicity requiring treatment withdrawal and included the following: Non-hematologic toxicity qualifying for DLT and Hematologic toxicity qualifying for DLT
Time Frame	within the first 28 days (cycle 1)

Outcome Measure Data

Analysis Population Description

Maximum Tolerated Dose (MTD) determining set: Consisted of all patients of the safety set who either received sufficient study treatment as defined in the minimum exposure criteria in Cycle 1 (patients had to have 100% of the planned dose of each compound), and had sufficient safety evaluations or discontinued due to DLT in Cycle 1.

Arm/Group Title	PAN + 5-Aza 20 mg	PAN + 5-Aza 30 mg	PAN + 5-Aza 40 mg
Arm/Group Description	In this escalating phase, participants took panobinostat of 20 mg delivered orally at Day 3, Day 5, Day 8, Day 10, Day 12, Day 15 and a fixed dose of 5-Azacytidine (5-Aza) at 75 mg/m2/day for 7 days in Week 1 of each cycle.	In this escalating phase, participants took panobinostat of 30 mg delivered orally at Day 3, Day 5, Day 8, Day 10, Day 12, Day 15 and a fixed dose of 5-Azacytidine (5-Aza) at 75 mg/m2/day for 7 days in Week 1 of each cycle.	In this escalating phase, participants took panobinostat of 40 mg delivered orally at Day 3, Day 5, Day 8, Day 10, Day 12, Day 15 and a fixed dose of 5-Azacytidine (5-Aza) at 75 mg/m2/day for 7 days in Week 1 of each cycle.
Measure Participants	5	14	7
Number [DLTs]	2	6	4

3. Primary Outcome

Title	Composite Complete Response (Phase Llb)
Description	Composite complete response is defined as complete response (CR), Complete response with incomplete blood count recovery (CRi) or bone marrow complete response (BM-CR) as defined by the International Working Group (IWG) response criteria.
Time Frame	48 months

Outcome Measure Data

Analysis Population Description

Full analysis set: Consisted of all patients who were randomized to one of the two treatment arms

Arm/Group Title	Panobinostat + 5-Azacytidine	5-Azacytidine
Arm/Group Description	In phase II: Panobinostat : Rapid Phase II doses at 30 mg delivered orally at Day 3, Day 5, Day 8, Day 10, Day 12, Day 15. In both phases, dose of 5-Azacytidine was 75 mg/m^2, subcutaneously Daily for Day 1 to Day 7.	The dose of 5-Aza was fixed at 75 mg/m2/day for 7 days in Week 1 of each cycle. 5-Aza was sourced locally, except in 4 countries (Hungary, Switzerland, UK, and Spain, for which a central purchase was used by Novartis. Dose of 5-Azacytidine : 75 mg/m^2 subcutaneously daily from Day 1 to Day 7.
Measure Participants	40	42
Number (95% Confidence Interval) [Percentage of participants]	27.5 458.3%	14.3 79.4%

4. Secondary Outcome

Title	Clinical Response Other Than Composite Clinical Response for Myeloid Dysplastic Syndromes(MDS)/Chronic Myelomonocytic Leukemia (CMML) Patients Per Investigator (Phase Llb)
Description	This is the best overall response as measured by Clinical response. Clinical response is defined as having complete remission (CR), bone marrow complete remission (BM-CR), partial remission or hematologic improvement (HI) as defined by the International Working Group (IWG) response criteria.
Time Frame	48 months

Outcome Measure Data

Analysis Population Description

Full analysis set: Consisted of all patients who were randomized to one of the two treatment arms

Arm/Group Title	Panobinostat + 5-Azacytidine	5-Azacytidine
Arm/Group Description	In phase II: Panobinostat : Rapid Phase II doses at 30 mg delivered orally at Day 3, Day 5, Day 8, Day 10, Day 12, Day 15. In both phases, dose of 5-Azacytidine was 75 mg/m^2, subcutaneously Daily for Day 1 to Day 7.	The dose of 5-Aza was fixed at 75 mg/m2/day for 7 days in Week 1 of each cycle. 5-Aza was sourced locally, except in 4 countries (Hungary, Switzerland, UK, and Spain, for which a central purchase was used by Novartis. Dose of 5-Azacytidine : 75 mg/m^2 subcutaneously daily from Day 1 to Day 7.
Measure Participants	31	29
Number (95% Confidence Interval) [Percentage of participants]	41.9 698.3%	41.4 230%

5. Secondary Outcome

Title	Clinical Response Other Than Composite Clinical Response for Acute Myelogenous Leukemia (AML) Patients Per Investigator (Phase Llb)
Description	This is the best overall response as measured by Clinical response. Clinical response is defined as having complete remission (CR), complete remission with incomplete blood count recovery (CRi) or partial remission as defined by the International Working Group (IWG) response criteria.
Time Frame	48 months

Outcome Measure Data

Analysis Population Description

Full analysis set: Consisted of all patients who were randomized to one of the two treatment arms

Arm/Group Title	Panobinostat + 5-Azacytidine	5-Azacytidine
Arm/Group Description	In phase II: Panobinostat : Rapid Phase II doses at 30 mg delivered orally at Day 3, Day 5, Day 8, Day 10, Day 12, Day 15. In both phases, dose of 5-Azacytidine was 75 mg/m^2, subcutaneously Daily for Day 1 to Day 7.	The dose of 5-Aza was fixed at 75 mg/m2/day for 7 days in Week 1 of each cycle. 5-Aza was sourced locally, except in 4 countries (Hungary, Switzerland, UK, and Spain, for which a central purchase was used by Novartis. Dose of 5-Azacytidine : 75 mg/m^2 subcutaneously daily from Day 1 to Day 7.
Measure Participants	9	13
Number (95% Confidence Interval) [Percentage of participants]	22.2 370%	30.8 171.1%

6. Secondary Outcome

Title	Overall Response Rate (ORR) Assessed by Best Overall Response: Participants With MDS/CMML Per Investigator (Phase Llb)
Description	Best overall response as measured by complete remission (CR) or bone marrow CR (BM-CR) or partial remission (PR) or hematologic improvement (HI). Overall response patients achieved other than the composite CR by individual response category: CR, CRi, mCR or PR as defined by the International Working Group (IWG) response criteria.
Time Frame	48 months

Outcome Measure Data

Analysis Population Description

Full analysis set (FAS): Consisted of all patients who were randomized to one of the two treatment arms.

Arm/Group Title	Panobinostat + 5-Azacytidine	5-Azacytidine
Arm/Group Description	In phase II: Panobinostat : Rapid Phase II doses at 30 mg delivered orally at Day 3, Day 5, Day 8, Day 10, Day 12, Day 15. In both phases, dose of 5-Azacytidine was 75 mg/m^2, subcutaneously Daily for Day 1 to Day 7.	The dose of 5-Aza was fixed at 75 mg/m2/day for 7 days in Week 1 of each cycle. 5-Aza was sourced locally, except in 4 countries (Hungary, Switzerland, UK, and Spain, for which a central purchase was used by Novartis. Dose of 5-Azacytidine : 75 mg/m^2 subcutaneously daily from Day 1 to Day 7.
Measure Participants	31	29
Clinical response (CR, BM-CR, PR, HI)	41.9 698.3%	41.4 230%
Complete remission (CR)	16.1 268.3%	6.9 38.3%
Bone marrow CR (BM-CR)	12.9 215%	3.4 18.9%
Partial remission (PR)	0.0 0%	6.9 38.3%

7. Secondary Outcome

Title	Overall Response Rate (ORR) Assessed by Best Overall Response: Participants With AML Per Investigator (Phase Llb)
Description	Best overall response as measured by complete remission (CR) or complete response with incomplete blood count recovery (CRi) or partial remission (PR). Overall response patients achieved other than the composite CR by individual response category: CR, CRi or PR.
Time Frame	48 months

Outcome Measure Data

Analysis Population Description

Full analysis set (FAS): Consisted of all patients who were randomized to one of the two treatment arms.

Arm/Group Title	Panobinostat + 5-Azacytidine	5-Azacytidine
Arm/Group Description	In phase II: Panobinostat : Rapid Phase II doses at 30 mg delivered orally at Day 3, Day 5, Day 8, Day 10, Day 12, Day 15. In both phases, dose of 5-Azacytidine was 75 mg/m^2, subcutaneously Daily for Day 1 to Day 7.	The dose of 5-Aza was fixed at 75 mg/m2/day for 7 days in Week 1 of each cycle. 5-Aza was sourced locally, except in 4 countries (Hungary, Switzerland, UK, and Spain, for which a central purchase was used by Novartis. Dose of 5-Azacytidine : 75 mg/m^2 subcutaneously daily from Day 1 to Day 7.
Measure Participants	9	13
Clinical response (CR, CRi, PR)	22.2 370%	30.8 171.1%
Complete remission (CR)	11.1 185%	15.4 85.6%
Compl remiss. with incompl blood cnt recovery(CRi)	11.1 185%	7.7 42.8%
Partial remission (PR)	0.0 0%	7.7 42.8%

8. Secondary Outcome

Title	Hematologic Improvement (HI) for Myeloid Dysplastic Syndromes(MDS)/Chronic Myelomonocytic Leukemia (CMML) Patients Per Investigator (Phase Llb)
Description	Hematologic response consists of Erythroid response (HI-E), Platelet response (HI-P) and Neutrophil response (HI-N). HI-E: Hgb increase by ≥ 1.5 g/dL over pretreatment & relevant reduction of units of RBC transfusions by an absolute number of at least 4 units of PRBCs/8 weeks compared with the pretreatment transfusion number in the previous 8 weeks. Only RBC transfusions given for a Hgb of ≤ 9.0 g/dL pretreatment will count in the RBC transfusion response evaluation. HI-P: Absolute increase of ≥ 30 x 109/L over pretreatment or patients starting with ≥ 20 x 109/L platelets OR increase from <20 x 109/L at pretreatment to > 20 x 109/L and by at least 100%. HI-N: At least 100% increase and an absolute increase > 0.5 x 109/L over pretreatment value.
Time Frame	48 months

Outcome Measure Data

Analysis Population Description

Full analysis set: Consisted of all patients who were randomized to one of the two treatment arms

Arm/Group Title	Panobinostat + 5-Azacytidine	5-Azacytidine
Arm/Group Description	In phase II: Panobinostat : Rapid Phase II doses at 30 mg delivered orally at Day 3, Day 5, Day 8, Day 10, Day 12, Day 15. In both phases, dose of 5-Azacytidine was 75 mg/m^2, subcutaneously Daily for Day 1 to Day 7.	The dose of 5-Aza was fixed at 75 mg/m2/day for 7 days in Week 1 of each cycle. 5-Aza was sourced locally, except in 4 countries (Hungary, Switzerland, UK, and Spain, for which a central purchase was used by Novartis. Dose of 5-Azacytidine : 75 mg/m^2 subcutaneously daily from Day 1 to Day 7.
Measure Participants	31	29
Erythroid response (HI-E)	25.8 430%	31.0 172.2%
Platelet response (HI-P)	35.5 591.7%	24.1 133.9%
Neutrophil response (HI-N)	19.4 323.3%	13.8 76.7%

9. Secondary Outcome

Title	1-year Survival Rate (Phase Llb)
Description	Overall survival was defined as the time from date of randomization to date of death due to any cause. If a patient was not known to have died, survival was censored at the date of last contact. Patients not known to have died were censored for 'Lost to follow-up' if the time between their last contact date and the analysis cut-off date was longer than 3 months and 2 weeks (104 days) during the first year after study evaluation completion, and longer than 6 months and 2 weeks (194 days), thereafter. The 1-year survival rate was obtained from the Kaplan-Meier analysis of overall survival, and its variance was estimated by Greenwood's formula.
Time Frame	12 months

Outcome Measure Data

Analysis Population Description

Full analysis set: Consisted of all patients who were randomized to one of the two treatment arms

Arm/Group Title	Panobinostat + 5-Azacytidine	5-Azacytidine
Arm/Group Description	In phase II: Panobinostat : Rapid Phase II doses at 30 mg delivered orally at Day 3, Day 5, Day 8, Day 10, Day 12, Day 15. In both phases, dose of 5-Azacytidine was 75 mg/m^2, subcutaneously Daily for Day 1 to Day 7.	The dose of 5-Aza was fixed at 75 mg/m2/day for 7 days in Week 1 of each cycle. 5-Aza was sourced locally, except in 4 countries (Hungary, Switzerland, UK, and Spain, for which a central purchase was used by Novartis. Dose of 5-Azacytidine : 75 mg/m^2 subcutaneously daily from Day 1 to Day 7.
Measure Participants	40	42
Median (95% Confidence Interval) [months]	14.9	15.6

