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Clinical Trial Results:
A PHASE 3, DOUBLE-BLIND, RANDOMIZED STUDY TO COMPARE THE EFFICACY AND SAFETY OF LUSPATERCEPT (ACE-536) VERSUS PLACEBO FOR THE TREATMENT OF ANEMIA DUE TO IPSS-R VERY LOW, LOW, OR INTERMEDIATE RISK MYELODYSPLASTIC SYNDROMES IN SUBJECTS WITH RING SIDEROBLASTS WHO REQUIRE RED BLOOD CELL TRANSFUSIONS

Summary
EudraCT number	2015-003454-41
Trial protocol	DE ES NL BE SE IT
Global end of trial date	26 Nov 2020

Results information
Results version number	v1
This version publication date	05 Dec 2021
First version publication date	05 Dec 2021
Other versions	v2

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

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Trial information

Top of page

Sponsor protocol code

ACE-536-MDS-001

ISRCTN number

US NCT number

WHO universal trial number (UTN)

Sponsor organisation name

Bristol-Myers Squibb

Sponsor organisation address

Chaussée 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

22 Feb 2021

Is this the analysis of the primary completion data?

Global end of trial reached?

Yes

Global end of trial date

26 Nov 2020

Was the trial ended prematurely?

Main objective of the trial

To evaluate RBC transfusion independence (RBC-TI) of luspatercept compared with placebo for the treatment of anemia due to IPSS-R very low, low, or intermediate risk MDS in subjects with ring sideroblasts who require red blood cell (RBC) transfusions.

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

09 Feb 2016

Long term follow-up planned

Independent data monitoring committee (IDMC) involvement?

Yes

Number of subjects enrolled per country

Country: Number of subjects enrolled

Belgium: 16

Country: Number of subjects enrolled

Canada: 14

Country: Number of subjects enrolled

France: 36

Country: Number of subjects enrolled

Germany: 14

Country: Number of subjects enrolled

Italy: 34

Country: Number of subjects enrolled

Netherlands: 7

Country: Number of subjects enrolled

Spain: 31

Country: Number of subjects enrolled

Sweden: 10

Country: Number of subjects enrolled

Turkey: 7

Country: Number of subjects enrolled

United Kingdom: 24

Country: Number of subjects enrolled

United States: 36

Worldwide total number of subjects

229

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

174

85 years and over

Subject disposition

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Recruitment details

Screening details

229 participants were randomized and treated.

Period 1 title

Overall Study (overall period)

Is this the baseline period?

Yes

Allocation method

Randomised - controlled

Blinding used

Double blind

Roles blinded

Investigator, Monitor, Subject, Carer, Data analyst, Assessor

Are arms mutually exclusive

Yes

Luspatercept

Arm description

Luspatercept 1.0 mg/Kg SC on Day 1 of each 21-day treatment cycle

Arm type

Experimental

Investigational medicinal product name

Luspatercept

Investigational medicinal product code

Other name

ACE-536

Pharmaceutical forms

Powder and solvent for solution for injection

Routes of administration

Subcutaneous use

Dosage and administration details

1.0 mg/kg subcutaneously injection every 3 weeks (administered on Day 1 of each 21-day treatment cycle)

Placebo

Arm description

Placebo (Volume equivalent to experimental arm) SC on Day 1 of each 21-day treatment cycle

Arm type

Placebo

Investigational medicinal product name

Normal Saline

Investigational medicinal product code

Other name

Pharmaceutical forms

Solution for injection/infusion

Routes of administration

Subcutaneous use

Dosage and administration details

Volume equivalent to experimental arm, subcutaneously injection every 3 weeks

Number of subjects in period 1	Luspatercept	Placebo
Started	153	76
Completed	4	12
Not completed	149	64
Adverse event, serious fatal	45	24
Consent withdrawn by subject	35	13
Other reasons	12	5
Lost to follow-up	5	1
Transition to rollover protocol	52	21

