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Clinical Trial Results:
A Phase 3, Multicenter, Randomized, Open-Label, Study of Azacitidine (Vidaza®) Versus Conventional Care Regimens for the Treatment of Older Subjects with Newly Diagnosed Acute Myeloid Leukemia

Summary
EudraCT number	2009-012346-23
Trial protocol	CZ DE BE FR GB ES NL AT IT
Global end of trial date	25 Jul 2016

Results information
Results version number	v1(current)
This version publication date	10 Aug 2017
First version publication date	10 Aug 2017
Other versions

Trial Information
Subject Disposition
Baseline Characteristics
End Points
Adverse Events
More Information

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Trial information

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Sponsor protocol code

AZA-AML-001

ISRCTN number

US NCT number

NCT01074047

WHO universal trial number (UTN)

Sponsor organisation name

Celgene Corporation

Sponsor organisation address

86 Morris Avenue, Summit, United States, 07901

Public contact

Clinical Trial Disclosure, Celgene Corporation, 01 888-260-1599, ClinicalTrialDisclosure@Celgene.com

Scientific contact

C.L. Beach Executive Medical Director, Celgene Corporation, 01 913-266-0302, CLBeach@celgene.com

Is trial part of an agreed paediatric investigation plan (PIP)

Does article 45 of REGULATION (EC) No 1901/2006 apply to this trial?

Does article 46 of REGULATION (EC) No 1901/2006 apply to this trial?

Analysis stage

Final

Date of interim/final analysis

28 Feb 2017

Is this the analysis of the primary completion data?

Global end of trial reached?

Yes

Global end of trial date

25 Jul 2016

Was the trial ended prematurely?

Main objective of the trial

The primary objective of the study is to demonstrate superiority in overall survival (OS) of azacitidine compared with the combined conventional care regimens in subjects ≥ 65 years old who have newly diagnosed acute myeloid leukemia (AML) with > 30% bone marrow blasts.

Protection of trial subjects

Patient Confidentiality, Personal Data Protection and Biomarker Consent

Background therapy

Evidence for comparator

Actual start date of recruitment

04 Oct 2010

Long term follow-up planned

Yes

Long term follow-up rationale

Safety, Regulatory reason

Long term follow-up duration

24 Months

Independent data monitoring committee (IDMC) involvement?

Yes

Number of subjects enrolled per country

Country: Number of subjects enrolled

Canada: 62

Country: Number of subjects enrolled

Poland: 62

Country: Number of subjects enrolled

Italy: 56

Country: Number of subjects enrolled

France: 45

Country: Number of subjects enrolled

Korea, Democratic People's Republic of: 47

Country: Number of subjects enrolled

Spain: 35

Country: Number of subjects enrolled

Germany: 32

Country: Number of subjects enrolled

United Kingdom: 26

Country: Number of subjects enrolled

Australia: 23

Country: Number of subjects enrolled

Belgium: 23

Country: Number of subjects enrolled

Russian Federation: 16

Country: Number of subjects enrolled

Taiwan: 15

Country: Number of subjects enrolled

Czech Republic: 12

Country: Number of subjects enrolled

Israel: 13

Country: Number of subjects enrolled

United States: 7

Country: Number of subjects enrolled

China: 6

Country: Number of subjects enrolled

Austria: 6

Country: Number of subjects enrolled

Netherlands: 2

Worldwide total number of subjects

488

EEA total number of subjects

299

Number of subjects enrolled per age group

In utero

Preterm newborn - gestational age < 37 wk

Newborns (0-27 days)

Infants and toddlers (28 days-23 months)

Children (2-11 years)

Adolescents (12-17 years)

Adults (18-64 years)

From 65 to 84 years

460

85 years and over

Subject disposition

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Recruitment details

This was a multicenter, international Phase 3 study conducted at 107 investigational sites in 18 countries including South Korea, China, Taiwan, Australia, Canada, United States, Poland, Russia, Czech Republic, Israel, France, Italy, Spain, Germany, United Kingdom, Belgium, Austria and the Netherlands.

Screening details

Participants were randomized to either azacitidine or a conventional care regimen (CCR) assigned by the physician prior to randomization. Participants randomized to azacitidine and continuing to receive azacitidine at the time of study closure who did not meet any of the withdrawal criteria had the option of entering an extension phase.

Period 1 title

Treatment Phase

Is this the baseline period?

Yes

Allocation method

Randomised - controlled

Blinding used

Not blinded

Are arms mutually exclusive

Yes

Azacitidine (AZA)

Arm description

Azacitidine 75 mg/m2/day by subcutaneous injection [SC] for 7 days every 28 days, with a 21-day rest period (optimally for at least 6 cycles) plus best supportive care as needed, including antibiotics and blood product transfusions, growth factors, per physician's discretion.

Arm type

Experimental

Investigational medicinal product name

Azacitidine

Investigational medicinal product code

L01BC07

Other name

Vidaza

Pharmaceutical forms

Powder for solution for injection

Routes of administration

Subcutaneous use

Dosage and administration details

Azacitidine 75 mg/m2 every day (QD) by subcutaneous injection [SC] for 7 days every 28 days, with a 21-day rest period.

Conventional Care Regimens (CCR)

Arm description

#1 Intensive Chemotherapy: Cytarabine 100-200 mg/m² as a continuous intravenous infusion (CIVI) for 7 days and daunorubicin 45 to 60 mg/m² daily (QD) IV on Days 1, 2 and 3 or Idarubicin 9-12 mg/m² IV QD for 3 days. Consolidation Therapy (Cycle 2 and 3) = Cytarabine 100-200 mg/m² as a CIVI for 3 to 7 days and daunorubicin 45 to 60 mg/m² QD or Idarubicin 9-12 mg/m² IV QD on Days 1 and 2. Consolidation therapy started between Day 28 and Day 70 from start of induction therapy, upon recovery of absolute neutrophil count (ANC) above 1.0 x 10^9/L and platelets above 75 x 10^9/L. The second cycle started between Day 28 and Day 70 from start of first consolidation therapy. Best supportive care (BSC) of antibiotics and transfusions, were given as needed. # 2 Low-dose cytarabine 20 mg SC twice a day (BID) for 10 days every 28 days, plus BSC # 3 BSC only includes transfusion of blood products, antibiotics, antifungals and nutritional help.

Arm type

Active comparator

Investigational medicinal product name

Cytarabine

Investigational medicinal product code

Other name

Cytosine arabinoside Tarabine PFS Ara-C Cytosar-U Depocyt

Pharmaceutical forms

Powder and solvent for solution for infusion

Routes of administration

Intravenous use

Dosage and administration details

Cytarabine 100-200 mg/m2 as a continuous intravenous infusion (CIVI) for 7 days during induction therapy followed by Cytarabine 100-200 mg/m2 as a CIVI for 3 to 7 days during consolidation therapy.

Investigational medicinal product name

Daunorubicin

Investigational medicinal product code

Other name

Cerubidine, Daunorubicin Hydrochloride for Injection, Daunoxome

Pharmaceutical forms

Powder and solvent for solution for infusion

Routes of administration

Intravenous use

Dosage and administration details

Daunorubicin 45 to 60 mg/m² QD by intravenous (IV) infusion on Days 1, 2 and 3 during induction therapy and QD on days 1 and 2 during consolidation therapy.

Investigational medicinal product name

Idarubicin

Investigational medicinal product code

Other name

Idamycin

Pharmaceutical forms

Powder and solvent for solution for infusion

Routes of administration

Intravenous use

Dosage and administration details

Idarubicin 9-12 mg/m² IV QD for 3 days

Investigational medicinal product name

Low-dose Cytarabine

Investigational medicinal product code

Other name

Cytarabine ARA-C Cytosar-U

Pharmaceutical forms

Powder and solvent for cutaneous solution

Routes of administration

Subcutaneous use

Dosage and administration details

Low-dose cytarabine 20 mg SC twice a day (BID) for 10 days every 28 days, plus BSC

Investigational medicinal product name

Transfusion of blood products, antibiotics, antifungals and nutritional help

Investigational medicinal product code

Other name

Pharmaceutical forms

Capsule, hard, Concentrate for solution for injection/infusion

Routes of administration

Intravenous use, Oral use

Dosage and administration details

Transfusion of blood products, antibiotics, antifungals and nutritional help as needed.

Number of subjects in period 1	Azacitidine (AZA)	Conventional Care Regimens (CCR)
Started	241	247
Treated Population	236	240
Safety Population	236	235
Evaluable Population	179	191
Completed	24	13
Not completed	217	234
Adverse event, serious fatal	53	58
Consent withdrawn by subject	27	48
Adverse event, non-fatal	89	66
Miscellaneous	32	39
Lost to follow-up	-	1
Disease Progression	16	21
Protocol deviation	-	1

Period 2 title

Extension Phase

Is this the baseline period?

Allocation method

Not applicable

Blinding used

Not blinded

Azacitidine (AZA)

Arm description

Azacitidine 75 mg/m2/day by SC injection for 7 days every 28 days, with a 21 day rest period (optimally for at least 6 cycles) plus best supportive care as needed, including antibiotics and blood product transfusions, growth factors, per physician's discretion. Participants receiving AZA at the time the parent study was closed, were given the option to enter the extension phase at the same dose and schedule as long as they were not progressing or experienced toxicities.

Arm type

Experimental

Investigational medicinal product name

Azacitidine

Investigational medicinal product code

L01BC07

Other name

Vidaza

Pharmaceutical forms

Powder for solution for injection

Routes of administration

Subcutaneous use

Dosage and administration details

Azacitidine 75 mg/m2 every day (QD) by subcutaneous injection [SC] for 7 days every 28 days, with a 21-day rest period.

Number of subjects in period 2 ^[1]	Azacitidine (AZA)
Started	24
Safety Population	22
Completed	0
Not completed	24
Adverse event, serious fatal	5
Consent withdrawn by subject	2
Physician decision	1
Adverse event, non-fatal	5
Two subjects did not join extension phase	2
Disease Progression	9

Notes
[1] - The number of subjects starting the period is not consistent with the number completing the preceding period. It is expected the number of subjects starting the subsequent period will be the same as the number completing the preceding period.
Justification: Two patients elected not to participate in the extension phase and reason the number is less starting in the extension phase.

Baseline characteristics

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Reporting group title

Azacitidine (AZA)

Reporting group description

Reporting group title

Conventional Care Regimens (CCR)

Reporting group description

Reporting group values	Azacitidine (AZA)	Conventional Care Regimens (CCR)	Total
Number of subjects	241	247	488
Age Categorical
Units: Subjects
<75 years	103	120	223
≥75 years	138	127	265
Age Continuous
Units: years
arithmetic mean (standard deviation)	75.4 ( 5.6 )	75.1 ( 5.57 )	-
Gender, Male/Female
Units: Subjects
Female	102	98	200
Male	139	149	288
Eastern Cooperative Oncology Group (ECOG) Performance Status
ECOG performance status is used by doctors and researchers to assess how a participant's disease is progressing, assess how the disease affects the daily living activities of the participant and determine appropriate treatment and prognosis. 0 = Fully Active (Most Favorable Activity), 1 = Restricted activity but ambulatory, 2 = Ambulatory but unable to carry out work activities, 3 = Limited Self Care; 4 = Completely Disabled, No self care (Least Favorable Activity)
Units: Subjects
0 = Fully Active	54	57	111
1 = Restrictive but Ambulatory	132	132	264
2 = Ambulatory but unable to work	55	58	113
3 = Limited Self-Care	0	0	0
4 = Completely disabled	0	0	0
World Health Organization Acute Myeloid Leukemia (AML) Classification
WHO categories include: 1. Those with AML with recurrent genetic abnormalities. Includes subtypes with multiple chromosome translocations and mutations. 2. Those with AML with myelodysplasia-related changes. Includes those with prior myelodysplastic syndrome (MDS) or myeloproliferative disease and has transformed to AML. 3. Those with therapy related myeloid neoplasms and have had prior chemotherapy and/or radiation and subsequently develop AML or MDS 4. Those with AML not otherwise specified and include subtypes that do not fall into the above categories.
Units: Subjects
AML with myelodysplasia-related changes	75	83	158
Therapy-related myeloid neoplasms	8	12	20
AML with recurrent genetic abnormalities	5	9	14
AML not otherwise specified	153	143	296
Study Specific Characteristic \| Bone Marrow Blasts
Baseline clinical characteristics, including percentage of bone marrow blasts were assessed centrally and locally. Central values are included here. Baseline blasts were the last non-missing value on or prior to the date of randomization. The bone marrow blasts cells are not typically found in the circulating blood of healthy individuals. Abnormal immature white blood cells (blasts) fill the bone marrow and spill into the bloodstream.
Units: Percentage of Bone Marrow Blasts
arithmetic mean (standard deviation)	66.6 ( 24.71 )	70.2 ( 22.8 )	-

End points

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Reporting group title

Azacitidine (AZA)

Reporting group description

Reporting group title

Conventional Care Regimens (CCR)

Reporting group description

Reporting group title

Azacitidine (AZA)

Reporting group description

Primary: Kaplan-Meier Estimates for Overall Survival

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End point title

Kaplan-Meier Estimates for Overall Survival

End point description

Overall Survival was defined as the time from randomization to death from any cause. Overall survival was calculated by the formula: date of death - date of randomization + 1. Participants surviving at the end of the follow-up period or who withdrew consent to follow-up were censored at the date of last contact. Participants who were lost to follow-up were censored at the date last known alive. ITT population defined as all subjects who were randomized, independent of whether they received study treatment or not. Includes participants who died and subjects who were censored.

End point type

Primary

End point timeframe

Day 1 (randomization) to 40 months

End point values	Azacitidine (AZA)	Conventional Care Regimens (CCR)
Number of subjects analysed	241	247
Units: months
median (confidence interval 95%)	10.4 (8 to 12.7)	6.5 (5 to 8.6)

Statistical Analysis 1

Statistical analysis description

The hazard ratio is from a Cox proportional hazards model stratified by ECOG performance status and cytogenetic risk status.

Comparison groups

Azacitidine (AZA) v Conventional Care Regimens (CCR)

Number of subjects included in analysis

488

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.1009 ^[1]

Method

Logrank

Parameter type

Hazard ratio (HR)

Point estimate

0.85

Confidence interval

level

95%

sides

2-sided

lower limit

0.69

upper limit

1.03

Notes
[1] - The p-value is two-sided from a log-rank test stratified by ECOG performance status, and cytogenetic risk status.

Statistical Analysis 2

Statistical analysis description

The hazard ratio is from an unstratified Cox proportional hazards model.

Comparison groups

Azacitidine (AZA) v Conventional Care Regimens (CCR)

Number of subjects included in analysis

488

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.0829 ^[2]

Method

Logrank

Parameter type

Hazard ratio (HR)

Point estimate

0.84

Confidence interval

level

95%

sides

2-sided

lower limit

0.69

upper limit

1.02

Notes
[2] - The p-value is two-sided from a log-rank test stratified by ECOG performance status, and cytogenetic risk status.

Secondary: One-Year Overall Survival Rate

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End point title

One-Year Overall Survival Rate

End point description

Kaplan Meier methods were used to estimate the 1-year survival probabilities for time to death from any cause. ITT population defined as all subjects who were randomized, independent of whether they received study treatment or not. Includes those who died and subjects who were censored.

End point type

Secondary

End point timeframe

From Day 1 (randomization) to 40 months

End point values	Azacitidine (AZA)	Conventional Care Regimens (CCR)
Number of subjects analysed	241	247
Units: percentage of participants
number (confidence interval 95%)	46.5 (40.1 to 52.7)	34.3 (28.3 to 40.3)

Statistical Analysis 1

Statistical analysis description

Estimates of the 1-year (365 day) survival probabilities and corresponding 95% confidence intervals (CI) were presented by treatment group. The CI for the difference in the 1-year survival probabilities was derived using Greenwoods variance estimate.

Comparison groups

Azacitidine (AZA) v Conventional Care Regimens (CCR)

Number of subjects included in analysis

488

Analysis specification

Pre-specified

Analysis type

superiority

Method

Parameter type

Difference

Point estimate

12.26

Confidence interval

level

95%

sides

2-sided

lower limit

3.5

upper limit

Secondary: Event-Free Survival (EFS)

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End point title

Event-Free Survival (EFS)

End point description

EFS was defined as the interval from the date of randomization to the date of treatment failure, progressive disease, relapse after complete remission (CR) or complete remission with incomplete blood count recovery (CRi), death from any cause, or lost to follow-up, whichever occurs first. Participants who were still alive without any of these events were censored at the date of their last response assessment. ITT population defined as all subjects who were randomized, independent of whether they received study treatment or not. Includes those who died and subjects who were censored.

End point type

Secondary

End point timeframe

Day 1 (randomization) to date of treatment failure, progressive disease, relapse after Complete Remission (CR) or Complete remission with incomplete blood count recovery (CRi), death from any cause. Day 1 (randomization) to 40 months

End point values	Azacitidine (AZA)	Conventional Care Regimens (CCR)
Number of subjects analysed	241	247
Units: months
median (confidence interval 95%)	6.7 (5 to 8.8)	4.8 (3.8 to 6)

Statistical Analysis 1

Statistical analysis description

The hazard ratio is from an unstratified Cox proportional hazards model.

Comparison groups

Azacitidine (AZA) v Conventional Care Regimens (CCR)

Number of subjects included in analysis

488

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.1495 ^[3]

Method

Logrank

Parameter type

Hazard ratio (HR)

Point estimate

0.87

Confidence interval

level

95%

sides

2-sided

lower limit

0.72

upper limit

1.05

Notes
[3] - 2 sided unstratified

Secondary: Relapse-Free Survival (RFS) for Subjects who Achieved a Complete Remission (CR) or Complete remission with Incomplete Blood Count Recovery (CRi)

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End point title

Relapse-Free Survival (RFS) for Subjects who Achieved a Complete Remission (CR) or Complete remission with Incomplete Blood Count Recovery (CRi)

End point description

Relapse-free survival was defined as the interval from the date of first documented CR or CRi to the date of relapse, death from any cause, or lost to follow-up, whichever occurred first. Includes subjects who were still alive and in continuous CR or CRi were censored at the date of their last response assessment.

End point type

Secondary

End point timeframe

Day 1 of first documented CR or CRi to the date of relapse, death from any cause, or lost to follow-up. Day 1 (randomization) to 40 months

End point values	Azacitidine (AZA)	Conventional Care Regimens (CCR)
Number of subjects analysed	67	62
Units: months
median (confidence interval 95%)	9.3 (6.7 to 12.4)	10.5 (7.3 to 12.3)

Statistical Analysis 1

Statistical analysis description

The hazard ratio is from an unstratified Cox proportional hazards model.

Comparison groups

Azacitidine (AZA) v Conventional Care Regimens (CCR)

Number of subjects included in analysis

129

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.5832 ^[4]

Method

Logrank

Parameter type

Hazard ratio (HR)

Point estimate

1.11

Confidence interval

level

95%

sides

2-sided

lower limit

0.75

upper limit

1.66

Notes
[4] - 2 sided unstratified

Secondary: Percentage of Subjects who Achieved a Morphologic CR + CRi as Determined by the Independent Review Committee (IRC) Based on International Working Group (IWG) Response Criteria for Acute Myeloid Leukemia (AML)

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End point title

Percentage of Subjects who Achieved a Morphologic CR + CRi as Determined by the Independent Review Committee (IRC) Based on International Working Group (IWG) Response Criteria for Acute Myeloid Leukemia (AML)

End point description

A complete remission (CR) is defined as a leukemia-free state defined as less than 5% blasts in a BM aspirate with marrow spicules and with at least 200 nucleated cells (there should be no blasts with Auer rods), an absolute neutrophil count (ANC) of ≥ 1 x 10^9/L, a platelet count ≥ 100 x 10^9/L, and transfusion independence (no transfusions for 1 week prior to each assessment). No duration of these findings is required for confirmation of this response. A CR with incomplete blood count recovery (CRi) is defined as <5% BM blasts with the ANC count < 1 x 10^9/L and/or the platelet count may be < 100 x 10^9/L. Where the date of the hematology assessment used is the earliest on or following the date of the BM sample up to 8 days after the BM date. ITT population.