10. Secondary Outcome

Title	Time to Progression (TTP) (Phase Llb)
Description	Time to progression (TTP) was defined as the time from the date of randomization to the date of the first documented PD per investigator's assessment or death due to study indication. Time to progression was analyzed by the Kaplan Meier method. Based on the Guidelines for Implementation of international working group (IWG) response criteria in AML, MDS and CMML according to Cheson 2003 and 2006.
Time Frame	48 months

Outcome Measure Data

Analysis Population Description

Full analysis set: Consisted of all patients who were randomized to one of the two treatment arms

Arm/Group Title	Panobinostat + 5-Azacytidine	5-Azacytidine
Arm/Group Description	In phase II: Panobinostat : Rapid Phase II doses at 30 mg delivered orally at Day 3, Day 5, Day 8, Day 10, Day 12, Day 15. In both phases, dose of 5-Azacytidine was 75 mg/m^2, subcutaneously Daily for Day 1 to Day 7.	The dose of 5-Aza was fixed at 75 mg/m2/day for 7 days in Week 1 of each cycle. 5-Aza was sourced locally, except in 4 countries (Hungary, Switzerland, UK, and Spain, for which a central purchase was used by Novartis. Dose of 5-Azacytidine : 75 mg/m^2 subcutaneously daily from Day 1 to Day 7.
Measure Participants	40	42
Median (95% Confidence Interval) [months]	NA	15.2