Baseline characteristics

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Reporting group title

Luspatercept

Reporting group description

Luspatercept 1.0 mg/Kg SC on Day 1 of each 21-day treatment cycle

Reporting group title

Placebo

Reporting group description

Placebo (Volume equivalent to experimental arm) SC on Day 1 of each 21-day treatment cycle

Reporting group values	Luspatercept	Placebo	Total
Number of subjects	153	76	229
Age categorical
Units: Subjects
Adults (18-64 years)	29	16	45
From 65-84 years	120	54	174
85 years and over	4	6	10
Age Continuous
Units: Years
arithmetic mean (standard deviation)	70.5 ( 8.68 )	70.7 ( 10.88 )	-
Sex: Female, Male
Units: Participants
Female	59	26	85
Male	94	50	144
Race/Ethnicity, Customized
Units: Subjects
Black or African American	1	0	1
White	107	51	158
Not Collected or Reported	44	24	68
Other	1	1	2
Ethnicity (NIH/OMB)
Units: Subjects
Hispanic or Latino	3	4	7
Not Hispanic or Latino	115	52	167
Unknown or Not Reported	35	20	55

End points

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Reporting group title

Luspatercept

Reporting group description

Luspatercept 1.0 mg/Kg SC on Day 1 of each 21-day treatment cycle

Reporting group title

Placebo

Reporting group description

Placebo (Volume equivalent to experimental arm) SC on Day 1 of each 21-day treatment cycle

Primary: Percentage Of Participants Who Achieved Red Blood Cell Transfusion Independence (RBC-TI) ≥ 8 Weeks From Week 1 to Week 24

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End point title

Percentage Of Participants Who Achieved Red Blood Cell Transfusion Independence (RBC-TI) ≥ 8 Weeks From Week 1 to Week 24

End point description

RBC-TI response was defined as the absence of any Red Blood Cells (RBC) transfusion during any consecutive 56-day (8-week) period (ie, Days 1 to 56, Days 2 to 57, Days 3 to 58, etc.) during the first 24 weeks of study treatment. Participants had to have at least 56 days (≥ 8 weeks) of transfusion independence prior to (and including) the Week 24 cut-off date to qualify as a responder. Participants who failed to achieve RBC-TI at least 56 days prior to or on the cut-off date were counted as non-responders.

End point type

Primary

End point timeframe

From Week 1 through Week 24 of study treatment

End point values	Luspatercept	Placebo
Number of subjects analysed	153	76
Units: Percent of Participants
number (confidence interval 95%)	37.91 (30.20 to 46.10)	13.16 (6.49 to 22.87)

RBC-TI ≥ 8 weeks_1

Comparison groups

Luspatercept v Placebo

Number of subjects included in analysis

229

Analysis specification

Pre-specified

Analysis type

P-value

< 0.0001

Method

Cochran-Mantel-Haenszel

Parameter type

Common Risk Difference on Response Rate

Point estimate

24.56

Confidence interval

level

95%

sides

2-sided

lower limit

14.48

upper limit

34.64

RBC-TI ≥ 8 weeks_2

Comparison groups

Luspatercept v Placebo

Number of subjects included in analysis

229

Analysis specification

Pre-specified

Analysis type

P-value

< 0.0001

Method

Cochran-Mantel-Haenszel

Parameter type

Odds ratio (OR)

Point estimate

5.065

Confidence interval

level

95%

sides

2-sided

lower limit

2.278

upper limit

11.259

Secondary: Percentage of Participants Who Achieved Red Blood Cell Transfusion Independence (RBC-TI) ≥ 12 Weeks From Week 1 to Week 24

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End point title

Percentage of Participants Who Achieved Red Blood Cell Transfusion Independence (RBC-TI) ≥ 12 Weeks From Week 1 to Week 24

End point description

RBC-TI Response was defined as the absence of any Red Blood Cells (RBC) transfusion during any consecutive 84-day (12-week) period (ie, Days 1 to 84, Days 2 to 85, Days 3 to 86, etc.) during the first 24 weeks of treatment.