End point type

Secondary

End point timeframe

Day 1 (randomization) to 40 months

End point values	Azacitidine (AZA)	Conventional Care Regimens (CCR)
Number of subjects analysed	241	247
Units: percentage of subjects
number (not applicable)	27.8	25.1

Statistical Analysis 1

Comparison groups

Azacitidine (AZA) v Conventional Care Regimens (CCR)

Number of subjects included in analysis

488

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.5384

Method

Fisher exact

Confidence interval

Secondary: Duration of Remission Assessed by the IRC Based on Kaplan-Meier Estimates

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End point title

Duration of Remission Assessed by the IRC Based on Kaplan-Meier Estimates

End point description

The time from the date CR or CRi was first documented until the date of documented relapse from CR/CRi. Duration of remission was defined only for those subjects who achieved a CR or CRi, as determined by the IRC. Subjects who were lost to follow-up without documented relapse, or were alive at last follow-up without documented relapse were censored at the date of their last response assessment. Includes those with a CR or CRi.

End point type

Secondary

End point timeframe

Day 1 (randomization) to 40 months; date of the first documented CR or CRi until date of first documented relapse.

End point values	Azacitidine (AZA)	Conventional Care Regimens (CCR)
Number of subjects analysed	67	62
Units: months
median (confidence interval 95%)	10.4 (7.2 to 15.2)	12.3 (9 to 17)

No statistical analyses for this end point

Secondary: Number of Subjects who Achieved a Cytogenetic Complete Remission (CRc-10) as Determined by the IRC

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End point title

Number of Subjects who Achieved a Cytogenetic Complete Remission (CRc-10) as Determined by the IRC

End point description

The CRc is a normal karyotype defined as no clonal abnormalities after review of at least 10 metaphases using conventional cytogenetic techniques. Cytogenetic complete remission rate (CRc) is based on the following criteria: 1) CR criteria met and 2) an abnormal karyotype is present at baseline and 3) there is reversion to normal karyotype at the time of CR (based on ≥ 10 metaphases), where date of cytogenetic sample = date of BM sample used for the CR assessment. ITT population defined as all subjects who were randomized, independent of whether they received study treatment or not. Includes subjects who died and participants who were censored.

End point type

Secondary

End point timeframe

Day 1 (randomization) to 40 months

End point values	Azacitidine (AZA)	Conventional Care Regimens (CCR)
Number of subjects analysed	241	247
Units: participants	5	15

Statistical Analysis

Comparison groups

Azacitidine (AZA) v Conventional Care Regimens (CCR)

Number of subjects included in analysis

488

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.0376

Method

Fisher exact

Confidence interval

Secondary: Number of Subjects with Adverse Events (AEs).

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End point title

Number of Subjects with Adverse Events (AEs).

End point description

AEs = any noxious, unintended, or untoward medical occurrence that may appear or worsen during the course of a study. It may be a new intercurrent illness, a worsening concomitant illness, an injury, or any concomitant impairment of the participant’s health, regardless of cause. Serious AE (SAE) = any AE which results in death; is life-threatening; requires inpatient hospitalization or prolongation of existing hospitalization; results in persistent or significant disability/incapacity; is a congenital anomaly/birth defect; constitutes an important medical event. The severity of AEs were graded based upon the participants symptoms according to the Common Terminology Criteria for Adverse Events (CTCAE, Version 4.0); AEs were evaluated for severity according to the following scale: Grade 1 = Mild – transient or mild discomfort; no medical intervention required; Grade 2 = Moderate – mild to moderate limitation in activity; Grade 3 = Severe; Grade 4 = Life threatening; Grade 5 = Death.

End point type

Secondary

End point timeframe

Day 1 (randomization) up to last visit completed 22 Jan 2014; Up to 40 months

End point values	Azacitidine (AZA)	Conventional Care Regimens (CCR)
Number of subjects analysed	236	235
Units: subjects
At least one Treatment Emergent AE	234	231
At least one TEAE related to study drug	188	163
Grade 3-4 adverse event	207	204
Grade 3-4 adverse event related to any study drug	125	119
At least one Grade 5 (leading to death) TEAE	56	70
Grade 5 adverse event related to any study drug	12	14
Serious TEAE	188	175
Serious TEAE related to any study drug	87	70
TEAE leading to discontinuation of study drug	110	79
Study drug-related TEAE leading to discontinuation	22	25
TEAE leading to study drug dose reduction	8	4
TEAE leading to study drug dose interruption	116	65
TEAE causing study drug dose reduction/disruption	13	7

No statistical analyses for this end point

Secondary: Health Related Quality of Life (HRQoL): Change from Baseline in the European Organization for Research and Treatment of Cancer Cancer Quality of Life Questionnaire for Patients with Cancer (EORTC QLQ-C30) Fatigue Domain

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End point title

Health Related Quality of Life (HRQoL): Change from Baseline in the European Organization for Research and Treatment of Cancer Cancer Quality of Life Questionnaire for Patients with Cancer (EORTC QLQ-C30) Fatigue Domain

End point description

The European Organization for Research and Treatment of Cancer (EORTC) Core Quality of Life (QOL) questionnaire (EORTC QLQ-C30) is a 30-question tool used to assess the overall QOL in cancer patients. It consists of 15 domains: 1 global health status (GHS) scale, 5 functional scales (Physical, Role, Cognitive, Emotional, Social), and 9 symptom scales/items (Fatigue, Nausea and Vomiting, Pain, Dyspnea, Sleep Disturbance, Appetite Loss, Constipation, Diarrhea, Financial Impact). The EORTC QLQ-C30 Fatigue Scale is scored between 0 and 100, with a high score indicating a higher level of symptoms. Negative change from Baseline values indicate reduction in fatigue (i.e. improvement in symptom) and positive values indicate increases in fatigue (i.e. worsening of symptom). The HRQoL Evaluable population included only participants with a baseline QoL assessment and at least 1 follow-up assessment. Time windows were applied post-hoc to increase the size of the analyzable population.

End point type

Secondary

End point timeframe

Baseline to Cycle 3; at approximately 3 months

End point values	Azacitidine (AZA)	Conventional Care Regimens (CCR)
Number of subjects analysed	135	101
Units: units on a scale
arithmetic mean (standard deviation)	-1.5 ( 24.69 )	-1.9 ( 27.54 )

No statistical analyses for this end point

Secondary: Health Related Quality of Life (HRQoL): Change from Baseline in the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire for Patients with Cancer (EORTC QLQ-C30) Fatigue Domain

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End point title

Health Related Quality of Life (HRQoL): Change from Baseline in the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire for Patients with Cancer (EORTC QLQ-C30) Fatigue Domain

End point description

End point type

Secondary

End point timeframe

Baseline to Cycle 5, at approximately 5 months

End point values	Azacitidine (AZA)	Conventional Care Regimens (CCR)
Number of subjects analysed	112	66
Units: units on a scale
arithmetic mean (standard deviation)	-2.8 ( 27.36 )	-7.1 ( 27.61 )

No statistical analyses for this end point

Secondary: Health Related Quality of Life (HRQoL): Change from Baseline in the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire for Patients with Cancer (EORTC QLQ-C30) Fatigue Domain

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End point title

End point description

End point type

Secondary

End point timeframe

Baseline to Cycle 7, at approximately 7 months

End point values	Azacitidine (AZA)	Conventional Care Regimens (CCR)
Number of subjects analysed	94	53
Units: units on a scale
arithmetic mean (standard deviation)	-6.1 ( 26.9 )	-12.2 ( 30.45 )

No statistical analyses for this end point

Secondary: Health Related Quality of Life (HRQoL): Change from Baseline in the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire for Patients with Cancer (EORTC QLQ-C30) Fatigue Domain

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End point title

End point description

End point type

Secondary

End point timeframe

Baseline to Cycle 9, at approximately 9 months

End point values	Azacitidine (AZA)	Conventional Care Regimens (CCR)
Number of subjects analysed	80	36
Units: units on a scale
arithmetic mean (standard deviation)	-9 ( 27.9 )	-10.2 ( 33.85 )

No statistical analyses for this end point

Secondary: Health Related Quality of Life (HRQoL): Change from Baseline in the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire for Patients with Cancer (EORTC QLQ-C30) Fatigue Domain

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End point title

End point description

End point type

Secondary

End point timeframe

Baseline to End of Study; at approximately 11-12 months

End point values	Azacitidine (AZA)	Conventional Care Regimens (CCR)
Number of subjects analysed	87	80
Units: units on a scale
arithmetic mean (standard deviation)	8.9 ( 33.54 )	6.1 ( 34.19 )

No statistical analyses for this end point

Secondary: HRQoL: Change from Baseline in the EORTC QLQ-C30 Dyspnea

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End point title

HRQoL: Change from Baseline in the EORTC QLQ-C30 Dyspnea

End point description

The European Organization for Research and Treatment of Cancer (EORTC) Core Quality of Life (QOL) questionnaire (EORTC QLQ-C30) is a 30-question tool used to assess the overall QOL in cancer patients. It consists of 15 domains: 1 global health status (GHS) scale, 5 functional scales (Physical, Role, Cognitive, Emotional, Social), and 9 symptom scales/items (Fatigue, Nausea and Vomiting, Pain, Dyspnea, Sleep Disturbance, Appetite Loss, Constipation, Diarrhea, Financial Impact). The EORTC QLQ-C30 Dyspnea scale is scored between 0 and 100, with a high score indicating a higher level of symptoms. Negative change from Baseline values indicate decreased dyspnea (i.e. improvement in symptom) and positive values indicate increased dyspnea (i.e. worsening of symptom). The HRQoL Evaluable population included only participants with a baseline QoL assessment and at least 1 follow-up assessment. Time windows were applied post-hoc to increase the size of the analyzable population.

End point type

Secondary

End point timeframe

Baseline to Cycle 3, at approximately 3 months

End point values	Azacitidine (AZA)	Conventional Care Regimens (CCR)
Number of subjects analysed	136	101
Units: units on a scale
arithmetic mean (standard deviation)	5.1 ( 26.88 )	-1.7 ( 30.69 )

No statistical analyses for this end point

Secondary: HRQoL: Change from Baseline in the EORTC QLQ-C30 Dyspnea

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End point title

HRQoL: Change from Baseline in the EORTC QLQ-C30 Dyspnea

End point description

The European Organization for Research and Treatment of Cancer (EORTC) Core Quality of Life (QOL) questionnaire (EORTC QLQ-C30) is a 30-question tool used to assess the overall QOL in cancer patients. It consists of 15 domains: 1 global health status (GHS) scale, 5 functional scales (Physical, Role, Cognitive, Emotional, Social), and 9 symptom scales/items (Fatigue, Nausea and Vomiting, Pain, Dyspnea, Sleep Disturbance, Appetite Loss, Constipation, Diarrhea, Financial Impact). The EORTC QLQ-C30 Dyspnea scale is scored between 0 and 100, with a high score indicating a higher level of symptoms. Negative change from Baseline values indicate decreased dyspnea (i.e. improvement in symptom) and positive values indicate increased dyspnea (i.e. worsening of symptom). The HRQoL Evaluable population included only participants with a baseline QoL assessment and at least 1 follow-up assessment. Time windows were applied post-hoc to increase the size of the analyzable population.

End point type

Secondary

End point timeframe

Baseline to Cycle 5, at approximately 5 months

End point values	Azacitidine (AZA)	Conventional Care Regimens (CCR)
Number of subjects analysed	112	66
Units: units on a scale
arithmetic mean (standard deviation)	3.9 ( 27.49 )	-6.6 ( 28.18 )

No statistical analyses for this end point

Secondary: HRQoL: Change from Baseline in the EORTC QLQ-C30 Dyspnea

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End point title

HRQoL: Change from Baseline in the EORTC QLQ-C30 Dyspnea

End point description

The European Organization for Research and Treatment of Cancer (EORTC) Core Quality of Life (QOL) questionnaire (EORTC QLQ-C30) is a 30-question tool used to assess the overall QOLin cancer patients. It consists of 15 domains: 1 global health status (GHS) scale, 5 functional scales (Physical, Role, Cognitive, Emotional, Social), and 9 symptom scales/items (Fatigue, Nausea and Vomiting, Pain, Dyspnea, Sleep Disturbance, Appetite Loss, Constipation, Diarrhea, Financial Impact). The EORTC QLQ-C30 Dyspnea scale is scored between 0 and 100, with a high score indicating a higher level of symptoms. Negative change from Baseline values indicate decreased dyspnea (i.e. improvement in symptom) and positive values indicate increased dyspnea (i.e. worsening of symptom). The HRQoL Evaluable population included only participants with a baseline QoL assessment and at least 1 follow-up assessment. Time windows were applied post-hoc to increase the size of the analyzable population.

End point type

Secondary

End point timeframe

Baseline to Cycle 7, at approximately 7 months

End point values	Azacitidine (AZA)	Conventional Care Regimens (CCR)
Number of subjects analysed	94	53
Units: units on a scale
arithmetic mean (standard deviation)	0.4 ( 29.93 )	-8.8 ( 28.61 )

No statistical analyses for this end point

Secondary: HRQoL: Change from Baseline in the EORTC QLQ-C30 Dyspnea

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End point title

HRQoL: Change from Baseline in the EORTC QLQ-C30 Dyspnea

End point description

The EORTC Core Quality of Life (QOL) questionnaire (EORTC QLQ-C30) is a 30-question tool used to assess the overall QOL in cancer patients. It consists of 15 domains: 1 global health status (GHS) scale, 5 functional scales (Physical, Role, Cognitive, Emotional, Social), and 9 symptom scales/items (Fatigue, Nausea and Vomiting, Pain, Dyspnea, Sleep Disturbance, Appetite Loss, Constipation, Diarrhea, Financial Impact). The dyspnea scale is scored between 0 and 100, with a high score indicating a higher level of symptoms. Negative change from baseline values indicate decreased dyspnea and positive values indicate increased dyspnea. The HRQoL Evaluable population included only yhose with a baseline QoL assessment and at least 1 follow-up assessment. Time windows were applied post-hoc to increase the size of the analyzable population. The analysis included 157 from the azacitidine group and 134 in the CCR group, a smaller number than the ITT population.

End point type

Secondary

End point timeframe

Baseline to Cycle 9, at approximately 9 months

End point values	Azacitidine (AZA)	Conventional Care Regimens (CCR)
Number of subjects analysed	81	36
Units: units on a scale
arithmetic mean (standard deviation)	-4.9 ( 26.93 )	-2.8 ( 26.87 )

No statistical analyses for this end point

Secondary: HRQoL: Change from Baseline in the EORTC QLQ-C30 Dyspnea

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End point title

HRQoL: Change from Baseline in the EORTC QLQ-C30 Dyspnea

End point description

The European Organization for Research and Treatment of Cancer (EORTC) Core Quality of Life (QOL) questionnaire (EORTC QLQ-C30) is a 30-question tool used to assess the overall QOL in cancer patients. It consists of 15 domains: 1 global health status (GHS) scale, 5 functional scales (Physical, Role, Cognitive, Emotional, Social), and 9 symptom scales/items (Fatigue, Nausea and Vomiting, Pain, Dyspnea, Sleep Disturbance, Appetite Loss, Constipation, Diarrhea, Financial Impact). The EORTC QLQ-C30 Physical Functioning scale is scored between 0 and 100, with a high score indicating a higher level of symptoms. Negative change from Baseline values indicate decreased dyspnea (i.e. improvement in symptom) and positive values indicate increased dyspnea (i.e. worsening of symptom). The HRQoL Evaluable population included only participants with a baseline QoL assessment and at least 1 follow-up assessment. Time windows were applied post-hoc to increase the size of the analyzable population.

End point type

Secondary

End point timeframe

Baseline to end of study, at approximately 11-12 months

End point values	Azacitidine (AZA)	Conventional Care Regimens (CCR)
Number of subjects analysed	87	80
Units: units on a scale
arithmetic mean (standard deviation)	12.6 ( 31.43 )	6.3 ( 35.22 )

Statistical Analysis 2

Comparison groups

Azacitidine (AZA) v Conventional Care Regimens (CCR)

Number of subjects included in analysis

167

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.1164 ^[5]

Method

t-test, 2-sided

Confidence interval

Notes
[5] - p-value for CCR is calculated using the paired t-test on the observed domain score, comparing with baseline.

Secondary: HRQoL: Change from Baseline in the EORTC QLQ-C30 Physical Functioning Domain

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End point title

HRQoL: Change from Baseline in the EORTC QLQ-C30 Physical Functioning Domain

End point description

The European Organization for Research and Treatment of Cancer (EORTC) Core Quality of Life (QOL) questionnaire (EORTC QLQ-C30) is a 30-question tool used to assess the overall QOL in cancer patients. It consists of 15 domains: 1 global health status (GHS) scale, 5 functional scales (Physical, Role, Cognitive, Emotional, Social), and 9 symptom scales/items (Fatigue, Nausea and Vomiting, Pain, Dyspnea, Sleep Disturbance, Appetite Loss, Constipation, Diarrhea, Financial Impact). The EORTC QLQ-C30 Physical Functioning Scale is scored between 0 and 100, with a high score indicating better functioning. Negative change from Baseline values indicate deterioration in functioning and positive values indicate improvement. The HRQoL Evaluable population included only participants with a baseline QoL assessment and at least 1 follow-up assessment. Time windows were applied post-hoc to increase the size of the analyzable population.

End point type

Secondary

End point timeframe

Baseline to Cycle 3, at approximately 3 months

End point values	Azacitidine (AZA)	Conventional Care Regimens (CCR)
Number of subjects analysed	136	102
Units: units on a scale
arithmetic mean (standard deviation)	-4.2 ( 17.98 )	-0.3 ( 18.85 )

No statistical analyses for this end point

Secondary: HRQoL: Change from Baseline in the EORTC QLQ-C30 Physical Functioning Domain

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End point title

HRQoL: Change from Baseline in the EORTC QLQ-C30 Physical Functioning Domain

End point description

The European Organization for Research and Treatment of Cancer (EORTC) Core Quality of Life (QOL) questionnaire (EORTC QLQ-C30) is a 30-question tool used to assess the overall QOL in cancer patients. It consists of 15 domains: 1 global health status (GHS) scale, 5 functional scales (Physical, Role, Cognitive, Emotional, Social), and 9 symptom scales/items (Fatigue, Nausea and Vomiting, Pain, Dyspnea, Sleep Disturbance, Appetite Loss, Constipation, Diarrhea, Financial Impact). The EORTC QLQ-C30 Physical Functioning Scale is scored between 0 and 100, with a high score indicating better functioning. Negative change from Baseline values indicate deterioration in functioning and positive values indicate improvement. The HRQoL Evaluable population included only participants with a baseline QoL assessment and at least 1 follow-up assessment. Time windows were applied post-hoc to increase the size of the analyzable population.

End point type

Secondary

End point timeframe

Baseline to Cycle 5, at approximately 5 months

End point values	Azacitidine (AZA)	Conventional Care Regimens (CCR)
Number of subjects analysed	112	67
Units: units on a scale
arithmetic mean (standard deviation)	-4.4 ( 19.25 )	-1.3 ( 20.41 )

No statistical analyses for this end point

Secondary: HRQoL: Change from Baseline in the EORTC QLQ-C30 Physical Functioning Domain

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End point title

HRQoL: Change from Baseline in the EORTC QLQ-C30 Physical Functioning Domain

End point description

The European Organization for Research and Treatment of Cancer (EORTC) Core Quality of Life (QOL) questionnaire (EORTC QLQ-C30) is a 30-question tool used to assess the overall QOL in cancer patients. It consists of 15 domains: 1 global health status (GHS) scale, 5 functional scales (Physical, Role, Cognitive, Emotional, Social), and 9 symptom scales/items (Fatigue, Nausea and Vomiting, Pain, Dyspnea, Sleep Disturbance, Appetite Loss, Constipation, Diarrhea, Financial Impact). The EORTC QLQ-C30 Physical Functioning Scale is scored between 0 and 100, with a high score indicating better functioning. Negative change from Baseline values indicate deterioration in functioning and positive values indicate improvement. The HRQoL Evaluable population included only participants with a baseline QoL assessment and at least 1 follow-up assessment. Time windows were applied post-hoc to increase the size of the analyzable population.

