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Clinical Trial Results:
A PHASE 3, MULTICENTER, RANDOMIZED, DOUBLE-BLIND STUDY TO COMPARE THE EFFICACY AND SAFETY OF ORAL AZACITIDINE PLUS BEST SUPPORTIVE CARE VERSUS PLACEBO PLUS BEST SUPPORTIVE CARE IN SUBJECTS WITH RED BLOOD CELL TRANSFUSION-DEPENDENT ANEMIA AND THROMBOCYTOPENIA DUE TO IPSS LOWER-RISK MYELODYSPLASTIC SYNDROMES

Summary
EudraCT number	2012-002471-34
Trial protocol	BE NO SE ES CZ PT LT IT NL GB DE FI DK FR GR
Global end of trial date	21 Dec 2023

Results information
Results version number	v1(current)
This version publication date	01 Jan 2025
First version publication date	01 Jan 2025
Other versions

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

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Trial information

Top of page

Sponsor protocol code

AZA-MDS-003

ISRCTN number

US NCT number

WHO universal trial number (UTN)

Sponsor organisation name

Bristol-Myers Squibb

Sponsor organisation address

Chaussee de la Hulpe 185, Brussels, Belgium, 1170

Public contact

EU Study Start-Up Unit, Bristol-Myers Squibb International Corporation, Clinical.Trials@bms.com

Scientific contact

Bristol-Myers Squibb Study Director, Bristol-Myers Squibb, Clinical.Trials@bms.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

02 Feb 2024

Is this the analysis of the primary completion data?

Global end of trial reached?

Yes

Global end of trial date

21 Dec 2023

Was the trial ended prematurely?

Main objective of the trial

The primary objective of the study is to evaluate RBC transfusion independence in the 2 treatment arms (oral azacitidine plus best supportive care versus placebo plus best supportive care) in subjects with RBC transfusion-dependent anemia and thrombocytopenia due to IPSS lower-risk MDS.

Protection of trial subjects

The study was in compliance with the ethical principles derived from the Declaration of Helsinki and in compliance with all International Conference on Harmonization Good Clinical Practice Guidelines. All the local regulatory requirements pertinent to safety of trial participants were followed.

Background therapy

Evidence for comparator

Actual start date of recruitment

26 Apr 2013

Long term follow-up planned

Independent data monitoring committee (IDMC) involvement?

Yes

Number of subjects enrolled per country

Country: Number of subjects enrolled

Australia: 18

Country: Number of subjects enrolled

Belgium: 5

Country: Number of subjects enrolled

Canada: 11

Country: Number of subjects enrolled

Czechia: 10

Country: Number of subjects enrolled

Finland: 2

Country: Number of subjects enrolled

France: 8

Country: Number of subjects enrolled

Germany: 27

Country: Number of subjects enrolled

Greece: 3

Country: Number of subjects enrolled

Israel: 4

Country: Number of subjects enrolled

Italy: 46

Country: Number of subjects enrolled

Korea, Republic of: 1

Country: Number of subjects enrolled

Mexico: 3

Country: Number of subjects enrolled

Netherlands: 2

Country: Number of subjects enrolled

Poland: 7

Country: Number of subjects enrolled

Portugal: 11

Country: Number of subjects enrolled

Spain: 24

Country: Number of subjects enrolled

Sweden: 3

Country: Number of subjects enrolled

Türkiye: 1

Country: Number of subjects enrolled

United Kingdom: 18

Country: Number of subjects enrolled

United States: 12

Worldwide total number of subjects

216

EEA total number of subjects

148

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

172

85 years and over

Subject disposition

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Recruitment details

Participants were randomized at 101 sites globally. The sites were located in: Europe (76), North America (13), Asia/Pacific (10), and Latin America (2). Results are reported as of the data cut-off date of 25 January 2019.

Screening details

Participants were stratified by: average baseline (BL) Red Blood Cell (RBC) transfusion requirement (≤ 4 units versus > 4 units of RBC per 28 days), BL platelet transfusion status (dependent or independent), country of enrollment and Eastern Cooperative Oncology Group (ECOG) Performance Status (PS) (0 to 1 versus 2).

Period 1 title

Overall Study (overall period)

Is this the baseline period?

Yes

Allocation method

Randomised - controlled

Blinding used

Double blind

Roles blinded

Subject, Investigator

Are arms mutually exclusive

Yes

Oral Azacitidine Plus Best Supportive Care

Arm description

Participants received 300 mg oral azacitidine tablets daily (QD) on days 1 to 21 of each 28-day treatment cycle and best supportive care (BSC) which included and was not limited to packed RBC (packed red blood cell [pRBC] and whole blood), platelet transfusions (single donor or pooled donor), antibiotic, antiviral and/or antifungal therapy, nutritional support, and granulocyte colony stimulating factors (G-CSF) for participants who experienced neutropenic fever/infections.

Arm type

Experimental

Investigational medicinal product name

Azacitidine

Investigational medicinal product code

Other name

Pharmaceutical forms

Tablet

Routes of administration

Oral use

Dosage and administration details

Participants received 300 mg oral azacitidine tablets daily (QD) on days 1 to 21 of each 28-day treatment cycle

Placebo Plus Best Supportive Care

Arm description

Participants received identically matching placebo tablets QD on days 1 to 21 of each 28-day treatment cycle and BSC which included but was not limited to, pRBC and whole blood, platelet transfusions (single donor or pooled donor), antibiotic, antiviral and/or antifungal therapy, nutritional support, and G-CSF for participants who experienced neutropenic fever/infections.

Arm type

Placebo

Investigational medicinal product name

Placebo

Investigational medicinal product code

Other name

Pharmaceutical forms

Tablet

Routes of administration

Oral use

Dosage and administration details

Participants received placebo tablets daily (QD) on days 1 to 21 of each 28-day treatment cycle

Number of subjects in period 1	Oral Azacitidine Plus Best Supportive Care	Placebo Plus Best Supportive Care
Started	107	109
Completed	0	0
Not completed	107	109
Adverse event, serious fatal	79	86
Consent withdrawn by subject	13	12
Adverse event, non-fatal	3	-
Other reasons	11	8
Lost to follow-up	-	3
Lack of efficacy	1	-

Baseline characteristics

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Reporting group title

Oral Azacitidine Plus Best Supportive Care

Reporting group description

Reporting group title

Placebo Plus Best Supportive Care

Reporting group description

Reporting group values	Oral Azacitidine Plus Best Supportive Care	Placebo Plus Best Supportive Care	Total
Number of subjects	107	109	216
Age categorical
Units: Subjects
Adults (18-64 years)	16	14	30
From 65-84 years	85	87	172
85 years and over	6	8	14
Age Continuous
Units: years
arithmetic mean (standard deviation)	73.0 ( 9.23 )	73.1 ( 8.36 )	-
Sex: Female, Male
Units: participants
Female	28	30	58
Male	79	79	158
Race/Ethnicity, Customized
Units: Subjects
White	96	99	195
Black or African American	1	0	1
Asian	2	3	5
Native Hawaiian or Other Pacific Islanders	0	0	0
American Indian or Alaska Native	0	0	0
Japanese	0	0	0
Other	8	7	15
Race/Ethnicity, Customized
Units: Subjects
Hispanic or Latino	4	9	13
Not Hispanic or Latino	91	93	184
Not Reported	12	7	19
Myelodysplastic Syndrome (MDS) World Health Organization (WHO) 2008 Classification
The WHO classification recognizes eight subtypes of MDS that are distinguished by the percentage of myeloblasts, presence or absence of ringed sideroblasts (i.e., erythroid precursors with iron deposits surrounding the nucleus), presence of a monocytosis or a deletion 5q.
Units: Subjects
RA = Refractory Anemia	4	3	7
RN = Refractory Neutropenia	0	0	0
RT = Refractory Thrombocytopenia	1	0	1
RARS = RA with Ringed Sideroblasts	3	2	5
RCMD = R Cytopenia w/ Multilineage Dysplasia	80	73	153
RAEB-1 RA with Excess Blasts - 1	17	29	46
RAEB-2 RA with Excess Blasts - 2	0	0	0
MDS-U (MDS-unclassified)	2	2	4
del (5q) MDS Associated with Isolated del 5q	0	0	0
International Prognostic Scoring System (IPSS)
The international prognostic scoring system (IPSS) is a standard for risk assessment in primary myelodysplastic syndromes (MDS) that categorizes prognoses taking into account cytogenetics, cytopenias, blasts and blood counts. The IPSS prognostic subgroups consist of low-, intermediate-1-, intermediate-2-, and high-risk groups. The scale is 0-3.5 at 0.5 increments. Scores of 0=Low; 0.5-1.0=Int-1; 1.5-2.0=Int-2; 2.5-3.5=High risk which corresponds to poorer prognosis.
Units: Subjects
Low	0	0	0
Intermediate 1 (0..5-1.0)	106	109	215
Intermediate 2 (1.5-2.0)	1	0	1
High	0	0	0
Platelet Transfusion Status
Participants with thrombocytopenia were defined by 2 platelet counts that were ≤ 75 × 10^9/cells/L with a platelet measurement ≥ 21 days apart. For those who were platelet transfusion-dependent at baseline and did not achieve platelet transfusion independence (TI) ≥ 56 days (8 weeks) during study treatment were considered as non-responders. For participants who were not platelet transfusion-dependent at baseline, development of platelet transfusion dependence, ie, ≥ 2 platelet transfusions in any 56-day (8 week) period during study treatment and were considered worse outcome.
Units: Subjects
Dependent	30	35	65
Independent	77	74	151
Eastern Cooperative Oncology Group (ECOG) Performance Status
ECOG performance status is used to describe a patient’s level of functioning in terms of their ability to care for themselves, daily activity, and physical ability (walking, working, etc.). The scale ranges from 0 to 5: 0 = Fully active, no restrictions; 1 = Restricted activity but ambulatory, able to carry out work of a light nature; 2 = Ambulatory and capable of all self-care but unable to carry out work activities; 3 = Capable to only limited self-care, confined to bed or chair more than 50% of waking hours; 4 = Completely disabled, no self-care, confined to bed or chair; 5 = Dead.
Units: Subjects
Grade 0-1	91	94	185
Grade 2	16	15	31
Grade 3	0	0	0
Grade 4	0	0	0
Grade 5	0	0	0
Average Red Blood Cell Transfusion Requirement (units per 28 days)
The average red blood cell (RBC) transfusion units per 28 days is derived using transfusion records before randomization date to randomization date - 84 days (if enrolled under original protocol or protocol amendment 1), or to randomization date - 56 days (if enrolled under protocol 2). "99999"=N/A
Units: units per 28 days
median (full range (min-max))	3.33 (1.3 to 10.0)	3.33 (1.3 to 9.5)	-
Platelet Count
"99999"=N/A
Units: 10^9 cells/L
arithmetic mean (standard deviation)	27.0 ( 15.97 )	27.9 ( 18.11 )	-
Hemoglobin
"99999"=N/A
Units: g/dL
arithmetic mean (standard deviation)	8.22 ( 0.988 )	8.04 ( 0.960 )	-

End points

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Reporting group title

Oral Azacitidine Plus Best Supportive Care

Reporting group description

Reporting group title

Placebo Plus Best Supportive Care

Reporting group description

Primary: Percentage of Participants who Achieved Red Blood Cell (RBC) Transfusion Independence for ≥ 56 Days

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End point title

Percentage of Participants who Achieved Red Blood Cell (RBC) Transfusion Independence for ≥ 56 Days

End point description

RBC transfusion (tfx) independence was defined as the absence of any RBC transfusion during any consecutive “rolling” 56 days within the treatment period. Participants who did not receive any RBC transfusion during a consecutive rolling 56 days (i.e., day 1 to day 56, day 2 to day 57) were considered as a 56-day RBC transfusion independent responder.

End point type

Primary

End point timeframe

Each participant was assessed for at least 56 days or more; from the date of randomization of study drug up to the data cut-off date of 25 January 2019, approximately 5 months.

End point values	Oral Azacitidine Plus Best Supportive Care	Placebo Plus Best Supportive Care
Number of subjects analysed	107	109
Units: Percentage of Participants
number (confidence interval 95%)	30.8 (22.1 to 39.6)	11.9 (5.8 to 18.0)

RBC Transfusion Independence for ≥ 56 Days

Comparison groups

Placebo Plus Best Supportive Care v Oral Azacitidine Plus Best Supportive Care

Number of subjects included in analysis

216

Analysis specification

Pre-specified

Analysis type

P-value

= 0.0005 ^[1]

Method

Stratified Mantel-Haenszel Chi-squared

Parameter type

Rate Difference

Point estimate

18.9

Confidence interval

level

95%

sides

2-sided

lower limit

8.3

upper limit

29.6

Notes
[1] - 2 sided

Secondary: Duration of RBC Transfusion Independence Among Participants who Achieved RBC Transfusion Independence for at Least 56 Days

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End point title

Duration of RBC Transfusion Independence Among Participants who Achieved RBC Transfusion Independence for at Least 56 Days

End point description

Duration of RBC transfusion independence was analyzed only for participants who achieved RBC transfusion independence of ≥ 56 days on treatment. Duration of RBC transfusion independence was defined as the time from the date transfusion independence is first observed (day 1 of a ≥ 56 days period without a transfusion) until the date the participants had a subsequently documented RBC transfusion. In the event a participant had more than one ≥56 days rolling periods which met the RBC independence criteria, the duration with the longest rolling period was used in the analysis. Participants who maintained RBC TI through the end of the treatment period were censored at the date of treatment discontinuation, death, or 1 day before the start of the subsequent MDS treatment (if any), whichever occurred first, or the particiapnts latest available assessment date in the database if the treatment was still on-going. "99999"=N/A

End point type

Secondary

End point timeframe

From the date of randomization of study drug up to

End point values	Oral Azacitidine Plus Best Supportive Care	Placebo Plus Best Supportive Care
Number of subjects analysed	33	13
Units: months
median (confidence interval 95%)	11.1 (8.2 to 26.0)	12.0 (2.3 to 99999)

Duration of RBC Transfusion Independence

Comparison groups

Placebo Plus Best Supportive Care v Oral Azacitidine Plus Best Supportive Care

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

P-value

= 0.0005

Method

Two-sided Unstratified Log Rank Test

Parameter type

Odds ratio (OR)

Point estimate

3.34

Confidence interval

level

95%

sides

2-sided

lower limit

1.64

upper limit

6.79

Secondary: Time to RBC Transfusion Independence for at Least 56 Days Among Participants who Achieved RBC Transfusion Independence for at Least 56 Days

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End point title

Time to RBC Transfusion Independence for at Least 56 Days Among Participants who Achieved RBC Transfusion Independence for at Least 56 Days

End point description

Time to RBC transfusion independence of ≥ 56 days was defined as the time between randomization and the date onset of transfusion independence was first observed (ie, Day 1 of 56 without any RBC transfusions).