End point type

Secondary

End point timeframe

From Week 1 through Week 24 of study treatment

End point values	Luspatercept	Placebo
Number of subjects analysed	153	76
Units: Percent of Participants
number (confidence interval 95%)	28.10 (21.14 to 35.93)	7.89 (2.95 to 16.40)

RBC-TI ≥ 12 weeks_1

Comparison groups

Luspatercept v Placebo

Number of subjects included in analysis

229

Analysis specification

Pre-specified

Analysis type

P-value

= 0.0002

Method

Cochran-Mantel-Haenszel

Parameter type

Common Risk Difference on Response Rate

Point estimate

Confidence interval

level

95%

sides

2-sided

lower limit

10.92

upper limit

29.08

RBC-TI ≥ 12 weeks_2

Comparison groups

Luspatercept v Placebo

Number of subjects included in analysis

229

Analysis specification

Pre-specified

Analysis type

P-value

= 0.0002

Method

Cochran-Mantel-Haenszel

Parameter type

Odds ratio (OR)

Point estimate

5.071

Confidence interval

level

95%

sides

2-sided

lower limit

2.002

upper limit

12.844

Secondary: Percentage of Participants Who Achieved Red Blood Cell Transfusion Independence (RBC-TI) ≥ 12 Weeks From Week 1 to Week 48

Top of page

End point title

Percentage of Participants Who Achieved Red Blood Cell Transfusion Independence (RBC-TI) ≥ 12 Weeks From Week 1 to Week 48

End point description

End point type

Secondary

End point timeframe

From Week 1 through Week 48 of study treatment

End point values	Luspatercept	Placebo
Number of subjects analysed	153	76
Units: Percent of Participants
number (confidence interval 95%)	33.33 (25.93 to 41.40)	11.84 (5.56 to 21.29)

RBC-TI ≥ 12 weeks_3

Comparison groups

Luspatercept v Placebo

Number of subjects included in analysis

229

Analysis specification

Pre-specified

Analysis type

P-value

= 0.0003

Method

Cochran-Mantel-Haenszel

Parameter type

Common Risk Difference on Response Rate

Point estimate

21.37

Confidence interval

level

95%

sides

2-sided

lower limit

11.23

upper limit

31.51

RBC-TI ≥ 12 weeks_4

Comparison groups

Luspatercept v Placebo

Number of subjects included in analysis

229

Analysis specification

Pre-specified

Analysis type

P-value

= 0.0003

Method

Cochran-Mantel-Haenszel

Parameter type

Odds ratio (OR)

Point estimate

4.045

Confidence interval

level

95%

sides

2-sided

lower limit

1.827

upper limit

8.956

Secondary: Percentage of Participants Who Achieved Red Blood Cell Transfusion Independence (RBC-TI) ≥ 8 Weeks From Week 1 Through Week 48

Top of page

End point title

Percentage of Participants Who Achieved Red Blood Cell Transfusion Independence (RBC-TI) ≥ 8 Weeks From Week 1 Through Week 48

End point description

RBC-TI response was defined as the absence of any Red Blood Cells (RBC) transfusion during any consecutive 56-day (8-week) period (ie, Days 1 to 56, Days 2 to 57, Days 3 to 58, etc.) during Week 1 through Week 48. Participants had to have at least 56 days (≥ 8 weeks) of transfusion independence prior to (and including) the Week 48 cut-off date to qualify as a responder. Participants who failed to achieve RBC-TI at least 56 days prior to Week 48 were counted as non-responders.