End point type

Secondary

End point timeframe

Baseline to Cycle 7, at approximately 7 months

End point values	Azacitidine (AZA)	Conventional Care Regimens (CCR)
Number of subjects analysed	94	54
Units: units on a scale
arithmetic mean (standard deviation)	1.6 ( 18.75 )	1.5 ( 23.08 )

No statistical analyses for this end point

Secondary: HRQoL: Change from Baseline in the EORTC QLQ-C30 Physical Functioning Domain

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End point title

HRQoL: Change from Baseline in the EORTC QLQ-C30 Physical Functioning Domain

End point description

The European Organization for Research and Treatment of Cancer (EORTC) Core Quality of Life (QOL) questionnaire (EORTC QLQ-C30) is a 30-question tool used to assess the overall QOL in cancer patients. It consists of 15 domains: 1 global health status (GHS) scale, 5 functional scales (Physical, Role, Cognitive, Emotional, Social), and 9 symptom scales/items (Fatigue, Nausea and Vomiting, Pain, Dyspnea, Sleep Disturbance, Appetite Loss, Constipation, Diarrhea, Financial Impact). The EORTC QLQ-C30 Physical Functioning Scale is scored between 0 and 100, with a high score indicating better functioning. Negative change from Baseline values indicate deterioration in functioning and positive values indicate improvement. The HRQoL Evaluable population included only participants with a baseline QoL assessment and at least 1 follow-up assessment. Time windows were applied post-hoc to increase the size of the analyzable population.

End point type

Secondary

End point timeframe

Baseline to Cycle 9, at approximately 9 months

End point values	Azacitidine (AZA)	Conventional Care Regimens (CCR)
Number of subjects analysed	81	36
Units: units on a scale
arithmetic mean (standard deviation)	3.5 ( 18.26 )	-0.4 ( 22.81 )

No statistical analyses for this end point

Secondary: HRQoL: Change from Baseline in the EORTC QLQ-C30 Physical Functioning Domain

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End point title

HRQoL: Change from Baseline in the EORTC QLQ-C30 Physical Functioning Domain

End point description

The European Organization for Research and Treatment of Cancer (EORTC) Core Quality of Life (QOL) questionnaire (EORTC QLQ-C30) is a 30-question tool used to assess the overall QOL in cancer patients. It consists of 15 domains: 1 global health status (GHS) scale, 5 functional scales (Physical, Role, Cognitive, Emotional, Social), and 9 symptom scales/items (Fatigue, Nausea and Vomiting, Pain, Dyspnea, Sleep Disturbance, Appetite Loss, Constipation, Diarrhea, Financial Impact). The EORTC QLQ-C30 Physical Functioning Scale is scored between 0 and 100, with a high score indicating better functioning. Negative change from Baseline values indicate deterioration in functioning and positive values indicate improvement. The HRQoL Evaluable population included only participants with a baseline QoL assessment and at least 1 follow-up assessment. Time windows were applied post-hoc to increase the size of the analyzable population.

End point type

Secondary

End point timeframe

Baseline to end of study, at approximately 11-12 months

End point values	Azacitidine (AZA)	Conventional Care Regimens (CCR)
Number of subjects analysed	87	81
Units: units on a scale
arithmetic mean (standard deviation)	-13 ( 26.74 )	-9.4 ( 26.43 )

No statistical analyses for this end point

Secondary: HRQoL: Change from Baseline in the EORTC QLQ-C30 Global Health Status-/Quality of Life Domain

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End point title

HRQoL: Change from Baseline in the EORTC QLQ-C30 Global Health Status-/Quality of Life Domain

End point description

The European Organization for Research and Treatment of Cancer (EORTC) Core Quality of Life (QOL) questionnaire (EORTC QLQ-C30) is a 30-question tool used to assess the overall QOL in cancer patients. It consists of 15 domains: 1 global health status (GHS) scale, 5 functional scales (Physical, Role, Cognitive, Emotional, Social), and 9 symptom scales/items (Fatigue, Nausea and Vomiting, Pain, Dyspnea, Sleep Disturbance, Appetite Loss, Constipation, Diarrhea, Financial Impact). The EORTC QLQ-C30 Global Health Status/QOL scale is scored between 0 and 100, with a high score indicating better Global Health Status/QOL. Negative change from Baseline values indicate deterioration in Global Health Status/QOL and positive values indicate improvement. The HRQoL Evaluable population included only participants with a baseline QoL assessment and at least 1 follow-up assessment. Time windows were applied post-hoc to increase the size of the analyzable population.

End point type

Secondary

End point timeframe

Baseline to Cycle 3, at approximately 3 months

End point values	Azacitidine (AZA)	Conventional Care Regimens (CCR)
Number of subjects analysed	134	101
Units: units on a scale
arithmetic mean (standard deviation)	0.9 ( 20.97 )	3.8 ( 26.42 )

No statistical analyses for this end point

Secondary: HRQoL: Change from Baseline in the EORTC QLQ-C30 Global Health Status-/Quality of Life Domain

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End point title

HRQoL: Change from Baseline in the EORTC QLQ-C30 Global Health Status-/Quality of Life Domain

End point description

The European Organization for Research and Treatment of Cancer (EORTC) Core Quality of Life (QOL) questionnaire (EORTC QLQ-C30) is a 30-question tool used to assess the overall QOL in cancer patients. It consists of 15 domains: 1 global health status (GHS) scale, 5 functional scales (Physical, Role, Cognitive, Emotional, Social), and 9 symptom scales/items (Fatigue, Nausea and Vomiting, Pain, Dyspnea, Sleep Disturbance, Appetite Loss, Constipation, Diarrhea, Financial Impact). The EORTC QLQ-C30 Global Health Status/QOL scale is scored between 0 and 100, with a high score indicating better Global Health Status/QOL. Negative change from Baseline values indicate deterioration in Global Health Status/QOL and positive values indicate improvement. The HRQoL Evaluable population included only participants with a baseline QoL assessment and at least 1 follow-up assessment. Time windows were applied post-hoc to increase the size of the analyzable population.

End point type

Secondary

End point timeframe

Baseline to Cycle 5, at approximately 5 months

End point values	Azacitidine (AZA)	Conventional Care Regimens (CCR)
Number of subjects analysed	112	66
Units: units on a scale
arithmetic mean (standard deviation)	1.6 ( 22.5 )	9 ( 24.82 )

No statistical analyses for this end point

Secondary: HRQoL: Change from Baseline in the EORTC QLQ-C30 Global Health Status-/Quality of Life Domain

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End point title

HRQoL: Change from Baseline in the EORTC QLQ-C30 Global Health Status-/Quality of Life Domain

End point description

The European Organization for Research and Treatment of Cancer (EORTC) Core Quality of Life (QOL) questionnaire (EORTC QLQ-C30) is a 30-question tool used to assess the overall QOL in cancer patients. It consists of 15 domains: 1 global health status (GHS) scale, 5 functional scales (Physical, Role, Cognitive, Emotional, Social), and 9 symptom scales/items (Fatigue, Nausea and Vomiting, Pain, Dyspnea, Sleep Disturbance, Appetite Loss, Constipation, Diarrhea, Financial Impact). The EORTC QLQ-C30 Global Health Status/QOL scale is scored between 0 and 100, with a high score indicating better Global Health Status/QOL. Negative change from Baseline values indicate deterioration in Global Health Status/QOL and positive values indicate improvement. The HRQoL Evaluable population included only participants with a baseline QoL assessment and at least 1 follow-up assessment. Time windows were applied post-hoc to increase the size of the analyzable population.

End point type

Secondary

End point timeframe

Baseline to Cycle 7, at approximately 7 months

End point values	Azacitidine (AZA)	Conventional Care Regimens (CCR)
Number of subjects analysed	94	52
Units: units on a scale
arithmetic mean (standard deviation)	5.1 ( 25.84 )	8.7 ( 27.91 )

No statistical analyses for this end point

Secondary: HRQoL: Change from Baseline in the EORTC QLQ-C30 Global Health Status-/Quality of Life Domain

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End point title

HRQoL: Change from Baseline in the EORTC QLQ-C30 Global Health Status-/Quality of Life Domain

End point description

The European Organization for Research and Treatment of Cancer (EORTC) Core Quality of Life (QOL) questionnaire (EORTC QLQ-C30) is a 30-question tool used to assess the overall QOL in cancer patients. It consists of 15 domains: 1 global health status (GHS) scale, 5 functional scales (Physical, Role, Cognitive, Emotional, Social), and 9 symptom scales/items (Fatigue, Nausea and Vomiting, Pain, Dyspnea, Sleep Disturbance, Appetite Loss, Constipation, Diarrhea, Financial Impact). The EORTC QLQ-C30 Global Health Status/QOL scale is scored between 0 and 100, with a high score indicating better Global Health Status/QOL. Negative change from Baseline values indicate deterioration in Global Health Status/QOL and positive values indicate improvement. The HRQoL Evaluable population included only participants with a baseline QoL assessment and at least 1 follow-up assessment. Time windows were applied post-hoc to increase the size of the analyzable population.

End point type

Secondary

End point timeframe

Baseline to Cycle 9, at approximately 9 months

End point values	Azacitidine (AZA)	Conventional Care Regimens (CCR)
Number of subjects analysed	80	36
Units: units on a scale
arithmetic mean (standard deviation)	7.8 ( 27.28 )	10.4 ( 23.09 )

No statistical analyses for this end point

Secondary: HRQoL: Change from Baseline in the EORTC QLQ-C30 Global Health Status-/Quality of Life Domain

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End point title

HRQoL: Change from Baseline in the EORTC QLQ-C30 Global Health Status-/Quality of Life Domain

End point description

The European Organization for Research and Treatment of Cancer (EORTC) Core Quality of Life (QOL) questionnaire (EORTC QLQ-C30) is a 30-question tool used to assess the overall QOL in cancer patients. It consists of 15 domains: 1 global health status (GHS) scale, 5 functional scales (Physical, Role, Cognitive, Emotional, Social), and 9 symptom scales/items (Fatigue, Nausea and Vomiting, Pain, Dyspnea, Sleep Disturbance, Appetite Loss, Constipation, Diarrhea, Financial Impact). The EORTC QLQ-C30 Global Health Status/QOL scale is scored between 0 and 100, with a high score indicating better Global Health Status/QOL. Negative change from Baseline values indicate deterioration in Global Health Status/QOL and positive values indicate improvement. The HRQoL Evaluable population included only participants with a baseline QoL assessment and at least 1 follow-up assessment. Time windows were applied post-hoc to increase the size of the analyzable population.

End point type

Secondary

End point timeframe

Baseline to end of study, at approximately 11-12 months

End point values	Azacitidine (AZA)	Conventional Care Regimens (CCR)
Number of subjects analysed	87	80
Units: units on a scale
arithmetic mean (standard deviation)	-4.4 ( 29.2 )	-6.1 ( 27.9 )

No statistical analyses for this end point

Secondary: Healthcare Resource Utilization (HRU): Number of subjects with a hospitalization

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End point title

Healthcare Resource Utilization (HRU): Number of subjects with a hospitalization

End point description

HRU was defined as any consumption of healthcare resources directly or indirectly related to the treatment of the patient. HRU Analysis may help in evaluating potential costs and budget impact of new treatments from a payer perspective. HRU was analyzed for the HRQoL Evaluable Population, a smaller sample than either the ITT population or safety population. Duration of therapy differed between treatment groups.

End point type

Secondary

End point timeframe

Day 1 (randomization) to 40 months

End point values	Azacitidine (AZA)	Conventional Care Regimens (CCR)
Number of subjects analysed	157	134
Units: participants	139	111

No statistical analyses for this end point

Secondary: Healthcare Resource Utilization (HRU): Rate of Inpatient Hospitalizations Per Year

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End point title

Healthcare Resource Utilization (HRU): Rate of Inpatient Hospitalizations Per Year

End point description

HRU was defined as any consumption of healthcare resources directly or indirectly related to the treatment of the patient. HRU Analysis may help in evaluating potential costs and budget impact of new treatments from a payer perspective. The rate of inpatient hospitalizations per patient year was calculated as the total number of hospitalizations divided by the total number of patient-years followed in the study period. Patient-years (PY) were calculated as the duration from baseline to last available HRQL assessment for each patient.HRU was analyzed for the HRQoL Evaluable Population, a smaller sample than either the ITT population or safety population. Duration of therapy differed between treatment groups. Rate-per-patient year values adjust for these differences.

End point type

Secondary

End point timeframe

Day 1 (randomization) to 40 months

End point values	Azacitidine (AZA)	Conventional Care Regimens (CCR)
Number of subjects analysed	157	134
Units: hospitalizations per patient year
number (not applicable)	7.95	4.82

No statistical analyses for this end point

Secondary: HRU: Number of Subjects Receiving Transfusions

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End point title

HRU: Number of Subjects Receiving Transfusions

End point description

Count of study participants who had transfusions during the treatment phase. HRU is defined as any consumption of healthcare resources directly or indirectly related to the treatment of the patient. HRU Analysis may help in evaluating potential costs and budget impact of new treatments from a payer perspective. HRU was analyzed for the HRQoL Evaluable Population, a smaller sample than either the ITT population or safety population.

End point type

Secondary

End point timeframe

Day 1 (randomization) to 40 months

End point values	Azacitidine (AZA)	Conventional Care Regimens (CCR)
Number of subjects analysed	157	134
Units: subjects	154	134

No statistical analyses for this end point

Secondary: HRU: Rate of Transfusions per Patient Year

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End point title

HRU: Rate of Transfusions per Patient Year

End point description

HRU is defined as any consumption of healthcare resources directly or indirectly related to the treatment of the patient. HRU Analysis may help in evaluating potential costs and budget impact of new treatments from a payer perspective. The rate of transfusions per patient year was calculated as the total number of transfusions divided by the total number of patient-years followed in the study period. Patient-years (PY) were calculated as the duration from baseline to last available HRQL assessment for each patient. HRU was analyzed for the HRQoL Evaluable Population, a smaller sample than either the ITT population or safety population. Duration of therapy differed between treatment groups. Rate-per-patient year values adjust for these differences.

End point type

Secondary

End point timeframe

Day 1 (randomization) to 40 months

End point values	Azacitidine (AZA)	Conventional Care Regimens (CCR)
Number of subjects analysed	157	134
Units: Transfusions per Patient Year
number (not applicable)	34.23	36.04

No statistical analyses for this end point

Secondary: Number of Participants in the Extension Phase With Treatment Emergent Adverse Events (TEAEs)

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End point title

Number of Participants in the Extension Phase With Treatment Emergent Adverse Events (TEAEs)

End point description

End point type

Secondary

End point timeframe

From the date of informed consent for the Extension Phase of the study through to the date of last dose of study drug + 28 days up to last visit completed 25 July 2016; maximum duration of exposure to Azacitidine in the extension phase was 871 days

End point values	Azacitidine (AZA)
Number of subjects analysed	22
Units: participants
At least one Treatment Emergent AE	20
At least one TEAE related to study drug	13
At least one Grade 3-4 adverse event	13
At least 1 Grade 3-4 TEAE related to study drug	7
At least 1 Grade 5 TEAE	4
At least 1 Grade 5 TEAE related to study drug	0
At least 1 serious TEAE	10
At least 1 serious TEAE related to study drug	1
At least one serious Grade 3-4 TEAE	8
TEAE leading to discontinuation of study drug	3
Study drug-related TEAE leading to discontinuation	1
TEAE leading to study drug dose reduction	1
TEAE leading to study drug dose interruption only	17
TEAE causing study dose reduction/interruption	2

No statistical analyses for this end point

Adverse events

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Timeframe for reporting adverse events

From first dose to 1) last dose + 28 days for azacitidine and low-dose cytarabine; 2) last dose + 70 days for intensive chemotherapy; 3) discontinuation for BSC only;median duration was 191.5, 65.0, 125.0, 124.5 and 360.0 days for each group respectively

Adverse event reporting additional description

Adverse Events reported for the Azacitidone treatment group are those that occurred in the treatment phase, adverse events reported in the Azacitidine extension group occurred during the extension phase

Assessment type

Systematic

Dictionary name

MedDRA

Dictionary version

16.1

Reporting group title

Azacitidine

Reporting group description

Azacitidine 75 mg/m2/day by subcutaneous injection [SC] for 7 days every 28 days, with a 21 day rest period (optimally for at least 6 cycles) plus best supportive care as needed, including antibiotics and blood product transfusions, growth factors, per physician's discretion.

Reporting group title

BSC Only

Reporting group description

BSC only = transfusion of blood products, antibiotics, antifungals and nutritional supplements

Reporting group title

Low-dose Cytarabine

Reporting group description

Low-dose cytarabine 20 mg subcutaneously twice a day (BID) for 10 days every 28 days, plus BSC

Reporting group title

Intensive Chemotherapy

Reporting group description

Intensive Chemotherapy: Cytarabine 100-200 mg/m2 as a continuous intravenous infusion (CIVI) for 7 days and daunorubicin 45 to 60 mg/m2 daily (QD) IV on Days 1, 2 and 3 or Idarubicin 9-12 mg/m2 IV QD for 3 days. Consolidation Therapy (Cycle 2 and 3) = Cytarabine 100-200 mg/m2 as a CIVI for 3 to 7 days and daunorubicin 45 to 60 mg/m2 QD or Idarubicin 9-12 mg/m2 IV QD on Days 1 and 2. The first consolidation therapy started between Day 28 and Day 70 from start of induction therapy, upon recovery of absolute neutrophil count (ANC) above 1.0 x 10^9/L and platelets above 75 x 10^9/L. The second cycle started between Day 28 and Day 70 from start of first consolidation therapy. Best supportive care (BSC) of antibiotics and transfusions, were given as needed