Adverse Events

Time Frame	Adverse Event (AE) timeframe: Adverse events were collected from first dose of study treatment until end of study treatment plus 28 days post treatment, up to maximum duration 397.1 weeks.
Adverse Event Reporting Description	Adverse Event (AE): Any sign or symptom that occurs during the study treatment plus the 28 days post treatment. 2 patients randomized to PAN+5AZA received only 5AZA & no PAN & were part of the safety set for 5AZA group. Also, 2 patients rand. to 5AZA did not receive any treatment & were not part of the safety set but were part of the FAS for the 5AZA group
Arm/Group Title	Phase Ib PAN + 5-Aza 20mg		Phase Ib PAN + 5-Aza 30mg		Phase Ib PAN + 5-Aza 40mg		Phase IIb PAN + 5-Aza		Phase IIb 5-Aza		Phase Ib and IIb
Arm/Group Description	In this escalating phase, participants took panobinostat of 20 mg delivered orally at Day 3, Day 5, Day 8, Day 10, Day 12, Day 15 and a fixed dose of 5-Azacytidine (5-Aza) at 75 g/m2/day for 7 days in Week 1 of each cycle		In this escalating phase, participants took panobinostat of 30 mg delivered orally at Day 3, Day 5, Day 8, Day 10, Day 12, Day 15 and a fixed dose of 5-Azacytidine (5-Aza) at 75 mg/m2/day for 7 days in Week 1 of each cycle		In this escalating phase, participants took panobinostat of 40 mg delivered orally at Day 3, Day 5, Day 8, Day 10, Day 12, Day 15 and a fixed dose of 5-Azacytidine (5-Aza) at 75 mg/m2/day for 7 days in Week 1 of each cycle		In phase II: Panobinostat : Rapid Phase II doses at 30 mg delivered orally at Day 3, Day 5, Day 8, Day 10, Day 12, Day 15. In both phases, dose of 5-Azacytidine was 75 mg/m^2, subcutaneously Daily for Day 1 to Day 7.		The dose of 5-Aza was fixed at 75 mg/m2/day for 7 days in Week 1 of each cycle. 5-Aza was sourced locally, except in 4 countries (Hungary, Switzerland, UK, and Spain, for which a central purchase was used by Novartis. Dose of 5-Azacytidine: 75 mg/m^2 subcutaneously daily from Day 1 to Day		Patients in the Panobinostat + 5-Azacytidine arm and in the 5-Azacytidine arm
All Cause Mortality
	Phase Ib PAN + 5-Aza 20mg		Phase Ib PAN + 5-Aza 30mg		Phase Ib PAN + 5-Aza 40mg		Phase IIb PAN + 5-Aza		Phase IIb 5-Aza		Phase Ib and IIb
	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	0/6 (0%)		1/18 (5.6%)		2/7 (28.6%)		6/38 (15.8%)		3/42 (7.1%)		12/111 (10.8%)
Serious Adverse Events
	Phase Ib PAN + 5-Aza 20mg		Phase Ib PAN + 5-Aza 30mg		Phase Ib PAN + 5-Aza 40mg		Phase IIb PAN + 5-Aza		Phase IIb 5-Aza		Phase Ib and IIb
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	5/6 (83.3%)		15/18 (83.3%)		6/7 (85.7%)		28/38 (73.7%)		28/42 (66.7%)		82/111 (73.9%)
Blood and lymphatic system disorders
Anaemia	0/6 (0%)		0/18 (0%)		0/7 (0%)		2/38 (5.3%)		0/42 (0%)		2/111 (1.8%)
Anaemia of malignant disease	0/6 (0%)		0/18 (0%)		0/7 (0%)		0/38 (0%)		1/42 (2.4%)		1/111 (0.9%)
Febrile neutropenia	2/6 (33.3%)		6/18 (33.3%)		3/7 (42.9%)		10/38 (26.3%)		6/42 (14.3%)		27/111 (24.3%)
Haemolytic anaemia	0/6 (0%)		0/18 (0%)		0/7 (0%)		0/38 (0%)		1/42 (2.4%)		1/111 (0.9%)
Leukopenia	0/6 (0%)		0/18 (0%)		0/7 (0%)		1/38 (2.6%)		0/42 (0%)		1/111 (0.9%)
Neutropenia	0/6 (0%)		1/18 (5.6%)		0/7 (0%)		2/38 (5.3%)		2/42 (4.8%)		5/111 (4.5%)
Pancytopenia	0/6 (0%)		0/18 (0%)		0/7 (0%)		1/38 (2.6%)		1/42 (2.4%)		2/111 (1.8%)
Thrombocytopenia	0/6 (0%)		0/18 (0%)		1/7 (14.3%)		3/38 (7.9%)		3/42 (7.1%)		7/111 (6.3%)
Cardiac disorders
Acute myocardial infarction	0/6 (0%)		1/18 (5.6%)		0/7 (0%)		1/38 (2.6%)		0/42 (0%)		2/111 (1.8%)
Angina pectoris	0/6 (0%)		1/18 (5.6%)		0/7 (0%)		0/38 (0%)		1/42 (2.4%)		2/111 (1.8%)
Atrial fibrillation	1/6 (16.7%)		1/18 (5.6%)		1/7 (14.3%)		0/38 (0%)		0/42 (0%)		3/111 (2.7%)
Atrial flutter	0/6 (0%)		0/18 (0%)		0/7 (0%)		1/38 (2.6%)		0/42 (0%)		1/111 (0.9%)
Cardiac failure	0/6 (0%)		0/18 (0%)		0/7 (0%)		1/38 (2.6%)		0/42 (0%)		1/111 (0.9%)
Cardio-respiratory arrest	0/6 (0%)		0/18 (0%)		0/7 (0%)		0/38 (0%)		1/42 (2.4%)		1/111 (0.9%)
Coronary artery disease	0/6 (0%)		0/18 (0%)		0/7 (0%)		0/38 (0%)		1/42 (2.4%)		1/111 (0.9%)
Left ventricular hypertrophy	0/6 (0%)		0/18 (0%)		0/7 (0%)		0/38 (0%)		1/42 (2.4%)		1/111 (0.9%)
Myocarditis	0/6 (0%)		1/18 (5.6%)		0/7 (0%)		0/38 (0%)		0/42 (0%)		1/111 (0.9%)
Eye disorders
Diplopia	0/6 (0%)		0/18 (0%)		0/7 (0%)		0/38 (0%)		1/42 (2.4%)		1/111 (0.9%)
Uveitis	0/6 (0%)		0/18 (0%)		0/7 (0%)		0/38 (0%)		1/42 (2.4%)		1/111 (0.9%)
Vision blurred	0/6 (0%)		0/18 (0%)		0/7 (0%)		0/38 (0%)		1/42 (2.4%)		1/111 (0.9%)
Gastrointestinal disorders
Colitis	0/6 (0%)		2/18 (11.1%)		0/7 (0%)		1/38 (2.6%)		0/42 (0%)		3/111 (2.7%)
Constipation	0/6 (0%)		1/18 (5.6%)		0/7 (0%)		1/38 (2.6%)		0/42 (0%)		2/111 (1.8%)
Diarrhoea	0/6 (0%)		1/18 (5.6%)		0/7 (0%)		1/38 (2.6%)		1/42 (2.4%)		3/111 (2.7%)
Duodenitis	0/6 (0%)		1/18 (5.6%)		0/7 (0%)		0/38 (0%)		0/42 (0%)		1/111 (0.9%)
Gastritis	0/6 (0%)		1/18 (5.6%)		0/7 (0%)		0/38 (0%)		0/42 (0%)		1/111 (0.9%)
Gastroenteritis eosinophilic	0/6 (0%)		1/18 (5.6%)		0/7 (0%)		0/38 (0%)		0/42 (0%)		1/111 (0.9%)
Gastrointestinal haemorrhage	0/6 (0%)		1/18 (5.6%)		0/7 (0%)		1/38 (2.6%)		1/42 (2.4%)		3/111 (2.7%)
Large intestinal haemorrhage	0/6 (0%)		0/18 (0%)		0/7 (0%)		0/38 (0%)		1/42 (2.4%)		1/111 (0.9%)
Melaena	0/6 (0%)		0/18 (0%)		0/7 (0%)		0/38 (0%)		2/42 (4.8%)		2/111 (1.8%)
Nausea	0/6 (0%)		1/18 (5.6%)		0/7 (0%)		1/38 (2.6%)		0/42 (0%)		2/111 (1.8%)
Rectal haemorrhage	0/6 (0%)		0/18 (0%)		0/7 (0%)		0/38 (0%)		1/42 (2.4%)		1/111 (0.9%)
Small intestinal obstruction	0/6 (0%)		0/18 (0%)		1/7 (14.3%)		0/38 (0%)		0/42 (0%)		1/111 (0.9%)
Tongue haematoma	0/6 (0%)		0/18 (0%)		0/7 (0%)		1/38 (2.6%)		0/42 (0%)		1/111 (0.9%)
Volvulus	0/6 (0%)		0/18 (0%)		0/7 (0%)		1/38 (2.6%)		0/42 (0%)		1/111 (0.9%)
Vomiting	0/6 (0%)		1/18 (5.6%)		0/7 (0%)		1/38 (2.6%)		0/42 (0%)		2/111 (1.8%)
General disorders
Asthenia	2/6 (33.3%)		0/18 (0%)		2/7 (28.6%)		0/38 (0%)		0/42 (0%)		4/111 (3.6%)
Death	0/6 (0%)		0/18 (0%)		0/7 (0%)		1/38 (2.6%)		0/42 (0%)		1/111 (0.9%)
Fatigue	0/6 (0%)		1/18 (5.6%)		0/7 (0%)		0/38 (0%)		0/42 (0%)		1/111 (0.9%)
Pyrexia	0/6 (0%)		2/18 (11.1%)		0/7 (0%)		3/38 (7.9%)		0/42 (0%)		5/111 (4.5%)
Hepatobiliary disorders
Hyperbilirubinaemia	0/6 (0%)		0/18 (0%)		1/7 (14.3%)		0/38 (0%)		0/42 (0%)		1/111 (0.9%)
Infections and infestations
Abscess soft tissue	0/6 (0%)		0/18 (0%)		0/7 (0%)		0/38 (0%)		1/42 (2.4%)		1/111 (0.9%)
Bacteraemia	0/6 (0%)		0/18 (0%)		0/7 (0%)		0/38 (0%)		1/42 (2.4%)		1/111 (0.9%)
Bacterial sepsis	0/6 (0%)		1/18 (5.6%)		0/7 (0%)		1/38 (2.6%)		0/42 (0%)		2/111 (1.8%)
Breast cellulitis	0/6 (0%)		0/18 (0%)		0/7 (0%)		1/38 (2.6%)		0/42 (0%)		1/111 (0.9%)
Bronchopulmonary aspergillosis	0/6 (0%)		0/18 (0%)		0/7 (0%)		0/38 (0%)		1/42 (2.4%)		1/111 (0.9%)
Cellulitis	0/6 (0%)		1/18 (5.6%)		0/7 (0%)		1/38 (2.6%)		2/42 (4.8%)		4/111 (3.6%)
Diverticulitis	0/6 (0%)		1/18 (5.6%)		0/7 (0%)		0/38 (0%)		1/42 (2.4%)		2/111 (1.8%)
Erysipelas	0/6 (0%)		0/18 (0%)		0/7 (0%)		1/38 (2.6%)		0/42 (0%)		1/111 (0.9%)
Escherichia bacteraemia	0/6 (0%)		0/18 (0%)		0/7 (0%)		0/38 (0%)		1/42 (2.4%)		1/111 (0.9%)
Escherichia infection	0/6 (0%)		0/18 (0%)		0/7 (0%)		1/38 (2.6%)		0/42 (0%)		1/111 (0.9%)
Gastrointestinal infection	0/6 (0%)		0/18 (0%)		0/7 (0%)		1/38 (2.6%)		0/42 (0%)		1/111 (0.9%)
Herpes simplex	0/6 (0%)		0/18 (0%)		0/7 (0%)		0/38 (0%)		1/42 (2.4%)		1/111 (0.9%)
Impetigo	0/6 (0%)		1/18 (5.6%)		0/7 (0%)		0/38 (0%)		0/42 (0%)		1/111 (0.9%)
Infection	0/6 (0%)		0/18 (0%)		0/7 (0%)		0/38 (0%)		1/42 (2.4%)		1/111 (0.9%)
Lower respiratory tract infection	0/6 (0%)		0/18 (0%)		0/7 (0%)		0/38 (0%)		1/42 (2.4%)		1/111 (0.9%)
Lung infection	1/6 (16.7%)		0/18 (0%)		0/7 (0%)		0/38 (0%)		0/42 (0%)		1/111 (0.9%)
Neutropenic sepsis	0/6 (0%)		0/18 (0%)		0/7 (0%)		0/38 (0%)		3/42 (7.1%)		3/111 (2.7%)
Oral bacterial infection	0/6 (0%)		0/18 (0%)		0/7 (0%)		1/38 (2.6%)		0/42 (0%)		1/111 (0.9%)
Parotitis	0/6 (0%)		0/18 (0%)		0/7 (0%)		0/38 (0%)		1/42 (2.4%)		1/111 (0.9%)
Perirectal abscess	0/6 (0%)		1/18 (5.6%)		0/7 (0%)		0/38 (0%)		0/42 (0%)		1/111 (0.9%)
Pharyngeal abscess	0/6 (0%)		0/18 (0%)		0/7 (0%)		0/38 (0%)		1/42 (2.4%)		1/111 (0.9%)
Pneumonia	0/6 (0%)		2/18 (11.1%)		2/7 (28.6%)		8/38 (21.1%)		4/42 (9.5%)		16/111 (14.4%)