End point type

Secondary

End point timeframe

From the date of randomization of study drug up to the data cut-off date of 25 January 2019; median duration of treatment to oral azacitidine was 5.29 months and 5.36 months for placebo

End point values	Oral Azacitidine Plus Best Supportive Care	Placebo Plus Best Supportive Care
Number of subjects analysed	33	13
Units: Months
median (full range (min-max))	2.37 (0.0 to 10.9)	2.04 (0.0 to 14.3)

No statistical analyses for this end point

Secondary: Duration of RBC Transfusion Reduction for Participants who Achieved RBC Transfusion Reduction of at Least 4 units of RBCs for at Least 8 Weeks

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End point title

Duration of RBC Transfusion Reduction for Participants who Achieved RBC Transfusion Reduction of at Least 4 units of RBCs for at Least 8 Weeks

End point description

A participant was considered as a RBC transfusion reduction responder if the participant had at least 4 units reduction in transfusion units over any consecutive 56 days period compared to the baseline transfusion units in 56 days.

End point type

Secondary

End point timeframe

From the date of randomization of study drug up to the treatment period; up to the data cut-off date of 25 January 2019; median duration of treatment to oral azacitidine was 5.29 months and 5.36 months for placebo

End point values	Oral Azacitidine Plus Best Supportive Care	Placebo Plus Best Supportive Care
Number of subjects analysed	45	34
Units: months
median (confidence interval 95%)	10.0 (7.1 to 13.3)	2.3 (2.0 to 5.0)

No statistical analyses for this end point

Secondary: Percentage of Participants who Achieved Red Blood Cell Transfusion Independence for ≥ 84 days

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End point title

Percentage of Participants who Achieved Red Blood Cell Transfusion Independence for ≥ 84 days

End point description

RBC transfusion independence was defined as the absence of any RBC transfusion during any consecutive “rolling” 84 days within the treatment period. Participants who did not receive any RBC transfusion during a consecutive rolling 84 days (i.e., day 1 to day 84, day 2 to day 85) were considered as a 84-day RBC transfusion independent responder.

End point type

Secondary

End point timeframe

End point values	Oral Azacitidine Plus Best Supportive Care	Placebo Plus Best Supportive Care
Number of subjects analysed	107	109
Units: Percentage of Participants
number (confidence interval 95%)	28.0 (19.5 to 36.5)	6.4 (1.8 to 11.0)

RBC Transfusion Independence for ≥ 84 days

Comparison groups

Placebo Plus Best Supportive Care v Oral Azacitidine Plus Best Supportive Care

Number of subjects included in analysis

216

Analysis specification

Pre-specified

Analysis type

P-value

< 0.0001 ^[2]

Method

Stratified Mantel-Haenszel; Chi-squared

Parameter type

Rate Difference

Point estimate

21.6

Confidence interval

level

95%

sides

2-sided

lower limit

11.9

upper limit

31.3

Notes
[2] - 2 sided

Secondary: Duration of RBC Transfusion Independence Among Participants who Achieved RBC Transfusion Independence for at Least 84 Days

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End point title

Duration of RBC Transfusion Independence Among Participants who Achieved RBC Transfusion Independence for at Least 84 Days

End point description

Duration of RBC transfusion independence was analyzed only for participants who achieved RBC transfusion independence of ≥ 84 days on treatment. Duration of RBC transfusion independence was defined as the time from the date transfusion independence is first observed (day 1 of a ≥ 84 days period without a transfusion) until the date the participants had a subsequently documented RBC transfusion. In case a participant had more than one ≥84 days rolling periods which met the RBC independence criteria, the duration with the longest rolling period was used in the analysis. "99999"=N/A

End point type

Secondary

End point timeframe

End point values	Oral Azacitidine Plus Best Supportive Care	Placebo Plus Best Supportive Care
Number of subjects analysed	30	7
Units: months
median (confidence interval 95%)	11.1 (8.2 to 26.0)	99999 (5.0 to 99999)

Duration of RBC Transfusion Independence

Comparison groups

Placebo Plus Best Supportive Care v Oral Azacitidine Plus Best Supportive Care

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

P-value

= 0.4347

Method

Two-Sided Unstratified Log Rank Test

Confidence interval

Secondary: Time to RBC Transfusion Independence for at Least 84 Days Among Participants who Achieved RBC Transfusion Independence for at Least 84 Days

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End point title

Time to RBC Transfusion Independence for at Least 84 Days Among Participants who Achieved RBC Transfusion Independence for at Least 84 Days

End point description

Time to RBC transfusion independence of ≥ 84 days was defined as the time between randomization and the date onset of transfusion independence was first observed (i.e., Day 1 of 84 without any RBC transfusions).

End point type

Secondary

End point timeframe

End point values	Oral Azacitidine Plus Best Supportive Care	Placebo Plus Best Supportive Care
Number of subjects analysed	30	7
Units: Months
median (full range (min-max))	2.64 (0.0 to 9.9)	4.01 (0.5 to 14.3)

No statistical analyses for this end point

Secondary: Percentage of Participants with an Erythroid Hematological Improvement (HI-E) Response According to 2006 IWG Criteria

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End point title

Percentage of Participants with an Erythroid Hematological Improvement (HI-E) Response According to 2006 IWG Criteria

End point description

Erythroid HI-E improvement was defined as a hemoglobin increase of ≥ 1.5 g/dL; or a reduction in units of RBC transfusions by an absolute number of at least 4 RBC transfusions/8 weeks compared with the pretreatment transfusion number in the previous 8 weeks. Only RBC transfusions given for a hemoglobin of ≤ 9.0 g/dL on treatment were counted in the RBC transfusion response evaluation.

End point type

Secondary

End point timeframe

End point values	Oral Azacitidine Plus Best Supportive Care	Placebo Plus Best Supportive Care
Number of subjects analysed	107	109
Units: Percentage of Participants
number (confidence interval 95%)
HI-E Response	43.0 (33.6 to 52.4)	32.1 (23.3 to 40.9)
≥ 1.5 g/dL Hemoglobin Increase	23.4 (15.3 to 31.4)	5.5 (1.2 to 9.8)
RBC Transfusion Reduction	42.1 (32.7 to 51.4)	31.2 (22.5 to 39.9)

Erythroid Hematological Improvement (HI-E)

Comparison groups

Placebo Plus Best Supportive Care v Oral Azacitidine Plus Best Supportive Care

Number of subjects included in analysis

216

Analysis specification

Pre-specified

Analysis type

^[3]

P-value

= 0.1467

Method

Stratified Mantel-Haenszel. Chi-squared

Parameter type

Rate Difference

Point estimate

10.9

Confidence interval

level

95%

sides

2-sided

lower limit

-2

upper limit

23.7

Notes
[3] - HI-E

Erythroid Hematological Improvement (HI-E)

Comparison groups

Placebo Plus Best Supportive Care v Oral Azacitidine Plus Best Supportive Care

Number of subjects included in analysis

216

Analysis specification

Pre-specified

Analysis type

^[4]

P-value

= 0.1431

Method

Stratified Mantel-Haenszel. Chi-squared

Parameter type

Rate Difference

Point estimate

10.9

Confidence interval

level

95%

sides

2-sided

lower limit

-1.9

upper limit

23.6

Notes
[4] - RBC Transfusion Reduction

Erythroid Hematological Improvement (HI-E)

Comparison groups

Placebo Plus Best Supportive Care v Oral Azacitidine Plus Best Supportive Care

Number of subjects included in analysis

216

Analysis specification

Pre-specified

Analysis type

^[5]

P-value

= 0.0002

Method

Stratified Mantel-Haenszel. Chi-squared

Parameter type

Rate Diffrence

Point estimate

17.9

Confidence interval

level

95%

sides

2-sided

lower limit

8.8

upper limit

26.9

Notes
[5] - ≥ 1.5 g/dL Hemoglobin Increase

Secondary: Percentage of Participants with a Hematological Improvement Response in Platelets (HI-P) According to 2006 IWG Criteria

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End point title

Percentage of Participants with a Hematological Improvement Response in Platelets (HI-P) According to 2006 IWG Criteria

End point description

HI-P response was defined according to IWG 2006 criteria (Cheson, 2006) and as: 1. Absolute increase of ≥ 30 X 10^9/L for participants^ starting with > 20 X 10^9/L platelets; 2. Increase from < 20 X 10^9/L to > 20 X 10^9/L and by at least 100%. HI-P must have lasted at least 8 weeks.

End point type

Secondary

End point timeframe

End point values	Oral Azacitidine Plus Best Supportive Care	Placebo Plus Best Supportive Care
Number of subjects analysed	107	109
Units: Percentage of Participants
number (confidence interval 95%)	24.3 (16.2 to 32.4)	7.3 (2.4 to 12.2)

HI-P

Comparison groups

Placebo Plus Best Supportive Care v Oral Azacitidine Plus Best Supportive Care

Number of subjects included in analysis

216

Analysis specification

Pre-specified

Analysis type

P-value

= 0.0007

Method

Stratified Mantel-Haenszel. Chi-squared

Parameter type

Rate Difference

Point estimate

Confidence interval

level

95%

sides

2-sided

lower limit

7.5

upper limit

26.4

Secondary: Percentage of Participants who Achieved Platelet Transfusion Independence with a Duration of ≥ 8 weeks (56 days)

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End point title

Percentage of Participants who Achieved Platelet Transfusion Independence with a Duration of ≥ 8 weeks (56 days)

End point description

Platelet transfusion independence was defined as the absence of any platelet transfusion during any consecutive “rolling” 56 days during the treatment period, (ie, Day 1 to 56, Day 2 to 57, Days 3 to 58, etc.). Participants were considered platelet transfusion dependent at baseline if they had received ≥ 2 platelet transfusions during the 56 days immediately preceding randomization and had no consecutive 28-day period during which no platelet transfusions were administered.

End point type

Secondary

End point timeframe

End point values	Oral Azacitidine Plus Best Supportive Care	Placebo Plus Best Supportive Care
Number of subjects analysed	30	35
Units: Percentage Participants
number (not applicable)	16.7	14.3

No statistical analyses for this end point

Secondary: Time to Platelet Transfusion Independence

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End point title

Time to Platelet Transfusion Independence

End point description

Time to platelet transfusion independence was defined as the time between randomization and the first documented date of onset of transfusion independence (ie, Day 1 of 56 without any platelet transfusions). "99999"=N/A

End point type

Secondary

End point timeframe

End point values	Oral Azacitidine Plus Best Supportive Care	Placebo Plus Best Supportive Care
Number of subjects analysed	5	5
Units: Months
median (full range (min-max))	9.6 (9.6 to 10.9)	99999 (99999 to 99999)

No statistical analyses for this end point

Secondary: Percentage of Participants with a Hematologic Response According to the 2006 IWG Criteria for MDS

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End point title

Percentage of Participants with a Hematologic Response According to the 2006 IWG Criteria for MDS

End point description

Hematologic response was defined as: • A complete response (CR): <5% myeloblasts, and normal maturation of all cell lines; Peripheral blood (PB) shows: hemoglobin >10 g/dL, neutrophils ≥1.0x10^9/L, platelets ≥100x10^9/dL, blasts (0%) • Partial Response (PR): same as CR bone marrow (BM) shows blasts decreased by ≥ 50% over pre-treatment but still > 5%; Cellularity and morphology not relevant • Marrow CR: BM: ≤ 5% myeloblasts and decrease by ≥ 50% over pre-treatment PB • Stable disease (SD): failure to achieve at least PR, but no evidence of progression for > 8 wks • Failure: death during treatment or disease progression • Disease Progression for those with: - Less than 5% blasts: ≥ 50% increase in blasts to > 5% blasts - 5%-10% blasts:≥ 50% increase to > 10% blasts - 10%-20% blasts:≥ 50% increase to > 20% blasts - 20%-30% blasts ≥ 50% increase to > 30% blasts Any of the following: - ≥ 50% decrease from maximum remission/response in granulocytes or platelets

End point type

Secondary

End point timeframe

Response was assessed every 3 cycles; up to the data cut-off date of 25 Jan 2019; median duration of exposure to oral azacitidine was 86.0 days and 119.0 days for placebo

End point values	Oral Azacitidine Plus Best Supportive Care	Placebo Plus Best Supportive Care
Number of subjects analysed	107	109
Units: Percentage of Participants
number (not applicable)
Complete Response (CR)	7.7	0
Partial Response	0	0
Marrow CR	23.1	4.2
Stable Disease (SD)	2.8	30.3
Disease Progression	62.6	46.8
Failure due to Death	0.9	0.9

No statistical analyses for this end point

Secondary: Overall Survival (OS)

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End point title

Overall Survival (OS)

End point description

Overall survival was defined as the time from randomization to death from any cause and was calculated using randomization date and date of death, or date of last follow-up for censored participants. All subjects were followed until drop out (withdrawal of consent from further data collection or lost to follow-up), death, or study closure. Participants who dropped out or were alive at study closure (or at the time of the interim analysis) had their OS times censored at the time of last contact, as appropriate.

End point type

Secondary

End point timeframe

From randomization up to death from any cause; up to a maximum of approximately 10 years on study; median duration of treatment to oral azacitidine was 5.29 months and 5.36 months for placebo

End point values	Oral Azacitidine Plus Best Supportive Care	Placebo Plus Best Supportive Care
Number of subjects analysed	107	109
Units: Months
median (confidence interval 95%)	17.3 (12.9 to 20.8)	16.7 (12.8 to 24.0)

Comparison groups

Placebo Plus Best Supportive Care v Oral Azacitidine Plus Best Supportive Care

Number of subjects included in analysis

216

Analysis specification

Pre-specified

Analysis type

P-value

= 0.6257

Method

Logrank

Parameter type

Cox proportional hazard

Point estimate

1.08

Confidence interval

level

95%

sides

2-sided

lower limit

0.79

upper limit

1.49

Secondary: Percentage of Participants with Significant Bleeding Events

Top of page

End point title

Percentage of Participants with Significant Bleeding Events

End point description

Clinically significant bleeding event was defined as: any intracranial or retroperitoneal bleed; bleeding requiring transfusions of > 2 units of blood/blood products; bleeding associated with a decrease in hemoglobin of > 2 g/dL; or bleeding from any site requiring transfusions of > 2 units of blood.

End point type

Secondary

End point timeframe

From date of randomization until 28 days after the last dose of IP; up to data cut off date of 25 January 2019; median duration of treatment to oral azacitidine was 5.29 months and 5.36 months for placebo

End point values	Oral Azacitidine Plus Best Supportive Care	Placebo Plus Best Supportive Care
Number of subjects analysed	107	109
Units: Percentage of Participants
number (not applicable)	8.4	9.2

No statistical analyses for this end point

Secondary: Percentage of Participants who Progressed to Acute Myeloid Leukemia (AML)

Top of page

End point title

Percentage of Participants who Progressed to Acute Myeloid Leukemia (AML)

End point description

Participants with a documented diagnosis of AML arising from previous MDS documented diagnosis.