Reporting group title

Azacitidine-extension

Reporting group description

Serious adverse events	Azacitidine	BSC Only	Low-dose Cytarabine	Intensive Chemotherapy	Azacitidine-extension
Total subjects affected by serious adverse events
subjects affected / exposed	188 / 236 (79.66%)	30 / 40 (75.00%)	118 / 153 (77.12%)	27 / 42 (64.29%)	10 / 22 (45.45%)
number of deaths (all causes)	56	23	38	9	4
number of deaths resulting from adverse events	12	0	10	4	0
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
ACUTE MYELOID LEUKAEMIA
subjects affected / exposed	26 / 236 (11.02%)	12 / 40 (30.00%)	17 / 153 (11.11%)	0 / 42 (0.00%)	1 / 22 (4.55%)
occurrences causally related to treatment / all	1 / 34	0 / 17	2 / 22	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 12	0 / 10	1 / 10	0 / 0	0 / 1
CHLOROMA
subjects affected / exposed	2 / 236 (0.85%)	0 / 40 (0.00%)	0 / 153 (0.00%)	0 / 42 (0.00%)	0 / 22 (0.00%)
occurrences causally related to treatment / all	0 / 2	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
LEUKAEMIC INFILTRATION BRAIN
subjects affected / exposed	0 / 236 (0.00%)	0 / 40 (0.00%)	1 / 153 (0.65%)	0 / 42 (0.00%)	0 / 22 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
OVARIAN CANCER METASTATIC
subjects affected / exposed	1 / 236 (0.42%)	0 / 40 (0.00%)	0 / 153 (0.00%)	0 / 42 (0.00%)	0 / 22 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
TUMOUR FLARE
subjects affected / exposed	1 / 236 (0.42%)	0 / 40 (0.00%)	0 / 153 (0.00%)	0 / 42 (0.00%)	0 / 22 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Vascular disorders
DEEP VEIN THROMBOSIS
subjects affected / exposed	2 / 236 (0.85%)	1 / 40 (2.50%)	0 / 153 (0.00%)	0 / 42 (0.00%)	0 / 22 (0.00%)
occurrences causally related to treatment / all	0 / 2	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
HAEMATOMA
subjects affected / exposed	2 / 236 (0.85%)	0 / 40 (0.00%)	0 / 153 (0.00%)	0 / 42 (0.00%)	0 / 22 (0.00%)
occurrences causally related to treatment / all	0 / 2	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
HYPERTENSION
subjects affected / exposed	1 / 236 (0.42%)	0 / 40 (0.00%)	0 / 153 (0.00%)	0 / 42 (0.00%)	0 / 22 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
HYPOTENSION
subjects affected / exposed	4 / 236 (1.69%)	1 / 40 (2.50%)	0 / 153 (0.00%)	0 / 42 (0.00%)	0 / 22 (0.00%)
occurrences causally related to treatment / all	2 / 4	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0
PERIPHERAL ISCHAEMIA
subjects affected / exposed	1 / 236 (0.42%)	0 / 40 (0.00%)	0 / 153 (0.00%)	0 / 42 (0.00%)	0 / 22 (0.00%)
occurrences causally related to treatment / all	1 / 1	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
PHLEBITIS
subjects affected / exposed	1 / 236 (0.42%)	0 / 40 (0.00%)	0 / 153 (0.00%)	0 / 42 (0.00%)	0 / 22 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
THROMBOPHLEBITIS SUPERFICIAL
subjects affected / exposed	1 / 236 (0.42%)	0 / 40 (0.00%)	0 / 153 (0.00%)	0 / 42 (0.00%)	0 / 22 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
General disorders and administration site conditions
ASTHENIA
subjects affected / exposed	4 / 236 (1.69%)	1 / 40 (2.50%)	3 / 153 (1.96%)	0 / 42 (0.00%)	0 / 22 (0.00%)
occurrences causally related to treatment / all	3 / 4	0 / 1	0 / 3	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
CHEST PAIN
subjects affected / exposed	0 / 236 (0.00%)	0 / 40 (0.00%)	2 / 153 (1.31%)	1 / 42 (2.38%)	0 / 22 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	3 / 3	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
CHILLS
subjects affected / exposed	1 / 236 (0.42%)	0 / 40 (0.00%)	1 / 153 (0.65%)	0 / 42 (0.00%)	0 / 22 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
DEATH
subjects affected / exposed	3 / 236 (1.27%)	0 / 40 (0.00%)	2 / 153 (1.31%)	0 / 42 (0.00%)	0 / 22 (0.00%)
occurrences causally related to treatment / all	1 / 3	0 / 0	0 / 2	0 / 0	0 / 0
deaths causally related to treatment / all	1 / 3	0 / 0	0 / 2	0 / 0	0 / 0
FATIGUE
subjects affected / exposed	3 / 236 (1.27%)	0 / 40 (0.00%)	1 / 153 (0.65%)	1 / 42 (2.38%)	0 / 22 (0.00%)
occurrences causally related to treatment / all	2 / 3	0 / 0	0 / 1	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
GENERAL PHYSICAL HEALTH DETERIORATION
subjects affected / exposed	1 / 236 (0.42%)	0 / 40 (0.00%)	1 / 153 (0.65%)	0 / 42 (0.00%)	0 / 22 (0.00%)
occurrences causally related to treatment / all	1 / 1	0 / 0	1 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
HYPERTHERMIA
subjects affected / exposed	1 / 236 (0.42%)	0 / 40 (0.00%)	0 / 153 (0.00%)	0 / 42 (0.00%)	0 / 22 (0.00%)
occurrences causally related to treatment / all	1 / 1	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
INJECTION SITE EXTRAVASATION
subjects affected / exposed	1 / 236 (0.42%)	0 / 40 (0.00%)	0 / 153 (0.00%)	0 / 42 (0.00%)	0 / 22 (0.00%)
occurrences causally related to treatment / all	1 / 1	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
INJECTION SITE REACTION
subjects affected / exposed	2 / 236 (0.85%)	0 / 40 (0.00%)	0 / 153 (0.00%)	0 / 42 (0.00%)	0 / 22 (0.00%)
occurrences causally related to treatment / all	2 / 2	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
MALAISE
subjects affected / exposed	1 / 236 (0.42%)	0 / 40 (0.00%)	0 / 153 (0.00%)	0 / 42 (0.00%)	0 / 22 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
MULTI-ORGAN FAILURE
subjects affected / exposed	1 / 236 (0.42%)	0 / 40 (0.00%)	2 / 153 (1.31%)	0 / 42 (0.00%)	0 / 22 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 3	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 1	0 / 0	0 / 1	0 / 0	0 / 0
OEDEMA PERIPHERAL
subjects affected / exposed	0 / 236 (0.00%)	1 / 40 (2.50%)	0 / 153 (0.00%)	0 / 42 (0.00%)	0 / 22 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
PAIN
subjects affected / exposed	1 / 236 (0.42%)	0 / 40 (0.00%)	1 / 153 (0.65%)	0 / 42 (0.00%)	0 / 22 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
PYREXIA
subjects affected / exposed	25 / 236 (10.59%)	3 / 40 (7.50%)	16 / 153 (10.46%)	2 / 42 (4.76%)	0 / 22 (0.00%)
occurrences causally related to treatment / all	13 / 35	0 / 3	7 / 21	0 / 2	0 / 0
deaths causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 1	0 / 0
SUDDEN CARDIAC DEATH
subjects affected / exposed	1 / 236 (0.42%)	0 / 40 (0.00%)	1 / 153 (0.65%)	0 / 42 (0.00%)	0 / 22 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	1 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 1	0 / 0	1 / 1	0 / 0	0 / 0
SUDDEN DEATH
subjects affected / exposed	2 / 236 (0.85%)	0 / 40 (0.00%)	0 / 153 (0.00%)	0 / 42 (0.00%)	0 / 22 (0.00%)
occurrences causally related to treatment / all	1 / 2	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	1 / 2	0 / 0	0 / 0	0 / 0	0 / 0
Immune system disorders
ANAPHYLACTIC SHOCK
subjects affected / exposed	1 / 236 (0.42%)	0 / 40 (0.00%)	0 / 153 (0.00%)	0 / 42 (0.00%)	0 / 22 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Respiratory, thoracic and mediastinal disorders
ACUTE PULMONARY OEDEMA
subjects affected / exposed	1 / 236 (0.42%)	0 / 40 (0.00%)	1 / 153 (0.65%)	0 / 42 (0.00%)	0 / 22 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
ACUTE RESPIRATORY DISTRESS SYNDROME
subjects affected / exposed	1 / 236 (0.42%)	0 / 40 (0.00%)	0 / 153 (0.00%)	1 / 42 (2.38%)	0 / 22 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0
ACUTE RESPIRATORY FAILURE
subjects affected / exposed	2 / 236 (0.85%)	0 / 40 (0.00%)	0 / 153 (0.00%)	1 / 42 (2.38%)	0 / 22 (0.00%)
occurrences causally related to treatment / all	0 / 2	0 / 0	0 / 0	1 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
ASTHMA
subjects affected / exposed	0 / 236 (0.00%)	1 / 40 (2.50%)	0 / 153 (0.00%)	0 / 42 (0.00%)	0 / 22 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
CHRONIC OBSTRUCTIVE PULMONARY DISEASE
subjects affected / exposed	0 / 236 (0.00%)	0 / 40 (0.00%)	1 / 153 (0.65%)	0 / 42 (0.00%)	0 / 22 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 3	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
DYSPNOEA
subjects affected / exposed	5 / 236 (2.12%)	1 / 40 (2.50%)	3 / 153 (1.96%)	1 / 42 (2.38%)	0 / 22 (0.00%)
occurrences causally related to treatment / all	1 / 5	0 / 1	0 / 3	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
EPISTAXIS
subjects affected / exposed	2 / 236 (0.85%)	0 / 40 (0.00%)	1 / 153 (0.65%)	0 / 42 (0.00%)	0 / 22 (0.00%)
occurrences causally related to treatment / all	0 / 2	0 / 0	1 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
LUNG DISORDER
subjects affected / exposed	1 / 236 (0.42%)	0 / 40 (0.00%)	2 / 153 (1.31%)	0 / 42 (0.00%)	0 / 22 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	1 / 2	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
ORGANISING PNEUMONIA
subjects affected / exposed	1 / 236 (0.42%)	0 / 40 (0.00%)	0 / 153 (0.00%)	0 / 42 (0.00%)	0 / 22 (0.00%)
occurrences causally related to treatment / all	1 / 1	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
OROPHARYNGEAL PAIN
subjects affected / exposed	1 / 236 (0.42%)	0 / 40 (0.00%)	0 / 153 (0.00%)	0 / 42 (0.00%)	0 / 22 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
PLEURAL EFFUSION
subjects affected / exposed	2 / 236 (0.85%)	0 / 40 (0.00%)	2 / 153 (1.31%)	1 / 42 (2.38%)	0 / 22 (0.00%)
occurrences causally related to treatment / all	1 / 2	0 / 0	0 / 3	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0
PNEUMONIA ASPIRATION
subjects affected / exposed	0 / 236 (0.00%)	1 / 40 (2.50%)	0 / 153 (0.00%)	0 / 42 (0.00%)	0 / 22 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 2	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0
PNEUMONITIS
subjects affected / exposed	1 / 236 (0.42%)	0 / 40 (0.00%)	1 / 153 (0.65%)	0 / 42 (0.00%)	0 / 22 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 2	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
PRODUCTIVE COUGH
subjects affected / exposed	1 / 236 (0.42%)	0 / 40 (0.00%)	0 / 153 (0.00%)	0 / 42 (0.00%)	0 / 22 (0.00%)
occurrences causally related to treatment / all	1 / 1	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
PULMONARY ALVEOLAR HAEMORRHAGE
subjects affected / exposed	1 / 236 (0.42%)	0 / 40 (0.00%)	0 / 153 (0.00%)	0 / 42 (0.00%)	0 / 22 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0
PULMONARY EMBOLISM
subjects affected / exposed	1 / 236 (0.42%)	0 / 40 (0.00%)	1 / 153 (0.65%)	0 / 42 (0.00%)	0 / 22 (0.00%)
occurrences causally related to treatment / all	0 / 2	0 / 0	0 / 3	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
PULMONARY HAEMORRHAGE
subjects affected / exposed	0 / 236 (0.00%)	1 / 40 (2.50%)	1 / 153 (0.65%)	0 / 42 (0.00%)	0 / 22 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 2	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 1	0 / 1	0 / 0	0 / 0
PULMONARY OEDEMA
subjects affected / exposed	2 / 236 (0.85%)	0 / 40 (0.00%)	2 / 153 (1.31%)	0 / 42 (0.00%)	0 / 22 (0.00%)
occurrences causally related to treatment / all	0 / 2	0 / 0	1 / 2	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
RESPIRATORY FAILURE
subjects affected / exposed	3 / 236 (1.27%)	1 / 40 (2.50%)	6 / 153 (3.92%)	2 / 42 (4.76%)	0 / 22 (0.00%)
occurrences causally related to treatment / all	3 / 4	0 / 1	3 / 7	0 / 3	0 / 0
deaths causally related to treatment / all	1 / 2	0 / 1	1 / 1	0 / 2	0 / 0
Psychiatric disorders
CONFUSIONAL STATE
subjects affected / exposed	1 / 236 (0.42%)	0 / 40 (0.00%)	0 / 153 (0.00%)	0 / 42 (0.00%)	0 / 22 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Investigations
TROPONIN INCREASED
subjects affected / exposed	0 / 236 (0.00%)	0 / 40 (0.00%)	0 / 153 (0.00%)	1 / 42 (2.38%)	0 / 22 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
URINE OUTPUT DECREASED
subjects affected / exposed	0 / 236 (0.00%)	1 / 40 (2.50%)	0 / 153 (0.00%)	0 / 42 (0.00%)	0 / 22 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0
WEIGHT DECREASED
subjects affected / exposed	0 / 236 (0.00%)	0 / 40 (0.00%)	1 / 153 (0.65%)	0 / 42 (0.00%)	0 / 22 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Injury, poisoning and procedural complications
ALLERGIC TRANSFUSION REACTION
subjects affected / exposed	0 / 236 (0.00%)	0 / 40 (0.00%)	1 / 153 (0.65%)	0 / 42 (0.00%)	0 / 22 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
ANKLE FRACTURE
subjects affected / exposed	1 / 236 (0.42%)	0 / 40 (0.00%)	0 / 153 (0.00%)	0 / 42 (0.00%)	0 / 22 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
CONCUSSION
subjects affected / exposed	1 / 236 (0.42%)	0 / 40 (0.00%)	0 / 153 (0.00%)	0 / 42 (0.00%)	0 / 22 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
CRANIOCEREBRAL INJURY
subjects affected / exposed	1 / 236 (0.42%)	0 / 40 (0.00%)	0 / 153 (0.00%)	0 / 42 (0.00%)	0 / 22 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
FALL
subjects affected / exposed	2 / 236 (0.85%)	0 / 40 (0.00%)	0 / 153 (0.00%)	0 / 42 (0.00%)	0 / 22 (0.00%)
occurrences causally related to treatment / all	0 / 2	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
FEMUR FRACTURE
subjects affected / exposed	1 / 236 (0.42%)	0 / 40 (0.00%)	1 / 153 (0.65%)	0 / 42 (0.00%)	0 / 22 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
HIP FRACTURE
subjects affected / exposed	0 / 236 (0.00%)	0 / 40 (0.00%)	1 / 153 (0.65%)	0 / 42 (0.00%)	0 / 22 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
LIGAMENT SPRAIN
subjects affected / exposed	1 / 236 (0.42%)	0 / 40 (0.00%)	0 / 153 (0.00%)	0 / 42 (0.00%)	0 / 22 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
RIB FRACTURE
subjects affected / exposed	1 / 236 (0.42%)	0 / 40 (0.00%)	0 / 153 (0.00%)	0 / 42 (0.00%)	0 / 22 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
ROAD TRAFFIC ACCIDENT
subjects affected / exposed	1 / 236 (0.42%)	0 / 40 (0.00%)	0 / 153 (0.00%)	0 / 42 (0.00%)	0 / 22 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0
SUBDURAL HAEMATOMA
subjects affected / exposed	1 / 236 (0.42%)	0 / 40 (0.00%)	0 / 153 (0.00%)	0 / 42 (0.00%)	0 / 22 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
TENDON RUPTURE
subjects affected / exposed	1 / 236 (0.42%)	0 / 40 (0.00%)	0 / 153 (0.00%)	0 / 42 (0.00%)	0 / 22 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
TRANSFUSION REACTION
subjects affected / exposed	1 / 236 (0.42%)	0 / 40 (0.00%)	0 / 153 (0.00%)	0 / 42 (0.00%)	0 / 22 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Cardiac disorders
ACUTE CORONARY SYNDROME
subjects affected / exposed	2 / 236 (0.85%)	0 / 40 (0.00%)	1 / 153 (0.65%)	0 / 42 (0.00%)	0 / 22 (0.00%)
occurrences causally related to treatment / all	0 / 2	0 / 0	0 / 2	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 1	0 / 0	0 / 1	0 / 0	0 / 0
ACUTE LEFT VENTRICULAR FAILURE
subjects affected / exposed	1 / 236 (0.42%)	0 / 40 (0.00%)	0 / 153 (0.00%)	0 / 42 (0.00%)	0 / 22 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
ACUTE MYOCARDIAL INFARCTION
subjects affected / exposed	3 / 236 (1.27%)	0 / 40 (0.00%)	0 / 153 (0.00%)	1 / 42 (2.38%)	0 / 22 (0.00%)
occurrences causally related to treatment / all	0 / 4	0 / 0	0 / 0	1 / 1	0 / 0
deaths causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0
ANGINA PECTORIS
subjects affected / exposed	0 / 236 (0.00%)	0 / 40 (0.00%)	1 / 153 (0.65%)	0 / 42 (0.00%)	1 / 22 (4.55%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
ATRIAL FIBRILLATION
subjects affected / exposed	7 / 236 (2.97%)	1 / 40 (2.50%)	3 / 153 (1.96%)	2 / 42 (4.76%)	0 / 22 (0.00%)
occurrences causally related to treatment / all	0 / 7	0 / 1	0 / 4	2 / 3	0 / 0
deaths causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0
CARDIAC ARREST
subjects affected / exposed	0 / 236 (0.00%)	0 / 40 (0.00%)	1 / 153 (0.65%)	0 / 42 (0.00%)	0 / 22 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 2	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0
CARDIAC FAILURE
subjects affected / exposed	2 / 236 (0.85%)	0 / 40 (0.00%)	1 / 153 (0.65%)	1 / 42 (2.38%)	0 / 22 (0.00%)
occurrences causally related to treatment / all	1 / 2	0 / 0	0 / 2	1 / 1	0 / 0
deaths causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0
CARDIAC FAILURE ACUTE
subjects affected / exposed	0 / 236 (0.00%)	0 / 40 (0.00%)	0 / 153 (0.00%)	1 / 42 (2.38%)	0 / 22 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	2 / 2	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	1 / 1	0 / 0
CARDIAC FAILURE CONGESTIVE
subjects affected / exposed	0 / 236 (0.00%)	1 / 40 (2.50%)	0 / 153 (0.00%)	0 / 42 (0.00%)	0 / 22 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
CARDIO-RESPIRATORY ARREST
subjects affected / exposed	1 / 236 (0.42%)	0 / 40 (0.00%)	0 / 153 (0.00%)	0 / 42 (0.00%)	0 / 22 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0
CARDIOVASCULAR INSUFFICIENCY
subjects affected / exposed	1 / 236 (0.42%)	0 / 40 (0.00%)	2 / 153 (1.31%)	1 / 42 (2.38%)	0 / 22 (0.00%)
occurrences causally related to treatment / all	1 / 1	0 / 0	2 / 2	1 / 1	0 / 0
deaths causally related to treatment / all	1 / 1	0 / 0	1 / 1	1 / 1	0 / 0
ISCHAEMIC CARDIOMYOPATHY
subjects affected / exposed	1 / 236 (0.42%)	0 / 40 (0.00%)	0 / 153 (0.00%)	0 / 42 (0.00%)	0 / 22 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
LEFT VENTRICULAR FAILURE
subjects affected / exposed	1 / 236 (0.42%)	0 / 40 (0.00%)	0 / 153 (0.00%)	0 / 42 (0.00%)	0 / 22 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
MYOCARDIAL INFARCTION
subjects affected / exposed	0 / 236 (0.00%)	0 / 40 (0.00%)	1 / 153 (0.65%)	0 / 42 (0.00%)	1 / 22 (4.55%)
occurrences causally related to treatment / all	0 / 0	0 / 0	2 / 2	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	1 / 1	0 / 0	0 / 0
PERICARDIAL EFFUSION
subjects affected / exposed	1 / 236 (0.42%)	0 / 40 (0.00%)	0 / 153 (0.00%)	1 / 42 (2.38%)	0 / 22 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
PERICARDITIS
subjects affected / exposed	1 / 236 (0.42%)	0 / 40 (0.00%)	1 / 153 (0.65%)	0 / 42 (0.00%)	0 / 22 (0.00%)
occurrences causally related to treatment / all	1 / 1	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
SUPRAVENTRICULAR TACHYCARDIA
subjects affected / exposed	0 / 236 (0.00%)	0 / 40 (0.00%)	1 / 153 (0.65%)	0 / 42 (0.00%)	0 / 22 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	1 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
VENTRICULAR TACHYCARDIA
subjects affected / exposed	1 / 236 (0.42%)	0 / 40 (0.00%)	0 / 153 (0.00%)	0 / 42 (0.00%)	0 / 22 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Nervous system disorders
CEREBRAL HAEMORRHAGE