Pulmonary sepsis	0/6 (0%)		0/18 (0%)		0/7 (0%)		1/38 (2.6%)		0/42 (0%)		1/111 (0.9%)
Sepsis	0/6 (0%)		1/18 (5.6%)		0/7 (0%)		4/38 (10.5%)		4/42 (9.5%)		9/111 (8.1%)
Septic shock	1/6 (16.7%)		0/18 (0%)		1/7 (14.3%)		2/38 (5.3%)		0/42 (0%)		4/111 (3.6%)
Sinusitis	0/6 (0%)		0/18 (0%)		1/7 (14.3%)		0/38 (0%)		0/42 (0%)		1/111 (0.9%)
Staphylococcal sepsis	0/6 (0%)		0/18 (0%)		1/7 (14.3%)		0/38 (0%)		0/42 (0%)		1/111 (0.9%)
Tooth infection	0/6 (0%)		0/18 (0%)		0/7 (0%)		0/38 (0%)		1/42 (2.4%)		1/111 (0.9%)
Urinary tract infection	0/6 (0%)		1/18 (5.6%)		0/7 (0%)		1/38 (2.6%)		0/42 (0%)		2/111 (1.8%)
Injury, poisoning and procedural complications
Femur fracture	0/6 (0%)		0/18 (0%)		0/7 (0%)		1/38 (2.6%)		0/42 (0%)		1/111 (0.9%)
Hip fracture	0/6 (0%)		0/18 (0%)		0/7 (0%)		1/38 (2.6%)		0/42 (0%)		1/111 (0.9%)
Skin laceration	0/6 (0%)		0/18 (0%)		1/7 (14.3%)		0/38 (0%)		0/42 (0%)		1/111 (0.9%)
Toxicity to various agents	0/6 (0%)		0/18 (0%)		1/7 (14.3%)		0/38 (0%)		0/42 (0%)		1/111 (0.9%)
Transfusion reaction	0/6 (0%)		0/18 (0%)		0/7 (0%)		0/38 (0%)		1/42 (2.4%)		1/111 (0.9%)
Ulna fracture	0/6 (0%)		0/18 (0%)		0/7 (0%)		1/38 (2.6%)		0/42 (0%)		1/111 (0.9%)
Investigations
Alanine aminotransferase increased	0/6 (0%)		0/18 (0%)		0/7 (0%)		1/38 (2.6%)		0/42 (0%)		1/111 (0.9%)
Aspartate aminotransferase increased	0/6 (0%)		0/18 (0%)		0/7 (0%)		1/38 (2.6%)		0/42 (0%)		1/111 (0.9%)
Blood creatine phosphokinase increased	0/6 (0%)		0/18 (0%)		1/7 (14.3%)		0/38 (0%)		0/42 (0%)		1/111 (0.9%)
Blood creatinine increased	0/6 (0%)		0/18 (0%)		0/7 (0%)		1/38 (2.6%)		0/42 (0%)		1/111 (0.9%)
Electrocardiogram ST segment depression	0/6 (0%)		0/18 (0%)		0/7 (0%)		1/38 (2.6%)		0/42 (0%)		1/111 (0.9%)
Electrocardiogram T wave inversion	0/6 (0%)		1/18 (5.6%)		0/7 (0%)		1/38 (2.6%)		0/42 (0%)		2/111 (1.8%)
Gamma-glutamyltransferase increased	0/6 (0%)		0/18 (0%)		0/7 (0%)		1/38 (2.6%)		0/42 (0%)		1/111 (0.9%)
Haemoglobin decreased	0/6 (0%)		0/18 (0%)		0/7 (0%)		0/38 (0%)		1/42 (2.4%)		1/111 (0.9%)
Heart rate increased	0/6 (0%)		0/18 (0%)		1/7 (14.3%)		0/38 (0%)		0/42 (0%)		1/111 (0.9%)
Troponin T increased	0/6 (0%)		0/18 (0%)		1/7 (14.3%)		0/38 (0%)		0/42 (0%)		1/111 (0.9%)
Metabolism and nutrition disorders
Decreased appetite	0/6 (0%)		0/18 (0%)		0/7 (0%)		1/38 (2.6%)		0/42 (0%)		1/111 (0.9%)
Dehydration	0/6 (0%)		2/18 (11.1%)		0/7 (0%)		0/38 (0%)		1/42 (2.4%)		3/111 (2.7%)
Hyperglycaemia	0/6 (0%)		0/18 (0%)		1/7 (14.3%)		0/38 (0%)		1/42 (2.4%)		2/111 (1.8%)
Musculoskeletal and connective tissue disorders
Arthralgia	0/6 (0%)		0/18 (0%)		0/7 (0%)		1/38 (2.6%)		0/42 (0%)		1/111 (0.9%)
Arthritis	1/6 (16.7%)		0/18 (0%)		0/7 (0%)		0/38 (0%)		1/42 (2.4%)		2/111 (1.8%)
Back pain	0/6 (0%)		2/18 (11.1%)		0/7 (0%)		0/38 (0%)		0/42 (0%)		2/111 (1.8%)
Pain in extremity	0/6 (0%)		0/18 (0%)		0/7 (0%)		0/38 (0%)		1/42 (2.4%)		1/111 (0.9%)
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Benign anorectal neoplasm	0/6 (0%)		0/18 (0%)		0/7 (0%)		1/38 (2.6%)		0/42 (0%)		1/111 (0.9%)
Large cell lung cancer metastatic	0/6 (0%)		0/18 (0%)		0/7 (0%)		0/38 (0%)		1/42 (2.4%)		1/111 (0.9%)
Meningioma	0/6 (0%)		0/18 (0%)		0/7 (0%)		0/38 (0%)		1/42 (2.4%)		1/111 (0.9%)
Nervous system disorders
Cerebral haemorrhage	0/6 (0%)		1/18 (5.6%)		0/7 (0%)		0/38 (0%)		0/42 (0%)		1/111 (0.9%)
Dysarthria	0/6 (0%)		0/18 (0%)		0/7 (0%)		0/38 (0%)		1/42 (2.4%)		1/111 (0.9%)
Haemorrhage intracranial	0/6 (0%)		0/18 (0%)		0/7 (0%)		0/38 (0%)		1/42 (2.4%)		1/111 (0.9%)
Headache	0/6 (0%)		0/18 (0%)		0/7 (0%)		0/38 (0%)		2/42 (4.8%)		2/111 (1.8%)
Syncope	0/6 (0%)		0/18 (0%)		0/7 (0%)		0/38 (0%)		1/42 (2.4%)		1/111 (0.9%)
Renal and urinary disorders
Acute kidney injury	0/6 (0%)		1/18 (5.6%)		1/7 (14.3%)		0/38 (0%)		0/42 (0%)		2/111 (1.8%)
Pollakiuria	0/6 (0%)		0/18 (0%)		0/7 (0%)		0/38 (0%)		1/42 (2.4%)		1/111 (0.9%)
Prerenal failure	0/6 (0%)		0/18 (0%)		0/7 (0%)		1/38 (2.6%)		0/42 (0%)		1/111 (0.9%)
Renal failure	0/6 (0%)		0/18 (0%)		1/7 (14.3%)		0/38 (0%)		0/42 (0%)		1/111 (0.9%)
Urinary retention	0/6 (0%)		0/18 (0%)		0/7 (0%)		0/38 (0%)		1/42 (2.4%)		1/111 (0.9%)
Respiratory, thoracic and mediastinal disorders
Dyspnoea	0/6 (0%)		0/18 (0%)		0/7 (0%)		0/38 (0%)		2/42 (4.8%)		2/111 (1.8%)
Epistaxis	0/6 (0%)		0/18 (0%)		0/7 (0%)		1/38 (2.6%)		0/42 (0%)		1/111 (0.9%)
Haemoptysis	0/6 (0%)		1/18 (5.6%)		0/7 (0%)		0/38 (0%)		0/42 (0%)		1/111 (0.9%)
Pleural effusion	1/6 (16.7%)		0/18 (0%)		0/7 (0%)		0/38 (0%)		1/42 (2.4%)		2/111 (1.8%)
Pulmonary haemorrhage	0/6 (0%)		1/18 (5.6%)		0/7 (0%)		1/38 (2.6%)		0/42 (0%)		2/111 (1.8%)
Pulmonary oedema	0/6 (0%)		0/18 (0%)		0/7 (0%)		0/38 (0%)		1/42 (2.4%)		1/111 (0.9%)
Respiratory failure	0/6 (0%)		0/18 (0%)		0/7 (0%)		1/38 (2.6%)		1/42 (2.4%)		2/111 (1.8%)
Skin and subcutaneous tissue disorders
Angioedema	0/6 (0%)		1/18 (5.6%)		0/7 (0%)		0/38 (0%)		0/42 (0%)		1/111 (0.9%)
Vascular disorders
Embolism venous	0/6 (0%)		1/18 (5.6%)		0/7 (0%)		0/38 (0%)		0/42 (0%)		1/111 (0.9%)
Haematoma	0/6 (0%)		0/18 (0%)		0/7 (0%)		0/38 (0%)		1/42 (2.4%)		1/111 (0.9%)
Hypotension	0/6 (0%)		1/18 (5.6%)		0/7 (0%)		0/38 (0%)		1/42 (2.4%)		2/111 (1.8%)
Peripheral artery occlusion	0/6 (0%)		1/18 (5.6%)		0/7 (0%)		0/38 (0%)		0/42 (0%)		1/111 (0.9%)
Other (Not Including Serious) Adverse Events
	Phase Ib PAN + 5-Aza 20mg		Phase Ib PAN + 5-Aza 30mg		Phase Ib PAN + 5-Aza 40mg		Phase IIb PAN + 5-Aza		Phase IIb 5-Aza		Phase Ib and IIb
	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	6/6 (100%)		18/18 (100%)		7/7 (100%)		38/38 (100%)		38/42 (90.5%)		107/111 (96.4%)
Blood and lymphatic system disorders
Anaemia	2/6 (33.3%)		8/18 (44.4%)		4/7 (57.1%)		12/38 (31.6%)		14/42 (33.3%)		40/111 (36%)
Febrile neutropenia	0/6 (0%)		3/18 (16.7%)		0/7 (0%)		6/38 (15.8%)		2/42 (4.8%)		11/111 (9.9%)
Leukocytosis	0/6 (0%)		2/18 (11.1%)		0/7 (0%)		0/38 (0%)		1/42 (2.4%)		3/111 (2.7%)
Leukopenia	1/6 (16.7%)		4/18 (22.2%)		1/7 (14.3%)		4/38 (10.5%)		1/42 (2.4%)		11/111 (9.9%)
Lymphopenia	0/6 (0%)		0/18 (0%)		0/7 (0%)		2/38 (5.3%)		0/42 (0%)		2/111 (1.8%)
Neutropenia	2/6 (33.3%)		8/18 (44.4%)		3/7 (42.9%)		16/38 (42.1%)		10/42 (23.8%)		39/111 (35.1%)
Pancytopenia	0/6 (0%)		0/18 (0%)		0/7 (0%)		3/38 (7.9%)		1/42 (2.4%)		4/111 (3.6%)
Splenomegaly	0/6 (0%)		1/18 (5.6%)		0/7 (0%)		0/38 (0%)		0/42 (0%)		1/111 (0.9%)
Thrombocytopenia	3/6 (50%)		12/18 (66.7%)		4/7 (57.1%)		18/38 (47.4%)		10/42 (23.8%)		47/111 (42.3%)
Thrombocytosis	0/6 (0%)		1/18 (5.6%)		0/7 (0%)		0/38 (0%)		2/42 (4.8%)		3/111 (2.7%)
Thrombotic microangiopathy	0/6 (0%)		1/18 (5.6%)		0/7 (0%)		0/38 (0%)		0/42 (0%)		1/111 (0.9%)
Cardiac disorders
Angina pectoris	1/6 (16.7%)		1/18 (5.6%)		0/7 (0%)		1/38 (2.6%)		0/42 (0%)		3/111 (2.7%)
Arrhythmia	1/6 (16.7%)		0/18 (0%)		0/7 (0%)		0/38 (0%)		1/42 (2.4%)		2/111 (1.8%)
Atrial fibrillation	1/6 (16.7%)		1/18 (5.6%)		2/7 (28.6%)		3/38 (7.9%)		1/42 (2.4%)		8/111 (7.2%)
Atrial flutter	0/6 (0%)		1/18 (5.6%)		0/7 (0%)		0/38 (0%)		0/42 (0%)		1/111 (0.9%)
Bundle branch block left	1/6 (16.7%)		0/18 (0%)		0/7 (0%)		0/38 (0%)		0/42 (0%)		1/111 (0.9%)
Cardiac failure acute	0/6 (0%)		0/18 (0%)		1/7 (14.3%)		0/38 (0%)		0/42 (0%)		1/111 (0.9%)
Extrasystoles	1/6 (16.7%)		0/18 (0%)		0/7 (0%)		0/38 (0%)		0/42 (0%)		1/111 (0.9%)
Hypertensive heart disease	0/6 (0%)		1/18 (5.6%)		0/7 (0%)		0/38 (0%)		0/42 (0%)		1/111 (0.9%)
Myocarditis	0/6 (0%)		1/18 (5.6%)		0/7 (0%)		0/38 (0%)		0/42 (0%)		1/111 (0.9%)
Palpitations	0/6 (0%)		3/18 (16.7%)		0/7 (0%)		0/38 (0%)		0/42 (0%)		3/111 (2.7%)
Pericardial effusion	0/6 (0%)		0/18 (0%)		1/7 (14.3%)		0/38 (0%)		0/42 (0%)		1/111 (0.9%)
Sinus tachycardia	0/6 (0%)		0/18 (0%)		1/7 (14.3%)		2/38 (5.3%)		0/42 (0%)		3/111 (2.7%)
Tachycardia	1/6 (16.7%)		1/18 (5.6%)		2/7 (28.6%)		0/38 (0%)		1/42 (2.4%)		5/111 (4.5%)
Ventricular extrasystoles	0/6 (0%)		1/18 (5.6%)		0/7 (0%)		0/38 (0%)		0/42 (0%)		1/111 (0.9%)
Ear and labyrinth disorders
Ear disorder	0/6 (0%)		0/18 (0%)		1/7 (14.3%)		0/38 (0%)		0/42 (0%)		1/111 (0.9%)
Ear pain	0/6 (0%)		1/18 (5.6%)		0/7 (0%)		0/38 (0%)		2/42 (4.8%)		3/111 (2.7%)
Hypoacusis	1/6 (16.7%)		0/18 (0%)		0/7 (0%)		0/38 (0%)		1/42 (2.4%)		2/111 (1.8%)