End point type

Secondary

End point timeframe

From randomization of study drug to the end up to final data cut-off date of 25 January 2019; maximum follow-up time was 67.9 months for azacitidine and 64.8 months for placebo group

End point values	Oral Azacitidine Plus Best Supportive Care	Placebo Plus Best Supportive Care
Number of subjects analysed	107	109
Units: Percentage of Participants
number (not applicable)	7.5	16.5

No statistical analyses for this end point

Secondary: Time to Progression to Acute Myeloid Leukemia (AML) Among Participants who Progressed to AML

Top of page

End point title

Time to Progression to Acute Myeloid Leukemia (AML) Among Participants who Progressed to AML

End point description

Time to AML progression was defined as the time from the date of randomization until the date the subject has documented progression to AML. For participants who had progression to AML documented in MLL central lab report, the earliest sample collection date with the diagnosis of “s-AML arising from previous MDS” was used as the date to AML progression. "99999"=N/A

End point type

Secondary

End point timeframe

From randomization of study drug to progression of AML; up to a maximum of approximately 10 years on study; median duration of treatment to oral azacitidine was 5.29 months and 5.36 months for placebo

End point values	Oral Azacitidine Plus Best Supportive Care	Placebo Plus Best Supportive Care
Number of subjects analysed	8	18
Units: Months
median (full range (min-max))	99999 (99999 to 99999)	99999 (99999 to 99999)

No statistical analyses for this end point

Secondary: Number of Participants with Treatment Emergent Adverse Events (TEAE)

Top of page

End point title

Number of Participants with Treatment Emergent Adverse Events (TEAE)

End point description

A TEAE was defined as an adverse event that begins or worsens in intensity of frequency on or after the first dose of study drug through 28 days after last dose of study drug. A serious adverse event (SAE) is any: • Death; • Life-threatening event; • Any inpatient hospitalization or prolongation of existing hospitalization; • Persistent or significant disability or incapacity; • Congenital anomaly or birth defect; • Any other important medical event The investigator determined the relationship of an AE to study drug based on the timing of the AE relative to drug administration and whether or not other drugs, therapeutic interventions, or underlying conditions could provide a sufficient explanation for the event. The severity of an AE was evaluated by the investigator according to National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE) (Version 4.0) where Grade 1 = Mild, Grade 2 = Moderate, Grade 3 = Severe, Grade 4 = Life-threatening and Grade 5 = Death.

End point type

Secondary

End point timeframe

From first dose of IP up to 28 days after the last dose of IP; up to a maximum of approximately 10 years on study; median duration of treatment to oral azacitaidine was 5.29 months and 5.36 months for placebo

End point values	Oral Azacitidine Plus Best Supportive Care	Placebo Plus Best Supportive Care
Number of subjects analysed	107	109
Units: Participants
≥ 1 TEAE	107	108
≥ 1 TEAE Related to Study Drug	102	54
≥ 1 Serious TEAE	83	69
≥ 1 Serious TEAE Related to Study Drug	38	8
≥ 1 Grade (GR) 3-4 TEAE	98	81
≥ 1 Grade 3-4 TEAE Related to Study Drug	73	20
≥ 1 Grade (GR) 3-4 Serious TEAE	79	56
≥ 1 GR 3-4 Serious TEAE Related to Study Drug	38	5
≥ 1 TEAE Leading to Death	25	14
≥ 1 TEAE Related to Study Drug Leading to Death	9	2
≥ 1 TEAE Leading to Dose Reduction	31	4
≥ 1 TEAE Leading to Dose Interruption	68	40
≥ 1 TEAE Leading to Dose Interruption/Reduction	29	2
≥ 1 TEAE Leading to Treatment Discontinuation	34	31

No statistical analyses for this end point

Secondary: Mean Change From Baseline in the Social Well-Being Component of the Functional Assessment of Cancer Therapy-Anemia Instrument at Cycle 6

Top of page

End point title

Mean Change From Baseline in the Social Well-Being Component of the Functional Assessment of Cancer Therapy-Anemia Instrument at Cycle 6

End point description

The FACT-An questionnaire is a 47-item, cancer specific questionnaire consisting of a core 27 items measuring 4 general domains physical well being (PWG), social/family (SWB), emotional well being (EWB) and Functional Well-Being (FWB) and an additional 20-item anemia questionnaire that measures fatigue associated items and 7 non-fatigue items. The scales are formatted on 1 to 4 pages for self-administration using a 5-point Likert rating scale (0 = Not at all; 1 = A little bit; 2 = Somewhat; 3 = Quite a Bit and 4 = Very much). Also, general health related quality of life (HRQoL), the FACT-An measures the impact of fatigue and other anemia-related symptoms on patient functioning and is used to assess the effect of treatments in various therapeutic areas, including MDS. The instrument and the fatigue and non-fatigue subscales are scored by summing points from all questions, then converting this sum to a 100 point scale; 0 indicates the poorest QOL and 100 denotes the highest QOL.

End point type

Secondary

End point timeframe

Baseline to Cycle 6 Day 1

End point values	Oral Azacitidine Plus Best Supportive Care	Placebo Plus Best Supportive Care
Number of subjects analysed	42	49
Units: Units on a Scale
arithmetic mean (standard deviation)	-0.4 ( 3.96 )	-1.1 ( 4.69 )

Social Well-Being

Comparison groups

Placebo Plus Best Supportive Care v Oral Azacitidine Plus Best Supportive Care

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

P-value

= 0.446

Method

t-test, 2-sided

Confidence interval

Secondary: Mean Change From Baseline in the Physical Well-Being Component of the Functional Assessment of Cancer Therapy-Anemia (FACT-An) Endpoints at Cycle 6

Top of page

End point title

Mean Change From Baseline in the Physical Well-Being Component of the Functional Assessment of Cancer Therapy-Anemia (FACT-An) Endpoints at Cycle 6

End point description

End point type

Secondary

End point timeframe

Baseline to Cycle 6 Day 1

End point values	Oral Azacitidine Plus Best Supportive Care	Placebo Plus Best Supportive Care
Number of subjects analysed	42	49
Units: Units on a Scale
arithmetic mean (standard deviation)	0.2 ( 4.12 )	-0.8 ( 3.91 )

FACT-An

Comparison groups

Placebo Plus Best Supportive Care v Oral Azacitidine Plus Best Supportive Care

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

P-value

= 0.214

Method

t-test, 2-sided

Confidence interval

Secondary: Mean Change From Baseline in the Functional Well-Being Component of the FACT-An Instrument at Cycle 6

Top of page

End point title

Mean Change From Baseline in the Functional Well-Being Component of the FACT-An Instrument at Cycle 6

End point description

End point type

Secondary

End point timeframe

Baseline to Cycle 6 Day 1

End point values	Oral Azacitidine Plus Best Supportive Care	Placebo Plus Best Supportive Care
Number of subjects analysed	42	49
Units: Units on a Scale
arithmetic mean (standard deviation)	0.5 ( 3.95 )	-1.2 ( 4.45 )

Functional Well-Being

Comparison groups

Placebo Plus Best Supportive Care v Oral Azacitidine Plus Best Supportive Care

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

P-value

= 0.058

Method

t-test, 2-sided

Confidence interval

Secondary: Mean Change From Baseline in the Emotional Well-Being Component of the Functional Assessment of Cancer Therapy-Anemia Instrument at Cycle 6

Top of page

End point title

Mean Change From Baseline in the Emotional Well-Being Component of the Functional Assessment of Cancer Therapy-Anemia Instrument at Cycle 6

End point description

End point type

Secondary

End point timeframe

Baseline to Cycle 6 Day 1

End point values	Oral Azacitidine Plus Best Supportive Care	Placebo Plus Best Supportive Care
Number of subjects analysed	42	49
Units: Units on a Scale
arithmetic mean (standard deviation)	1.3 ( 4.33 )	0.2 ( 4.35 )

Emotional Well-Being

Comparison groups

Placebo Plus Best Supportive Care v Oral Azacitidine Plus Best Supportive Care

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

P-value

= 0.248

Method

t-test, 2-sided

Confidence interval

Secondary: Mean Change From Baseline in the Anemia Subscale within FACT-An Instrument at Cycle 6

Top of page

End point title

Mean Change From Baseline in the Anemia Subscale within FACT-An Instrument at Cycle 6

End point description

End point type

Secondary

End point timeframe

Baseline to Cycle 6 Day 1

End point values	Oral Azacitidine Plus Best Supportive Care	Placebo Plus Best Supportive Care
Number of subjects analysed	42	49
Units: Units on a Scale
arithmetic mean (standard deviation)	2.9 ( 11.81 )	-0.6 ( 10.39 )

Anemia

Comparison groups

Placebo Plus Best Supportive Care v Oral Azacitidine Plus Best Supportive Care

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

P-value

= 0.13

Method

t-test, 2-sided

Confidence interval

Secondary: Mean Change From Baseline in the Fatigue-Related Subscale within the FACT-An Instrument at Cycle 6

Top of page

End point title

Mean Change From Baseline in the Fatigue-Related Subscale within the FACT-An Instrument at Cycle 6

End point description

End point type

Secondary

End point timeframe

Baseline to Cycle 6 Day 1

End point values	Oral Azacitidine Plus Best Supportive Care	Placebo Plus Best Supportive Care
Number of subjects analysed	42	49
Units: Units on a Scale
arithmetic mean (standard deviation)	2.1 ( 8.74 )	-0.6 ( 7.84 )

Fatigue

Comparison groups

Placebo Plus Best Supportive Care v Oral Azacitidine Plus Best Supportive Care

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

P-value

= 0.123

Method

t-test, 2-sided

Confidence interval

Secondary: Mean Change From Baseline in the Functional Assessment of Cancer Therapy-Anemia Trial Outcome Index (FACT-An TOI) Summary Scale within the FACT-An Instrument at Cycle 6

Top of page

End point title

Mean Change From Baseline in the Functional Assessment of Cancer Therapy-Anemia Trial Outcome Index (FACT-An TOI) Summary Scale within the FACT-An Instrument at Cycle 6

End point description

The FACT-G and FACT-An score are summed to form the FACT-An total score. The FACT-An Trial Outcome Index (TOI) consists of the summation of a "summary scale" and includes the Physical Well-being, (PWB; 7 items; score range, 0–28), the Functional Well-being (7 items; score range, 0–28) and the Anemia subscale consisting of 20 items on the same five-point scale, with 13 of them measuring fatigue related symptoms (FS) and seven measuring non-FS. The FACT-An TOI has been demonstrated to be a sensitive indicator of clinical outcomes in a number of diseases including MDS. The Fact-TOI score ranges from 0 to 136. Higher scores on all scales of the Fact-An and subscales on the FACT-TOI reflect better quality of life or fewer symptoms.

End point type

Secondary

End point timeframe

Baseline to Cycle 6 Day 1

End point values	Oral Azacitidine Plus Best Supportive Care	Placebo Plus Best Supportive Care
Number of subjects analysed	42	49
Units: Units on a Scale
arithmetic mean (standard deviation)	3.7 ( 17.29 )	-2.7 ( 15.45 )

FACT-An TOI

Comparison groups

Placebo Plus Best Supportive Care v Oral Azacitidine Plus Best Supportive Care

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

P-value

= 0.069

Method

t-test, 2-sided

Confidence interval

Secondary: Mean Change From Baseline in the Functional Assessment of Cancer Therapy-Anemia-General (FACT-G) Summary Scale within the FACT-An Instrument at Cycle 6

Top of page

End point title

Mean Change From Baseline in the Functional Assessment of Cancer Therapy-Anemia-General (FACT-G) Summary Scale within the FACT-An Instrument at Cycle 6

End point description

The FACT-An is a 47-item, cancer-specific questionnaire consisting of a core 27-item general questionnaire (i.e., the Functional Assessment of Cancer Therapy-General [FACT-G]) The FACT-G measures the 4 domains on a 5-point scale ranging from 0 (not at all) to 4 (very much). The 4 domains are: • Physical Well-being (PWB; 7 items; score range, 0–28), • Social/Family Well-being (SWB; 7 items; score range, 0–28), • Emotional Well-being (EWB; 6 items; score range, 0–24), and • Functional Well-being (7 items; score range, 0–28). The FACT-G is a summation composed of a "summary scale" including the PWB, SWB, EWB and FWB. The FACT-G score range is from 0 to 108. For all summary scales including FACT-G, a higher score indicates better HRQoL or lower level of symptoms.

End point type

Secondary

End point timeframe

Baseline to Cycle 6 Day 1

End point values	Oral Azacitidine Plus Best Supportive Care	Placebo Plus Best Supportive Care
Number of subjects analysed	42	49
Units: Units on a Scale
arithmetic mean (standard deviation)	1.6 ( 12.00 )	-2.9 ( 12.11 )

FACT-G

Comparison groups

Placebo Plus Best Supportive Care v Oral Azacitidine Plus Best Supportive Care

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

P-value

= 0.078

Method

t-test, 2-sided

Confidence interval

Secondary: Mean Change From Baseline in the Functional Assessment of Cancer Therapy-Anemia-Total Score at Cycle 6

Top of page

End point title

Mean Change From Baseline in the Functional Assessment of Cancer Therapy-Anemia-Total Score at Cycle 6

End point description

The FACT-G and the anemia subscale (AnS) are summed to form the FACT-An total score and the total score ranges from 0 to 188. The FACT-G measures the 4 domains on a 5-point scale ranging from 0 (not at all) to 4 (very much). The 4 domains are: • Physical Well-being (PWB; 7 items; score range, 0–28), • Social/Family Well-being (SWB; 7 items; score range, 0–28), • Emotional Well-being (EWB; 6 items; score range, 0–24), and • Functional Well-being (7 items; score range, 0–28). The AnS consists of 20 items on the same 5-point scale, with 13 of them measuring fatigue-related symptoms (FS) and 7 measuring non-FS. The AnS and FS scores can range from 0-80 and 0-52, respectively. For all domains and summary subscales, a higher score indicates better HRQoL or lower level of symptoms.

End point type

Secondary

End point timeframe

Baseline to Cycle 6 Day 1

End point values	Oral Azacitidine Plus Best Supportive Care	Placebo Plus Best Supportive Care
Number of subjects analysed	42	49
Units: Units on a Scale
arithmetic mean (standard deviation)	4.5 ( 21.88 )	-3.5 ( 20.62 )

Anemia Total Score

Comparison groups

Placebo Plus Best Supportive Care v Oral Azacitidine Plus Best Supportive Care

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

P-value

= 0.073

Method

t-test, 2-sided

Confidence interval

Secondary: Percentage of Participants with a Clinically Meaningful Improvment (CMI) From Baseline on the Social Well-Being Domain within the FACT-An Instrument at Cycle 6

Top of page

End point title

Percentage of Participants with a Clinically Meaningful Improvment (CMI) From Baseline on the Social Well-Being Domain within the FACT-An Instrument at Cycle 6

End point description

A clinically meaningful improvement or deterioration was defined by domain specific thresholds of change from baseline. The FACT-An questionnaire is a 47-item, cancer specific questionnaire consisting of a core 27 items measuring 4 general domains physical well being, social/family, emotional well being and Functional Well-Being and an additional 20-item anemia questionnaire that measures fatigue and 7 non-fatigue items. The scales are formatted on 4 pages for self-administration using a 5-point Likert rating scale (0 = Not at all; 1 = A little bit; 2 = Somewhat; 3 = Quite a Bit and 4 = Very much). Also, general HRQoL measures the impact of fatigue and other anemia-related symptoms on patient functioning and is used to assess the effect of treatments in various areas, including MDS. The instrument and the fatigue and non-fatigue subscales are scored by summing points from all questions, then converting this sum to a 100 point scale; 0 = the poorest QOL and 100 = the highest QOL.