subjects affected / exposed	1 / 236 (0.42%)	2 / 40 (5.00%)	0 / 153 (0.00%)	1 / 42 (2.38%)	0 / 22 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 4	0 / 0	2 / 2	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 2	0 / 0	1 / 1	0 / 0
CEREBRAL INFARCTION
subjects affected / exposed	2 / 236 (0.85%)	0 / 40 (0.00%)	0 / 153 (0.00%)	0 / 42 (0.00%)	1 / 22 (4.55%)
occurrences causally related to treatment / all	0 / 2	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1
CEREBROVASCULAR ACCIDENT
subjects affected / exposed	1 / 236 (0.42%)	0 / 40 (0.00%)	2 / 153 (1.31%)	0 / 42 (0.00%)	0 / 22 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 2	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0
COGNITIVE DISORDER
subjects affected / exposed	1 / 236 (0.42%)	0 / 40 (0.00%)	0 / 153 (0.00%)	0 / 42 (0.00%)	0 / 22 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
CONVULSION
subjects affected / exposed	1 / 236 (0.42%)	0 / 40 (0.00%)	0 / 153 (0.00%)	0 / 42 (0.00%)	0 / 22 (0.00%)
occurrences causally related to treatment / all	1 / 1	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
DIZZINESS
subjects affected / exposed	5 / 236 (2.12%)	0 / 40 (0.00%)	0 / 153 (0.00%)	0 / 42 (0.00%)	1 / 22 (4.55%)
occurrences causally related to treatment / all	0 / 6	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
FEBRILE CONVULSION
subjects affected / exposed	0 / 236 (0.00%)	1 / 40 (2.50%)	0 / 153 (0.00%)	0 / 42 (0.00%)	0 / 22 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
HAEMORRHAGE INTRACRANIAL
subjects affected / exposed	2 / 236 (0.85%)	0 / 40 (0.00%)	0 / 153 (0.00%)	1 / 42 (2.38%)	0 / 22 (0.00%)
occurrences causally related to treatment / all	0 / 3	0 / 0	0 / 0	0 / 2	0 / 0
deaths causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 1	0 / 0
HEADACHE
subjects affected / exposed	1 / 236 (0.42%)	0 / 40 (0.00%)	0 / 153 (0.00%)	0 / 42 (0.00%)	0 / 22 (0.00%)
occurrences causally related to treatment / all	1 / 1	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
LOSS OF CONSCIOUSNESS
subjects affected / exposed	1 / 236 (0.42%)	0 / 40 (0.00%)	0 / 153 (0.00%)	0 / 42 (0.00%)	0 / 22 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
ORTHOSTATIC INTOLERANCE
subjects affected / exposed	1 / 236 (0.42%)	0 / 40 (0.00%)	0 / 153 (0.00%)	0 / 42 (0.00%)	0 / 22 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
PRESYNCOPE
subjects affected / exposed	2 / 236 (0.85%)	1 / 40 (2.50%)	0 / 153 (0.00%)	0 / 42 (0.00%)	0 / 22 (0.00%)
occurrences causally related to treatment / all	0 / 2	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
SUBARACHNOID HAEMORRHAGE
subjects affected / exposed	2 / 236 (0.85%)	0 / 40 (0.00%)	0 / 153 (0.00%)	0 / 42 (0.00%)	0 / 22 (0.00%)
occurrences causally related to treatment / all	0 / 2	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
SYNCOPE
subjects affected / exposed	4 / 236 (1.69%)	0 / 40 (0.00%)	2 / 153 (1.31%)	1 / 42 (2.38%)	1 / 22 (4.55%)
occurrences causally related to treatment / all	1 / 5	0 / 0	1 / 2	0 / 1	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
TRANSIENT ISCHAEMIC ATTACK
subjects affected / exposed	0 / 236 (0.00%)	0 / 40 (0.00%)	1 / 153 (0.65%)	0 / 42 (0.00%)	0 / 22 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Blood and lymphatic system disorders
AGRANULOCYTOSIS
subjects affected / exposed	0 / 236 (0.00%)	0 / 40 (0.00%)	1 / 153 (0.65%)	0 / 42 (0.00%)	0 / 22 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	1 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
ANAEMIA
subjects affected / exposed	10 / 236 (4.24%)	1 / 40 (2.50%)	11 / 153 (7.19%)	0 / 42 (0.00%)	1 / 22 (4.55%)
occurrences causally related to treatment / all	9 / 12	0 / 1	10 / 15	0 / 0	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
DISSEMINATED INTRAVASCULAR COAGULATION
subjects affected / exposed	1 / 236 (0.42%)	0 / 40 (0.00%)	0 / 153 (0.00%)	0 / 42 (0.00%)	0 / 22 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
FEBRILE BONE MARROW APLASIA
subjects affected / exposed	2 / 236 (0.85%)	0 / 40 (0.00%)	3 / 153 (1.96%)	0 / 42 (0.00%)	0 / 22 (0.00%)
occurrences causally related to treatment / all	0 / 3	0 / 0	3 / 3	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
FEBRILE NEUTROPENIA
subjects affected / exposed	59 / 236 (25.00%)	12 / 40 (30.00%)	38 / 153 (24.84%)	7 / 42 (16.67%)	4 / 22 (18.18%)
occurrences causally related to treatment / all	34 / 90	0 / 14	30 / 55	5 / 7	0 / 5
deaths causally related to treatment / all	0 / 2	0 / 0	0 / 0	0 / 0	0 / 1
LEUKOCYTOSIS
subjects affected / exposed	4 / 236 (1.69%)	0 / 40 (0.00%)	1 / 153 (0.65%)	0 / 42 (0.00%)	0 / 22 (0.00%)
occurrences causally related to treatment / all	0 / 4	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
LEUKOPENIA
subjects affected / exposed	1 / 236 (0.42%)	0 / 40 (0.00%)	2 / 153 (1.31%)	0 / 42 (0.00%)	0 / 22 (0.00%)
occurrences causally related to treatment / all	1 / 1	0 / 0	2 / 2	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
LYMPHADENOPATHY
subjects affected / exposed	1 / 236 (0.42%)	0 / 40 (0.00%)	0 / 153 (0.00%)	0 / 42 (0.00%)	0 / 22 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
NEUTROPENIA
subjects affected / exposed	5 / 236 (2.12%)	1 / 40 (2.50%)	3 / 153 (1.96%)	1 / 42 (2.38%)	0 / 22 (0.00%)
occurrences causally related to treatment / all	4 / 5	0 / 1	2 / 3	2 / 2	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
PANCYTOPENIA
subjects affected / exposed	0 / 236 (0.00%)	0 / 40 (0.00%)	1 / 153 (0.65%)	0 / 42 (0.00%)	0 / 22 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	1 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
THROMBOCYTOPENIA
subjects affected / exposed	6 / 236 (2.54%)	0 / 40 (0.00%)	14 / 153 (9.15%)	0 / 42 (0.00%)	0 / 22 (0.00%)
occurrences causally related to treatment / all	4 / 7	0 / 0	12 / 17	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
THROMBOTIC THROMBOCYTOPENIC PURPURA
subjects affected / exposed	1 / 236 (0.42%)	0 / 40 (0.00%)	0 / 153 (0.00%)	0 / 42 (0.00%)	0 / 22 (0.00%)
occurrences causally related to treatment / all	1 / 1	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Eye disorders
CATARACT
subjects affected / exposed	1 / 236 (0.42%)	0 / 40 (0.00%)	0 / 153 (0.00%)	0 / 42 (0.00%)	0 / 22 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
CONJUNCTIVAL HAEMORRHAGE
subjects affected / exposed	1 / 236 (0.42%)	0 / 40 (0.00%)	0 / 153 (0.00%)	0 / 42 (0.00%)	0 / 22 (0.00%)
occurrences causally related to treatment / all	1 / 1	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Gastrointestinal disorders
ABDOMINAL PAIN
subjects affected / exposed	1 / 236 (0.42%)	0 / 40 (0.00%)	1 / 153 (0.65%)	0 / 42 (0.00%)	1 / 22 (4.55%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 1	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
ABDOMINAL PAIN LOWER
subjects affected / exposed	0 / 236 (0.00%)	0 / 40 (0.00%)	2 / 153 (1.31%)	0 / 42 (0.00%)	0 / 22 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 2	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
ANAL HAEMORRHAGE
subjects affected / exposed	0 / 236 (0.00%)	1 / 40 (2.50%)	1 / 153 (0.65%)	0 / 42 (0.00%)	0 / 22 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
ASCITES
subjects affected / exposed	0 / 236 (0.00%)	0 / 40 (0.00%)	0 / 153 (0.00%)	1 / 42 (2.38%)	0 / 22 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
COLITIS
subjects affected / exposed	1 / 236 (0.42%)	0 / 40 (0.00%)	0 / 153 (0.00%)	0 / 42 (0.00%)	0 / 22 (0.00%)
occurrences causally related to treatment / all	2 / 2	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
CONSTIPATION
subjects affected / exposed	0 / 236 (0.00%)	0 / 40 (0.00%)	0 / 153 (0.00%)	0 / 42 (0.00%)	1 / 22 (4.55%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
DIARRHOEA
subjects affected / exposed	4 / 236 (1.69%)	0 / 40 (0.00%)	4 / 153 (2.61%)	0 / 42 (0.00%)	0 / 22 (0.00%)
occurrences causally related to treatment / all	2 / 4	0 / 0	4 / 5	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	1 / 1	0 / 0	0 / 0
DIVERTICULUM INTESTINAL
subjects affected / exposed	1 / 236 (0.42%)	0 / 40 (0.00%)	0 / 153 (0.00%)	0 / 42 (0.00%)	0 / 22 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
DUODENAL ULCER HAEMORRHAGE
subjects affected / exposed	0 / 236 (0.00%)	0 / 40 (0.00%)	0 / 153 (0.00%)	0 / 42 (0.00%)	1 / 22 (4.55%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
DYSPHAGIA
subjects affected / exposed	0 / 236 (0.00%)	0 / 40 (0.00%)	1 / 153 (0.65%)	0 / 42 (0.00%)	0 / 22 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	1 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
ENTERITIS
subjects affected / exposed	0 / 236 (0.00%)	1 / 40 (2.50%)	0 / 153 (0.00%)	0 / 42 (0.00%)	0 / 22 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
ENTEROCOLITIS
subjects affected / exposed	1 / 236 (0.42%)	0 / 40 (0.00%)	0 / 153 (0.00%)	0 / 42 (0.00%)	0 / 22 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
GASTRITIS
subjects affected / exposed	1 / 236 (0.42%)	0 / 40 (0.00%)	0 / 153 (0.00%)	0 / 42 (0.00%)	0 / 22 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
GASTROINTESTINAL HAEMORRHAGE
subjects affected / exposed	1 / 236 (0.42%)	1 / 40 (2.50%)	4 / 153 (2.61%)	0 / 42 (0.00%)	0 / 22 (0.00%)
occurrences causally related to treatment / all	0 / 2	0 / 1	1 / 4	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 1	0 / 1	0 / 0	0 / 0	0 / 0
HAEMATEMESIS
subjects affected / exposed	1 / 236 (0.42%)	0 / 40 (0.00%)	0 / 153 (0.00%)	0 / 42 (0.00%)	0 / 22 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
ILEUS
subjects affected / exposed	1 / 236 (0.42%)	0 / 40 (0.00%)	0 / 153 (0.00%)	0 / 42 (0.00%)	0 / 22 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
INTESTINAL ISCHAEMIA
subjects affected / exposed	0 / 236 (0.00%)	0 / 40 (0.00%)	0 / 153 (0.00%)	0 / 42 (0.00%)	1 / 22 (4.55%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1
INTESTINAL OBSTRUCTION
subjects affected / exposed	1 / 236 (0.42%)	0 / 40 (0.00%)	0 / 153 (0.00%)	0 / 42 (0.00%)	0 / 22 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
MELAENA
subjects affected / exposed	1 / 236 (0.42%)	0 / 40 (0.00%)	1 / 153 (0.65%)	0 / 42 (0.00%)	0 / 22 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	1 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
MOUTH HAEMORRHAGE
subjects affected / exposed	1 / 236 (0.42%)	1 / 40 (2.50%)	0 / 153 (0.00%)	0 / 42 (0.00%)	0 / 22 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
NAUSEA
subjects affected / exposed	2 / 236 (0.85%)	0 / 40 (0.00%)	0 / 153 (0.00%)	0 / 42 (0.00%)	0 / 22 (0.00%)
occurrences causally related to treatment / all	0 / 2	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
RECTAL HAEMORRHAGE
subjects affected / exposed	1 / 236 (0.42%)	0 / 40 (0.00%)	1 / 153 (0.65%)	0 / 42 (0.00%)	0 / 22 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	1 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
RECTAL ULCER
subjects affected / exposed	1 / 236 (0.42%)	0 / 40 (0.00%)	0 / 153 (0.00%)	0 / 42 (0.00%)	0 / 22 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
STOMATITIS
subjects affected / exposed	1 / 236 (0.42%)	0 / 40 (0.00%)	0 / 153 (0.00%)	0 / 42 (0.00%)	1 / 22 (4.55%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
UPPER GASTROINTESTINAL HAEMORRHAGE
subjects affected / exposed	1 / 236 (0.42%)	0 / 40 (0.00%)	0 / 153 (0.00%)	0 / 42 (0.00%)	0 / 22 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
VOMITING
subjects affected / exposed	2 / 236 (0.85%)	0 / 40 (0.00%)	0 / 153 (0.00%)	0 / 42 (0.00%)	0 / 22 (0.00%)
occurrences causally related to treatment / all	2 / 2	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Hepatobiliary disorders
CHOLANGITIS
subjects affected / exposed	1 / 236 (0.42%)	0 / 40 (0.00%)	0 / 153 (0.00%)	0 / 42 (0.00%)	0 / 22 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
CHOLECYSTITIS
subjects affected / exposed	1 / 236 (0.42%)	0 / 40 (0.00%)	0 / 153 (0.00%)	0 / 42 (0.00%)	0 / 22 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
CHOLECYSTITIS ACUTE
subjects affected / exposed	1 / 236 (0.42%)	0 / 40 (0.00%)	1 / 153 (0.65%)	1 / 42 (2.38%)	0 / 22 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 1	0 / 2	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0
CHOLELITHIASIS
subjects affected / exposed	1 / 236 (0.42%)	0 / 40 (0.00%)	0 / 153 (0.00%)	0 / 42 (0.00%)	0 / 22 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
HEPATIC FAILURE
subjects affected / exposed	0 / 236 (0.00%)	0 / 40 (0.00%)	2 / 153 (1.31%)	0 / 42 (0.00%)	0 / 22 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 2	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
HYPERBILIRUBINAEMIA
subjects affected / exposed	0 / 236 (0.00%)	0 / 40 (0.00%)	0 / 153 (0.00%)	0 / 42 (0.00%)	1 / 22 (4.55%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Skin and subcutaneous tissue disorders
SKIN ULCER
subjects affected / exposed	1 / 236 (0.42%)	0 / 40 (0.00%)	0 / 153 (0.00%)	0 / 42 (0.00%)	0 / 22 (0.00%)
occurrences causally related to treatment / all	1 / 1	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Renal and urinary disorders
BLADDER MASS
subjects affected / exposed	1 / 236 (0.42%)	0 / 40 (0.00%)	0 / 153 (0.00%)	0 / 42 (0.00%)	0 / 22 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
HAEMATURIA
subjects affected / exposed	0 / 236 (0.00%)	1 / 40 (2.50%)	0 / 153 (0.00%)	0 / 42 (0.00%)	1 / 22 (4.55%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
RENAL COLIC
subjects affected / exposed	0 / 236 (0.00%)	0 / 40 (0.00%)	1 / 153 (0.65%)	0 / 42 (0.00%)	0 / 22 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
RENAL FAILURE
subjects affected / exposed	3 / 236 (1.27%)	0 / 40 (0.00%)	2 / 153 (1.31%)	0 / 42 (0.00%)	0 / 22 (0.00%)
occurrences causally related to treatment / all	2 / 4	0 / 0	0 / 2	0 / 0	0 / 0
deaths causally related to treatment / all	1 / 1	0 / 0	0 / 0	0 / 0	0 / 0
RENAL FAILURE ACUTE
subjects affected / exposed	3 / 236 (1.27%)	0 / 40 (0.00%)	2 / 153 (1.31%)	1 / 42 (2.38%)	0 / 22 (0.00%)
occurrences causally related to treatment / all	0 / 4	0 / 0	0 / 2	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0
RENAL FAILURE CHRONIC
subjects affected / exposed	0 / 236 (0.00%)	1 / 40 (2.50%)	0 / 153 (0.00%)	0 / 42 (0.00%)	0 / 22 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
RENAL IMPAIRMENT
subjects affected / exposed	0 / 236 (0.00%)	1 / 40 (2.50%)	0 / 153 (0.00%)	0 / 42 (0.00%)	0 / 22 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
RENAL TUBULAR NECROSIS
subjects affected / exposed	1 / 236 (0.42%)	0 / 40 (0.00%)	0 / 153 (0.00%)	0 / 42 (0.00%)	0 / 22 (0.00%)
occurrences causally related to treatment / all	0 / 2	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
URINARY RETENTION
subjects affected / exposed	0 / 236 (0.00%)	0 / 40 (0.00%)	1 / 153 (0.65%)	0 / 42 (0.00%)	0 / 22 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Musculoskeletal and connective tissue disorders
ARTHRALGIA
subjects affected / exposed	2 / 236 (0.85%)	0 / 40 (0.00%)	0 / 153 (0.00%)	0 / 42 (0.00%)	0 / 22 (0.00%)
occurrences causally related to treatment / all	0 / 4	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
ARTHRITIS
subjects affected / exposed	1 / 236 (0.42%)	0 / 40 (0.00%)	0 / 153 (0.00%)	0 / 42 (0.00%)	0 / 22 (0.00%)
occurrences causally related to treatment / all	0 / 2	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
BACK PAIN
subjects affected / exposed	3 / 236 (1.27%)	0 / 40 (0.00%)	1 / 153 (0.65%)	0 / 42 (0.00%)	0 / 22 (0.00%)
occurrences causally related to treatment / all	1 / 3	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
BONE PAIN
subjects affected / exposed	1 / 236 (0.42%)	0 / 40 (0.00%)	0 / 153 (0.00%)	0 / 42 (0.00%)	0 / 22 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
HAEMARTHROSIS
subjects affected / exposed	0 / 236 (0.00%)	0 / 40 (0.00%)	1 / 153 (0.65%)	0 / 42 (0.00%)	0 / 22 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
MUSCULAR WEAKNESS
subjects affected / exposed	2 / 236 (0.85%)	0 / 40 (0.00%)	0 / 153 (0.00%)	0 / 42 (0.00%)	0 / 22 (0.00%)
occurrences causally related to treatment / all	0 / 2	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
MYALGIA
subjects affected / exposed	1 / 236 (0.42%)	0 / 40 (0.00%)	0 / 153 (0.00%)	0 / 42 (0.00%)	0 / 22 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
OSTEOARTHRITIS
subjects affected / exposed	0 / 236 (0.00%)	0 / 40 (0.00%)	0 / 153 (0.00%)	0 / 42 (0.00%)	1 / 22 (4.55%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
PAIN IN EXTREMITY
subjects affected / exposed	0 / 236 (0.00%)	1 / 40 (2.50%)	0 / 153 (0.00%)	0 / 42 (0.00%)	0 / 22 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
SPINAL OSTEOARTHRITIS
subjects affected / exposed	0 / 236 (0.00%)	0 / 40 (0.00%)	1 / 153 (0.65%)	0 / 42 (0.00%)	0 / 22 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Infections and infestations
ABSCESS NECK
subjects affected / exposed	1 / 236 (0.42%)	0 / 40 (0.00%)	0 / 153 (0.00%)	0 / 42 (0.00%)	0 / 22 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
ABSCESS SOFT TISSUE
subjects affected / exposed	1 / 236 (0.42%)	0 / 40 (0.00%)	0 / 153 (0.00%)	0 / 42 (0.00%)	0 / 22 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
ACUTE SINUSITIS
subjects affected / exposed	1 / 236 (0.42%)	0 / 40 (0.00%)	0 / 153 (0.00%)	0 / 42 (0.00%)	0 / 22 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
AEROMONA INFECTION
subjects affected / exposed	0 / 236 (0.00%)	0 / 40 (0.00%)	1 / 153 (0.65%)	0 / 42 (0.00%)	0 / 22 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
ANAL ABSCESS
subjects affected / exposed	1 / 236 (0.42%)	0 / 40 (0.00%)	0 / 153 (0.00%)	0 / 42 (0.00%)	0 / 22 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
APPENDICITIS
subjects affected / exposed	1 / 236 (0.42%)	0 / 40 (0.00%)	0 / 153 (0.00%)	0 / 42 (0.00%)	0 / 22 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
ARTHRITIS INFECTIVE
subjects affected / exposed	1 / 236 (0.42%)	0 / 40 (0.00%)	0 / 153 (0.00%)	0 / 42 (0.00%)	0 / 22 (0.00%)
occurrences causally related to treatment / all	1 / 1	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
ASPERGILLUS INFECTION
subjects affected / exposed	0 / 236 (0.00%)	1 / 40 (2.50%)	0 / 153 (0.00%)	0 / 42 (0.00%)	0 / 22 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 2	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0
BACTERAEMIA