Otorrhoea	0/6 (0%)		1/18 (5.6%)		0/7 (0%)		0/38 (0%)		0/42 (0%)		1/111 (0.9%)
Tinnitus	0/6 (0%)		0/18 (0%)		1/7 (14.3%)		0/38 (0%)		0/42 (0%)		1/111 (0.9%)
Vertigo	1/6 (16.7%)		2/18 (11.1%)		0/7 (0%)		0/38 (0%)		1/42 (2.4%)		4/111 (3.6%)
Endocrine disorders
Hypothyroidism	1/6 (16.7%)		0/18 (0%)		0/7 (0%)		0/38 (0%)		0/42 (0%)		1/111 (0.9%)
Thyroid disorder	0/6 (0%)		1/18 (5.6%)		0/7 (0%)		0/38 (0%)		0/42 (0%)		1/111 (0.9%)
Eye disorders
Blepharitis	0/6 (0%)		0/18 (0%)		1/7 (14.3%)		0/38 (0%)		0/42 (0%)		1/111 (0.9%)
Cataract	1/6 (16.7%)		0/18 (0%)		0/7 (0%)		0/38 (0%)		0/42 (0%)		1/111 (0.9%)
Diplopia	0/6 (0%)		0/18 (0%)		1/7 (14.3%)		0/38 (0%)		0/42 (0%)		1/111 (0.9%)
Eye irritation	0/6 (0%)		2/18 (11.1%)		0/7 (0%)		0/38 (0%)		0/42 (0%)		2/111 (1.8%)
Optic atrophy	1/6 (16.7%)		0/18 (0%)		0/7 (0%)		0/38 (0%)		0/42 (0%)		1/111 (0.9%)
Pupillary reflex impaired	1/6 (16.7%)		0/18 (0%)		0/7 (0%)		0/38 (0%)		0/42 (0%)		1/111 (0.9%)
Vision blurred	0/6 (0%)		0/18 (0%)		1/7 (14.3%)		0/38 (0%)		0/42 (0%)		1/111 (0.9%)
Visual impairment	1/6 (16.7%)		0/18 (0%)		0/7 (0%)		1/38 (2.6%)		0/42 (0%)		2/111 (1.8%)
Gastrointestinal disorders
Abdominal distension	0/6 (0%)		1/18 (5.6%)		0/7 (0%)		0/38 (0%)		0/42 (0%)		1/111 (0.9%)
Abdominal pain	3/6 (50%)		6/18 (33.3%)		1/7 (14.3%)		6/38 (15.8%)		2/42 (4.8%)		18/111 (16.2%)
Abdominal pain upper	1/6 (16.7%)		4/18 (22.2%)		1/7 (14.3%)		2/38 (5.3%)		2/42 (4.8%)		10/111 (9%)
Abdominal wall haematoma	0/6 (0%)		1/18 (5.6%)		1/7 (14.3%)		0/38 (0%)		0/42 (0%)		2/111 (1.8%)
Abdominal wall mass	0/6 (0%)		0/18 (0%)		1/7 (14.3%)		0/38 (0%)		0/42 (0%)		1/111 (0.9%)
Anal fistula	0/6 (0%)		1/18 (5.6%)		0/7 (0%)		0/38 (0%)		0/42 (0%)		1/111 (0.9%)
Anal incontinence	1/6 (16.7%)		0/18 (0%)		1/7 (14.3%)		0/38 (0%)		0/42 (0%)		2/111 (1.8%)
Anal skin tags	1/6 (16.7%)		1/18 (5.6%)		0/7 (0%)		0/38 (0%)		0/42 (0%)		2/111 (1.8%)
Angina bullosa haemorrhagica	0/6 (0%)		0/18 (0%)		1/7 (14.3%)		1/38 (2.6%)		1/42 (2.4%)		3/111 (2.7%)
Ascites	1/6 (16.7%)		0/18 (0%)		0/7 (0%)		0/38 (0%)		0/42 (0%)		1/111 (0.9%)
Constipation	2/6 (33.3%)		11/18 (61.1%)		3/7 (42.9%)		10/38 (26.3%)		16/42 (38.1%)		42/111 (37.8%)
Diarrhoea	4/6 (66.7%)		15/18 (83.3%)		4/7 (57.1%)		22/38 (57.9%)		9/42 (21.4%)		54/111 (48.6%)
Dry mouth	0/6 (0%)		1/18 (5.6%)		1/7 (14.3%)		3/38 (7.9%)		0/42 (0%)		5/111 (4.5%)
Dyschezia	1/6 (16.7%)		2/18 (11.1%)		0/7 (0%)		0/38 (0%)		0/42 (0%)		3/111 (2.7%)
Dyspepsia	1/6 (16.7%)		2/18 (11.1%)		1/7 (14.3%)		0/38 (0%)		1/42 (2.4%)		5/111 (4.5%)
Dysphagia	0/6 (0%)		1/18 (5.6%)		1/7 (14.3%)		0/38 (0%)		0/42 (0%)		2/111 (1.8%)
Epigastric discomfort	0/6 (0%)		1/18 (5.6%)		1/7 (14.3%)		0/38 (0%)		0/42 (0%)		2/111 (1.8%)
Flatulence	1/6 (16.7%)		3/18 (16.7%)		0/7 (0%)		0/38 (0%)		2/42 (4.8%)		6/111 (5.4%)
Gastritis	0/6 (0%)		2/18 (11.1%)		0/7 (0%)		0/38 (0%)		0/42 (0%)		2/111 (1.8%)
Gastroenteritis eosinophilic	0/6 (0%)		1/18 (5.6%)		0/7 (0%)		0/38 (0%)		0/42 (0%)		1/111 (0.9%)
Gastrointestinal oedema	0/6 (0%)		1/18 (5.6%)		0/7 (0%)		0/38 (0%)		0/42 (0%)		1/111 (0.9%)
Gastrointestinal pain	0/6 (0%)		1/18 (5.6%)		0/7 (0%)		0/38 (0%)		0/42 (0%)		1/111 (0.9%)
Gastrooesophageal reflux disease	0/6 (0%)		0/18 (0%)		1/7 (14.3%)		2/38 (5.3%)		1/42 (2.4%)		4/111 (3.6%)
Gingival bleeding	1/6 (16.7%)		3/18 (16.7%)		0/7 (0%)		1/38 (2.6%)		1/42 (2.4%)		6/111 (5.4%)
Gingival pain	0/6 (0%)		1/18 (5.6%)		0/7 (0%)		0/38 (0%)		1/42 (2.4%)		2/111 (1.8%)
Haematochezia	0/6 (0%)		0/18 (0%)		1/7 (14.3%)		0/38 (0%)		0/42 (0%)		1/111 (0.9%)
Haemorrhoidal haemorrhage	1/6 (16.7%)		0/18 (0%)		0/7 (0%)		1/38 (2.6%)		0/42 (0%)		2/111 (1.8%)
Haemorrhoids	2/6 (33.3%)		2/18 (11.1%)		1/7 (14.3%)		5/38 (13.2%)		1/42 (2.4%)		11/111 (9.9%)
Intra-abdominal haematoma	1/6 (16.7%)		0/18 (0%)		0/7 (0%)		0/38 (0%)		0/42 (0%)		1/111 (0.9%)
Lip swelling	0/6 (0%)		1/18 (5.6%)		0/7 (0%)		0/38 (0%)		0/42 (0%)		1/111 (0.9%)
Loose tooth	0/6 (0%)		1/18 (5.6%)		0/7 (0%)		0/38 (0%)		1/42 (2.4%)		2/111 (1.8%)
Melaena	0/6 (0%)		1/18 (5.6%)		0/7 (0%)		0/38 (0%)		0/42 (0%)		1/111 (0.9%)
Mouth haemorrhage	0/6 (0%)		3/18 (16.7%)		0/7 (0%)		1/38 (2.6%)		2/42 (4.8%)		6/111 (5.4%)
Mouth ulceration	0/6 (0%)		1/18 (5.6%)		0/7 (0%)		1/38 (2.6%)		1/42 (2.4%)		3/111 (2.7%)
Nausea	4/6 (66.7%)		14/18 (77.8%)		7/7 (100%)		23/38 (60.5%)		18/42 (42.9%)		66/111 (59.5%)
Noninfective gingivitis	0/6 (0%)		1/18 (5.6%)		0/7 (0%)		0/38 (0%)		0/42 (0%)		1/111 (0.9%)
Pancreatitis	0/6 (0%)		1/18 (5.6%)		0/7 (0%)		0/38 (0%)		0/42 (0%)		1/111 (0.9%)
Parotid gland enlargement	0/6 (0%)		1/18 (5.6%)		0/7 (0%)		0/38 (0%)		1/42 (2.4%)		2/111 (1.8%)
Proctalgia	1/6 (16.7%)		2/18 (11.1%)		0/7 (0%)		0/38 (0%)		0/42 (0%)		3/111 (2.7%)
Rectal haemorrhage	1/6 (16.7%)		0/18 (0%)		1/7 (14.3%)		1/38 (2.6%)		0/42 (0%)		3/111 (2.7%)
Retroperitoneal haematoma	0/6 (0%)		1/18 (5.6%)		0/7 (0%)		0/38 (0%)		0/42 (0%)		1/111 (0.9%)
Stomatitis	0/6 (0%)		0/18 (0%)		0/7 (0%)		2/38 (5.3%)		4/42 (9.5%)		6/111 (5.4%)
Swollen tongue	1/6 (16.7%)		0/18 (0%)		0/7 (0%)		0/38 (0%)		0/42 (0%)		1/111 (0.9%)
Tongue coated	1/6 (16.7%)		0/18 (0%)		0/7 (0%)		0/38 (0%)		0/42 (0%)		1/111 (0.9%)
Tooth impacted	0/6 (0%)		0/18 (0%)		1/7 (14.3%)		0/38 (0%)		0/42 (0%)		1/111 (0.9%)
Toothache	0/6 (0%)		3/18 (16.7%)		1/7 (14.3%)		1/38 (2.6%)		3/42 (7.1%)		8/111 (7.2%)
Vomiting	5/6 (83.3%)		9/18 (50%)		4/7 (57.1%)		16/38 (42.1%)		12/42 (28.6%)		46/111 (41.4%)
General disorders
Asthenia	2/6 (33.3%)		6/18 (33.3%)		1/7 (14.3%)		10/38 (26.3%)		6/42 (14.3%)		25/111 (22.5%)
Catheter site discharge	0/6 (0%)		1/18 (5.6%)		0/7 (0%)		0/38 (0%)		0/42 (0%)		1/111 (0.9%)
Catheter site erythema	0/6 (0%)		0/18 (0%)		1/7 (14.3%)		0/38 (0%)		0/42 (0%)		1/111 (0.9%)
Catheter site haematoma	0/6 (0%)		1/18 (5.6%)		0/7 (0%)		0/38 (0%)		0/42 (0%)		1/111 (0.9%)
Catheter site pain	0/6 (0%)		1/18 (5.6%)		0/7 (0%)		0/38 (0%)		0/42 (0%)		1/111 (0.9%)
Catheter site phlebitis	0/6 (0%)		1/18 (5.6%)		0/7 (0%)		0/38 (0%)		0/42 (0%)		1/111 (0.9%)
Chest pain	0/6 (0%)		2/18 (11.1%)		0/7 (0%)		0/38 (0%)		0/42 (0%)		2/111 (1.8%)
Chills	0/6 (0%)		4/18 (22.2%)		2/7 (28.6%)		3/38 (7.9%)		3/42 (7.1%)		12/111 (10.8%)
Extravasation	0/6 (0%)		0/18 (0%)		1/7 (14.3%)		0/38 (0%)		0/42 (0%)		1/111 (0.9%)
Facial pain	0/6 (0%)		1/18 (5.6%)		1/7 (14.3%)		0/38 (0%)		0/42 (0%)		2/111 (1.8%)
Fatigue	4/6 (66.7%)		12/18 (66.7%)		6/7 (85.7%)		10/38 (26.3%)		16/42 (38.1%)		48/111 (43.2%)
Feeling cold	1/6 (16.7%)		0/18 (0%)		0/7 (0%)		0/38 (0%)		0/42 (0%)		1/111 (0.9%)
Feeling hot	0/6 (0%)		0/18 (0%)		1/7 (14.3%)		0/38 (0%)		0/42 (0%)		1/111 (0.9%)
Gait disturbance	0/6 (0%)		1/18 (5.6%)		2/7 (28.6%)		0/38 (0%)		0/42 (0%)		3/111 (2.7%)
General physical health deterioration	0/6 (0%)		2/18 (11.1%)		0/7 (0%)		1/38 (2.6%)		0/42 (0%)		3/111 (2.7%)
Generalised oedema	1/6 (16.7%)		1/18 (5.6%)		0/7 (0%)		1/38 (2.6%)		0/42 (0%)		3/111 (2.7%)
Injection site bruising	0/6 (0%)		1/18 (5.6%)		0/7 (0%)		1/38 (2.6%)		0/42 (0%)		2/111 (1.8%)
Injection site erythema	0/6 (0%)		5/18 (27.8%)		0/7 (0%)		3/38 (7.9%)		3/42 (7.1%)		11/111 (9.9%)
Injection site haematoma	0/6 (0%)		1/18 (5.6%)		0/7 (0%)		0/38 (0%)		0/42 (0%)		1/111 (0.9%)
Injection site haemorrhage	0/6 (0%)		2/18 (11.1%)		0/7 (0%)		1/38 (2.6%)		0/42 (0%)		3/111 (2.7%)
Injection site irritation	0/6 (0%)		1/18 (5.6%)		0/7 (0%)		0/38 (0%)		0/42 (0%)		1/111 (0.9%)
Injection site pain	1/6 (16.7%)		5/18 (27.8%)		0/7 (0%)		2/38 (5.3%)		3/42 (7.1%)		11/111 (9.9%)
Injection site pruritus	0/6 (0%)		0/18 (0%)		1/7 (14.3%)		0/38 (0%)		0/42 (0%)		1/111 (0.9%)
Injection site rash	1/6 (16.7%)		1/18 (5.6%)		0/7 (0%)		2/38 (5.3%)		1/42 (2.4%)		5/111 (4.5%)
Injection site reaction	0/6 (0%)		2/18 (11.1%)		1/7 (14.3%)		3/38 (7.9%)		2/42 (4.8%)		8/111 (7.2%)
Localised oedema	0/6 (0%)		1/18 (5.6%)		0/7 (0%)		0/38 (0%)		0/42 (0%)		1/111 (0.9%)
Malaise	1/6 (16.7%)		0/18 (0%)		0/7 (0%)		1/38 (2.6%)		4/42 (9.5%)		6/111 (5.4%)
Mass	0/6 (0%)		0/18 (0%)		1/7 (14.3%)		0/38 (0%)		0/42 (0%)		1/111 (0.9%)
Mucosal inflammation	1/6 (16.7%)		0/18 (0%)		0/7 (0%)		0/38 (0%)		0/42 (0%)		1/111 (0.9%)
Non-cardiac chest pain	2/6 (33.3%)		2/18 (11.1%)		1/7 (14.3%)		4/38 (10.5%)		2/42 (4.8%)		11/111 (9.9%)
Oedema peripheral	2/6 (33.3%)		4/18 (22.2%)		4/7 (57.1%)		8/38 (21.1%)		9/42 (21.4%)		27/111 (24.3%)