End point type

Secondary

End point timeframe

From Week 1 through Week 48 of study treatment

End point values	Luspatercept	Placebo
Number of subjects analysed	153	76
Units: Percentage of Participants
number (confidence interval 95%)	45.10 (37.05 to 53.34)	15.79 (8.43 to 25.96)

RBC-TI ≥ 8 weeks_4

Comparison groups

Luspatercept v Placebo

Number of subjects included in analysis

229

Analysis specification

Pre-specified

Analysis type

P-value

< 0.0001

Method

Cochran-Mantel-Haenszel

Parameter type

Odds ratio (OR)

Point estimate

5.306

Confidence interval

level

95%

sides

2-sided

lower limit

2.526

upper limit

11.146

RBC-TI ≥ 8 weeks_3

Comparison groups

Luspatercept v Placebo

Number of subjects included in analysis

229

Analysis specification

Pre-specified

Analysis type

P-value

< 0.0001

Method

Cochran-Mantel-Haenszel

Parameter type

Common Risk Difference on Response Rate

Point estimate

29.55

Confidence interval

level

95%

sides

2-sided

lower limit

18.73

upper limit

40.36

Secondary: Change From Baseline in RBC Units Transfused Over Fixed 16-Week Period

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End point title

Change From Baseline in RBC Units Transfused Over Fixed 16-Week Period

End point description

Mean change in total number of Red Blood Cells (RBC) units transfused over a fixed 16-week period (Week 9-24 or Week 33-48) from the total number of RBC units transfused in the 16 weeks immediately on or prior to first dose of study treatment.

End point type

Secondary

End point timeframe

At Baseline (16 weeks prior to first dose of study treatment) and Weeks 9 to 24 or Weeks 33 to 48

End point values	Luspatercept	Placebo
Number of subjects analysed	128	68
Units: Units
arithmetic mean (standard deviation)
Weeks 9 to 24	-3.0 ( 5.17 )	0.4 ( 4.25 )
Weeks 33 to 48	-4.9 ( 4.22 )	-3.9 ( 7.14 )

No statistical analyses for this end point

Secondary: Percentage of Participants who Achieved a Modified Hematologic Erythroid Response (mHI-E) Over any Consecutive 56-Day Period

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End point title

Percentage of Participants who Achieved a Modified Hematologic Erythroid Response (mHI-E) Over any Consecutive 56-Day Period

End point description

A modified HI-E response was defined as the percentage of participants meeting the modified HI-E per the International Working Group (IWG) sustained over 56-day consecutive period during the Treatment period. For participants with a baseline RBC transfusion burden of ≥ 4 units/8 weeks, a mHI-E was defined as a reduction in RBC transfusion of at least 4 units/8 weeks; for participants with baseline RBC transfusion burden of <4 units/8 weeks, mHI-E, was defined as a mean increase in hemoglobin of ≥ 1.5 g/dL for 8 weeks in the absence of RBC transfusions.

End point type

Secondary

End point timeframe

Week 1 through 24 or Week 1 Through Week 48

End point values	Luspatercept	Placebo
Number of subjects analysed	153	76
Units: Percentage of Participants
number (confidence interval 95%)
Week 1 Through Week 24	52.9 (44.72 to 61.05)	11.8 (5.56 to 21.29)
Week 1 Through Week 48	58.8 (50.59 to 66.71)	17.1 (9.43 to 27.47)

mHI-E_2

Statistical analysis description

Week 1 - 48

Comparison groups

Luspatercept v Placebo

Number of subjects included in analysis

229

Analysis specification

Pre-specified

Analysis type

P-value

< 0.0001

Method

Cochran-Mantel-Haenszel

Confidence interval

mHI-E_1

Statistical analysis description

Week 1 -24

Comparison groups

Luspatercept v Placebo

Number of subjects included in analysis

229

Analysis specification

Pre-specified

Analysis type

P-value

< 0.0001

Method

Cochran-Mantel-Haenszel

Confidence interval

Secondary: Percentage of Participants Who Achieved a Mean Hemoglobin (Hgb) Increase of at Least 1.0 g/dL Over any Consecutive 56-Day Period in Absence of Red Blood Cells (RBC) Transfusions

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End point title

Percentage of Participants Who Achieved a Mean Hemoglobin (Hgb) Increase of at Least 1.0 g/dL Over any Consecutive 56-Day Period in Absence of Red Blood Cells (RBC) Transfusions

End point description

A mean hgb increase of ≥ 1.0 g/dL was analyzed as the percentage of participants with a hgb increase ≥ 1.0 g/dL compared with baseline (after applying the 14/3 day rule) that was sustained over any consecutive 56-day (8-week) period in the absence of RBC transfusions during the treatment period. (Week 1 through Week 24 and Week 1 through Week 48).