subjects affected / exposed	2 / 236 (0.85%)	0 / 40 (0.00%)	1 / 153 (0.65%)	0 / 42 (0.00%)	1 / 22 (4.55%)
occurrences causally related to treatment / all	0 / 2	0 / 0	0 / 1	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
BRONCHITIS
subjects affected / exposed	3 / 236 (1.27%)	0 / 40 (0.00%)	1 / 153 (0.65%)	0 / 42 (0.00%)	0 / 22 (0.00%)
occurrences causally related to treatment / all	2 / 4	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
BRONCHOPNEUMONIA
subjects affected / exposed	4 / 236 (1.69%)	1 / 40 (2.50%)	1 / 153 (0.65%)	0 / 42 (0.00%)	0 / 22 (0.00%)
occurrences causally related to treatment / all	2 / 4	0 / 1	0 / 2	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0
BRONCHOPULMONARY ASPERGILLOSIS
subjects affected / exposed	3 / 236 (1.27%)	1 / 40 (2.50%)	0 / 153 (0.00%)	0 / 42 (0.00%)	1 / 22 (4.55%)
occurrences causally related to treatment / all	1 / 4	0 / 1	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
CANDIDA INFECTION
subjects affected / exposed	0 / 236 (0.00%)	0 / 40 (0.00%)	1 / 153 (0.65%)	0 / 42 (0.00%)	0 / 22 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
CELLULITIS
subjects affected / exposed	5 / 236 (2.12%)	4 / 40 (10.00%)	3 / 153 (1.96%)	1 / 42 (2.38%)	0 / 22 (0.00%)
occurrences causally related to treatment / all	1 / 6	0 / 7	1 / 3	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 1	0 / 0
CELLULITIS ORBITAL
subjects affected / exposed	1 / 236 (0.42%)	0 / 40 (0.00%)	0 / 153 (0.00%)	0 / 42 (0.00%)	0 / 22 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
CLOSTRIDIUM DIFFICILE COLITIS
subjects affected / exposed	2 / 236 (0.85%)	0 / 40 (0.00%)	1 / 153 (0.65%)	0 / 42 (0.00%)	0 / 22 (0.00%)
occurrences causally related to treatment / all	1 / 2	0 / 0	1 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
CLOSTRIDIUM DIFFICILE INFECTION
subjects affected / exposed	1 / 236 (0.42%)	0 / 40 (0.00%)	1 / 153 (0.65%)	0 / 42 (0.00%)	0 / 22 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
CORYNEBACTERIUM SEPSIS
subjects affected / exposed	1 / 236 (0.42%)	0 / 40 (0.00%)	0 / 153 (0.00%)	0 / 42 (0.00%)	0 / 22 (0.00%)
occurrences causally related to treatment / all	1 / 1	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
CYSTITIS
subjects affected / exposed	0 / 236 (0.00%)	0 / 40 (0.00%)	1 / 153 (0.65%)	0 / 42 (0.00%)	0 / 22 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
DEVICE RELATED INFECTION
subjects affected / exposed	0 / 236 (0.00%)	0 / 40 (0.00%)	1 / 153 (0.65%)	0 / 42 (0.00%)	0 / 22 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
DEVICE RELATED SEPSIS
subjects affected / exposed	2 / 236 (0.85%)	0 / 40 (0.00%)	0 / 153 (0.00%)	0 / 42 (0.00%)	0 / 22 (0.00%)
occurrences causally related to treatment / all	0 / 2	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
DIVERTICULITIS
subjects affected / exposed	4 / 236 (1.69%)	0 / 40 (0.00%)	0 / 153 (0.00%)	0 / 42 (0.00%)	0 / 22 (0.00%)
occurrences causally related to treatment / all	2 / 6	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
ENTEROBACTER PNEUMONIA
subjects affected / exposed	1 / 236 (0.42%)	0 / 40 (0.00%)	0 / 153 (0.00%)	0 / 42 (0.00%)	0 / 22 (0.00%)
occurrences causally related to treatment / all	1 / 1	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
ENTEROCOCCAL BACTERAEMIA
subjects affected / exposed	0 / 236 (0.00%)	1 / 40 (2.50%)	1 / 153 (0.65%)	0 / 42 (0.00%)	0 / 22 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	2 / 2	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
ENTEROCOCCAL SEPSIS
subjects affected / exposed	1 / 236 (0.42%)	0 / 40 (0.00%)	0 / 153 (0.00%)	0 / 42 (0.00%)	0 / 22 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
EPIGLOTTITIS
subjects affected / exposed	1 / 236 (0.42%)	0 / 40 (0.00%)	0 / 153 (0.00%)	0 / 42 (0.00%)	0 / 22 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
ERYSIPELAS
subjects affected / exposed	1 / 236 (0.42%)	0 / 40 (0.00%)	0 / 153 (0.00%)	0 / 42 (0.00%)	0 / 22 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
ESCHERICHIA BACTERAEMIA
subjects affected / exposed	3 / 236 (1.27%)	0 / 40 (0.00%)	1 / 153 (0.65%)	0 / 42 (0.00%)	0 / 22 (0.00%)
occurrences causally related to treatment / all	0 / 3	0 / 0	1 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
ESCHERICHIA INFECTION
subjects affected / exposed	1 / 236 (0.42%)	0 / 40 (0.00%)	0 / 153 (0.00%)	0 / 42 (0.00%)	0 / 22 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
ESCHERICHIA SEPSIS
subjects affected / exposed	4 / 236 (1.69%)	0 / 40 (0.00%)	0 / 153 (0.00%)	0 / 42 (0.00%)	0 / 22 (0.00%)
occurrences causally related to treatment / all	0 / 4	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
FURUNCLE
subjects affected / exposed	1 / 236 (0.42%)	0 / 40 (0.00%)	0 / 153 (0.00%)	0 / 42 (0.00%)	0 / 22 (0.00%)
occurrences causally related to treatment / all	1 / 1	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
GASTROENTERITIS
subjects affected / exposed	1 / 236 (0.42%)	0 / 40 (0.00%)	1 / 153 (0.65%)	0 / 42 (0.00%)	0 / 22 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
GASTROENTERITIS CLOSTRIDIAL
subjects affected / exposed	1 / 236 (0.42%)	0 / 40 (0.00%)	0 / 153 (0.00%)	0 / 42 (0.00%)	0 / 22 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
GASTROINTESTINAL FUNGAL INFECTION
subjects affected / exposed	0 / 236 (0.00%)	0 / 40 (0.00%)	1 / 153 (0.65%)	0 / 42 (0.00%)	0 / 22 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	1 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
GROIN ABSCESS
subjects affected / exposed	1 / 236 (0.42%)	0 / 40 (0.00%)	0 / 153 (0.00%)	0 / 42 (0.00%)	0 / 22 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
HERPES ZOSTER
subjects affected / exposed	1 / 236 (0.42%)	0 / 40 (0.00%)	0 / 153 (0.00%)	0 / 42 (0.00%)	0 / 22 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
INFECTED CYST
subjects affected / exposed	1 / 236 (0.42%)	0 / 40 (0.00%)	0 / 153 (0.00%)	0 / 42 (0.00%)	0 / 22 (0.00%)
occurrences causally related to treatment / all	1 / 1	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
INFECTION
subjects affected / exposed	0 / 236 (0.00%)	0 / 40 (0.00%)	1 / 153 (0.65%)	0 / 42 (0.00%)	1 / 22 (4.55%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
INFECTIVE EXACERBATION OF CHRONIC OBSTRUCTIVE AIRWAYS DISEASE
subjects affected / exposed	0 / 236 (0.00%)	0 / 40 (0.00%)	1 / 153 (0.65%)	0 / 42 (0.00%)	0 / 22 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 2	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0
KLEBSIELLA BACTERAEMIA
subjects affected / exposed	0 / 236 (0.00%)	0 / 40 (0.00%)	1 / 153 (0.65%)	0 / 42 (0.00%)	0 / 22 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	1 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
KLEBSIELLA SEPSIS
subjects affected / exposed	1 / 236 (0.42%)	0 / 40 (0.00%)	0 / 153 (0.00%)	0 / 42 (0.00%)	0 / 22 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
LIVER ABSCESS
subjects affected / exposed	0 / 236 (0.00%)	0 / 40 (0.00%)	0 / 153 (0.00%)	0 / 42 (0.00%)	1 / 22 (4.55%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
LOBAR PNEUMONIA
subjects affected / exposed	2 / 236 (0.85%)	0 / 40 (0.00%)	2 / 153 (1.31%)	0 / 42 (0.00%)	0 / 22 (0.00%)
occurrences causally related to treatment / all	1 / 2	0 / 0	2 / 2	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
LOWER RESPIRATORY TRACT INFECTION
subjects affected / exposed	1 / 236 (0.42%)	1 / 40 (2.50%)	1 / 153 (0.65%)	0 / 42 (0.00%)	0 / 22 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 2	1 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0
LUNG ABSCESS
subjects affected / exposed	1 / 236 (0.42%)	0 / 40 (0.00%)	0 / 153 (0.00%)	0 / 42 (0.00%)	0 / 22 (0.00%)
occurrences causally related to treatment / all	0 / 2	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
LUNG INFECTION
subjects affected / exposed	2 / 236 (0.85%)	0 / 40 (0.00%)	1 / 153 (0.65%)	0 / 42 (0.00%)	0 / 22 (0.00%)
occurrences causally related to treatment / all	0 / 3	0 / 0	1 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
MUMPS
subjects affected / exposed	1 / 236 (0.42%)	0 / 40 (0.00%)	0 / 153 (0.00%)	0 / 42 (0.00%)	0 / 22 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
NASOPHARYNGITIS
subjects affected / exposed	1 / 236 (0.42%)	0 / 40 (0.00%)	0 / 153 (0.00%)	0 / 42 (0.00%)	0 / 22 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
NEUTROPENIC SEPSIS
subjects affected / exposed	7 / 236 (2.97%)	2 / 40 (5.00%)	4 / 153 (2.61%)	1 / 42 (2.38%)	0 / 22 (0.00%)
occurrences causally related to treatment / all	0 / 12	0 / 3	0 / 7	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 1	0 / 0	0 / 1	0 / 0	0 / 0
ORAL CANDIDIASIS
subjects affected / exposed	1 / 236 (0.42%)	0 / 40 (0.00%)	0 / 153 (0.00%)	0 / 42 (0.00%)	0 / 22 (0.00%)
occurrences causally related to treatment / all	1 / 1	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
OROPHARYNGITIS FUNGAL
subjects affected / exposed	0 / 236 (0.00%)	0 / 40 (0.00%)	0 / 153 (0.00%)	1 / 42 (2.38%)	0 / 22 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
PARAINFLUENZAE VIRUS INFECTION
subjects affected / exposed	1 / 236 (0.42%)	0 / 40 (0.00%)	0 / 153 (0.00%)	0 / 42 (0.00%)	0 / 22 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
PERIORBITAL CELLULITIS
subjects affected / exposed	0 / 236 (0.00%)	1 / 40 (2.50%)	0 / 153 (0.00%)	0 / 42 (0.00%)	0 / 22 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 2	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0
PERIRECTAL ABSCESS
subjects affected / exposed	1 / 236 (0.42%)	0 / 40 (0.00%)	0 / 153 (0.00%)	0 / 42 (0.00%)	0 / 22 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
PERITONITIS
subjects affected / exposed	0 / 236 (0.00%)	0 / 40 (0.00%)	1 / 153 (0.65%)	0 / 42 (0.00%)	0 / 22 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
PHARYNGITIS
subjects affected / exposed	2 / 236 (0.85%)	0 / 40 (0.00%)	2 / 153 (1.31%)	0 / 42 (0.00%)	0 / 22 (0.00%)
occurrences causally related to treatment / all	1 / 2	0 / 0	1 / 2	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
PHARYNGOTONSILLITIS
subjects affected / exposed	1 / 236 (0.42%)	0 / 40 (0.00%)	0 / 153 (0.00%)	0 / 42 (0.00%)	0 / 22 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
PNEUMONIA
subjects affected / exposed	48 / 236 (20.34%)	3 / 40 (7.50%)	29 / 153 (18.95%)	3 / 42 (7.14%)	2 / 22 (9.09%)
occurrences causally related to treatment / all	31 / 81	0 / 6	15 / 42	2 / 3	1 / 3
deaths causally related to treatment / all	8 / 15	0 / 3	1 / 6	0 / 0	0 / 0
PNEUMONIA FUNGAL
subjects affected / exposed	3 / 236 (1.27%)	0 / 40 (0.00%)	1 / 153 (0.65%)	0 / 42 (0.00%)	0 / 22 (0.00%)
occurrences causally related to treatment / all	2 / 3	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
PNEUMONIA KLEBSIELLA
subjects affected / exposed	0 / 236 (0.00%)	0 / 40 (0.00%)	1 / 153 (0.65%)	0 / 42 (0.00%)	0 / 22 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
PNEUMONIA MYCOPLASMAL
subjects affected / exposed	1 / 236 (0.42%)	0 / 40 (0.00%)	0 / 153 (0.00%)	0 / 42 (0.00%)	0 / 22 (0.00%)
occurrences causally related to treatment / all	2 / 2	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	1 / 1	0 / 0	0 / 0	0 / 0	0 / 0
PNEUMONIA PARAINFLUENZAE VIRAL
subjects affected / exposed	1 / 236 (0.42%)	0 / 40 (0.00%)	0 / 153 (0.00%)	0 / 42 (0.00%)	0 / 22 (0.00%)
occurrences causally related to treatment / all	1 / 1	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
PNEUMONIA PSEUDOMONAS AERUGINOSA
subjects affected / exposed	1 / 236 (0.42%)	0 / 40 (0.00%)	0 / 153 (0.00%)	0 / 42 (0.00%)	0 / 22 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
PNEUMONIA STAPHYLOCOCCAL
subjects affected / exposed	0 / 236 (0.00%)	0 / 40 (0.00%)	1 / 153 (0.65%)	0 / 42 (0.00%)	0 / 22 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
PNEUMONIA STREPTOCOCCAL
subjects affected / exposed	0 / 236 (0.00%)	0 / 40 (0.00%)	0 / 153 (0.00%)	1 / 42 (2.38%)	0 / 22 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	1 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
PSEUDOMEMBRANOUS COLITIS
subjects affected / exposed	3 / 236 (1.27%)	0 / 40 (0.00%)	1 / 153 (0.65%)	0 / 42 (0.00%)	0 / 22 (0.00%)
occurrences causally related to treatment / all	1 / 4	0 / 0	1 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0
PSEUDOMONAL BACTERAEMIA
subjects affected / exposed	0 / 236 (0.00%)	0 / 40 (0.00%)	1 / 153 (0.65%)	0 / 42 (0.00%)	1 / 22 (4.55%)
occurrences causally related to treatment / all	0 / 0	0 / 0	1 / 1	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
PSEUDOMONAL SEPSIS
subjects affected / exposed	3 / 236 (1.27%)	0 / 40 (0.00%)	2 / 153 (1.31%)	0 / 42 (0.00%)	0 / 22 (0.00%)
occurrences causally related to treatment / all	1 / 3	0 / 0	1 / 2	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
RESPIRATORY TRACT INFECTION
subjects affected / exposed	0 / 236 (0.00%)	2 / 40 (5.00%)	2 / 153 (1.31%)	0 / 42 (0.00%)	0 / 22 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 3	0 / 3	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 1	0 / 1	0 / 0	0 / 0
SEPSIS
subjects affected / exposed	12 / 236 (5.08%)	1 / 40 (2.50%)	9 / 153 (5.88%)	2 / 42 (4.76%)	0 / 22 (0.00%)
occurrences causally related to treatment / all	4 / 14	0 / 1	5 / 12	0 / 2	0 / 0
deaths causally related to treatment / all	0 / 2	0 / 0	1 / 4	0 / 0	0 / 0
SEPTIC SHOCK
subjects affected / exposed	4 / 236 (1.69%)	1 / 40 (2.50%)	4 / 153 (2.61%)	4 / 42 (9.52%)	0 / 22 (0.00%)
occurrences causally related to treatment / all	1 / 5	0 / 2	2 / 5	3 / 4	0 / 0
deaths causally related to treatment / all	0 / 3	0 / 1	1 / 3	1 / 1	0 / 0
SINUSITIS
subjects affected / exposed	3 / 236 (1.27%)	0 / 40 (0.00%)	0 / 153 (0.00%)	0 / 42 (0.00%)	1 / 22 (4.55%)
occurrences causally related to treatment / all	1 / 3	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
SINUSITIS FUNGAL
subjects affected / exposed	0 / 236 (0.00%)	0 / 40 (0.00%)	0 / 153 (0.00%)	1 / 42 (2.38%)	0 / 22 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
SOFT TISSUE INFECTION
subjects affected / exposed	1 / 236 (0.42%)	0 / 40 (0.00%)	0 / 153 (0.00%)	0 / 42 (0.00%)	0 / 22 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
STAPHYLOCOCCAL BACTERAEMIA
subjects affected / exposed	1 / 236 (0.42%)	0 / 40 (0.00%)	0 / 153 (0.00%)	1 / 42 (2.38%)	0 / 22 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	1 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
STAPHYLOCOCCAL SEPSIS
subjects affected / exposed	0 / 236 (0.00%)	0 / 40 (0.00%)	0 / 153 (0.00%)	1 / 42 (2.38%)	0 / 22 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
SYSTEMIC CANDIDA
subjects affected / exposed	0 / 236 (0.00%)	0 / 40 (0.00%)	0 / 153 (0.00%)	0 / 42 (0.00%)	1 / 22 (4.55%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
TONSILLITIS
subjects affected / exposed	0 / 236 (0.00%)	0 / 40 (0.00%)	2 / 153 (1.31%)	0 / 42 (0.00%)	0 / 22 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	1 / 2	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
TOOTH INFECTION
subjects affected / exposed	2 / 236 (0.85%)	0 / 40 (0.00%)	0 / 153 (0.00%)	0 / 42 (0.00%)	0 / 22 (0.00%)
occurrences causally related to treatment / all	1 / 2	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
UPPER RESPIRATORY TRACT INFECTION
subjects affected / exposed	2 / 236 (0.85%)	0 / 40 (0.00%)	0 / 153 (0.00%)	0 / 42 (0.00%)	0 / 22 (0.00%)
occurrences causally related to treatment / all	1 / 2	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
URINARY TRACT INFECTION
subjects affected / exposed	7 / 236 (2.97%)	1 / 40 (2.50%)	3 / 153 (1.96%)	0 / 42 (0.00%)	0 / 22 (0.00%)
occurrences causally related to treatment / all	1 / 7	0 / 1	1 / 3	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
UROSEPSIS
subjects affected / exposed	2 / 236 (0.85%)	0 / 40 (0.00%)	0 / 153 (0.00%)	0 / 42 (0.00%)	0 / 22 (0.00%)
occurrences causally related to treatment / all	0 / 3	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0
VAGINITIS GARDNERELLA
subjects affected / exposed	0 / 236 (0.00%)	0 / 40 (0.00%)	1 / 153 (0.65%)	0 / 42 (0.00%)	0 / 22 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
VULVAL ABSCESS
subjects affected / exposed	1 / 236 (0.42%)	0 / 40 (0.00%)	0 / 153 (0.00%)	0 / 42 (0.00%)	0 / 22 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
ZYGOMYCOSIS
subjects affected / exposed	0 / 236 (0.00%)	0 / 40 (0.00%)	0 / 153 (0.00%)	1 / 42 (2.38%)	0 / 22 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Metabolism and nutrition disorders
CACHEXIA
subjects affected / exposed	1 / 236 (0.42%)	0 / 40 (0.00%)	2 / 153 (1.31%)	0 / 42 (0.00%)	0 / 22 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	3 / 3	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	1 / 1	0 / 0	0 / 0
DECREASED APPETITE
subjects affected / exposed	0 / 236 (0.00%)	0 / 40 (0.00%)	0 / 153 (0.00%)	0 / 42 (0.00%)	1 / 22 (4.55%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
DEHYDRATION
subjects affected / exposed	3 / 236 (1.27%)	0 / 40 (0.00%)	0 / 153 (0.00%)	0 / 42 (0.00%)	0 / 22 (0.00%)
occurrences causally related to treatment / all	1 / 4	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
FAILURE TO THRIVE
subjects affected / exposed	0 / 236 (0.00%)	0 / 40 (0.00%)	1 / 153 (0.65%)	0 / 42 (0.00%)	0 / 22 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	1 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
FLUID OVERLOAD
subjects affected / exposed	1 / 236 (0.42%)	0 / 40 (0.00%)	0 / 153 (0.00%)	0 / 42 (0.00%)	0 / 22 (0.00%)
occurrences causally related to treatment / all	1 / 1	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
HYPERGLYCAEMIA
subjects affected / exposed	0 / 236 (0.00%)	1 / 40 (2.50%)	0 / 153 (0.00%)	0 / 42 (0.00%)	0 / 22 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
HYPOKALAEMIA
subjects affected / exposed	2 / 236 (0.85%)	0 / 40 (0.00%)	0 / 153 (0.00%)	0 / 42 (0.00%)	0 / 22 (0.00%)
occurrences causally related to treatment / all	0 / 9	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
HYPONATRAEMIA
subjects affected / exposed	2 / 236 (0.85%)	0 / 40 (0.00%)	0 / 153 (0.00%)	0 / 42 (0.00%)	0 / 22 (0.00%)
occurrences causally related to treatment / all	1 / 2	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
TUMOUR LYSIS SYNDROME
subjects affected / exposed	0 / 236 (0.00%)	0 / 40 (0.00%)	1 / 153 (0.65%)	0 / 42 (0.00%)	0 / 22 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0