Pain	1/6 (16.7%)		0/18 (0%)		2/7 (28.6%)		2/38 (5.3%)		1/42 (2.4%)		6/111 (5.4%)
Peripheral swelling	0/6 (0%)		2/18 (11.1%)		1/7 (14.3%)		1/38 (2.6%)		1/42 (2.4%)		5/111 (4.5%)
Puncture site erythema	1/6 (16.7%)		0/18 (0%)		0/7 (0%)		0/38 (0%)		2/42 (4.8%)		3/111 (2.7%)
Pyrexia	2/6 (33.3%)		8/18 (44.4%)		4/7 (57.1%)		18/38 (47.4%)		9/42 (21.4%)		41/111 (36.9%)
Swelling	0/6 (0%)		1/18 (5.6%)		0/7 (0%)		0/38 (0%)		0/42 (0%)		1/111 (0.9%)
Thirst	0/6 (0%)		0/18 (0%)		1/7 (14.3%)		1/38 (2.6%)		0/42 (0%)		2/111 (1.8%)
Hepatobiliary disorders
Hepatomegaly	0/6 (0%)		1/18 (5.6%)		0/7 (0%)		0/38 (0%)		0/42 (0%)		1/111 (0.9%)
Hyperbilirubinaemia	0/6 (0%)		1/18 (5.6%)		0/7 (0%)		0/38 (0%)		0/42 (0%)		1/111 (0.9%)
Immune system disorders
Allergic oedema	0/6 (0%)		1/18 (5.6%)		0/7 (0%)		0/38 (0%)		0/42 (0%)		1/111 (0.9%)
Allergy to chemicals	0/6 (0%)		1/18 (5.6%)		0/7 (0%)		0/38 (0%)		0/42 (0%)		1/111 (0.9%)
Drug hypersensitivity	0/6 (0%)		2/18 (11.1%)		0/7 (0%)		2/38 (5.3%)		0/42 (0%)		4/111 (3.6%)
Hypersensitivity	0/6 (0%)		1/18 (5.6%)		0/7 (0%)		0/38 (0%)		0/42 (0%)		1/111 (0.9%)
Infections and infestations
Anal abscess	1/6 (16.7%)		0/18 (0%)		0/7 (0%)		0/38 (0%)		0/42 (0%)		1/111 (0.9%)
Anal fungal infection	0/6 (0%)		0/18 (0%)		1/7 (14.3%)		0/38 (0%)		0/42 (0%)		1/111 (0.9%)
Anal infection	0/6 (0%)		1/18 (5.6%)		0/7 (0%)		0/38 (0%)		0/42 (0%)		1/111 (0.9%)
Bacterial infection	1/6 (16.7%)		0/18 (0%)		1/7 (14.3%)		0/38 (0%)		0/42 (0%)		2/111 (1.8%)
Bronchitis	0/6 (0%)		1/18 (5.6%)		0/7 (0%)		2/38 (5.3%)		2/42 (4.8%)		5/111 (4.5%)
Candida infection	1/6 (16.7%)		1/18 (5.6%)		3/7 (42.9%)		0/38 (0%)		1/42 (2.4%)		6/111 (5.4%)
Carbuncle	0/6 (0%)		1/18 (5.6%)		0/7 (0%)		0/38 (0%)		0/42 (0%)		1/111 (0.9%)
Cellulitis	0/6 (0%)		2/18 (11.1%)		0/7 (0%)		1/38 (2.6%)		4/42 (9.5%)		7/111 (6.3%)
Chronic sinusitis	0/6 (0%)		0/18 (0%)		1/7 (14.3%)		0/38 (0%)		0/42 (0%)		1/111 (0.9%)
Clostridium difficile colitis	1/6 (16.7%)		0/18 (0%)		0/7 (0%)		0/38 (0%)		0/42 (0%)		1/111 (0.9%)
Clostridium difficile infection	1/6 (16.7%)		0/18 (0%)		0/7 (0%)		0/38 (0%)		0/42 (0%)		1/111 (0.9%)
Conjunctivitis	0/6 (0%)		1/18 (5.6%)		0/7 (0%)		3/38 (7.9%)		0/42 (0%)		4/111 (3.6%)
Device related infection	0/6 (0%)		1/18 (5.6%)		0/7 (0%)		0/38 (0%)		1/42 (2.4%)		2/111 (1.8%)
Diverticulitis	0/6 (0%)		2/18 (11.1%)		0/7 (0%)		0/38 (0%)		0/42 (0%)		2/111 (1.8%)
Enterobacter infection	0/6 (0%)		1/18 (5.6%)		0/7 (0%)		0/38 (0%)		0/42 (0%)		1/111 (0.9%)
Enterococcal infection	0/6 (0%)		0/18 (0%)		1/7 (14.3%)		0/38 (0%)		0/42 (0%)		1/111 (0.9%)
Folliculitis	0/6 (0%)		1/18 (5.6%)		0/7 (0%)		0/38 (0%)		0/42 (0%)		1/111 (0.9%)
Fungal infection	0/6 (0%)		1/18 (5.6%)		0/7 (0%)		0/38 (0%)		0/42 (0%)		1/111 (0.9%)
Fungal skin infection	0/6 (0%)		0/18 (0%)		1/7 (14.3%)		0/38 (0%)		0/42 (0%)		1/111 (0.9%)
Haemorrhoid infection	1/6 (16.7%)		0/18 (0%)		0/7 (0%)		0/38 (0%)		0/42 (0%)		1/111 (0.9%)
Herpes simplex	0/6 (0%)		0/18 (0%)		0/7 (0%)		2/38 (5.3%)		2/42 (4.8%)		4/111 (3.6%)
Herpes zoster	0/6 (0%)		1/18 (5.6%)		0/7 (0%)		0/38 (0%)		0/42 (0%)		1/111 (0.9%)
Human polyomavirus infection	0/6 (0%)		0/18 (0%)		1/7 (14.3%)		0/38 (0%)		0/42 (0%)		1/111 (0.9%)
Infection	0/6 (0%)		1/18 (5.6%)		0/7 (0%)		0/38 (0%)		0/42 (0%)		1/111 (0.9%)
Infectious colitis	0/6 (0%)		1/18 (5.6%)		0/7 (0%)		0/38 (0%)		0/42 (0%)		1/111 (0.9%)
Influenza	0/6 (0%)		1/18 (5.6%)		0/7 (0%)		0/38 (0%)		0/42 (0%)		1/111 (0.9%)
Localised infection	0/6 (0%)		1/18 (5.6%)		0/7 (0%)		0/38 (0%)		0/42 (0%)		1/111 (0.9%)
Mucormycosis	0/6 (0%)		0/18 (0%)		1/7 (14.3%)		0/38 (0%)		0/42 (0%)		1/111 (0.9%)
Nasopharyngitis	0/6 (0%)		1/18 (5.6%)		0/7 (0%)		1/38 (2.6%)		1/42 (2.4%)		3/111 (2.7%)
Oral candidiasis	0/6 (0%)		1/18 (5.6%)		0/7 (0%)		1/38 (2.6%)		2/42 (4.8%)		4/111 (3.6%)
Oral herpes	1/6 (16.7%)		3/18 (16.7%)		0/7 (0%)		1/38 (2.6%)		2/42 (4.8%)		7/111 (6.3%)
Pneumonia	0/6 (0%)		2/18 (11.1%)		0/7 (0%)		1/38 (2.6%)		3/42 (7.1%)		6/111 (5.4%)
Pseudomonas infection	0/6 (0%)		0/18 (0%)		1/7 (14.3%)		0/38 (0%)		0/42 (0%)		1/111 (0.9%)
Puncture site infection	1/6 (16.7%)		0/18 (0%)		0/7 (0%)		0/38 (0%)		0/42 (0%)		1/111 (0.9%)
Respiratory tract infection	0/6 (0%)		1/18 (5.6%)		0/7 (0%)		0/38 (0%)		0/42 (0%)		1/111 (0.9%)
Rhinitis	0/6 (0%)		1/18 (5.6%)		1/7 (14.3%)		2/38 (5.3%)		0/42 (0%)		4/111 (3.6%)
Sinusitis	0/6 (0%)		0/18 (0%)		1/7 (14.3%)		0/38 (0%)		0/42 (0%)		1/111 (0.9%)
Skin infection	0/6 (0%)		3/18 (16.7%)		0/7 (0%)		2/38 (5.3%)		1/42 (2.4%)		6/111 (5.4%)
Staphylococcal infection	1/6 (16.7%)		1/18 (5.6%)		1/7 (14.3%)		1/38 (2.6%)		1/42 (2.4%)		5/111 (4.5%)
Tooth abscess	0/6 (0%)		0/18 (0%)		1/7 (14.3%)		1/38 (2.6%)		0/42 (0%)		2/111 (1.8%)
Tooth infection	0/6 (0%)		0/18 (0%)		1/7 (14.3%)		0/38 (0%)		0/42 (0%)		1/111 (0.9%)
Upper respiratory tract infection	0/6 (0%)		0/18 (0%)		1/7 (14.3%)		3/38 (7.9%)		3/42 (7.1%)		7/111 (6.3%)
Urinary tract infection	0/6 (0%)		2/18 (11.1%)		1/7 (14.3%)		3/38 (7.9%)		4/42 (9.5%)		10/111 (9%)
Wound infection	0/6 (0%)		1/18 (5.6%)		0/7 (0%)		0/38 (0%)		0/42 (0%)		1/111 (0.9%)
Injury, poisoning and procedural complications
Allergic transfusion reaction	0/6 (0%)		3/18 (16.7%)		1/7 (14.3%)		1/38 (2.6%)		0/42 (0%)		5/111 (4.5%)
Arthropod bite	0/6 (0%)		3/18 (16.7%)		0/7 (0%)		0/38 (0%)		0/42 (0%)		3/111 (2.7%)
Contusion	0/6 (0%)		2/18 (11.1%)		2/7 (28.6%)		3/38 (7.9%)		2/42 (4.8%)		9/111 (8.1%)
Fall	0/6 (0%)		0/18 (0%)		2/7 (28.6%)		0/38 (0%)		0/42 (0%)		2/111 (1.8%)
Post procedural haematoma	1/6 (16.7%)		0/18 (0%)		0/7 (0%)		0/38 (0%)		0/42 (0%)		1/111 (0.9%)
Post procedural swelling	0/6 (0%)		1/18 (5.6%)		0/7 (0%)		0/38 (0%)		0/42 (0%)		1/111 (0.9%)
Procedural hypertension	0/6 (0%)		1/18 (5.6%)		0/7 (0%)		0/38 (0%)		0/42 (0%)		1/111 (0.9%)
Procedural pain	0/6 (0%)		1/18 (5.6%)		1/7 (14.3%)		0/38 (0%)		2/42 (4.8%)		4/111 (3.6%)
Tongue injury	1/6 (16.7%)		0/18 (0%)		0/7 (0%)		0/38 (0%)		0/42 (0%)		1/111 (0.9%)
Tooth fracture	0/6 (0%)		1/18 (5.6%)		0/7 (0%)		0/38 (0%)		0/42 (0%)		1/111 (0.9%)
Transfusion reaction	0/6 (0%)		2/18 (11.1%)		3/7 (42.9%)		0/38 (0%)		1/42 (2.4%)		6/111 (5.4%)
Investigations
Activated partial thromboplastin time prolonged	0/6 (0%)		0/18 (0%)		1/7 (14.3%)		1/38 (2.6%)		0/42 (0%)		2/111 (1.8%)
Alanine aminotransferase increased	0/6 (0%)		2/18 (11.1%)		1/7 (14.3%)		3/38 (7.9%)		2/42 (4.8%)		8/111 (7.2%)
Aspartate aminotransferase increased	0/6 (0%)		2/18 (11.1%)		1/7 (14.3%)		4/38 (10.5%)		1/42 (2.4%)		8/111 (7.2%)
Blood albumin decreased	0/6 (0%)		0/18 (0%)		0/7 (0%)		2/38 (5.3%)		1/42 (2.4%)		3/111 (2.7%)
Blood bicarbonate decreased	0/6 (0%)		0/18 (0%)		1/7 (14.3%)		0/38 (0%)		0/42 (0%)		1/111 (0.9%)
Blood bilirubin increased	0/6 (0%)		2/18 (11.1%)		0/7 (0%)		0/38 (0%)		0/42 (0%)		2/111 (1.8%)
Blood creatinine decreased	0/6 (0%)		0/18 (0%)		1/7 (14.3%)		0/38 (0%)		0/42 (0%)		1/111 (0.9%)
Blood creatinine increased	1/6 (16.7%)		5/18 (27.8%)		4/7 (57.1%)		4/38 (10.5%)		0/42 (0%)		14/111 (12.6%)
Blood folate decreased	0/6 (0%)		0/18 (0%)		1/7 (14.3%)		0/38 (0%)		0/42 (0%)		1/111 (0.9%)
Blood magnesium decreased	0/6 (0%)		0/18 (0%)		1/7 (14.3%)		0/38 (0%)		0/42 (0%)		1/111 (0.9%)
Blood phosphorus decreased	0/6 (0%)		0/18 (0%)		1/7 (14.3%)		0/38 (0%)		0/42 (0%)		1/111 (0.9%)
Blood potassium increased	0/6 (0%)		1/18 (5.6%)		0/7 (0%)		0/38 (0%)		0/42 (0%)		1/111 (0.9%)
Blood thyroid stimulating hormone decreased	1/6 (16.7%)		0/18 (0%)		0/7 (0%)		0/38 (0%)		0/42 (0%)		1/111 (0.9%)
Blood urine present	1/6 (16.7%)		1/18 (5.6%)		0/7 (0%)		0/38 (0%)		0/42 (0%)		2/111 (1.8%)
Breath sounds abnormal	0/6 (0%)		1/18 (5.6%)		0/7 (0%)		1/38 (2.6%)		0/42 (0%)		2/111 (1.8%)
C-reactive protein increased	1/6 (16.7%)		2/18 (11.1%)		2/7 (28.6%)		2/38 (5.3%)		1/42 (2.4%)		8/111 (7.2%)
Coagulation test abnormal	1/6 (16.7%)		0/18 (0%)		0/7 (0%)		0/38 (0%)		0/42 (0%)		1/111 (0.9%)
Electrocardiogram QT prolonged	0/6 (0%)		1/18 (5.6%)		1/7 (14.3%)		3/38 (7.9%)		0/42 (0%)		5/111 (4.5%)
Electrocardiogram T wave abnormal	0/6 (0%)		1/18 (5.6%)		0/7 (0%)		0/38 (0%)		0/42 (0%)		1/111 (0.9%)
Fibrin D dimer increased	0/6 (0%)		1/18 (5.6%)		0/7 (0%)		0/38 (0%)		0/42 (0%)		1/111 (0.9%)