End point type

Secondary

End point timeframe

Cycle 6 Day 1

End point values	Oral Azacitidine Plus Best Supportive Care	Placebo Plus Best Supportive Care
Number of subjects analysed	81	95
Units: Percentage of Participants
number (not applicable)	11.1	14.7

Social Well-Being

Comparison groups

Placebo Plus Best Supportive Care v Oral Azacitidine Plus Best Supportive Care

Number of subjects included in analysis

176

Analysis specification

Pre-specified

Analysis type

P-value

= 0.48

Method

Cochran-Mantel-Haenszel

Parameter type

Common Odds Raatio

Point estimate

0.72

Confidence interval

level

95%

sides

2-sided

lower limit

0.29

upper limit

1.78

Secondary: Percentage of Participants with a Clinically Meaningful Improvment (CMI) From Baseline on the Physical Well-Being Domain within the FACT-An Instrument at Cycle 6

Top of page

End point title

Percentage of Participants with a Clinically Meaningful Improvment (CMI) From Baseline on the Physical Well-Being Domain within the FACT-An Instrument at Cycle 6

End point description

End point type

Secondary

End point timeframe

Cycle 6 Day 1

End point values	Oral Azacitidine Plus Best Supportive Care	Placebo Plus Best Supportive Care
Number of subjects analysed	81	95
Units: Percentage of Participants
number (not applicable)	17.3	13.7

CMI

Comparison groups

Placebo Plus Best Supportive Care v Oral Azacitidine Plus Best Supportive Care

Number of subjects included in analysis

176

Analysis specification

Pre-specified

Analysis type

P-value

= 0.56

Method

Cochran-Mantel-Haenszel

Parameter type

Common Odds Raatio

Point estimate

0.77

Confidence interval

level

95%

sides

2-sided

lower limit

0.54

upper limit

1.3

Secondary: Percentage of Participants with a Clinically Meaningful Improvment (CMI) From Baseline on the Functional Well-Being Domain within the FACT-An Instrument at Cycle 6

Top of page

End point title

Percentage of Participants with a Clinically Meaningful Improvment (CMI) From Baseline on the Functional Well-Being Domain within the FACT-An Instrument at Cycle 6

End point description

End point type

Secondary

End point timeframe

Cycle 6 Day 1

End point values	Oral Azacitidine Plus Best Supportive Care	Placebo Plus Best Supportive Care
Number of subjects analysed	81	95
Units: Percentage of Participants
number (not applicable)	14.8	8.4

CMI

Comparison groups

Placebo Plus Best Supportive Care v Oral Azacitidine Plus Best Supportive Care

Number of subjects included in analysis

176

Analysis specification

Pre-specified

Analysis type

P-value

= 0.121

Method

Cochran-Mantel-Haenszel

Parameter type

Common Odds Ratio

Point estimate

2.14

Confidence interval

level

95%

sides

2-sided

lower limit

0.82

upper limit

5.57

Secondary: Percentage of Participants with a Clinically Meaningful Improvment (CMI) From Baseline on the Emotional Well-Being Domain within the FACT-An Instrument at Cycle 6

Top of page

End point title

Percentage of Participants with a Clinically Meaningful Improvment (CMI) From Baseline on the Emotional Well-Being Domain within the FACT-An Instrument at Cycle 6

End point description

End point type

Secondary

End point timeframe

Cycle 6 Day 1

End point values	Oral Azacitidine Plus Best Supportive Care	Placebo Plus Best Supportive Care
Number of subjects analysed	81	95
Units: Percentage of Participants
number (not applicable)	23.5	15.8

CMI

Comparison groups

Placebo Plus Best Supportive Care v Oral Azacitidine Plus Best Supportive Care

Number of subjects included in analysis

176

Analysis specification

Pre-specified

Analysis type

P-value

= 0.197

Method

Cochran-Mantel-Haenszel

Parameter type

Common Odds Ratio

Point estimate

1.67

Confidence interval

level

95%

sides

2-sided

lower limit

0.76

upper limit

3.65

Secondary: Percentage of Participants with a Clinically Meaningful Improvment (CMI) From Baseline on the Anemia Subscale Domain within the FACT-An Instrument at Cycle 6

Top of page

End point title

Percentage of Participants with a Clinically Meaningful Improvment (CMI) From Baseline on the Anemia Subscale Domain within the FACT-An Instrument at Cycle 6

End point description

End point type

Secondary

End point timeframe

Cycle 6 Day 1

End point values	Oral Azacitidine Plus Best Supportive Care	Placebo Plus Best Supportive Care
Number of subjects analysed	81	95
Units: Percentage of Participants
number (not applicable)	27.2	15.8

CMI

Comparison groups

Placebo Plus Best Supportive Care v Oral Azacitidine Plus Best Supportive Care

Number of subjects included in analysis

176

Analysis specification

Pre-specified

Analysis type

P-value

= 0.075

Method

Cochran-Mantel-Haenszel

Parameter type

Common Odds Ratio

Point estimate

Confidence interval

level

95%

sides

2-sided

lower limit

0.93

upper limit

4.3

Secondary: Percentage of Participants with a Clinically Meaningful Improvment (CMI) From Baseline in the Functional Assessment of Cancer Therapy-Anemia Trial Outcome Index Subscale Domain within the FACT-An Instrument at Cycle 6

Top of page

End point title

Percentage of Participants with a Clinically Meaningful Improvment (CMI) From Baseline in the Functional Assessment of Cancer Therapy-Anemia Trial Outcome Index Subscale Domain within the FACT-An Instrument at Cycle 6

End point description

End point type

Secondary

End point timeframe

Cycle 6 Day 1

End point values	Oral Azacitidine Plus Best Supportive Care	Placebo Plus Best Supportive Care
Number of subjects analysed	81	95
Units: Percentage of Participants
number (not applicable)	19.8	12.6

CMI

Comparison groups

Placebo Plus Best Supportive Care v Oral Azacitidine Plus Best Supportive Care

Number of subjects included in analysis

176

Analysis specification

Pre-specified

Analysis type

P-value

= 0.249

Method

Cochran-Mantel-Haenszel

Parameter type

Common Odds Ratio

Point estimate

1.65

Confidence interval

level

95%

sides

2-sided

lower limit

0.71

upper limit

3.83

Secondary: Percentage of Participants with a Clinically Meaningful Improvment (CMI) From Baseline in the Fatigue Related Symptoms Subscale Domain within the FACT-An Instrument at Cycle 6

Top of page

End point title

Percentage of Participants with a Clinically Meaningful Improvment (CMI) From Baseline in the Fatigue Related Symptoms Subscale Domain within the FACT-An Instrument at Cycle 6

End point description

End point type

Secondary

End point timeframe

Cycle 6 Day 1

End point values	Oral Azacitidine Plus Best Supportive Care	Placebo Plus Best Supportive Care
Number of subjects analysed	81	95
Units: Percentage of Participants
number (not applicable)	27.2	18.9

CMI

Comparison groups

Placebo Plus Best Supportive Care v Oral Azacitidine Plus Best Supportive Care

Number of subjects included in analysis

176

Analysis specification

Pre-specified

Analysis type

P-value

= 0.222

Method

Cochran-Mantel-Haenszel

Parameter type

Common Odds Ratio

Point estimate

1.58

Confidence interval

level

95%

sides

2-sided

lower limit

0.76

upper limit

3.29

Secondary: Percentage of Participants with a Clinically Meaningful Improvment (CMI) From Baseline in the Functional Assessment of Cancer Therapy-Anemia-General Subscale Domain within the FACT-An Instrument at Cycle 6

Top of page

End point title

Percentage of Participants with a Clinically Meaningful Improvment (CMI) From Baseline in the Functional Assessment of Cancer Therapy-Anemia-General Subscale Domain within the FACT-An Instrument at Cycle 6

End point description

End point type

Secondary

End point timeframe

Cycle 6 Day 1

End point values	Oral Azacitidine Plus Best Supportive Care	Placebo Plus Best Supportive Care
Number of subjects analysed	81	95
Units: Percentage of Participants
number (not applicable)	23.5	13.7

CMI

Comparison groups

Placebo Plus Best Supportive Care v Oral Azacitidine Plus Best Supportive Care

Number of subjects included in analysis

176

Analysis specification

Pre-specified

Analysis type

P-value

= 0.082

Method

Cochran-Mantel-Haenszel

Parameter type

Common Odds Ratio

Point estimate

2.03

Confidence interval

level

95%

sides

2-sided

lower limit

0.92

upper limit

4.48

Secondary: Percentage of Participants with a Clinically Meaningful Improvement (CMI) From Baseline in the Functional Assessment of Cancer Therapy Anemia-Total Score Domain within the FACT-An Instrument at Cycle 6

Top of page

End point title

Percentage of Participants with a Clinically Meaningful Improvement (CMI) From Baseline in the Functional Assessment of Cancer Therapy Anemia-Total Score Domain within the FACT-An Instrument at Cycle 6

End point description

End point type

Secondary

End point timeframe

Cycle 6 Day 1

End point values	Oral Azacitidine Plus Best Supportive Care	Placebo Plus Best Supportive Care
Number of subjects analysed	81	95
Units: Percentage of Participants
number (not applicable)	19.8	11.6

CMI

Comparison groups

Placebo Plus Best Supportive Care v Oral Azacitidine Plus Best Supportive Care

Number of subjects included in analysis

176

Analysis specification

Pre-specified

Analysis type

P-value

= 0.153

Method

Cochran-Mantel-Haenszel

Parameter type

Common Odds Ratio

Point estimate

1.86

Confidence interval

level

95%

sides

2-sided

lower limit

0.79

upper limit

4.34

Secondary: Percentage of Participants with Change from Baseline in Responses to the Fact-Anemia Item GP-5 - Cycle 2 Day 1 (C2D1)

Top of page

End point title

Percentage of Participants with Change from Baseline in Responses to the Fact-Anemia Item GP-5 - Cycle 2 Day 1 (C2D1)

End point description

The distribution (frequency and percentage) of the observed responses (i.e., “Not at all (0),” “A little bit (1),” “Somewhat (2),” “Quite a bit (3),” “Very much (4),” and missing) to Item GP-5 (“I am bothered by side effects of treatment” in the past seven days) of the FACT-An at each scheduled visit were summarized for each treatment group. The denominator for the percentage calculation per treatment group was based on the number of the FACT-An evaluable population at baseline. The distribution of change in responses (improved [i.e., change score from 1 to 4], no change [0], worsened by one level [-1], worsened by ≥2 levels [-2 to -4], and missing) from baseline at each post-baseline scheduled visit were summarized by treatment group.

End point type

Secondary

End point timeframe

From Baseline to Cycle 2 Day 1 (C2D1)

End point values	Oral Azacitidine Plus Best Supportive Care	Placebo Plus Best Supportive Care
Number of subjects analysed	81	95
Units: Percentage of Participants
number (not applicable)
Improved	2.5	10.5
No Change	30.9	49.5
Worsened by 1 Level	25.9	23.2
Worsened by 2 Levels	23.5	6.3
Missing	17.3	10.5

Fact-Anemia Item GP-5

Comparison groups

Placebo Plus Best Supportive Care v Oral Azacitidine Plus Best Supportive Care

Number of subjects included in analysis

176

Analysis specification

Pre-specified

Analysis type

P-value

< 0.001

Method

Fisher exact

Confidence interval

Secondary: Percentage of Participants with Change from Baseline in Responses to the Fact-Anemia Item GP-5 - Cycle 3 Day 1 (C3D1)

Top of page

End point title

Percentage of Participants with Change from Baseline in Responses to the Fact-Anemia Item GP-5 - Cycle 3 Day 1 (C3D1)

End point description

End point type

Secondary

End point timeframe

From Baseline to Cycle 3 Day 1 (C3D1)

End point values	Oral Azacitidine Plus Best Supportive Care	Placebo Plus Best Supportive Care
Number of subjects analysed	81	95
Units: Percentage of Participants
number (not applicable)
No Change	24.7	41.1
Worsened by 1 Level	16.0	18.9
Worsened by 2 Levels	23.5	13.7
Missing	28.4	15.8
Improved	7.4	10.5

Responses to the Fact-Anemia Item GP-5

Comparison groups

Placebo Plus Best Supportive Care v Oral Azacitidine Plus Best Supportive Care

Number of subjects included in analysis

176

Analysis specification

Pre-specified

Analysis type

P-value

= 0.046

Method

Fisher exact

Confidence interval

Secondary: Percentage of Participants with Change from Baseline in Responses to the Fact-Anemia Item GP-5 - Cycle 4 Day 1 (C4D1)

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End point title

Percentage of Participants with Change from Baseline in Responses to the Fact-Anemia Item GP-5 - Cycle 4 Day 1 (C4D1)

End point description

End point type

Secondary

End point timeframe

From Baseline to Cycle 4 Day 1 (C4D1)

End point values	Oral Azacitidine Plus Best Supportive Care	Placebo Plus Best Supportive Care
Number of subjects analysed	81	95
Units: Percentage of Participants
number (not applicable)
Improved	2.5	9.5
No Change	32.1	37.9
Worsened by 1 Level	16.0	14.7
Worsened by 2 Levels	14.8	6.3
Missing	34.6	31.6

Fact-Anemia Item GP-5

Comparison groups

Placebo Plus Best Supportive Care v Oral Azacitidine Plus Best Supportive Care

Number of subjects included in analysis

176

Analysis specification

Pre-specified

Analysis type

P-value

= 0.134

Method

Fisher exact

Confidence interval

Secondary: Percentage of Participants with Change from Baseline in Responses to the Fact-Anemia Item GP-5 - Cycle 5 Day 1 (C5D1)

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End point title

Percentage of Participants with Change from Baseline in Responses to the Fact-Anemia Item GP-5 - Cycle 5 Day 1 (C5D1)

End point description

End point type

Secondary

End point timeframe

From Baseline to Cycle 5 Day 1 (C5D1)

End point values	Oral Azacitidine Plus Best Supportive Care	Placebo Plus Best Supportive Care
Number of subjects analysed	81	95
Units: Percentage of Participants
number (not applicable)
Improved	2.5	7.4
No Change	25.9	34.7
Worsened by 1 Level	13.6	12.6
Worsened by 2 Levels	8.6	5.3
Missing	49.4	40.0