Frequency threshold for reporting non-serious adverse events: 5%

Non-serious adverse events	Azacitidine	BSC Only	Low-dose Cytarabine	Intensive Chemotherapy	Azacitidine-extension
Total subjects affected by non serious adverse events
subjects affected / exposed	226 / 236 (95.76%)	33 / 40 (82.50%)	151 / 153 (98.69%)	42 / 42 (100.00%)	18 / 22 (81.82%)
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
ACUTE MYELOID LEUKAEMIA
subjects affected / exposed	27 / 236 (11.44%)	2 / 40 (5.00%)	21 / 153 (13.73%)	1 / 42 (2.38%)	0 / 22 (0.00%)
occurrences all number	27	2	21	1	0
Vascular disorders
HAEMATOMA
subjects affected / exposed	16 / 236 (6.78%)	2 / 40 (5.00%)	7 / 153 (4.58%)	1 / 42 (2.38%)	2 / 22 (9.09%)
occurrences all number	22	2	13	1	2
HYPERTENSION
subjects affected / exposed	16 / 236 (6.78%)	1 / 40 (2.50%)	13 / 153 (8.50%)	4 / 42 (9.52%)	2 / 22 (9.09%)
occurrences all number	23	1	27	5	2
HYPOTENSION
subjects affected / exposed	19 / 236 (8.05%)	3 / 40 (7.50%)	14 / 153 (9.15%)	1 / 42 (2.38%)	1 / 22 (4.55%)
occurrences all number	24	3	14	1	1
PHLEBITIS
subjects affected / exposed	7 / 236 (2.97%)	2 / 40 (5.00%)	4 / 153 (2.61%)	2 / 42 (4.76%)	1 / 22 (4.55%)
occurrences all number	7	2	5	3	1
General disorders and administration site conditions
ASTHENIA
subjects affected / exposed	53 / 236 (22.46%)	8 / 40 (20.00%)	32 / 153 (20.92%)	5 / 42 (11.90%)	6 / 22 (27.27%)
occurrences all number	73	9	45	5	9
CATHETER SITE PAIN
subjects affected / exposed	3 / 236 (1.27%)	0 / 40 (0.00%)	1 / 153 (0.65%)	3 / 42 (7.14%)	0 / 22 (0.00%)
occurrences all number	3	0	1	3	0
CHILLS
subjects affected / exposed	11 / 236 (4.66%)	1 / 40 (2.50%)	7 / 153 (4.58%)	4 / 42 (9.52%)	0 / 22 (0.00%)
occurrences all number	12	1	13	7	0
FATIGUE
subjects affected / exposed	53 / 236 (22.46%)	10 / 40 (25.00%)	19 / 153 (12.42%)	4 / 42 (9.52%)	3 / 22 (13.64%)
occurrences all number	92	14	28	4	4
INJECTION SITE ERYTHEMA
subjects affected / exposed	29 / 236 (12.29%)	0 / 40 (0.00%)	0 / 153 (0.00%)	0 / 42 (0.00%)	1 / 22 (4.55%)
occurrences all number	73	0	0	0	1
INJECTION SITE PAIN
subjects affected / exposed	12 / 236 (5.08%)	0 / 40 (0.00%)	1 / 153 (0.65%)	0 / 42 (0.00%)	1 / 22 (4.55%)
occurrences all number	16	0	2	0	3
INJECTION SITE REACTION
subjects affected / exposed	30 / 236 (12.71%)	0 / 40 (0.00%)	0 / 153 (0.00%)	0 / 42 (0.00%)	0 / 22 (0.00%)
occurrences all number	47	0	0	0	0
MALAISE
subjects affected / exposed	7 / 236 (2.97%)	2 / 40 (5.00%)	3 / 153 (1.96%)	0 / 42 (0.00%)	0 / 22 (0.00%)
occurrences all number	7	2	6	0	0
MUCOSAL INFLAMMATION
subjects affected / exposed	8 / 236 (3.39%)	0 / 40 (0.00%)	14 / 153 (9.15%)	3 / 42 (7.14%)	0 / 22 (0.00%)
occurrences all number	10	0	15	4	0
OEDEMA
subjects affected / exposed	8 / 236 (3.39%)	0 / 40 (0.00%)	3 / 153 (1.96%)	1 / 42 (2.38%)	2 / 22 (9.09%)
occurrences all number	8	0	3	1	3
OEDEMA PERIPHERAL
subjects affected / exposed	55 / 236 (23.31%)	6 / 40 (15.00%)	33 / 153 (21.57%)	9 / 42 (21.43%)	2 / 22 (9.09%)
occurrences all number	62	6	40	11	2
PAIN
subjects affected / exposed	16 / 236 (6.78%)	5 / 40 (12.50%)	5 / 153 (3.27%)	3 / 42 (7.14%)	2 / 22 (9.09%)
occurrences all number	17	5	5	3	4
PYREXIA
subjects affected / exposed	77 / 236 (32.63%)	7 / 40 (17.50%)	56 / 153 (36.60%)	21 / 42 (50.00%)	4 / 22 (18.18%)
occurrences all number	130	15	91	42	6
Respiratory, thoracic and mediastinal disorders
COUGH
subjects affected / exposed	54 / 236 (22.88%)	6 / 40 (15.00%)	36 / 153 (23.53%)	6 / 42 (14.29%)	5 / 22 (22.73%)
occurrences all number	82	7	51	7	6
DYSPNOEA
subjects affected / exposed	41 / 236 (17.37%)	6 / 40 (15.00%)	35 / 153 (22.88%)	4 / 42 (9.52%)	1 / 22 (4.55%)
occurrences all number	54	7	46	5	3
DYSPNOEA EXERTIONAL
subjects affected / exposed	10 / 236 (4.24%)	2 / 40 (5.00%)	6 / 153 (3.92%)	0 / 42 (0.00%)	0 / 22 (0.00%)
occurrences all number	11	3	10	0	0
EPISTAXIS
subjects affected / exposed	29 / 236 (12.29%)	5 / 40 (12.50%)	21 / 153 (13.73%)	2 / 42 (4.76%)	4 / 22 (18.18%)
occurrences all number	50	8	39	4	4
HAEMOPTYSIS
subjects affected / exposed	9 / 236 (3.81%)	2 / 40 (5.00%)	4 / 153 (2.61%)	2 / 42 (4.76%)	0 / 22 (0.00%)
occurrences all number	11	2	4	2	0
HICCUPS
subjects affected / exposed	0 / 236 (0.00%)	1 / 40 (2.50%)	0 / 153 (0.00%)	3 / 42 (7.14%)	1 / 22 (4.55%)
occurrences all number	0	1	0	3	1
OROPHARYNGEAL PAIN
subjects affected / exposed	16 / 236 (6.78%)	2 / 40 (5.00%)	11 / 153 (7.19%)	4 / 42 (9.52%)	1 / 22 (4.55%)
occurrences all number	16	3	12	4	3
PLEURAL EFFUSION
subjects affected / exposed	12 / 236 (5.08%)	1 / 40 (2.50%)	2 / 153 (1.31%)	1 / 42 (2.38%)	2 / 22 (9.09%)
occurrences all number	14	1	4	1	3
PRODUCTIVE COUGH
subjects affected / exposed	9 / 236 (3.81%)	0 / 40 (0.00%)	10 / 153 (6.54%)	3 / 42 (7.14%)	1 / 22 (4.55%)
occurrences all number	15	0	12	3	2
Psychiatric disorders
AGITATION
subjects affected / exposed	6 / 236 (2.54%)	3 / 40 (7.50%)	3 / 153 (1.96%)	0 / 42 (0.00%)	1 / 22 (4.55%)
occurrences all number	6	3	3	0	1
ANXIETY
subjects affected / exposed	15 / 236 (6.36%)	4 / 40 (10.00%)	6 / 153 (3.92%)	2 / 42 (4.76%)	2 / 22 (9.09%)
occurrences all number	15	5	6	2	2
CONFUSIONAL STATE
subjects affected / exposed	14 / 236 (5.93%)	3 / 40 (7.50%)	8 / 153 (5.23%)	3 / 42 (7.14%)	1 / 22 (4.55%)
occurrences all number	16	3	9	5	1
INSOMNIA
subjects affected / exposed	36 / 236 (15.25%)	2 / 40 (5.00%)	11 / 153 (7.19%)	4 / 42 (9.52%)	1 / 22 (4.55%)
occurrences all number	45	2	15	4	2
Investigations
WEIGHT DECREASED
subjects affected / exposed	30 / 236 (12.71%)	3 / 40 (7.50%)	2 / 153 (1.31%)	1 / 42 (2.38%)	1 / 22 (4.55%)
occurrences all number	38	3	4	1	1
Injury, poisoning and procedural complications
CONTUSION
subjects affected / exposed	16 / 236 (6.78%)	3 / 40 (7.50%)	7 / 153 (4.58%)	2 / 42 (4.76%)	2 / 22 (9.09%)
occurrences all number	24	4	10	2	2
FALL
subjects affected / exposed	14 / 236 (5.93%)	2 / 40 (5.00%)	7 / 153 (4.58%)	1 / 42 (2.38%)	1 / 22 (4.55%)
occurrences all number	21	2	9	1	1
LACERATION
subjects affected / exposed	3 / 236 (1.27%)	0 / 40 (0.00%)	2 / 153 (1.31%)	0 / 42 (0.00%)	2 / 22 (9.09%)
occurrences all number	3	0	2	0	2
Cardiac disorders
ATRIAL FIBRILLATION
subjects affected / exposed	12 / 236 (5.08%)	2 / 40 (5.00%)	9 / 153 (5.88%)	1 / 42 (2.38%)	1 / 22 (4.55%)
occurrences all number	13	2	9	1	1
TACHYCARDIA
subjects affected / exposed	5 / 236 (2.12%)	3 / 40 (7.50%)	2 / 153 (1.31%)	2 / 42 (4.76%)	0 / 22 (0.00%)
occurrences all number	6	3	2	2	0
Nervous system disorders
DIZZINESS
subjects affected / exposed	42 / 236 (17.80%)	3 / 40 (7.50%)	15 / 153 (9.80%)	4 / 42 (9.52%)	1 / 22 (4.55%)
occurrences all number	61	4	22	4	1
HEADACHE
subjects affected / exposed	31 / 236 (13.14%)	1 / 40 (2.50%)	19 / 153 (12.42%)	6 / 42 (14.29%)	3 / 22 (13.64%)
occurrences all number	48	1	34	6	6
SCIATICA
subjects affected / exposed	4 / 236 (1.69%)	2 / 40 (5.00%)	2 / 153 (1.31%)	0 / 42 (0.00%)	0 / 22 (0.00%)
occurrences all number	5	2	2	0	0
Blood and lymphatic system disorders
ANAEMIA
subjects affected / exposed	41 / 236 (17.37%)	3 / 40 (7.50%)	32 / 153 (20.92%)	7 / 42 (16.67%)	4 / 22 (18.18%)
occurrences all number	135	3	134	17	25
FEBRILE NEUTROPENIA
subjects affected / exposed	28 / 236 (11.86%)	2 / 40 (5.00%)	21 / 153 (13.73%)	12 / 42 (28.57%)	0 / 22 (0.00%)
occurrences all number	37	2	30	18	0
LEUKOCYTOSIS
subjects affected / exposed	13 / 236 (5.51%)	2 / 40 (5.00%)	11 / 153 (7.19%)	0 / 42 (0.00%)	0 / 22 (0.00%)
occurrences all number	20	2	11	0	0
LEUKOPENIA
subjects affected / exposed	22 / 236 (9.32%)	0 / 40 (0.00%)	15 / 153 (9.80%)	6 / 42 (14.29%)	1 / 22 (4.55%)
occurrences all number	45	0	42	21	1
NEUTROPENIA
subjects affected / exposed	69 / 236 (29.24%)	1 / 40 (2.50%)	43 / 153 (28.10%)	14 / 42 (33.33%)	6 / 22 (27.27%)
occurrences all number	166	1	166	31	39
THROMBOCYTOPENIA
subjects affected / exposed	60 / 236 (25.42%)	2 / 40 (5.00%)	37 / 153 (24.18%)	9 / 42 (21.43%)	6 / 22 (27.27%)
occurrences all number	229	2	167	41	23
Gastrointestinal disorders
ABDOMINAL DISTENSION
subjects affected / exposed	3 / 236 (1.27%)	4 / 40 (10.00%)	4 / 153 (2.61%)	0 / 42 (0.00%)	0 / 22 (0.00%)
occurrences all number	4	4	6	0	0
ABDOMINAL PAIN
subjects affected / exposed	30 / 236 (12.71%)	3 / 40 (7.50%)	16 / 153 (10.46%)	7 / 42 (16.67%)	1 / 22 (4.55%)
occurrences all number	39	3	34	9	1
ABDOMINAL PAIN UPPER
subjects affected / exposed	19 / 236 (8.05%)	0 / 40 (0.00%)	6 / 153 (3.92%)	6 / 42 (14.29%)	0 / 22 (0.00%)
occurrences all number	23	0	10	7	0
CONSTIPATION
subjects affected / exposed	99 / 236 (41.95%)	9 / 40 (22.50%)	42 / 153 (27.45%)	16 / 42 (38.10%)	1 / 22 (4.55%)
occurrences all number	172	12	58	23	2
DIARRHOEA
subjects affected / exposed	87 / 236 (36.86%)	5 / 40 (12.50%)	34 / 153 (22.22%)	21 / 42 (50.00%)	5 / 22 (22.73%)
occurrences all number	157	7	46	36	7
DYSPEPSIA
subjects affected / exposed	16 / 236 (6.78%)	2 / 40 (5.00%)	14 / 153 (9.15%)	6 / 42 (14.29%)	0 / 22 (0.00%)
occurrences all number	25	2	22	6	0
HAEMORRHOIDS
subjects affected / exposed	14 / 236 (5.93%)	1 / 40 (2.50%)	7 / 153 (4.58%)	4 / 42 (9.52%)	3 / 22 (13.64%)
occurrences all number	15	1	7	5	3
MOUTH ULCERATION
subjects affected / exposed	11 / 236 (4.66%)	1 / 40 (2.50%)	8 / 153 (5.23%)	1 / 42 (2.38%)	0 / 22 (0.00%)
occurrences all number	11	1	10	1	0
NAUSEA
subjects affected / exposed	93 / 236 (39.41%)	3 / 40 (7.50%)	43 / 153 (28.10%)	24 / 42 (57.14%)	3 / 22 (13.64%)
occurrences all number	158	3	69	34	3
STOMATITIS
subjects affected / exposed	20 / 236 (8.47%)	2 / 40 (5.00%)	14 / 153 (9.15%)	4 / 42 (9.52%)	2 / 22 (9.09%)
occurrences all number	31	2	21	10	4
VOMITING
subjects affected / exposed	53 / 236 (22.46%)	3 / 40 (7.50%)	24 / 153 (15.69%)	8 / 42 (19.05%)	3 / 22 (13.64%)
occurrences all number	86	4	40	9	5
Skin and subcutaneous tissue disorders
ERYTHEMA
subjects affected / exposed	18 / 236 (7.63%)	0 / 40 (0.00%)	6 / 153 (3.92%)	3 / 42 (7.14%)	0 / 22 (0.00%)
occurrences all number	30	0	7	3	0
PETECHIAE
subjects affected / exposed	12 / 236 (5.08%)	0 / 40 (0.00%)	16 / 153 (10.46%)	1 / 42 (2.38%)	0 / 22 (0.00%)
occurrences all number	20	0	23	1	0
PRURITUS
subjects affected / exposed	25 / 236 (10.59%)	1 / 40 (2.50%)	10 / 153 (6.54%)	6 / 42 (14.29%)	0 / 22 (0.00%)
occurrences all number	33	1	10	8	0
RASH
subjects affected / exposed	26 / 236 (11.02%)	0 / 40 (0.00%)	14 / 153 (9.15%)	8 / 42 (19.05%)	1 / 22 (4.55%)
occurrences all number	36	0	18	12	1
SKIN LESION
subjects affected / exposed	4 / 236 (1.69%)	2 / 40 (5.00%)	5 / 153 (3.27%)	0 / 42 (0.00%)	1 / 22 (4.55%)
occurrences all number	5	2	5	0	1
SKIN ULCER
subjects affected / exposed	7 / 236 (2.97%)	2 / 40 (5.00%)	2 / 153 (1.31%)	1 / 42 (2.38%)	0 / 22 (0.00%)
occurrences all number	7	2	2	1	0
Renal and urinary disorders
HAEMATURIA
subjects affected / exposed	5 / 236 (2.12%)	3 / 40 (7.50%)	8 / 153 (5.23%)	1 / 42 (2.38%)	0 / 22 (0.00%)
occurrences all number	5	3	8	1	0
RENAL FAILURE
subjects affected / exposed	7 / 236 (2.97%)	2 / 40 (5.00%)	3 / 153 (1.96%)	3 / 42 (7.14%)	0 / 22 (0.00%)
occurrences all number	8	2	3	3	0
RENAL FAILURE ACUTE
subjects affected / exposed	4 / 236 (1.69%)	2 / 40 (5.00%)	3 / 153 (1.96%)	1 / 42 (2.38%)	0 / 22 (0.00%)
occurrences all number	9	2	3	1	0
URINARY INCONTINENCE
subjects affected / exposed	5 / 236 (2.12%)	2 / 40 (5.00%)	1 / 153 (0.65%)	2 / 42 (4.76%)	1 / 22 (4.55%)
occurrences all number	6	2	1	2	1
Musculoskeletal and connective tissue disorders
ARTHRALGIA
subjects affected / exposed	33 / 236 (13.98%)	2 / 40 (5.00%)	11 / 153 (7.19%)	3 / 42 (7.14%)	2 / 22 (9.09%)
occurrences all number	50	3	19	3	2
BACK PAIN
subjects affected / exposed	36 / 236 (15.25%)	5 / 40 (12.50%)	22 / 153 (14.38%)	2 / 42 (4.76%)	1 / 22 (4.55%)
occurrences all number	45	5	27	3	1
BONE PAIN
subjects affected / exposed	12 / 236 (5.08%)	2 / 40 (5.00%)	4 / 153 (2.61%)	0 / 42 (0.00%)	0 / 22 (0.00%)
occurrences all number	14	2	4	0	0
MUSCULOSKELETAL PAIN
subjects affected / exposed	21 / 236 (8.90%)	2 / 40 (5.00%)	3 / 153 (1.96%)	1 / 42 (2.38%)	2 / 22 (9.09%)
occurrences all number	27	2	3	1	2
PAIN IN EXTREMITY
subjects affected / exposed	26 / 236 (11.02%)	2 / 40 (5.00%)	11 / 153 (7.19%)	2 / 42 (4.76%)	2 / 22 (9.09%)
occurrences all number	35	3	11	2	2
Infections and infestations
CELLULITIS
subjects affected / exposed	13 / 236 (5.51%)	3 / 40 (7.50%)	7 / 153 (4.58%)	0 / 42 (0.00%)	0 / 22 (0.00%)
occurrences all number	16	4	13	0	0
LUNG INFECTION
subjects affected / exposed	1 / 236 (0.42%)	0 / 40 (0.00%)	3 / 153 (1.96%)	3 / 42 (7.14%)	0 / 22 (0.00%)
occurrences all number	1	0	4	7	0
NASOPHARYNGITIS
subjects affected / exposed	13 / 236 (5.51%)	2 / 40 (5.00%)	5 / 153 (3.27%)	0 / 42 (0.00%)	2 / 22 (9.09%)
occurrences all number	17	2	5	0	5
ORAL CANDIDIASIS
subjects affected / exposed	16 / 236 (6.78%)	4 / 40 (10.00%)	4 / 153 (2.61%)	3 / 42 (7.14%)	0 / 22 (0.00%)
occurrences all number	21	4	5	4	0
ORAL HERPES
subjects affected / exposed	15 / 236 (6.36%)	2 / 40 (5.00%)	8 / 153 (5.23%)	6 / 42 (14.29%)	0 / 22 (0.00%)
occurrences all number	16	2	10	6	0
PHARYNGITIS
subjects affected / exposed	9 / 236 (3.81%)	1 / 40 (2.50%)	5 / 153 (3.27%)	1 / 42 (2.38%)	2 / 22 (9.09%)
occurrences all number	10	1	6	1	2
PNEUMONIA
subjects affected / exposed	16 / 236 (6.78%)	0 / 40 (0.00%)	12 / 153 (7.84%)	4 / 42 (9.52%)	4 / 22 (18.18%)
occurrences all number	17	0	13	4	5
RESPIRATORY TRACT INFECTION
subjects affected / exposed	5 / 236 (2.12%)	2 / 40 (5.00%)	4 / 153 (2.61%)	0 / 42 (0.00%)	0 / 22 (0.00%)
occurrences all number	6	2	4	0	0
SKIN INFECTION
subjects affected / exposed	5 / 236 (2.12%)	0 / 40 (0.00%)	0 / 153 (0.00%)	1 / 42 (2.38%)	2 / 22 (9.09%)
occurrences all number	7	0	0	1	2
UPPER RESPIRATORY TRACT INFECTION
subjects affected / exposed	18 / 236 (7.63%)	1 / 40 (2.50%)	5 / 153 (3.27%)	1 / 42 (2.38%)	1 / 22 (4.55%)
occurrences all number	33	1	9	2	1
URINARY TRACT INFECTION
subjects affected / exposed	16 / 236 (6.78%)	3 / 40 (7.50%)	14 / 153 (9.15%)	0 / 42 (0.00%)	2 / 22 (9.09%)
occurrences all number	18	3	24	0	2
Metabolism and nutrition disorders
DECREASED APPETITE
subjects affected / exposed	61 / 236 (25.85%)	8 / 40 (20.00%)	33 / 153 (21.57%)	7 / 42 (16.67%)	2 / 22 (9.09%)
occurrences all number	100	12	55	11	4
DEHYDRATION
subjects affected / exposed	11 / 236 (4.66%)	2 / 40 (5.00%)	4 / 153 (2.61%)	1 / 42 (2.38%)	0 / 22 (0.00%)
occurrences all number	13	2	4	1	0
FLUID OVERLOAD
subjects affected / exposed	8 / 236 (3.39%)	2 / 40 (5.00%)	0 / 153 (0.00%)	3 / 42 (7.14%)	0 / 22 (0.00%)
occurrences all number	10	2	0	3	0
FLUID RETENTION
subjects affected / exposed	5 / 236 (2.12%)	0 / 40 (0.00%)	0 / 153 (0.00%)	3 / 42 (7.14%)	0 / 22 (0.00%)
occurrences all number	5	0	0	4	0
HYPOALBUMINAEMIA
subjects affected / exposed	11 / 236 (4.66%)	1 / 40 (2.50%)	11 / 153 (7.19%)	7 / 42 (16.67%)	1 / 22 (4.55%)
occurrences all number	22	1	13	10	1
HYPOCALCAEMIA
subjects affected / exposed	16 / 236 (6.78%)	0 / 40 (0.00%)	6 / 153 (3.92%)	3 / 42 (7.14%)	1 / 22 (4.55%)
occurrences all number	22	0	11	4	1
HYPOKALAEMIA
subjects affected / exposed	54 / 236 (22.88%)	6 / 40 (15.00%)	45 / 153 (29.41%)	16 / 42 (38.10%)	3 / 22 (13.64%)
occurrences all number	103	8	79	36	7
HYPOMAGNESAEMIA
subjects affected / exposed	21 / 236 (8.90%)	2 / 40 (5.00%)	9 / 153 (5.88%)	6 / 42 (14.29%)	1 / 22 (4.55%)
occurrences all number	40	2	16	14	2
HYPONATRAEMIA
subjects affected / exposed	9 / 236 (3.81%)	0 / 40 (0.00%)	12 / 153 (7.84%)	3 / 42 (7.14%)	1 / 22 (4.55%)
occurrences all number	17	0	15	5	1
HYPOPHOSPHATAEMIA
subjects affected / exposed	19 / 236 (8.05%)	2 / 40 (5.00%)	8 / 153 (5.23%)	6 / 42 (14.29%)	1 / 22 (4.55%)
occurrences all number	34	2	9	13	2