Glucose urine present	0/6 (0%)		0/18 (0%)		1/7 (14.3%)		0/38 (0%)		0/42 (0%)		1/111 (0.9%)
Haemoglobin decreased	0/6 (0%)		0/18 (0%)		0/7 (0%)		2/38 (5.3%)		1/42 (2.4%)		3/111 (2.7%)
Left ventricular end-diastolic pressure increased	0/6 (0%)		1/18 (5.6%)		0/7 (0%)		0/38 (0%)		0/42 (0%)		1/111 (0.9%)
Neutrophil count decreased	0/6 (0%)		1/18 (5.6%)		1/7 (14.3%)		6/38 (15.8%)		3/42 (7.1%)		11/111 (9.9%)
Nitrite urine present	0/6 (0%)		0/18 (0%)		1/7 (14.3%)		0/38 (0%)		0/42 (0%)		1/111 (0.9%)
Platelet count decreased	0/6 (0%)		1/18 (5.6%)		0/7 (0%)		8/38 (21.1%)		2/42 (4.8%)		11/111 (9.9%)
Protein urine present	0/6 (0%)		0/18 (0%)		1/7 (14.3%)		0/38 (0%)		0/42 (0%)		1/111 (0.9%)
Prothrombin time prolonged	0/6 (0%)		0/18 (0%)		1/7 (14.3%)		1/38 (2.6%)		0/42 (0%)		2/111 (1.8%)
Prothrombin time shortened	0/6 (0%)		0/18 (0%)		1/7 (14.3%)		0/38 (0%)		0/42 (0%)		1/111 (0.9%)
Troponin I increased	0/6 (0%)		1/18 (5.6%)		0/7 (0%)		0/38 (0%)		0/42 (0%)		1/111 (0.9%)
Troponin T increased	0/6 (0%)		1/18 (5.6%)		0/7 (0%)		0/38 (0%)		0/42 (0%)		1/111 (0.9%)
Urine output decreased	0/6 (0%)		0/18 (0%)		2/7 (28.6%)		0/38 (0%)		0/42 (0%)		2/111 (1.8%)
Urobilinogen urine increased	0/6 (0%)		0/18 (0%)		1/7 (14.3%)		0/38 (0%)		0/42 (0%)		1/111 (0.9%)
Vitamin D decreased	2/6 (33.3%)		0/18 (0%)		0/7 (0%)		0/38 (0%)		0/42 (0%)		2/111 (1.8%)
Weight decreased	1/6 (16.7%)		1/18 (5.6%)		1/7 (14.3%)		7/38 (18.4%)		6/42 (14.3%)		16/111 (14.4%)
White blood cell count decreased	0/6 (0%)		0/18 (0%)		0/7 (0%)		4/38 (10.5%)		0/42 (0%)		4/111 (3.6%)
White blood cells urine positive	0/6 (0%)		0/18 (0%)		1/7 (14.3%)		0/38 (0%)		0/42 (0%)		1/111 (0.9%)
Metabolism and nutrition disorders
Decreased appetite	3/6 (50%)		6/18 (33.3%)		5/7 (71.4%)		9/38 (23.7%)		6/42 (14.3%)		29/111 (26.1%)
Dehydration	0/6 (0%)		3/18 (16.7%)		3/7 (42.9%)		3/38 (7.9%)		1/42 (2.4%)		10/111 (9%)
Diabetes mellitus	0/6 (0%)		1/18 (5.6%)		0/7 (0%)		0/38 (0%)		0/42 (0%)		1/111 (0.9%)
Fluid overload	0/6 (0%)		0/18 (0%)		0/7 (0%)		0/38 (0%)		3/42 (7.1%)		3/111 (2.7%)
Fluid retention	0/6 (0%)		0/18 (0%)		1/7 (14.3%)		0/38 (0%)		0/42 (0%)		1/111 (0.9%)
Gout	0/6 (0%)		1/18 (5.6%)		1/7 (14.3%)		0/38 (0%)		0/42 (0%)		2/111 (1.8%)
Hypercreatininaemia	0/6 (0%)		1/18 (5.6%)		0/7 (0%)		0/38 (0%)		0/42 (0%)		1/111 (0.9%)
Hyperglycaemia	0/6 (0%)		2/18 (11.1%)		3/7 (42.9%)		2/38 (5.3%)		0/42 (0%)		7/111 (6.3%)
Hyperkalaemia	0/6 (0%)		2/18 (11.1%)		1/7 (14.3%)		1/38 (2.6%)		3/42 (7.1%)		7/111 (6.3%)
Hyperlipidaemia	0/6 (0%)		1/18 (5.6%)		0/7 (0%)		0/38 (0%)		1/42 (2.4%)		2/111 (1.8%)
Hypermagnesaemia	0/6 (0%)		1/18 (5.6%)		0/7 (0%)		0/38 (0%)		0/42 (0%)		1/111 (0.9%)
Hyperuricaemia	1/6 (16.7%)		5/18 (27.8%)		1/7 (14.3%)		2/38 (5.3%)		1/42 (2.4%)		10/111 (9%)
Hypoalbuminaemia	0/6 (0%)		1/18 (5.6%)		2/7 (28.6%)		0/38 (0%)		1/42 (2.4%)		4/111 (3.6%)
Hypocalcaemia	3/6 (50%)		7/18 (38.9%)		2/7 (28.6%)		2/38 (5.3%)		2/42 (4.8%)		16/111 (14.4%)
Hypokalaemia	1/6 (16.7%)		10/18 (55.6%)		3/7 (42.9%)		7/38 (18.4%)		6/42 (14.3%)		27/111 (24.3%)
Hypomagnesaemia	1/6 (16.7%)		3/18 (16.7%)		2/7 (28.6%)		2/38 (5.3%)		2/42 (4.8%)		10/111 (9%)
Hyponatraemia	0/6 (0%)		1/18 (5.6%)		3/7 (42.9%)		2/38 (5.3%)		1/42 (2.4%)		7/111 (6.3%)
Hypophosphataemia	1/6 (16.7%)		1/18 (5.6%)		2/7 (28.6%)		4/38 (10.5%)		1/42 (2.4%)		9/111 (8.1%)
Iron overload	0/6 (0%)		0/18 (0%)		1/7 (14.3%)		0/38 (0%)		0/42 (0%)		1/111 (0.9%)
Musculoskeletal and connective tissue disorders
Arthralgia	1/6 (16.7%)		5/18 (27.8%)		1/7 (14.3%)		3/38 (7.9%)		4/42 (9.5%)		14/111 (12.6%)
Arthritis	1/6 (16.7%)		0/18 (0%)		0/7 (0%)		0/38 (0%)		0/42 (0%)		1/111 (0.9%)
Back pain	1/6 (16.7%)		2/18 (11.1%)		2/7 (28.6%)		5/38 (13.2%)		4/42 (9.5%)		14/111 (12.6%)
Bone pain	1/6 (16.7%)		2/18 (11.1%)		2/7 (28.6%)		0/38 (0%)		0/42 (0%)		5/111 (4.5%)
Coccydynia	1/6 (16.7%)		0/18 (0%)		0/7 (0%)		0/38 (0%)		0/42 (0%)		1/111 (0.9%)
Joint effusion	1/6 (16.7%)		0/18 (0%)		0/7 (0%)		0/38 (0%)		0/42 (0%)		1/111 (0.9%)
Joint swelling	0/6 (0%)		1/18 (5.6%)		0/7 (0%)		1/38 (2.6%)		0/42 (0%)		2/111 (1.8%)
Limb discomfort	0/6 (0%)		1/18 (5.6%)		0/7 (0%)		0/38 (0%)		0/42 (0%)		1/111 (0.9%)
Muscle fatigue	1/6 (16.7%)		0/18 (0%)		0/7 (0%)		0/38 (0%)		0/42 (0%)		1/111 (0.9%)
Muscle spasms	0/6 (0%)		1/18 (5.6%)		0/7 (0%)		1/38 (2.6%)		1/42 (2.4%)		3/111 (2.7%)
Muscular weakness	0/6 (0%)		2/18 (11.1%)		1/7 (14.3%)		1/38 (2.6%)		2/42 (4.8%)		6/111 (5.4%)
Musculoskeletal chest pain	1/6 (16.7%)		1/18 (5.6%)		1/7 (14.3%)		0/38 (0%)		1/42 (2.4%)		4/111 (3.6%)
Musculoskeletal pain	1/6 (16.7%)		3/18 (16.7%)		1/7 (14.3%)		2/38 (5.3%)		3/42 (7.1%)		10/111 (9%)
Myalgia	0/6 (0%)		0/18 (0%)		0/7 (0%)		3/38 (7.9%)		2/42 (4.8%)		5/111 (4.5%)
Neck pain	0/6 (0%)		1/18 (5.6%)		1/7 (14.3%)		0/38 (0%)		1/42 (2.4%)		3/111 (2.7%)
Osteonecrosis	0/6 (0%)		1/18 (5.6%)		0/7 (0%)		0/38 (0%)		0/42 (0%)		1/111 (0.9%)
Pain in extremity	1/6 (16.7%)		4/18 (22.2%)		2/7 (28.6%)		4/38 (10.5%)		2/42 (4.8%)		13/111 (11.7%)
Rotator cuff syndrome	0/6 (0%)		1/18 (5.6%)		0/7 (0%)		0/38 (0%)		0/42 (0%)		1/111 (0.9%)
Spinal deformity	0/6 (0%)		0/18 (0%)		1/7 (14.3%)		0/38 (0%)		0/42 (0%)		1/111 (0.9%)
Spinal osteoarthritis	0/6 (0%)		0/18 (0%)		1/7 (14.3%)		0/38 (0%)		1/42 (2.4%)		2/111 (1.8%)
Spinal pain	0/6 (0%)		1/18 (5.6%)		0/7 (0%)		0/38 (0%)		1/42 (2.4%)		2/111 (1.8%)
Temporomandibular joint syndrome	0/6 (0%)		1/18 (5.6%)		0/7 (0%)		0/38 (0%)		0/42 (0%)		1/111 (0.9%)
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Benign lung neoplasm	0/6 (0%)		1/18 (5.6%)		0/7 (0%)		0/38 (0%)		0/42 (0%)		1/111 (0.9%)
Lipoma	0/6 (0%)		1/18 (5.6%)		0/7 (0%)		0/38 (0%)		0/42 (0%)		1/111 (0.9%)
Nervous system disorders
Balance disorder	0/6 (0%)		1/18 (5.6%)		0/7 (0%)		0/38 (0%)		0/42 (0%)		1/111 (0.9%)
Disturbance in attention	0/6 (0%)		1/18 (5.6%)		0/7 (0%)		0/38 (0%)		0/42 (0%)		1/111 (0.9%)
Dizziness	1/6 (16.7%)		4/18 (22.2%)		2/7 (28.6%)		5/38 (13.2%)		3/42 (7.1%)		15/111 (13.5%)
Dysgeusia	2/6 (33.3%)		4/18 (22.2%)		1/7 (14.3%)		3/38 (7.9%)		2/42 (4.8%)		12/111 (10.8%)
Dyskinesia	0/6 (0%)		0/18 (0%)		1/7 (14.3%)		1/38 (2.6%)		0/42 (0%)		2/111 (1.8%)
Facial paresis	0/6 (0%)		1/18 (5.6%)		0/7 (0%)		0/38 (0%)		0/42 (0%)		1/111 (0.9%)
Headache	2/6 (33.3%)		4/18 (22.2%)		4/7 (57.1%)		7/38 (18.4%)		7/42 (16.7%)		24/111 (21.6%)
Hypotonia	1/6 (16.7%)		0/18 (0%)		0/7 (0%)		0/38 (0%)		0/42 (0%)		1/111 (0.9%)
Neuralgia	0/6 (0%)		1/18 (5.6%)		0/7 (0%)		0/38 (0%)		0/42 (0%)		1/111 (0.9%)
Normal pressure hydrocephalus	0/6 (0%)		1/18 (5.6%)		0/7 (0%)		0/38 (0%)		0/42 (0%)		1/111 (0.9%)
Paraesthesia	0/6 (0%)		1/18 (5.6%)		0/7 (0%)		0/38 (0%)		0/42 (0%)		1/111 (0.9%)
Partial seizures	0/6 (0%)		0/18 (0%)		1/7 (14.3%)		0/38 (0%)		0/42 (0%)		1/111 (0.9%)
Polyneuropathy	0/6 (0%)		1/18 (5.6%)		0/7 (0%)		0/38 (0%)		0/42 (0%)		1/111 (0.9%)
Sciatica	1/6 (16.7%)		0/18 (0%)		0/7 (0%)		0/38 (0%)		1/42 (2.4%)		2/111 (1.8%)
Somnolence	1/6 (16.7%)		0/18 (0%)		2/7 (28.6%)		0/38 (0%)		0/42 (0%)		3/111 (2.7%)
Subarachnoid haemorrhage	0/6 (0%)		0/18 (0%)		1/7 (14.3%)		0/38 (0%)		0/42 (0%)		1/111 (0.9%)
Syncope	0/6 (0%)		2/18 (11.1%)		0/7 (0%)		2/38 (5.3%)		2/42 (4.8%)		6/111 (5.4%)
Tremor	0/6 (0%)		1/18 (5.6%)		0/7 (0%)		0/38 (0%)		1/42 (2.4%)		2/111 (1.8%)
Psychiatric disorders
Agitation	1/6 (16.7%)		0/18 (0%)		0/7 (0%)		1/38 (2.6%)		0/42 (0%)		2/111 (1.8%)
Anxiety	0/6 (0%)		1/18 (5.6%)		2/7 (28.6%)		1/38 (2.6%)		1/42 (2.4%)		5/111 (4.5%)
Confusional state	0/6 (0%)		1/18 (5.6%)		2/7 (28.6%)		1/38 (2.6%)		0/42 (0%)		4/111 (3.6%)
Delirium	0/6 (0%)		0/18 (0%)		0/7 (0%)		2/38 (5.3%)		0/42 (0%)		2/111 (1.8%)
Depression	0/6 (0%)		2/18 (11.1%)		0/7 (0%)		1/38 (2.6%)		0/42 (0%)		3/111 (2.7%)
Disorientation	1/6 (16.7%)		0/18 (0%)		1/7 (14.3%)		0/38 (0%)		0/42 (0%)		2/111 (1.8%)
Fear	1/6 (16.7%)		0/18 (0%)		0/7 (0%)		0/38 (0%)		0/42 (0%)		1/111 (0.9%)
Insomnia	1/6 (16.7%)		3/18 (16.7%)		3/7 (42.9%)		5/38 (13.2%)		3/42 (7.1%)		15/111 (13.5%)
Personality change	0/6 (0%)		0/18 (0%)		1/7 (14.3%)		0/38 (0%)		0/42 (0%)		1/111 (0.9%)
Sleep disorder	1/6 (16.7%)		0/18 (0%)		0/7 (0%)		0/38 (0%)		1/42 (2.4%)		2/111 (1.8%)
Renal and urinary disorders
Anuria	0/6 (0%)		0/18 (0%)		1/7 (14.3%)		0/38 (0%)		0/42 (0%)		1/111 (0.9%)