End point type

Secondary

End point timeframe

Week 1 though Week 24 and Week 1 through 48

End point values	Luspatercept	Placebo
Number of subjects analysed	153	76
Units: Percentage of Participants
number (confidence interval 95%)
Week 1 Through Week 24	35.3 (27.75 to 43.42)	7.9 (2.95 to 16.40)
Week 1 Through Week 48	41.2 (33.29 to 49.41)	10.5 (4.66 to 19.69)

Hgb increase_2

Statistical analysis description

Week 1 Through Week 48

Comparison groups

Luspatercept v Placebo

Number of subjects included in analysis

229

Analysis specification

Pre-specified

Analysis type

P-value

< 0.0001

Method

Fisher exact

Confidence interval

Hgb increase_1

Statistical analysis description

Week 1 Through Week 24

Comparison groups

Luspatercept v Placebo

Number of subjects included in analysis

229

Analysis specification

Pre-specified

Analysis type

P-value

< 0.0001

Method

Fisher exact

Confidence interval

Secondary: Duration of Red Blood Cell Transfusion Independence (RBC-TI) - Week 1 through Week 24

Top of page

End point title

Duration of Red Blood Cell Transfusion Independence (RBC-TI) - Week 1 through Week 24

End point description

Duration of RBC-TI was defined as the longest duration of response for participants who achieved RBC-TI of ≥ 8 weeks during the treatment period Week 1 through Week 24. Participants who maintained RBC-TI through the end of the treatment period were censored at the date of IP discontinuation or death, whichever occurred first. Median was estimated from unstratified Kaplan Meier method.

End point type

Secondary

End point timeframe

From start of study treatment to 16 weeks after last dose, up to approximately 70 weeks

End point values	Luspatercept	Placebo
Number of subjects analysed	58	10
Units: Weeks
median (confidence interval 95%)	30.6 (20.6 to 40.6)	13.6 (9.1 to 54.9)

RBC-TI Duration_1

Comparison groups

Luspatercept v Placebo

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

P-value

= 0.0445

Method

Logrank

Parameter type

Hazard ratio (HR)

Point estimate

0.446

Confidence interval

level

95%

sides

2-sided

lower limit

0.196

upper limit

1.013

Secondary: Duration of Red Blood Cell Transfusion Independence (RBC-TI) - Week 1 through Week 48

Top of page

End point title

Duration of Red Blood Cell Transfusion Independence (RBC-TI) - Week 1 through Week 48

End point description

Duration of RBC-TI was defined as the longest duration of response for participants who achieved RBC-TI of ≥ 8 weeks during the treatment period Week 1 through Week 48. Participants who maintained RBC-TI through the end of the treatment period were censored at the date of IP discontinuation or death, whichever occurred first. Median was estimated from unstratified Kaplan Meier method.

End point type

Secondary

End point timeframe

From start of study treatment to 16 weeks after last dose, up to approximately 76 weeks

End point values	Luspatercept	Placebo
Number of subjects analysed	69	12
Units: Weeks
median (confidence interval 95%)	30.6 (20.6 to 50.9)	18.6 (10.9 to 99999)

RBC-TI Duration_2

Comparison groups

Luspatercept v Placebo

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

P-value

= 0.5121

Method

Logrank

Parameter type

Hazard ratio (HR)

Point estimate

0.784

Confidence interval

level

95%

sides

2-sided

lower limit

0.362

upper limit

1.699

Secondary: Mean Change From Baseline in the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire (EORTC QLQ-C30) Global Quality of Life Score

Top of page

End point title

Mean Change From Baseline in the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire (EORTC QLQ-C30) Global Quality of Life Score

End point description

The EORTC questionnaire is a validated health-related quality of life (HRQoL) measure applicable to participants with any cancer diagnosis. Version 3.0 of the questionnaire was used in the study. It is composed of 30 items that address 15 domains, including one global health status, functional domains, and symptom domains. Domain scores are transformed to a 0 to 100 scale, where higher scores on the global quality of life score indicate better function. As such, a positive change from Baseline score indicates an improvement in quality of life.