More information

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Were there any global substantial amendments to the protocol? Yes

10 Feb 2010

1. Modify the language around the countries where comparator products were designated as non-investigational product and to remove one of the comparator anthracyclines. At the time the original protocol was finalized, comparator product in the US, Canada, and Australia was to be commercially available product obtained through the local hospital pharmacy or licensed distributor and designated as non-investigational product (NIP). In all other countries, comparator product was to be supplied and packaged by Celgene Corporation and designated as investigational product (IP). With this amendment, the IP and NIP language were modified to allow comparator product to be designated as NIP in more countries than the original three countries (US, Canada, and Australia). 2. The original protocol allowed the investigator to choose one of three allowed anthracyclines (daunorubicin, idarubicin, or mitoxantrone) as part of the intensive chemotherapy comparator arm. Due to the infrequent use of mitoxantrone in the investigational sites, this amendment eliminated mitoxantrone as one of the anthracycline choices. 3. A new Celgene global multi-lingual call center for medical emergencies was opened. The global multilingual call center was to be used as a back-up when the Clinical Research Physician/Medical Monitor was not available for medical emergencies. The contact information for the call center was added to the protocol. 4. Other administrative textual changes and clarifications.

18 Oct 2010

1. Updated the format of the investigational new drug (IND) number. 2. Added an additional medical monitor contact. 3. Clarified the blinding of the central pathology reviewer. 4. Added clarification for the allowed visit window. 5. Clarified the BM aspirate/biopsy and peripheral blood smear collection times by treatment group. 6. Clarified that the collection of follow-up therapies was not required at End-of Study Visit. 7. Added language to accommodate the use of a BM aspirate and biopsy collected for disease diagnosis as part of the standard of care. 8. Clarified the BM aspirate and peripheral blood smear collection times following the last treatment cycle in the intensive chemotherapy arm. 9. Added dose modification guidelines for low-dose cytarabine. 10. Modified the administration language for low-dose cytarabine to allow the study sites more flexibility for home administration. 11. Added guidance for the use of prophylactic myeloid growth factor used in the intensive chemotherapy arm. 12. Increased the minimum ANC threshold for administration of prophylactic antibiotics. 13. Clarified that the EORTC QLQ-C30 instrument was to be performed using a portable electronic tablet computer. 14. Clarified pregnancy reporting requirements.

28 Oct 2011

1. Added sponsor name and address to protocol cover page. 2. Clarified the emergency contact was also the monitor. 3. Removed the requirement for PI title and site number from the PI and coordinating PI signature pages. 4. Allowed a ± 3 day window around the start of a cycle beginning at Cycle 2 and beyond. 5. Clarified requirements for stained and unstained peripheral blood smears. 6. Clarified the calculation of BSA was performed on Day 1 of each cycle and study drug dosing should have been calculated based on the BSA obtained on Day 1 of each cycle. 7. Clarified when a BM biopsy was to be collected. 8. Clarified the minimum allowable analyzable metaphases for those with a normal karyotype. 9. Clarified the volume for BM biomarker samples. 10. Clarified the use of hydroxyurea during the Screening Period. 11. Added AML with antecedent hematologic disorder such as chronic myelogenous leukemia or myeloproliferative neoplasms to excluded conditions. 12. Allowed the use of myeloid growth factor in those with previous episodes of neutropenic infection and at risk of subsequent neutropenic infection. 13. Clarified that the investigator could contact the medical monitor if guidance on azacitidine or low-dose cytarabine dose modification was needed. 14. Clarified the mCR definition. 15. Clarified the treatment failure indeterminate cause definition. 16. Clarified the progressive disease definition for peripheral blood. 17. Clarified the PR definition. 18. Clarified that, for AEs and SAEs, severity also means intensity. 19. Clarified the reporting requirements for duration and action taken for AEs and SAEs. 20. Clarified the reporting procedures for females who became pregnant and female partners of male study subjects who became pregnant. 21. Updated the name of the EMA. 22. Clarified the selection process for authorship of publications related to the study. 23. Added instructions that azacitidine was not to be filtered when preparing it for SC administration.

03 Aug 2012

The primary purpose of this Protocol Amendment was to remove the planned interim analysis. The original AZA-AML-001 study protocol called for an interim analysis for efficacy at approximately 60% (224 deaths) of the total expected deaths in the study. This number of deaths was anticipated to occur at approximately the same time as enrollment in the study was nearing completion. Following the Protocol Assistance with EMA, Celgene included the interim analysis to ensure that the sample size could be re-calculated and adapted during the enrollment phase of the study. Of note, there was no intention for the interim analysis to serve as a means to terminate the study for futility. As mentioned above, the timing of the interim was expected to occur at approximately the time when enrollment was estimated to be completed. However, due to a death rate lower than anticipated, the number of deaths required for the planned interim analysis was not reached before enrollment completion. Therefore, the interim analysis was thought to serve little purpose at this point in the study as part of the alpha level would have been wastefully spent before reaching the final analysis. 1. Updated the title of the contact person in section Medical Monitor / Emergency Contact Information. 2. Clarified the definition for EFS. 3. Clarified the definition for RFS. 4. Clarified the definition for the analysis of the duration of remission. 5. Clarified the population used for the patient-reported outcome analysis, ie, a modified ITT population and not the full ITT population.

Were there any global interruptions to the trial? No

Limitations of the trial such as small numbers of subjects analysed or technical problems leading to unreliable data.

None reported

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Clinical trials

Clinical Trial Results: A Phase 3, Multicenter, Randomized, Open-Label, Study of Azacitidine (Vidaza®) Versus Conventional Care Regimens for the Treatment of Older Subjects with Newly Diagnosed Acute Myeloid Leukemia

Trial information

Trial information

Subject disposition

Subject disposition

Baseline characteristics

Baseline characteristics

End points

End points

Primary: Kaplan-Meier Estimates for Overall Survival

Primary: Kaplan-Meier Estimates for Overall Survival

Secondary: One-Year Overall Survival Rate

Secondary: One-Year Overall Survival Rate

Secondary: Event-Free Survival (EFS)

Secondary: Event-Free Survival (EFS)

Secondary: Relapse-Free Survival (RFS) for Subjects who Achieved a Complete Remission (CR) or Complete remission with Incomplete Blood Count Recovery (CRi)

Secondary: Relapse-Free Survival (RFS) for Subjects who Achieved a Complete Remission (CR) or Complete remission with Incomplete Blood Count Recovery (CRi)

Secondary: Percentage of Subjects who Achieved a Morphologic CR + CRi as Determined by the Independent Review Committee (IRC) Based on International Working Group (IWG) Response Criteria for Acute Myeloid Leukemia (AML)

Secondary: Percentage of Subjects who Achieved a Morphologic CR + CRi as Determined by the Independent Review Committee (IRC) Based on International Working Group (IWG) Response Criteria for Acute Myeloid Leukemia (AML)

Secondary: Duration of Remission Assessed by the IRC Based on Kaplan-Meier Estimates

Secondary: Duration of Remission Assessed by the IRC Based on Kaplan-Meier Estimates

Secondary: Number of Subjects who Achieved a Cytogenetic Complete Remission (CRc-10) as Determined by the IRC

Secondary: Number of Subjects who Achieved a Cytogenetic Complete Remission (CRc-10) as Determined by the IRC

Secondary: Number of Subjects with Adverse Events (AEs).

Secondary: Number of Subjects with Adverse Events (AEs).

Secondary: Health Related Quality of Life (HRQoL): Change from Baseline in the European Organization for Research and Treatment of Cancer Cancer Quality of Life Questionnaire for Patients with Cancer (EORTC QLQ-C30) Fatigue Domain

Secondary: Health Related Quality of Life (HRQoL): Change from Baseline in the European Organization for Research and Treatment of Cancer Cancer Quality of Life Questionnaire for Patients with Cancer (EORTC QLQ-C30) Fatigue Domain

Secondary: Health Related Quality of Life (HRQoL): Change from Baseline in the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire for Patients with Cancer (EORTC QLQ-C30) Fatigue Domain

Secondary: Health Related Quality of Life (HRQoL): Change from Baseline in the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire for Patients with Cancer (EORTC QLQ-C30) Fatigue Domain

Secondary: Health Related Quality of Life (HRQoL): Change from Baseline in the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire for Patients with Cancer (EORTC QLQ-C30) Fatigue Domain

Secondary: Health Related Quality of Life (HRQoL): Change from Baseline in the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire for Patients with Cancer (EORTC QLQ-C30) Fatigue Domain

Secondary: Health Related Quality of Life (HRQoL): Change from Baseline in the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire for Patients with Cancer (EORTC QLQ-C30) Fatigue Domain

Secondary: Health Related Quality of Life (HRQoL): Change from Baseline in the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire for Patients with Cancer (EORTC QLQ-C30) Fatigue Domain

Secondary: Health Related Quality of Life (HRQoL): Change from Baseline in the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire for Patients with Cancer (EORTC QLQ-C30) Fatigue Domain

Secondary: Health Related Quality of Life (HRQoL): Change from Baseline in the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire for Patients with Cancer (EORTC QLQ-C30) Fatigue Domain

Secondary: HRQoL: Change from Baseline in the EORTC QLQ-C30 Dyspnea

Secondary: HRQoL: Change from Baseline in the EORTC QLQ-C30 Dyspnea

Secondary: HRQoL: Change from Baseline in the EORTC QLQ-C30 Dyspnea

Secondary: HRQoL: Change from Baseline in the EORTC QLQ-C30 Dyspnea

Secondary: HRQoL: Change from Baseline in the EORTC QLQ-C30 Dyspnea

Secondary: HRQoL: Change from Baseline in the EORTC QLQ-C30 Dyspnea

Secondary: HRQoL: Change from Baseline in the EORTC QLQ-C30 Dyspnea

Secondary: HRQoL: Change from Baseline in the EORTC QLQ-C30 Dyspnea

Secondary: HRQoL: Change from Baseline in the EORTC QLQ-C30 Dyspnea

Secondary: HRQoL: Change from Baseline in the EORTC QLQ-C30 Dyspnea

Secondary: HRQoL: Change from Baseline in the EORTC QLQ-C30 Physical Functioning Domain

Secondary: HRQoL: Change from Baseline in the EORTC QLQ-C30 Physical Functioning Domain

Secondary: HRQoL: Change from Baseline in the EORTC QLQ-C30 Physical Functioning Domain

Secondary: HRQoL: Change from Baseline in the EORTC QLQ-C30 Physical Functioning Domain

Secondary: HRQoL: Change from Baseline in the EORTC QLQ-C30 Physical Functioning Domain

Secondary: HRQoL: Change from Baseline in the EORTC QLQ-C30 Physical Functioning Domain

Secondary: HRQoL: Change from Baseline in the EORTC QLQ-C30 Physical Functioning Domain

Secondary: HRQoL: Change from Baseline in the EORTC QLQ-C30 Physical Functioning Domain

Secondary: HRQoL: Change from Baseline in the EORTC QLQ-C30 Physical Functioning Domain

Secondary: HRQoL: Change from Baseline in the EORTC QLQ-C30 Physical Functioning Domain

Secondary: HRQoL: Change from Baseline in the EORTC QLQ-C30 Global Health Status-/Quality of Life Domain

Secondary: HRQoL: Change from Baseline in the EORTC QLQ-C30 Global Health Status-/Quality of Life Domain

Secondary: HRQoL: Change from Baseline in the EORTC QLQ-C30 Global Health Status-/Quality of Life Domain

Secondary: HRQoL: Change from Baseline in the EORTC QLQ-C30 Global Health Status-/Quality of Life Domain

Secondary: HRQoL: Change from Baseline in the EORTC QLQ-C30 Global Health Status-/Quality of Life Domain

Secondary: HRQoL: Change from Baseline in the EORTC QLQ-C30 Global Health Status-/Quality of Life Domain

Secondary: HRQoL: Change from Baseline in the EORTC QLQ-C30 Global Health Status-/Quality of Life Domain

Secondary: HRQoL: Change from Baseline in the EORTC QLQ-C30 Global Health Status-/Quality of Life Domain

Secondary: HRQoL: Change from Baseline in the EORTC QLQ-C30 Global Health Status-/Quality of Life Domain

Secondary: HRQoL: Change from Baseline in the EORTC QLQ-C30 Global Health Status-/Quality of Life Domain

Secondary: Healthcare Resource Utilization (HRU): Number of subjects with a hospitalization

Secondary: Healthcare Resource Utilization (HRU): Number of subjects with a hospitalization

Secondary: Healthcare Resource Utilization (HRU): Rate of Inpatient Hospitalizations Per Year

Secondary: Healthcare Resource Utilization (HRU): Rate of Inpatient Hospitalizations Per Year

Secondary: HRU: Number of Subjects Receiving Transfusions

Secondary: HRU: Number of Subjects Receiving Transfusions

Secondary: HRU: Rate of Transfusions per Patient Year

Secondary: HRU: Rate of Transfusions per Patient Year

Secondary: Number of Participants in the Extension Phase With Treatment Emergent Adverse Events (TEAEs)

Secondary: Number of Participants in the Extension Phase With Treatment Emergent Adverse Events (TEAEs)

Adverse events

Adverse events

More information

Substantial protocol amendments (globally)

Clinical Trial Results:
A Phase 3, Multicenter, Randomized, Open-Label, Study of Azacitidine (Vidaza®) Versus Conventional Care Regimens for the Treatment of Older Subjects with Newly Diagnosed Acute Myeloid Leukemia