Bladder pain	1/6 (16.7%)		1/18 (5.6%)		0/7 (0%)		0/38 (0%)		0/42 (0%)		2/111 (1.8%)
Dysuria	0/6 (0%)		1/18 (5.6%)		0/7 (0%)		2/38 (5.3%)		0/42 (0%)		3/111 (2.7%)
Haematuria	0/6 (0%)		0/18 (0%)		2/7 (28.6%)		0/38 (0%)		0/42 (0%)		2/111 (1.8%)
Haemorrhage urinary tract	0/6 (0%)		0/18 (0%)		1/7 (14.3%)		0/38 (0%)		0/42 (0%)		1/111 (0.9%)
Renal failure	0/6 (0%)		0/18 (0%)		1/7 (14.3%)		1/38 (2.6%)		0/42 (0%)		2/111 (1.8%)
Renal pain	0/6 (0%)		0/18 (0%)		1/7 (14.3%)		0/38 (0%)		0/42 (0%)		1/111 (0.9%)
Urinary incontinence	1/6 (16.7%)		0/18 (0%)		1/7 (14.3%)		0/38 (0%)		0/42 (0%)		2/111 (1.8%)
Urinary retention	0/6 (0%)		1/18 (5.6%)		1/7 (14.3%)		0/38 (0%)		0/42 (0%)		2/111 (1.8%)
Reproductive system and breast disorders
Scrotal erythema	1/6 (16.7%)		0/18 (0%)		0/7 (0%)		0/38 (0%)		0/42 (0%)		1/111 (0.9%)
Scrotal oedema	1/6 (16.7%)		0/18 (0%)		0/7 (0%)		0/38 (0%)		0/42 (0%)		1/111 (0.9%)
Scrotal pain	1/6 (16.7%)		0/18 (0%)		0/7 (0%)		0/38 (0%)		0/42 (0%)		1/111 (0.9%)
Vaginal haemorrhage	0/6 (0%)		1/18 (5.6%)		1/7 (14.3%)		0/38 (0%)		0/42 (0%)		2/111 (1.8%)
Respiratory, thoracic and mediastinal disorders
Asthma	0/6 (0%)		1/18 (5.6%)		0/7 (0%)		0/38 (0%)		0/42 (0%)		1/111 (0.9%)
Bronchial disorder	0/6 (0%)		1/18 (5.6%)		0/7 (0%)		0/38 (0%)		0/42 (0%)		1/111 (0.9%)
Bronchial obstruction	0/6 (0%)		1/18 (5.6%)		0/7 (0%)		0/38 (0%)		1/42 (2.4%)		2/111 (1.8%)
Bronchospasm	0/6 (0%)		0/18 (0%)		1/7 (14.3%)		0/38 (0%)		0/42 (0%)		1/111 (0.9%)
Bronchostenosis	0/6 (0%)		1/18 (5.6%)		0/7 (0%)		0/38 (0%)		0/42 (0%)		1/111 (0.9%)
Cough	2/6 (33.3%)		6/18 (33.3%)		2/7 (28.6%)		7/38 (18.4%)		6/42 (14.3%)		23/111 (20.7%)
Dysphonia	0/6 (0%)		0/18 (0%)		1/7 (14.3%)		1/38 (2.6%)		0/42 (0%)		2/111 (1.8%)
Dyspnoea	3/6 (50%)		6/18 (33.3%)		3/7 (42.9%)		2/38 (5.3%)		4/42 (9.5%)		18/111 (16.2%)
Dyspnoea exertional	1/6 (16.7%)		1/18 (5.6%)		0/7 (0%)		1/38 (2.6%)		1/42 (2.4%)		4/111 (3.6%)
Epistaxis	2/6 (33.3%)		4/18 (22.2%)		2/7 (28.6%)		5/38 (13.2%)		6/42 (14.3%)		19/111 (17.1%)
Haemoptysis	0/6 (0%)		1/18 (5.6%)		0/7 (0%)		0/38 (0%)		1/42 (2.4%)		2/111 (1.8%)
Hiccups	0/6 (0%)		1/18 (5.6%)		0/7 (0%)		1/38 (2.6%)		0/42 (0%)		2/111 (1.8%)
Hyperventilation	2/6 (33.3%)		0/18 (0%)		0/7 (0%)		0/38 (0%)		0/42 (0%)		2/111 (1.8%)
Hypoxia	0/6 (0%)		0/18 (0%)		1/7 (14.3%)		1/38 (2.6%)		2/42 (4.8%)		4/111 (3.6%)
Laryngeal inflammation	0/6 (0%)		1/18 (5.6%)		0/7 (0%)		0/38 (0%)		0/42 (0%)		1/111 (0.9%)
Lung infiltration	0/6 (0%)		1/18 (5.6%)		0/7 (0%)		0/38 (0%)		0/42 (0%)		1/111 (0.9%)
Nasal congestion	0/6 (0%)		2/18 (11.1%)		1/7 (14.3%)		0/38 (0%)		0/42 (0%)		3/111 (2.7%)
Oropharyngeal blistering	1/6 (16.7%)		0/18 (0%)		0/7 (0%)		0/38 (0%)		0/42 (0%)		1/111 (0.9%)
Oropharyngeal pain	3/6 (50%)		3/18 (16.7%)		3/7 (42.9%)		0/38 (0%)		5/42 (11.9%)		14/111 (12.6%)
Pharyngeal erythema	1/6 (16.7%)		0/18 (0%)		0/7 (0%)		0/38 (0%)		0/42 (0%)		1/111 (0.9%)
Pleural effusion	1/6 (16.7%)		2/18 (11.1%)		2/7 (28.6%)		1/38 (2.6%)		1/42 (2.4%)		7/111 (6.3%)
Productive cough	0/6 (0%)		1/18 (5.6%)		1/7 (14.3%)		0/38 (0%)		3/42 (7.1%)		5/111 (4.5%)
Pulmonary haemorrhage	0/6 (0%)		1/18 (5.6%)		0/7 (0%)		0/38 (0%)		0/42 (0%)		1/111 (0.9%)
Respiratory failure	1/6 (16.7%)		1/18 (5.6%)		0/7 (0%)		0/38 (0%)		0/42 (0%)		2/111 (1.8%)
Rhinitis allergic	1/6 (16.7%)		1/18 (5.6%)		1/7 (14.3%)		0/38 (0%)		0/42 (0%)		3/111 (2.7%)
Rhinorrhoea	0/6 (0%)		0/18 (0%)		0/7 (0%)		2/38 (5.3%)		1/42 (2.4%)		3/111 (2.7%)
Rhonchi	0/6 (0%)		1/18 (5.6%)		0/7 (0%)		1/38 (2.6%)		0/42 (0%)		2/111 (1.8%)
Sinus congestion	0/6 (0%)		1/18 (5.6%)		1/7 (14.3%)		0/38 (0%)		1/42 (2.4%)		3/111 (2.7%)
Tachypnoea	1/6 (16.7%)		0/18 (0%)		0/7 (0%)		0/38 (0%)		0/42 (0%)		1/111 (0.9%)
Upper-airway cough syndrome	0/6 (0%)		1/18 (5.6%)		0/7 (0%)		0/38 (0%)		0/42 (0%)		1/111 (0.9%)
Wheezing	0/6 (0%)		1/18 (5.6%)		0/7 (0%)		0/38 (0%)		0/42 (0%)		1/111 (0.9%)
Skin and subcutaneous tissue disorders
Alopecia	1/6 (16.7%)		2/18 (11.1%)		2/7 (28.6%)		0/38 (0%)		0/42 (0%)		5/111 (4.5%)
Angioedema	0/6 (0%)		1/18 (5.6%)		0/7 (0%)		0/38 (0%)		0/42 (0%)		1/111 (0.9%)
Decubitus ulcer	1/6 (16.7%)		1/18 (5.6%)		1/7 (14.3%)		0/38 (0%)		0/42 (0%)		3/111 (2.7%)
Dermatitis acneiform	0/6 (0%)		0/18 (0%)		1/7 (14.3%)		1/38 (2.6%)		0/42 (0%)		2/111 (1.8%)
Dermatitis allergic	2/6 (33.3%)		1/18 (5.6%)		1/7 (14.3%)		0/38 (0%)		2/42 (4.8%)		6/111 (5.4%)
Dry skin	0/6 (0%)		0/18 (0%)		0/7 (0%)		2/38 (5.3%)		0/42 (0%)		2/111 (1.8%)
Ecchymosis	0/6 (0%)		0/18 (0%)		2/7 (28.6%)		2/38 (5.3%)		1/42 (2.4%)		5/111 (4.5%)
Eczema	1/6 (16.7%)		0/18 (0%)		0/7 (0%)		1/38 (2.6%)		0/42 (0%)		2/111 (1.8%)
Erythema	1/6 (16.7%)		3/18 (16.7%)		1/7 (14.3%)		1/38 (2.6%)		4/42 (9.5%)		10/111 (9%)
Exfoliative rash	0/6 (0%)		0/18 (0%)		1/7 (14.3%)		1/38 (2.6%)		0/42 (0%)		2/111 (1.8%)
Hyperhidrosis	1/6 (16.7%)		2/18 (11.1%)		0/7 (0%)		0/38 (0%)		0/42 (0%)		3/111 (2.7%)
Koebner phenomenon	1/6 (16.7%)		0/18 (0%)		0/7 (0%)		0/38 (0%)		0/42 (0%)		1/111 (0.9%)
Nail disorder	0/6 (0%)		0/18 (0%)		1/7 (14.3%)		0/38 (0%)		0/42 (0%)		1/111 (0.9%)
Night sweats	1/6 (16.7%)		2/18 (11.1%)		1/7 (14.3%)		0/38 (0%)		0/42 (0%)		4/111 (3.6%)
Pain of skin	0/6 (0%)		0/18 (0%)		0/7 (0%)		2/38 (5.3%)		0/42 (0%)		2/111 (1.8%)
Papule	1/6 (16.7%)		0/18 (0%)		0/7 (0%)		0/38 (0%)		0/42 (0%)		1/111 (0.9%)
Petechiae	0/6 (0%)		7/18 (38.9%)		2/7 (28.6%)		3/38 (7.9%)		1/42 (2.4%)		13/111 (11.7%)
Pruritus	0/6 (0%)		2/18 (11.1%)		0/7 (0%)		4/38 (10.5%)		3/42 (7.1%)		9/111 (8.1%)
Psoriasis	1/6 (16.7%)		0/18 (0%)		0/7 (0%)		0/38 (0%)		0/42 (0%)		1/111 (0.9%)
Purpura	0/6 (0%)		2/18 (11.1%)		0/7 (0%)		0/38 (0%)		1/42 (2.4%)		3/111 (2.7%)
Rash	0/6 (0%)		4/18 (22.2%)		2/7 (28.6%)		6/38 (15.8%)		4/42 (9.5%)		16/111 (14.4%)
Rash erythematous	0/6 (0%)		1/18 (5.6%)		0/7 (0%)		0/38 (0%)		1/42 (2.4%)		2/111 (1.8%)
Rash maculo-papular	0/6 (0%)		0/18 (0%)		2/7 (28.6%)		2/38 (5.3%)		1/42 (2.4%)		5/111 (4.5%)
Skin exfoliation	0/6 (0%)		1/18 (5.6%)		0/7 (0%)		1/38 (2.6%)		1/42 (2.4%)		3/111 (2.7%)
Skin haemorrhage	0/6 (0%)		1/18 (5.6%)		0/7 (0%)		0/38 (0%)		1/42 (2.4%)		2/111 (1.8%)
Skin hyperpigmentation	0/6 (0%)		2/18 (11.1%)		0/7 (0%)		1/38 (2.6%)		0/42 (0%)		3/111 (2.7%)
Skin lesion	0/6 (0%)		1/18 (5.6%)		0/7 (0%)		0/38 (0%)		0/42 (0%)		1/111 (0.9%)
Skin plaque	1/6 (16.7%)		0/18 (0%)		0/7 (0%)		0/38 (0%)		0/42 (0%)		1/111 (0.9%)
Skin ulcer	0/6 (0%)		1/18 (5.6%)		1/7 (14.3%)		0/38 (0%)		0/42 (0%)		2/111 (1.8%)
Swelling face	0/6 (0%)		1/18 (5.6%)		0/7 (0%)		0/38 (0%)		0/42 (0%)		1/111 (0.9%)
Urticaria	0/6 (0%)		1/18 (5.6%)		0/7 (0%)		4/38 (10.5%)		0/42 (0%)		5/111 (4.5%)
Vascular disorders
Arteriosclerosis	0/6 (0%)		0/18 (0%)		1/7 (14.3%)		0/38 (0%)		0/42 (0%)		1/111 (0.9%)
Flushing	0/6 (0%)		1/18 (5.6%)		0/7 (0%)		1/38 (2.6%)		0/42 (0%)		2/111 (1.8%)
Haematoma	0/6 (0%)		3/18 (16.7%)		1/7 (14.3%)		2/38 (5.3%)		5/42 (11.9%)		11/111 (9.9%)
Hypertension	0/6 (0%)		4/18 (22.2%)		0/7 (0%)		0/38 (0%)		1/42 (2.4%)		5/111 (4.5%)
Hypotension	2/6 (33.3%)		2/18 (11.1%)		3/7 (42.9%)		2/38 (5.3%)		2/42 (4.8%)		11/111 (9.9%)
Lymphoedema	1/6 (16.7%)		0/18 (0%)		0/7 (0%)		0/38 (0%)		0/42 (0%)		1/111 (0.9%)
Pallor	0/6 (0%)		0/18 (0%)		1/7 (14.3%)		0/38 (0%)		0/42 (0%)		1/111 (0.9%)
Peripheral artery aneurysm	0/6 (0%)		1/18 (5.6%)		0/7 (0%)		0/38 (0%)		0/42 (0%)		1/111 (0.9%)
Peripheral artery occlusion	0/6 (0%)		1/18 (5.6%)		0/7 (0%)		0/38 (0%)		0/42 (0%)		1/111 (0.9%)
Peripheral artery thrombosis	0/6 (0%)		1/18 (5.6%)		0/7 (0%)		0/38 (0%)		0/42 (0%)		1/111 (0.9%)
Phlebitis	0/6 (0%)		1/18 (5.6%)		1/7 (14.3%)		0/38 (0%)		1/42 (2.4%)		3/111 (2.7%)
Phlebitis superficial	0/6 (0%)		1/18 (5.6%)		0/7 (0%)		0/38 (0%)		0/42 (0%)		1/111 (0.9%)
Poor venous access	1/6 (16.7%)		0/18 (0%)		0/7 (0%)		0/38 (0%)		0/42 (0%)		1/111 (0.9%)
Shock	0/6 (0%)		0/18 (0%)		1/7 (14.3%)		0/38 (0%)		0/42 (0%)		1/111 (0.9%)

Limitations/Caveats

[Not Specified]

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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. However, Novartis does not prohibit any investigator from publishing. Any publications from a single-site are postponed until the publication of pooled data (i.e.,data from all sites) in clinical trial or disclosure of trial results in their entirety.