Fact-Anemia Item GP-5

Comparison groups

Placebo Plus Best Supportive Care v Oral Azacitidine Plus Best Supportive Care

Number of subjects included in analysis

176

Analysis specification

Pre-specified

Analysis type

P-value

= 0.324

Method

Fisher exact

Confidence interval

Secondary: Percentage of Participants with Change from Baseline in Responses to the Fact-Anemia Item GP-5 - Cycle 6 Day 1 (C6 D1)

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End point title

Percentage of Participants with Change from Baseline in Responses to the Fact-Anemia Item GP-5 - Cycle 6 Day 1 (C6 D1)

End point description

End point type

Secondary

End point timeframe

From Baseline to Cycle 6 Day 1 (C6 D1)

End point values	Oral Azacitidine Plus Best Supportive Care	Placebo Plus Best Supportive Care
Number of subjects analysed	81	95
Units: Percentage of Participants
number (not applicable)
Improved	1.2	4.2
No Change	25.9	27.4
Worsened by 1 Level	9.9	12.6
Worsened by 2 Levels	14.8	7.4
Missing	48.1	48.4

Fact-Anemia Item GP-5

Comparison groups

Placebo Plus Best Supportive Care v Oral Azacitidine Plus Best Supportive Care

Number of subjects included in analysis

176

Analysis specification

Pre-specified

Analysis type

P-value

= 0.442

Method

Fisher exact

Confidence interval

Secondary: Percentage of Participants with Change from Baseline in Responses to the Fact-Anemia Item GP-5 - Cycle 7 Day 1 (C7D1)

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End point title

Percentage of Participants with Change from Baseline in Responses to the Fact-Anemia Item GP-5 - Cycle 7 Day 1 (C7D1)

End point description

End point type

Secondary

End point timeframe

From Baseline to Cycle 7 Day 1 (C7D1)

End point values	Oral Azacitidine Plus Best Supportive Care	Placebo Plus Best Supportive Care
Number of subjects analysed	81	95
Units: Percentage of Participants
number (not applicable)
Improved	1.2	1.1
No Change	25.9	21.1
Worsened by 1 Level	11.1	3.2
Worsened by 2 Levels	7.4	3.2
Missing	54.3	71.6

Fact-Anemia Item GP-5

Comparison groups

Placebo Plus Best Supportive Care v Oral Azacitidine Plus Best Supportive Care

Number of subjects included in analysis

176

Analysis specification

Pre-specified

Analysis type

P-value

= 0.063

Method

Fisher exact

Confidence interval

Secondary: Percentage of Participants with Change from Baseline in Responses to the Fact-Anemia Item GP-5 - End of Treatment

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End point title

Percentage of Participants with Change from Baseline in Responses to the Fact-Anemia Item GP-5 - End of Treatment

End point description

End point type

Secondary

End point timeframe

From Baseline to End of Treatment

End point values	Oral Azacitidine Plus Best Supportive Care	Placebo Plus Best Supportive Care
Number of subjects analysed	81	95
Units: Percentage of Participants
number (not applicable)
Improved	2.5	6.3
No Change	14.8	25.3
Worsened by 1 Level	9.9	8.4
Worsened by 2 Levels	9.9	12.6
Missing	63.0	47.4

Fact-Anemia Item GP-5

Comparison groups

Placebo Plus Best Supportive Care v Oral Azacitidine Plus Best Supportive Care

Number of subjects included in analysis

176

Analysis specification

Pre-specified

Analysis type

P-value

= 0.198

Method

Fisher exact

Confidence interval

Secondary: Percentage of Participants with Improved, Worsened, or No Change in the European Quality of Life–Five Dimension–Three Level (EQ-5D-3L) Mobility Dimension Responses at Cycle 6

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End point title

Percentage of Participants with Improved, Worsened, or No Change in the European Quality of Life–Five Dimension–Three Level (EQ-5D-3L) Mobility Dimension Responses at Cycle 6

End point description

The EQ-5D-3L is a generic, self-administered questionnaire that consists of 5 dimensions: mobility, self-care, pain, usual activities, and anxiety/depression. Each dimension has 3 levels of severity corresponding to no problems, some problems, and extreme problems. It also includes a Visual Analog Scale that recorded the respondent’s self-rated health on a vertical, 0–100 scale, where 100 = Best imaginable health state and 0 = Worst imaginable health state. Distribution of the observed responses (i.e., no problems, moderate problems, severe problems, and missing) of the 5 dimensions at each visit was summarized per arm. The denominator for the percentage calculation per group was based on the number of the EQ-5D-3L evaluable population at baseline. The distribution of change in responses (i.e., improved [by ≥1 level], no change, worsened [by ≥1 level], and missing) from baseline are reported.

End point type

Secondary

End point timeframe

From Baseline to Cycle 6 Day 1

End point values	Oral Azacitidine Plus Best Supportive Care	Placebo Plus Best Supportive Care
Number of subjects analysed	81	95
Units: Percentage of Participants
number (not applicable)
Improved	8.6	8.4
No Change	35.8	33.7
Worsened	7.4	9.5
Missing	48.1	48.4

EQ-5D-3L

Comparison groups

Placebo Plus Best Supportive Care v Oral Azacitidine Plus Best Supportive Care

Number of subjects included in analysis

176

Analysis specification

Pre-specified

Analysis type

P-value

= 0.972

Method

Fisher exact

Confidence interval

Secondary: Percentage of Participants with Improved, Worsened, or No Change in the European Quality of Life–Five Dimension–Three Level of Self-Care Dimension Responses at Cycle 6

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End point title

Percentage of Participants with Improved, Worsened, or No Change in the European Quality of Life–Five Dimension–Three Level of Self-Care Dimension Responses at Cycle 6

End point description

End point type

Secondary

End point timeframe

From Baseline to Cycle 6 Day 1

End point values	Oral Azacitidine Plus Best Supportive Care	Placebo Plus Best Supportive Care
Number of subjects analysed	81	95
Units: Percentage of Participants
number (not applicable)
Improved	2.5	4.2
No Change	42.0	44.2
Worsened	7.4	3.2
Missing	48.1	48.4

European Quality of Life

Comparison groups

Placebo Plus Best Supportive Care v Oral Azacitidine Plus Best Supportive Care

Number of subjects included in analysis

176

Analysis specification

Pre-specified

Analysis type

P-value

= 0.601

Method

Fisher exact

Confidence interval

Secondary: Percentage of Participants with Improved, Worsened, or No Change in the European Quality of Life–Five Dimension–Three Level Usual Activities Dimension Responses at Cycle 6

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End point title

Percentage of Participants with Improved, Worsened, or No Change in the European Quality of Life–Five Dimension–Three Level Usual Activities Dimension Responses at Cycle 6

End point description

TThe EQ-5D-3L is a generic, self-administered questionnaire that consists of 5 dimensions: mobility, self-care, pain, usual activities, and anxiety/depression. Each dimension has 3 levels of severity corresponding to no problems, some problems, and extreme problems. It also includes a Visual Analog Scale that recorded the respondent’s self-rated health on a vertical, 0–100 scale, where 100 = Best imaginable health state and 0 = Worst imaginable health state. Distribution of the observed responses (i.e., no problems, moderate problems, severe problems, and missing) of the 5 dimensions at each visit was summarized per arm. The denominator for the percentage calculation per group was based on the number of the EQ-5D-3L evaluable population at baseline. The distribution of change in responses (i.e., improved [by ≥1 level], no change, worsened [by ≥1 level], and missing) from baseline are reported.

End point type

Secondary

End point timeframe

From Baseline to Cycle 6 Day 1

End point values	Oral Azacitidine Plus Best Supportive Care	Placebo Plus Best Supportive Care
Number of subjects analysed	81	95
Units: Percentage of Participants
number (not applicable)
Improved	11.1	3.2
No Change	28.4	41.1
Worsened	12.3	7.4
Missing	48.1	48.4

EQ-5D-3L

Comparison groups

Placebo Plus Best Supportive Care v Oral Azacitidine Plus Best Supportive Care

Number of subjects included in analysis

176

Analysis specification

Pre-specified

Analysis type

P-value

= 0.07

Method

Fisher exact

Confidence interval

Secondary: Percentage of Participants with Improved, Worsened, or No Change in the European Quality of Life–Five Dimension–Three Level in the Pain/Discomfort Dimension Responses at Cycle 6

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End point title

Percentage of Participants with Improved, Worsened, or No Change in the European Quality of Life–Five Dimension–Three Level in the Pain/Discomfort Dimension Responses at Cycle 6

End point description

End point type

Secondary

End point timeframe

From Baseline to Cycle 6 Day 1

End point values	Oral Azacitidine Plus Best Supportive Care	Placebo Plus Best Supportive Care
Number of subjects analysed	81	95
Units: Percentage of Participants
number (not applicable)
Improved	13.6	8.4
No Change	33.3	32.6
Worsened	4.9	10.5
Missing	48.1	48.4

EQ-5D-3L

Comparison groups

Placebo Plus Best Supportive Care v Oral Azacitidine Plus Best Supportive Care

Number of subjects included in analysis

176

Analysis specification

Pre-specified

Analysis type

P-value

= 0.436

Method

Fisher exact

Confidence interval

Secondary: Percentage of Participants with Improved, Worsened, or No Change in the European Quality of Life–Five Dimension–Three Level in the Anxiety/Depression Dimension Responses at Cycle 6

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End point title

Percentage of Participants with Improved, Worsened, or No Change in the European Quality of Life–Five Dimension–Three Level in the Anxiety/Depression Dimension Responses at Cycle 6

End point description

End point type

Secondary

End point timeframe

From Baseline to Cycle 6 Day 1

End point values	Oral Azacitidine Plus Best Supportive Care	Placebo Plus Best Supportive Care
Number of subjects analysed	81	95
Units: Percentage of Participants
number (not applicable)
Improved	4.9	7.4
No Change	35.8	37.9
Worsened	11.1	6.3
Missing	48.1	48.4

EQ-5D-3L

Comparison groups

Placebo Plus Best Supportive Care v Oral Azacitidine Plus Best Supportive Care

Number of subjects included in analysis

176

Analysis specification

Pre-specified

Analysis type

P-value

= 0.683

Method

Fisher exact

Confidence interval

Secondary: Healthcare Resource Utilization (HRU): Number of Participants Who Were Hospitalized During the Treatment Period

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End point title

Healthcare Resource Utilization (HRU): Number of Participants Who Were Hospitalized During the Treatment Period

End point description

The number of reasons for hospitalizations and hospital admissions during the treatment period were monitored and include those associated with: AEs, protocol-driven procedures, transfusions, non-protocol procedures, elective procedures or those associated with social, practical or technical reasons in the absence of AEs. HRU was defined as any consumption of healthcare resources directly or indirectly related to the treatment of the patient.

End point type

Secondary

End point timeframe

From date of randomization up to 28 days after the last dose of study drug; up to data cut off date of 25 January 2019; median duration of treatment to oral azacitaidine was 5.29 months and 5.36 months for placebo

End point values	Oral Azacitidine Plus Best Supportive Care	Placebo Plus Best Supportive Care
Number of subjects analysed	107	109
Units: Participants
Adverse Events	79	65
Protocol Driven Procedures	2	7
Non-Protocol Driven Procedures	9	19
Transfusion	32	33
Procedure Planned Prior to Signing Consent	0	4
Elective Procedures	4	10
Social, Technical or Practical Reason except AEs	4	6

No statistical analyses for this end point

Secondary: Healthcare Resource Utilization (HRU): Total Number of Days Hospitalized Due to any Reason During the Treatment Period

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End point title

Healthcare Resource Utilization (HRU): Total Number of Days Hospitalized Due to any Reason During the Treatment Period

End point description

The total number of days hospitalized due to any reason during the treatment period was monitored. HRU was defined as any consumption of healthcare resources directly or indirectly related to the treatment of the patient.

End point type

Secondary

End point timeframe

End point values	Oral Azacitidine Plus Best Supportive Care	Placebo Plus Best Supportive Care
Number of subjects analysed	107	109
Units: Days	3513	2688

No statistical analyses for this end point

Secondary: Healthcare Resource Utilization (HRU): Total Number of Days Hospitalized Per Total Patient-Years

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End point title

Healthcare Resource Utilization (HRU): Total Number of Days Hospitalized Per Total Patient-Years

End point description

The number of days hospitalized per total patient years. HRU was defined as any consumption of healthcare resources directly or indirectly related to the treatment of the patient.

End point type

Secondary

End point timeframe

End point values	Oral Azacitidine Plus Best Supportive Care	Placebo Plus Best Supportive Care
Number of subjects analysed	107	109
Units: Days Per Total Patient Years
number (not applicable)	41.44	40.53

No statistical analyses for this end point

Adverse events

Top of page

Timeframe for reporting adverse events

Participants were assessed for all-cause mortality from their randomization to study completion, (up to approximately 10 years). SAEs and Other AEs were assessed from first dose to 28 days following last dose (up to approximately 6 months)

Adverse event reporting additional description

Median duration of treatment to oral azacitaidine was 5.29 months and 5.36 months for placebo

Assessment type

Systematic

Dictionary name

MedDRA

Dictionary version

26.0

Reporting group title

CC-486

Reporting group description

Reporting group title

Placebo

Reporting group description

Serious adverse events	CC-486	Placebo
Total subjects affected by serious adverse events
subjects affected / exposed	83 / 107 (77.57%)	69 / 109 (63.30%)
number of deaths (all causes)	83	86
number of deaths resulting from adverse events	27	14
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Bowen's disease
subjects affected / exposed	1 / 107 (0.93%)	0 / 109 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Bone neoplasm
subjects affected / exposed	1 / 107 (0.93%)	0 / 109 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Basal cell carcinoma
subjects affected / exposed	1 / 107 (0.93%)	1 / 109 (0.92%)
occurrences causally related to treatment / all	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Adenocarcinoma of colon
subjects affected / exposed	1 / 107 (0.93%)	0 / 109 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Acute myeloid leukaemia
subjects affected / exposed	1 / 107 (0.93%)	2 / 109 (1.83%)
occurrences causally related to treatment / all	0 / 1	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 0
Carcinoma in situ of skin
subjects affected / exposed	0 / 107 (0.00%)	1 / 109 (0.92%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Central nervous system leukaemia
subjects affected / exposed	0 / 107 (0.00%)	1 / 109 (0.92%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 1
Chronic myelomonocytic leukaemia
subjects affected / exposed	0 / 107 (0.00%)	1 / 109 (0.92%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Transformation to acute myeloid leukaemia
subjects affected / exposed	0 / 107 (0.00%)	6 / 109 (5.50%)
occurrences causally related to treatment / all	0 / 0	0 / 6
deaths causally related to treatment / all	0 / 0	0 / 0
Squamous cell carcinoma of skin
subjects affected / exposed	0 / 107 (0.00%)	1 / 109 (0.92%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Spinal cord neoplasm
subjects affected / exposed	1 / 107 (0.93%)	0 / 109 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Small intestine carcinoma
subjects affected / exposed	1 / 107 (0.93%)	0 / 109 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 1	0 / 0
Myelodysplastic syndrome with excess blasts
subjects affected / exposed	0 / 107 (0.00%)	1 / 109 (0.92%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Myelodysplastic syndrome
subjects affected / exposed	0 / 107 (0.00%)	3 / 109 (2.75%)
occurrences causally related to treatment / all	0 / 0	1 / 3
deaths causally related to treatment / all	0 / 0	1 / 2
Metastases to liver
subjects affected / exposed	1 / 107 (0.93%)	0 / 109 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Mantle cell lymphoma recurrent
subjects affected / exposed	1 / 107 (0.93%)	0 / 109 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Malignant neoplasm of unknown primary site
subjects affected / exposed	0 / 107 (0.00%)	1 / 109 (0.92%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Colon cancer
subjects affected / exposed	0 / 107 (0.00%)	1 / 109 (0.92%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Colorectal adenoma
subjects affected / exposed	1 / 107 (0.93%)	0 / 109 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Diffuse large B-cell lymphoma
subjects affected / exposed	1 / 107 (0.93%)	0 / 109 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Lip squamous cell carcinoma
subjects affected / exposed	1 / 107 (0.93%)	0 / 109 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Vascular disorders
Haematoma
subjects affected / exposed	1 / 107 (0.93%)	0 / 109 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Arteritis
subjects affected / exposed	0 / 107 (0.00%)	1 / 109 (0.92%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Polyarteritis nodosa
subjects affected / exposed	0 / 107 (0.00%)	1 / 109 (0.92%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Shock haemorrhagic
subjects affected / exposed	1 / 107 (0.93%)	0 / 109 (0.00%)
occurrences causally related to treatment / all	1 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
General disorders and administration site conditions
Gait disturbance
subjects affected / exposed	1 / 107 (0.93%)	0 / 109 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
General physical health deterioration
subjects affected / exposed	3 / 107 (2.80%)	1 / 109 (0.92%)
occurrences causally related to treatment / all	0 / 3	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 1
Hypothermia
subjects affected / exposed	1 / 107 (0.93%)	0 / 109 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Multiple organ dysfunction syndrome
subjects affected / exposed	2 / 107 (1.87%)	0 / 109 (0.00%)
occurrences causally related to treatment / all	0 / 2	0 / 0
deaths causally related to treatment / all	0 / 2	0 / 0
Pyrexia
subjects affected / exposed	8 / 107 (7.48%)	4 / 109 (3.67%)
occurrences causally related to treatment / all	1 / 9	0 / 5
deaths causally related to treatment / all	0 / 0	0 / 0
Sudden death
subjects affected / exposed	0 / 107 (0.00%)	1 / 109 (0.92%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 1
Fatigue
subjects affected / exposed	0 / 107 (0.00%)	1 / 109 (0.92%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Immune system disorders
Haemophagocytic lymphohistiocytosis
subjects affected / exposed	1 / 107 (0.93%)	0 / 109 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Reproductive system and breast disorders
Prostatitis
subjects affected / exposed	1 / 107 (0.93%)	0 / 109 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Respiratory, thoracic and mediastinal disorders
Pulmonary embolism
subjects affected / exposed	1 / 107 (0.93%)	0 / 109 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Pleuritic pain
subjects affected / exposed	0 / 107 (0.00%)	1 / 109 (0.92%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Pleurisy
subjects affected / exposed	1 / 107 (0.93%)	0 / 109 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Pleural effusion
subjects affected / exposed	1 / 107 (0.93%)	1 / 109 (0.92%)
occurrences causally related to treatment / all	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Laryngeal oedema
subjects affected / exposed	0 / 107 (0.00%)	1 / 109 (0.92%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Haemoptysis
subjects affected / exposed	0 / 107 (0.00%)	1 / 109 (0.92%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Epistaxis
subjects affected / exposed	2 / 107 (1.87%)	1 / 109 (0.92%)
occurrences causally related to treatment / all	0 / 2	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 0
Acute respiratory distress syndrome
subjects affected / exposed	1 / 107 (0.93%)	0 / 109 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Respiratory failure
subjects affected / exposed	1 / 107 (0.93%)	0 / 109 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 1	0 / 0
Pulmonary oedema
subjects affected / exposed	0 / 107 (0.00%)	2 / 109 (1.83%)
occurrences causally related to treatment / all	0 / 0	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 0
Psychiatric disorders
Bipolar disorder
subjects affected / exposed	0 / 107 (0.00%)	1 / 109 (0.92%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Confusional state
subjects affected / exposed	1 / 107 (0.93%)	2 / 109 (1.83%)
occurrences causally related to treatment / all	0 / 1	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 0
Investigations
Weight decreased
subjects affected / exposed	1 / 107 (0.93%)	0 / 109 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Gamma-glutamyltransferase increased
subjects affected / exposed	0 / 107 (0.00%)	1 / 109 (0.92%)
occurrences causally related to treatment / all	0 / 0	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Blood urea increased
subjects affected / exposed	1 / 107 (0.93%)	0 / 109 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Injury, poisoning and procedural complications
Arteriovenous fistula site haemorrhage
subjects affected / exposed	0 / 107 (0.00%)	1 / 109 (0.92%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Cystitis radiation
subjects affected / exposed	0 / 107 (0.00%)	1 / 109 (0.92%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Fall
subjects affected / exposed	4 / 107 (3.74%)	0 / 109 (0.00%)
occurrences causally related to treatment / all	1 / 5	0 / 0
deaths causally related to treatment / all	1 / 1	0 / 0
Febrile nonhaemolytic transfusion reaction
subjects affected / exposed	1 / 107 (0.93%)	0 / 109 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Upper limb fracture
subjects affected / exposed	1 / 107 (0.93%)	0 / 109 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Transfusion reaction
subjects affected / exposed	0 / 107 (0.00%)	1 / 109 (0.92%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Subdural haematoma
subjects affected / exposed	2 / 107 (1.87%)	0 / 109 (0.00%)
occurrences causally related to treatment / all	0 / 2	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Periorbital haematoma
subjects affected / exposed	1 / 107 (0.93%)	0 / 109 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Hip fracture
subjects affected / exposed	1 / 107 (0.93%)	0 / 109 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Head injury
subjects affected / exposed	1 / 107 (0.93%)	0 / 109 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Subdural haemorrhage
subjects affected / exposed	1 / 107 (0.93%)	0 / 109 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Cardiac disorders
Acute coronary syndrome
subjects affected / exposed	0 / 107 (0.00%)	1 / 109 (0.92%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Acute myocardial infarction
subjects affected / exposed	1 / 107 (0.93%)	0 / 109 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Atrial fibrillation
subjects affected / exposed	1 / 107 (0.93%)	2 / 109 (1.83%)
occurrences causally related to treatment / all	0 / 1	1 / 2
deaths causally related to treatment / all	0 / 0	0 / 0
Angina unstable
subjects affected / exposed	1 / 107 (0.93%)	0 / 109 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Angina pectoris
subjects affected / exposed	0 / 107 (0.00%)	1 / 109 (0.92%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Atrioventricular block complete
subjects affected / exposed	1 / 107 (0.93%)	0 / 109 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Atrioventricular block first degree
subjects affected / exposed	0 / 107 (0.00%)	1 / 109 (0.92%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Cardiac arrest
subjects affected / exposed	0 / 107 (0.00%)	1 / 109 (0.92%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 1
Cardiac failure
subjects affected / exposed	2 / 107 (1.87%)	2 / 109 (1.83%)
occurrences causally related to treatment / all	0 / 2	0 / 2
deaths causally related to treatment / all	0 / 1	0 / 0
Cardiac failure congestive
subjects affected / exposed	3 / 107 (2.80%)	0 / 109 (0.00%)
occurrences causally related to treatment / all	0 / 3	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Ventricular tachycardia
subjects affected / exposed	0 / 107 (0.00%)	1 / 109 (0.92%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Cardiogenic shock
subjects affected / exposed	1 / 107 (0.93%)	0 / 109 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 1	0 / 0
Long QT syndrome
subjects affected / exposed	0 / 107 (0.00%)	1 / 109 (0.92%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Myocardial infarction
subjects affected / exposed	1 / 107 (0.93%)	1 / 109 (0.92%)
occurrences causally related to treatment / all	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 1	0 / 1
Tachyarrhythmia
subjects affected / exposed	2 / 107 (1.87%)	0 / 109 (0.00%)
occurrences causally related to treatment / all	0 / 2	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Cardio-respiratory arrest
subjects affected / exposed	0 / 107 (0.00%)	1 / 109 (0.92%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 1
Nervous system disorders
Generalised tonic-clonic seizure
subjects affected / exposed	1 / 107 (0.93%)	0 / 109 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Epilepsy
subjects affected / exposed	1 / 107 (0.93%)	0 / 109 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Cerebral ischaemia
subjects affected / exposed	1 / 107 (0.93%)	0 / 109 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Cerebral haemorrhage
subjects affected / exposed	0 / 107 (0.00%)	1 / 109 (0.92%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 1
Presyncope
subjects affected / exposed	0 / 107 (0.00%)	1 / 109 (0.92%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Lethargy
subjects affected / exposed	1 / 107 (0.93%)	0 / 109 (0.00%)
occurrences causally related to treatment / all	1 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
IIIrd nerve paresis
subjects affected / exposed	0 / 107 (0.00%)	1 / 109 (0.92%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Haemorrhage intracranial
subjects affected / exposed	2 / 107 (1.87%)	0 / 109 (0.00%)
occurrences causally related to treatment / all	1 / 2	0 / 0
deaths causally related to treatment / all	1 / 2	0 / 0
Guillain-Barre syndrome
subjects affected / exposed	0 / 107 (0.00%)	1 / 109 (0.92%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Central nervous system lesion
subjects affected / exposed	1 / 107 (0.93%)	0 / 109 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 1	0 / 0
Sciatica
subjects affected / exposed	0 / 107 (0.00%)	1 / 109 (0.92%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Syncope
subjects affected / exposed	1 / 107 (0.93%)	0 / 109 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Transient ischaemic attack
subjects affected / exposed	1 / 107 (0.93%)	1 / 109 (0.92%)
occurrences causally related to treatment / all	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Status epilepticus
subjects affected / exposed	1 / 107 (0.93%)	0 / 109 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 1	0 / 0
Blood and lymphatic system disorders
Anaemia
subjects affected / exposed	7 / 107 (6.54%)	5 / 109 (4.59%)
occurrences causally related to treatment / all	3 / 8	0 / 5
deaths causally related to treatment / all	0 / 0	0 / 1
Blood loss anaemia
subjects affected / exposed	1 / 107 (0.93%)	0 / 109 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Bone marrow failure
subjects affected / exposed	2 / 107 (1.87%)	0 / 109 (0.00%)
occurrences causally related to treatment / all	2 / 2	0 / 0
deaths causally related to treatment / all	1 / 1	0 / 0
Thrombocytopenia
subjects affected / exposed	5 / 107 (4.67%)	1 / 109 (0.92%)
occurrences causally related to treatment / all	4 / 5	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Haemolytic anaemia
subjects affected / exposed	1 / 107 (0.93%)	0 / 109 (0.00%)
occurrences causally related to treatment / all	1 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Neutropenia
subjects affected / exposed	2 / 107 (1.87%)	1 / 109 (0.92%)
occurrences causally related to treatment / all	3 / 3	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Pancytopenia
subjects affected / exposed	1 / 107 (0.93%)	0 / 109 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Febrile neutropenia
subjects affected / exposed	29 / 107 (27.10%)	9 / 109 (8.26%)
occurrences causally related to treatment / all	28 / 45	4 / 13
deaths causally related to treatment / all	0 / 1	0 / 0
Gastrointestinal disorders
Abdominal pain
subjects affected / exposed	3 / 107 (2.80%)	0 / 109 (0.00%)
occurrences causally related to treatment / all	1 / 3	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Abdominal pain upper
subjects affected / exposed	1 / 107 (0.93%)	0 / 109 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Colitis
subjects affected / exposed	0 / 107 (0.00%)	1 / 109 (0.92%)
occurrences causally related to treatment / all	0 / 0	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Constipation
subjects affected / exposed	1 / 107 (0.93%)	0 / 109 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Diarrhoea
subjects affected / exposed	3 / 107 (2.80%)	0 / 109 (0.00%)
occurrences causally related to treatment / all	0 / 3	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Gastritis
subjects affected / exposed	1 / 107 (0.93%)	0 / 109 (0.00%)
occurrences causally related to treatment / all	1 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Neutropenic colitis
subjects affected / exposed	1 / 107 (0.93%)	0 / 109 (0.00%)
occurrences causally related to treatment / all	1 / 1	0 / 0
deaths causally related to treatment / all	1 / 1	0 / 0
Haemorrhoidal haemorrhage
subjects affected / exposed	0 / 107 (0.00%)	1 / 109 (0.92%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Intestinal obstruction
subjects affected / exposed	1 / 107 (0.93%)	0 / 109 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Intestinal perforation
subjects affected / exposed	1 / 107 (0.93%)	0 / 109 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 1	0 / 0
Intra-abdominal haemorrhage
subjects affected / exposed	1 / 107 (0.93%)	0 / 109 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 1	0 / 0
Melaena
subjects affected / exposed	0 / 107 (0.00%)	2 / 109 (1.83%)
occurrences causally related to treatment / all	0 / 0	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 0
Nausea
subjects affected / exposed	2 / 107 (1.87%)	0 / 109 (0.00%)
occurrences causally related to treatment / all	1 / 2	0 / 0
deaths causally related to treatment / all	0 / 1	0 / 0
Gastrointestinal haemorrhage
subjects affected / exposed	1 / 107 (0.93%)	2 / 109 (1.83%)
occurrences causally related to treatment / all	1 / 1	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 0
Oesophageal achalasia
subjects affected / exposed	1 / 107 (0.93%)	0 / 109 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Oesophageal varices haemorrhage
subjects affected / exposed	1 / 107 (0.93%)	0 / 109 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Oral mucosal blistering
subjects affected / exposed	1 / 107 (0.93%)	0 / 109 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Rectal haemorrhage
subjects affected / exposed	1 / 107 (0.93%)	1 / 109 (0.92%)
occurrences causally related to treatment / all	0 / 2	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Upper gastrointestinal haemorrhage
subjects affected / exposed	0 / 107 (0.00%)	1 / 109 (0.92%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Vomiting
subjects affected / exposed	1 / 107 (0.93%)	0 / 109 (0.00%)
occurrences causally related to treatment / all	1 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Hepatobiliary disorders
Biliary colic
subjects affected / exposed	0 / 107 (0.00%)	1 / 109 (0.92%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Cholecystitis
subjects affected / exposed	2 / 107 (1.87%)	1 / 109 (0.92%)
occurrences causally related to treatment / all	0 / 2	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Hyperbilirubinaemia
subjects affected / exposed	2 / 107 (1.87%)	0 / 109 (0.00%)
occurrences causally related to treatment / all	2 / 2	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Skin and subcutaneous tissue disorders
Rash
subjects affected / exposed	1 / 107 (0.93%)	0 / 109 (0.00%)
occurrences causally related to treatment / all	0 / 2	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Cutaneous vasculitis
subjects affected / exposed	1 / 107 (0.93%)	0 / 109 (0.00%)
occurrences causally related to treatment / all	1 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Renal and urinary disorders
Urinary tract obstruction
subjects affected / exposed	0 / 107 (0.00%)	1 / 109 (0.92%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Acute kidney injury
subjects affected / exposed	2 / 107 (1.87%)	3 / 109 (2.75%)
occurrences causally related to treatment / all	0 / 2	0 / 3
deaths causally related to treatment / all	0 / 0	0 / 0
Chronic kidney disease
subjects affected / exposed	1 / 107 (0.93%)	0 / 109 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Haematuria
subjects affected / exposed	0 / 107 (0.00%)	1 / 109 (0.92%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Pollakiuria
subjects affected / exposed	1 / 107 (0.93%)	0 / 109 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Prerenal failure
subjects affected / exposed	1 / 107 (0.93%)	0 / 109 (0.00%)
occurrences causally related to treatment / all	1 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Renal colic
subjects affected / exposed	1 / 107 (0.93%)	0 / 109 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Renal failure
subjects affected / exposed	2 / 107 (1.87%)	0 / 109 (0.00%)
occurrences causally related to treatment / all	1 / 2	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Urinary retention
subjects affected / exposed	1 / 107 (0.93%)	1 / 109 (0.92%)
occurrences causally related to treatment / all	0 / 1	1 / 2
deaths causally related to treatment / all	0 / 0	0 / 0
Musculoskeletal and connective tissue disorders
Polychondritis
subjects affected / exposed	1 / 107 (0.93%)	0 / 109 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Muscular weakness
subjects affected / exposed	1 / 107 (0.93%)	0 / 109 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Back pain
subjects affected / exposed	1 / 107 (0.93%)	0 / 109 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Infections and infestations
Abscess limb
subjects affected / exposed	1 / 107 (0.93%)	0 / 109 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
COVID-19 pneumonia
subjects affected / exposed	1 / 107 (0.93%)	0 / 109 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Atypical pneumonia
subjects affected / exposed	2 / 107 (1.87%)	0 / 109 (0.00%)
occurrences causally related to treatment / all	1 / 2	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Bacteraemia
subjects affected / exposed	0 / 107 (0.00%)	2 / 109 (1.83%)
occurrences causally related to treatment / all	0 / 0	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 0
Bronchitis
subjects affected / exposed	0 / 107 (0.00%)	1 / 109 (0.92%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Bronchopulmonary aspergillosis
subjects affected / exposed	2 / 107 (1.87%)	0 / 109 (0.00%)
occurrences causally related to treatment / all	1 / 2	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Arteriovenous fistula site infection
subjects affected / exposed	1 / 107 (0.93%)	0 / 109 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Cellulitis
subjects affected / exposed	1 / 107 (0.93%)	0 / 109 (0.00%)
occurrences causally related to treatment / all	0 / 2	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Klebsiella infection
subjects affected / exposed	1 / 107 (0.93%)	0 / 109 (0.00%)
occurrences causally related to treatment / all	1 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Coronavirus infection
subjects affected / exposed	1 / 107 (0.93%)	0 / 109 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Cystitis escherichia
subjects affected / exposed	0 / 107 (0.00%)	1 / 109 (0.92%)
occurrences causally related to treatment / all	0 / 0	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Device related infection
subjects affected / exposed	1 / 107 (0.93%)	0 / 109 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Diverticulitis
subjects affected / exposed	0 / 107 (0.00%)	1 / 109 (0.92%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Epididymitis
subjects affected / exposed	1 / 107 (0.93%)	0 / 109 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Escherichia sepsis
subjects affected / exposed	1 / 107 (0.93%)	0 / 109 (0.00%)
occurrences causally related to treatment / all	1 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Febrile infection
subjects affected / exposed	1 / 107 (0.93%)	1 / 109 (0.92%)
occurrences causally related to treatment / all	1 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Gastroenteritis
subjects affected / exposed	1 / 107 (0.93%)	0 / 109 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Gastroenteritis clostridial
subjects affected / exposed	0 / 107 (0.00%)	1 / 109 (0.92%)
occurrences causally related to treatment / all	0 / 0	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 0
Groin abscess
subjects affected / exposed	1 / 107 (0.93%)	0 / 109 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Haemophilus infection
subjects affected / exposed	0 / 107 (0.00%)	1 / 109 (0.92%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Infection
subjects affected / exposed	0 / 107 (0.00%)	1 / 109 (0.92%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Influenza
subjects affected / exposed	1 / 107 (0.93%)	0 / 109 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Clostridium difficile colitis
subjects affected / exposed	0 / 107 (0.00%)	1 / 109 (0.92%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Klebsiella sepsis
subjects affected / exposed	1 / 107 (0.93%)	0 / 109 (0.00%)
occurrences causally related to treatment / all	1 / 1	0 / 0
deaths causally related to treatment / all	1 / 1	0 / 0
Respiratory tract infection
subjects affected / exposed	1 / 107 (0.93%)	1 / 109 (0.92%)
occurrences causally related to treatment / all	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Lymph gland infection
subjects affected / exposed	0 / 107 (0.00%)	1 / 109 (0.92%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Meningitis
subjects affected / exposed	1 / 107 (0.93%)	0 / 109 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Meningitis bacterial
subjects affected / exposed	1 / 107 (0.93%)	0 / 109 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Myringitis
subjects affected / exposed	1 / 107 (0.93%)	0 / 109 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Neutropenic sepsis
subjects affected / exposed	5 / 107 (4.67%)	1 / 109 (0.92%)
occurrences causally related to treatment / all	4 / 5	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Pharyngeal abscess
subjects affected / exposed	0 / 107 (0.00%)	1 / 109 (0.92%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Pharyngitis
subjects affected / exposed	0 / 107 (0.00%)	2 / 109 (1.83%)
occurrences causally related to treatment / all	0 / 0	1 / 2
deaths causally related to treatment / all	0 / 0	0 / 0
Pneumonia
subjects affected / exposed	13 / 107 (12.15%)	12 / 109 (11.01%)
occurrences causally related to treatment / all	5 / 16	1 / 13
deaths causally related to treatment / all	0 / 1	0 / 1
Pneumonia aspiration
subjects affected / exposed	1 / 107 (0.93%)	0 / 109 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Pneumonia fungal
subjects affected / exposed	2 / 107 (1.87%)	0 / 109 (0.00%)
occurrences causally related to treatment / all	2 / 2	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Pneumonia pneumococcal
subjects affected / exposed	1 / 107 (0.93%)	0 / 109 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Prostatic abscess
subjects affected / exposed	0 / 107 (0.00%)	1 / 109 (0.92%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Pseudomonal sepsis
subjects affected / exposed	1 / 107 (0.93%)	0 / 109 (0.00%)
occurrences causally related to treatment / all	1 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Lower respiratory tract infection
subjects affected / exposed	1 / 107 (0.93%)	4 / 109 (3.67%)
occurrences causally related to treatment / all	0 / 1	1 / 5
deaths causally related to treatment / all	0 / 0	0 / 0
Respiratory tract infection bacterial
subjects affected / exposed	0 / 107 (0.00%)	1 / 109 (0.92%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Sepsis
subjects affected / exposed	8 / 107 (7.48%)	3 / 109 (2.75%)
occurrences causally related to treatment / all	4 / 12	1 / 3
deaths causally related to treatment / all	3 / 5	0 / 1
Septic shock
subjects affected / exposed	6 / 107 (5.61%)	3 / 109 (2.75%)
occurrences causally related to treatment / all	3 / 6	1 / 3
deaths causally related to treatment / all	3 / 5	1 / 3
Skin infection
subjects affected / exposed	1 / 107 (0.93%)	0 / 109 (0.00%)
occurrences causally related to treatment / all	1 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Staphylococcal infection
subjects affected / exposed	1 / 107 (0.93%)	1 / 109 (0.92%)
occurrences causally related to treatment / all	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Staphylococcal sepsis
subjects affected / exposed	0 / 107 (0.00%)	1 / 109 (0.92%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Tooth abscess
subjects affected / exposed	0 / 107 (0.00%)	1 / 109 (0.92%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Upper respiratory tract infection
subjects affected / exposed	4 / 107 (3.74%)	1 / 109 (0.92%)
occurrences causally related to treatment / all	0 / 4	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Urinary tract infection
subjects affected / exposed	2 / 107 (1.87%)	1 / 109 (0.92%)
occurrences causally related to treatment / all	0 / 2	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Urinary tract infection bacterial
subjects affected / exposed	1 / 107 (0.93%)	1 / 109 (0.92%)
occurrences causally related to treatment / all	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Viral sepsis
subjects affected / exposed	1 / 107 (0.93%)	0 / 109 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Metabolism and nutrition disorders
Dehydration
subjects affected / exposed	1 / 107 (0.93%)	1 / 109 (0.92%)
occurrences causally related to treatment / all	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Diabetic metabolic decompensation
subjects affected / exposed	1 / 107 (0.93%)	0 / 109 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Diabetes mellitus
subjects affected / exposed	0 / 107 (0.00%)	1 / 109 (0.92%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Diabetes mellitus inadequate control
subjects affected / exposed	1 / 107 (0.93%)	0 / 109 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Hyponatraemia
subjects affected / exposed	0 / 107 (0.00%)	1 / 109 (0.92%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Hypoglycaemia
subjects affected / exposed	1 / 107 (0.93%)	0 / 109 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Hyperkalaemia
subjects affected / exposed	1 / 107 (0.93%)	0 / 109 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0

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

Non-serious adverse events	CC-486	Placebo
Total subjects affected by non serious adverse events
subjects affected / exposed	107 / 107 (100.00%)	104 / 109 (95.41%)
Vascular disorders
Haematoma
subjects affected / exposed	11 / 107 (10.28%)	11 / 109 (10.09%)
occurrences all number	11	17
Hypertension
subjects affected / exposed	5 / 107 (4.67%)	7 / 109 (6.42%)
occurrences all number	5	7
Hypotension
subjects affected / exposed	6 / 107 (5.61%)	3 / 109 (2.75%)
occurrences all number	7	3
General disorders and administration site conditions
Asthenia
subjects affected / exposed	25 / 107 (23.36%)	20 / 109 (18.35%)
occurrences all number	35	26
Fatigue
subjects affected / exposed	25 / 107 (23.36%)	22 / 109 (20.18%)
occurrences all number	32	29
Pyrexia
subjects affected / exposed	32 / 107 (29.91%)	15 / 109 (13.76%)
occurrences all number	48	27
Oedema peripheral
subjects affected / exposed	30 / 107 (28.04%)	17 / 109 (15.60%)
occurrences all number	40	20
Respiratory, thoracic and mediastinal disorders
Epistaxis
subjects affected / exposed	28 / 107 (26.17%)	21 / 109 (19.27%)
occurrences all number	58	34
Dyspnoea
subjects affected / exposed	14 / 107 (13.08%)	15 / 109 (13.76%)
occurrences all number	16	15
Cough
subjects affected / exposed	16 / 107 (14.95%)	15 / 109 (13.76%)
occurrences all number	21	19
Psychiatric disorders
Insomnia
subjects affected / exposed	11 / 107 (10.28%)	6 / 109 (5.50%)
occurrences all number	13	6
Anxiety
subjects affected / exposed	9 / 107 (8.41%)	4 / 109 (3.67%)
occurrences all number	10	5
Confusional state
subjects affected / exposed	6 / 107 (5.61%)	1 / 109 (0.92%)
occurrences all number	6	1
Depression
subjects affected / exposed	7 / 107 (6.54%)	2 / 109 (1.83%)
occurrences all number	7	2
Investigations
Alanine aminotransferase increased
subjects affected / exposed	10 / 107 (9.35%)	6 / 109 (5.50%)
occurrences all number	11	10
Weight decreased
subjects affected / exposed	11 / 107 (10.28%)	3 / 109 (2.75%)
occurrences all number	13	3
Serum ferritin increased
subjects affected / exposed	6 / 107 (5.61%)	5 / 109 (4.59%)
occurrences all number	6	5
Injury, poisoning and procedural complications
Fall
subjects affected / exposed	6 / 107 (5.61%)	1 / 109 (0.92%)
occurrences all number	9	1
Contusion
subjects affected / exposed	16 / 107 (14.95%)	3 / 109 (2.75%)
occurrences all number	21	3
Cardiac disorders
Atrial fibrillation
subjects affected / exposed	7 / 107 (6.54%)	2 / 109 (1.83%)
occurrences all number	10	2
Cardiac failure
subjects affected / exposed	6 / 107 (5.61%)	1 / 109 (0.92%)
occurrences all number	6	1
Nervous system disorders
Dizziness
subjects affected / exposed	8 / 107 (7.48%)	9 / 109 (8.26%)
occurrences all number	9	10
Syncope
subjects affected / exposed	6 / 107 (5.61%)	1 / 109 (0.92%)
occurrences all number	12	1
Blood and lymphatic system disorders
Thrombocytopenia
subjects affected / exposed	30 / 107 (28.04%)	18 / 109 (16.51%)
occurrences all number	59	29
Neutropenia
subjects affected / exposed	52 / 107 (48.60%)	16 / 109 (14.68%)
occurrences all number	116	25
Leukopenia
subjects affected / exposed	10 / 107 (9.35%)	3 / 109 (2.75%)
occurrences all number	18	3
Anaemia
subjects affected / exposed	23 / 107 (21.50%)	17 / 109 (15.60%)
occurrences all number	65	41
Gastrointestinal disorders
Abdominal pain
subjects affected / exposed	16 / 107 (14.95%)	14 / 109 (12.84%)
occurrences all number	30	17
Constipation
subjects affected / exposed	51 / 107 (47.66%)	24 / 109 (22.02%)
occurrences all number	80	39
Gastrooesophageal reflux disease
subjects affected / exposed	6 / 107 (5.61%)	1 / 109 (0.92%)
occurrences all number	6	1
Diarrhoea
subjects affected / exposed	73 / 107 (68.22%)	26 / 109 (23.85%)
occurrences all number	152	32
Gingival bleeding
subjects affected / exposed	7 / 107 (6.54%)	4 / 109 (3.67%)
occurrences all number	13	8
Nausea
subjects affected / exposed	81 / 107 (75.70%)	25 / 109 (22.94%)
occurrences all number	132	33
Mouth haemorrhage
subjects affected / exposed	10 / 107 (9.35%)	7 / 109 (6.42%)
occurrences all number	13	12
Haemorrhoids
subjects affected / exposed	4 / 107 (3.74%)	6 / 109 (5.50%)
occurrences all number	4	6
Rectal haemorrhage
subjects affected / exposed	3 / 107 (2.80%)	8 / 109 (7.34%)
occurrences all number	3	11
Vomiting
subjects affected / exposed	67 / 107 (62.62%)	11 / 109 (10.09%)
occurrences all number	109	13
Skin and subcutaneous tissue disorders
Pruritus
subjects affected / exposed	6 / 107 (5.61%)	8 / 109 (7.34%)
occurrences all number	6	10
Petechiae
subjects affected / exposed	21 / 107 (19.63%)	20 / 109 (18.35%)
occurrences all number	30	23
Ecchymosis
subjects affected / exposed	6 / 107 (5.61%)	10 / 109 (9.17%)
occurrences all number	6	17
Renal and urinary disorders
Haematuria
subjects affected / exposed	4 / 107 (3.74%)	6 / 109 (5.50%)
occurrences all number	4	7
Musculoskeletal and connective tissue disorders
Back pain
subjects affected / exposed	15 / 107 (14.02%)	13 / 109 (11.93%)
occurrences all number	17	16
Arthralgia
subjects affected / exposed	11 / 107 (10.28%)	12 / 109 (11.01%)
occurrences all number	15	15
Pain in extremity
subjects affected / exposed	8 / 107 (7.48%)	4 / 109 (3.67%)
occurrences all number	9	4
Infections and infestations
Cellulitis
subjects affected / exposed	6 / 107 (5.61%)	3 / 109 (2.75%)
occurrences all number	7	3
Oral herpes
subjects affected / exposed	6 / 107 (5.61%)	3 / 109 (2.75%)
occurrences all number	6	3
Urinary tract infection
subjects affected / exposed	12 / 107 (11.21%)	5 / 109 (4.59%)
occurrences all number	15	5
Upper respiratory tract infection
subjects affected / exposed	7 / 107 (6.54%)	4 / 109 (3.67%)
occurrences all number	11	4
Pneumonia
subjects affected / exposed	10 / 107 (9.35%)	4 / 109 (3.67%)
occurrences all number	13	6
Metabolism and nutrition disorders
Iron overload
subjects affected / exposed	7 / 107 (6.54%)	11 / 109 (10.09%)
occurrences all number	8	11
Hypomagnesaemia
subjects affected / exposed	11 / 107 (10.28%)	5 / 109 (4.59%)
occurrences all number	16	5
Hypokalaemia
subjects affected / exposed	12 / 107 (11.21%)	10 / 109 (9.17%)
occurrences all number	21	11
Hyperkalaemia
subjects affected / exposed	6 / 107 (5.61%)	0 / 109 (0.00%)
occurrences all number	6	0
Hyperglycaemia
subjects affected / exposed	6 / 107 (5.61%)	2 / 109 (1.83%)
occurrences all number	7	2
Decreased appetite
subjects affected / exposed	27 / 107 (25.23%)	10 / 109 (9.17%)
occurrences all number	36	10

More information

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Were there any global substantial amendments to the protocol? Yes

21 Feb 2018

The duration of the study and enrollment period was extended due to slow enrollment; Based on Food and Drug Administration (FDA) recommendation, for subjects in Cycle 1 or 2 as of 31 Jan 2018, dose schedule was reduced to 14 days; Based on DMC recommendation to enhance hematotoxicity monitoring, the following information was added to Section 8.2.4. Dose Modifications: “Any subject who experiences febrile neutropenia ≥ Grade 3 will have IP held until fever has resolved; must be afebrile for 3 days before re-starting study drug. Administration of antibiotic, antiviral and antifungal therapy is strongly recommended"; Based on DMC recommendation, to enhance hematotoxicity monitoring, dose modification for neutropenia Grade 4 was updated; Based on DMC recommendation, to enhance hematotoxicity monitoring for Febrile Neutropenia, the following wording “Secondary prophylaxis with G-CSF may be considered” was changed to “Secondary prophylaxis with G-CSF is strongly recommended"; Based on DMC recommendation, to enhance hematotoxicity monitoring, Section 8.2.5. Re-treatment Criteria was updated to reflect that for subjects that experience hematotoxicity (absolute neutrophil count [ANC] or platelet drop to Grade 4, or 50% drop within Grade 4), hematologic recovery is required before starting the next cycle at Day 28. Hematology recovery is defined and a decision tree for hematologic recovery presents the rules in a friendly manner; Based on DMC recommendation, to enhance hematotoxicity monitoring, the following sentences were added: “Consider platelet transfusion if platelet counts are < 25 x 109/L; Based on DMC recommendation, add information to enhance hematotoxicity monitoring.

06 Aug 2018

This protocol is being amended to address the sponsor’s decision to close enrollment into the study and revise sample size.

28 Nov 2018

This protocol was amended to change the primary endpoint to RBC transfusion independence with duration ≥ 56 days (8 weeks) and to add an extension phase of CC-486 treatment once the trial is unblinded.

24 May 2022

Updated contact details for the Medical Monitor of the study; Therapeutic Area Head and their title were updated; New section added; Survival follow-up (FU) was updated by reducing the duration of survival FU to 35 days (± 7 days) after treatment discontinuation.

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

Trial information

Trial information

Subject disposition

Subject disposition

Baseline characteristics

Baseline characteristics

End points

End points

Primary: Percentage of Participants who Achieved Red Blood Cell (RBC) Transfusion Independence for ≥ 56 Days

Primary: Percentage of Participants who Achieved Red Blood Cell (RBC) Transfusion Independence for ≥ 56 Days

Secondary: Duration of RBC Transfusion Independence Among Participants who Achieved RBC Transfusion Independence for at Least 56 Days

Secondary: Duration of RBC Transfusion Independence Among Participants who Achieved RBC Transfusion Independence for at Least 56 Days

Secondary: Time to RBC Transfusion Independence for at Least 56 Days Among Participants who Achieved RBC Transfusion Independence for at Least 56 Days

Secondary: Time to RBC Transfusion Independence for at Least 56 Days Among Participants who Achieved RBC Transfusion Independence for at Least 56 Days

Secondary: Duration of RBC Transfusion Reduction for Participants who Achieved RBC Transfusion Reduction of at Least 4 units of RBCs for at Least 8 Weeks

Secondary: Duration of RBC Transfusion Reduction for Participants who Achieved RBC Transfusion Reduction of at Least 4 units of RBCs for at Least 8 Weeks

Secondary: Percentage of Participants who Achieved Red Blood Cell Transfusion Independence for ≥ 84 days

Secondary: Percentage of Participants who Achieved Red Blood Cell Transfusion Independence for ≥ 84 days

Secondary: Duration of RBC Transfusion Independence Among Participants who Achieved RBC Transfusion Independence for at Least 84 Days

Secondary: Duration of RBC Transfusion Independence Among Participants who Achieved RBC Transfusion Independence for at Least 84 Days

Secondary: Time to RBC Transfusion Independence for at Least 84 Days Among Participants who Achieved RBC Transfusion Independence for at Least 84 Days

Secondary: Time to RBC Transfusion Independence for at Least 84 Days Among Participants who Achieved RBC Transfusion Independence for at Least 84 Days

Secondary: Percentage of Participants with an Erythroid Hematological Improvement (HI-E) Response According to 2006 IWG Criteria

Secondary: Percentage of Participants with an Erythroid Hematological Improvement (HI-E) Response According to 2006 IWG Criteria

Secondary: Percentage of Participants with a Hematological Improvement Response in Platelets (HI-P) According to 2006 IWG Criteria

Secondary: Percentage of Participants with a Hematological Improvement Response in Platelets (HI-P) According to 2006 IWG Criteria

Secondary: Percentage of Participants who Achieved Platelet Transfusion Independence with a Duration of ≥ 8 weeks (56 days)

Secondary: Percentage of Participants who Achieved Platelet Transfusion Independence with a Duration of ≥ 8 weeks (56 days)

Secondary: Time to Platelet Transfusion Independence

Secondary: Time to Platelet Transfusion Independence

Secondary: Percentage of Participants with a Hematologic Response According to the 2006 IWG Criteria for MDS

Secondary: Percentage of Participants with a Hematologic Response According to the 2006 IWG Criteria for MDS

Secondary: Overall Survival (OS)

Secondary: Overall Survival (OS)

Secondary: Percentage of Participants with Significant Bleeding Events

Secondary: Percentage of Participants with Significant Bleeding Events

Secondary: Percentage of Participants who Progressed to Acute Myeloid Leukemia (AML)

Secondary: Percentage of Participants who Progressed to Acute Myeloid Leukemia (AML)

Secondary: Time to Progression to Acute Myeloid Leukemia (AML) Among Participants who Progressed to AML

Secondary: Time to Progression to Acute Myeloid Leukemia (AML) Among Participants who Progressed to AML

Secondary: Number of Participants with Treatment Emergent Adverse Events (TEAE)

Secondary: Number of Participants with Treatment Emergent Adverse Events (TEAE)

Secondary: Mean Change From Baseline in the Social Well-Being Component of the Functional Assessment of Cancer Therapy-Anemia Instrument at Cycle 6

Secondary: Mean Change From Baseline in the Social Well-Being Component of the Functional Assessment of Cancer Therapy-Anemia Instrument at Cycle 6

Secondary: Mean Change From Baseline in the Physical Well-Being Component of the Functional Assessment of Cancer Therapy-Anemia (FACT-An) Endpoints at Cycle 6

Secondary: Mean Change From Baseline in the Physical Well-Being Component of the Functional Assessment of Cancer Therapy-Anemia (FACT-An) Endpoints at Cycle 6

Secondary: Mean Change From Baseline in the Functional Well-Being Component of the FACT-An Instrument at Cycle 6

Secondary: Mean Change From Baseline in the Functional Well-Being Component of the FACT-An Instrument at Cycle 6

Secondary: Mean Change From Baseline in the Emotional Well-Being Component of the Functional Assessment of Cancer Therapy-Anemia Instrument at Cycle 6

Secondary: Mean Change From Baseline in the Emotional Well-Being Component of the Functional Assessment of Cancer Therapy-Anemia Instrument at Cycle 6

Secondary: Mean Change From Baseline in the Anemia Subscale within FACT-An Instrument at Cycle 6

Secondary: Mean Change From Baseline in the Anemia Subscale within FACT-An Instrument at Cycle 6

Secondary: Mean Change From Baseline in the Fatigue-Related Subscale within the FACT-An Instrument at Cycle 6

Secondary: Mean Change From Baseline in the Fatigue-Related Subscale within the FACT-An Instrument at Cycle 6

Secondary: Mean Change From Baseline in the Functional Assessment of Cancer Therapy-Anemia Trial Outcome Index (FACT-An TOI) Summary Scale within the FACT-An Instrument at Cycle 6

Secondary: Mean Change From Baseline in the Functional Assessment of Cancer Therapy-Anemia Trial Outcome Index (FACT-An TOI) Summary Scale within the FACT-An Instrument at Cycle 6

Secondary: Mean Change From Baseline in the Functional Assessment of Cancer Therapy-Anemia-General (FACT-G) Summary Scale within the FACT-An Instrument at Cycle 6

Secondary: Mean Change From Baseline in the Functional Assessment of Cancer Therapy-Anemia-General (FACT-G) Summary Scale within the FACT-An Instrument at Cycle 6

Secondary: Mean Change From Baseline in the Functional Assessment of Cancer Therapy-Anemia-Total Score at Cycle 6

Secondary: Mean Change From Baseline in the Functional Assessment of Cancer Therapy-Anemia-Total Score at Cycle 6

Secondary: Percentage of Participants with a Clinically Meaningful Improvment (CMI) From Baseline on the Social Well-Being Domain within the FACT-An Instrument at Cycle 6

Secondary: Percentage of Participants with a Clinically Meaningful Improvment (CMI) From Baseline on the Social Well-Being Domain within the FACT-An Instrument at Cycle 6

Secondary: Percentage of Participants with a Clinically Meaningful Improvment (CMI) From Baseline on the Physical Well-Being Domain within the FACT-An Instrument at Cycle 6

Secondary: Percentage of Participants with a Clinically Meaningful Improvment (CMI) From Baseline on the Physical Well-Being Domain within the FACT-An Instrument at Cycle 6

Secondary: Percentage of Participants with a Clinically Meaningful Improvment (CMI) From Baseline on the Functional Well-Being Domain within the FACT-An Instrument at Cycle 6

Secondary: Percentage of Participants with a Clinically Meaningful Improvment (CMI) From Baseline on the Functional Well-Being Domain within the FACT-An Instrument at Cycle 6

Secondary: Percentage of Participants with a Clinically Meaningful Improvment (CMI) From Baseline on the Emotional Well-Being Domain within the FACT-An Instrument at Cycle 6

Secondary: Percentage of Participants with a Clinically Meaningful Improvment (CMI) From Baseline on the Emotional Well-Being Domain within the FACT-An Instrument at Cycle 6

Secondary: Percentage of Participants with a Clinically Meaningful Improvment (CMI) From Baseline on the Anemia Subscale Domain within the FACT-An Instrument at Cycle 6

Secondary: Percentage of Participants with a Clinically Meaningful Improvment (CMI) From Baseline on the Anemia Subscale Domain within the FACT-An Instrument at Cycle 6

Secondary: Percentage of Participants with a Clinically Meaningful Improvment (CMI) From Baseline in the Functional Assessment of Cancer Therapy-Anemia Trial Outcome Index Subscale Domain within the FACT-An Instrument at Cycle 6

Secondary: Percentage of Participants with a Clinically Meaningful Improvment (CMI) From Baseline in the Functional Assessment of Cancer Therapy-Anemia Trial Outcome Index Subscale Domain within the FACT-An Instrument at Cycle 6

Secondary: Percentage of Participants with a Clinically Meaningful Improvment (CMI) From Baseline in the Fatigue Related Symptoms Subscale Domain within the FACT-An Instrument at Cycle 6

Secondary: Percentage of Participants with a Clinically Meaningful Improvment (CMI) From Baseline in the Fatigue Related Symptoms Subscale Domain within the FACT-An Instrument at Cycle 6

Secondary: Percentage of Participants with a Clinically Meaningful Improvment (CMI) From Baseline in the Functional Assessment of Cancer Therapy-Anemia-General Subscale Domain within the FACT-An Instrument at Cycle 6

Secondary: Percentage of Participants with a Clinically Meaningful Improvment (CMI) From Baseline in the Functional Assessment of Cancer Therapy-Anemia-General Subscale Domain within the FACT-An Instrument at Cycle 6

Secondary: Percentage of Participants with a Clinically Meaningful Improvement (CMI) From Baseline in the Functional Assessment of Cancer Therapy Anemia-Total Score Domain within the FACT-An Instrument at Cycle 6

Secondary: Percentage of Participants with a Clinically Meaningful Improvement (CMI) From Baseline in the Functional Assessment of Cancer Therapy Anemia-Total Score Domain within the FACT-An Instrument at Cycle 6

Secondary: Percentage of Participants with Change from Baseline in Responses to the Fact-Anemia Item GP-5 - Cycle 2 Day 1 (C2D1)