End point type

Secondary

End point timeframe

Baseline and Cycle 3, Day 1 (C3 D1), C5 D1, C7 D1, Week 25, every other cycle during extension phase (C1 D1, C3 D1, C5 D1, etc. up to C59 D1) and end of treatment. Each cycle is composed of 21 days.

End point values	Luspatercept	Placebo
Number of subjects analysed	149	76
Units: Score on a scale
arithmetic mean (standard deviation)
Cycle 3 Day 1 (C3 D1)	-4.1 ( 21.01 )	0.1 ( 15.95 )
C5 D1	-2.4 ( 20.73 )	2.2 ( 17.13 )
C7 D1	-2.1 ( 23.04 )	-0.6 ( 18.63 )
Week 25	-1.8 ( 21.75 )	0.2 ( 18.88 )
Extension Phase C1 D1	0.0 ( 25.32 )	6.3 ( 14.60 )
Extension Phase C3 D1	2.0 ( 19.68 )	-3.9 ( 26.86 )
Extension Phase C5 D1	0.8 ( 18.40 )	0.6 ( 20.04 )
Extension Phase C7 D1	-0.5 ( 20.03 )	3.8 ( 20.87 )
Extension Phase C9 D1	-2.4 ( 18.42 )	11.9 ( 19.75 )
Extension Phase C11 D1	-1.8 ( 19.53 )	4.8 ( 24.47 )
Extension Phase C13 D1	-2.6 ( 20.84 )	8.3 ( 24.15 )
Extension Phase C15 D1	3.1 ( 18.27 )	4.2 ( 27.26 )
Extension Phase C17 D1	-0.6 ( 19.03 )	13.9 ( 26.79 )
Extension Phase C19 D1	-1.6 ( 18.78 )	-16.7 ( 14.43 )
Extension Phase C21 D1	3.1 ( 18.32 )	4.2 ( 17.68 )
Extension Phase C23 D1	0.9 ( 17.84 )	16.7 ( 99999 )
Extension Phase C25 D1	-2.0 ( 18.15 )	16.7 ( 99999 )
Extension Phase C27 D1 0 subjects in Placebo.	2.5 ( 20.40 )	99999 ( 99999 )
Extension Phase C29 D1 0 subjects in Placebo.	2.1 ( 21.12 )	99999 ( 99999 )
Extension Phase C31 D1 0 subjects in Placebo.	-0.3 ( 15.93 )	99999 ( 99999 )
Extension Phase C33 D1 0 subjects in Placebo.	-1.5 ( 19.41 )	99999 ( 99999 )
Extension Phase C35 D1 0 subjects in Placebo.	3.6 ( 23.33 )	99999 ( 99999 )
Extension Phase C37 D1 0 subjects in Placebo.	0.5 ( 22.04 )	99999 ( 99999 )
Extension Phase C39 D1 0 subjects in Placebo.	0.3 ( 23.63 )	99999 ( 99999 )
Extension Phase C41 D1 0 subjects in Placebo.	6.6 ( 20.11 )	99999 ( 99999 )
Extension Phase C43 D1 0 subjects in Placebo.	4.8 ( 15.29 )	99999 ( 99999 )
Extension Phase C45 D1 0 subjects in Placebo.	-2.2 ( 21.24 )	99999 ( 99999 )
Extension Phase C47 D1 0 subjects in Placebo.	1.4 ( 19.08 )	99999 ( 99999 )
Extension Phase C49 D1 0 subjects in Placebo.	-3.8 ( 16.40 )	99999 ( 99999 )
Extension Phase C51 D1 0 subjects in Placebo.	8.3 ( 8.33 )	99999 ( 99999 )
Extension Phase C53 D1 0 subjects in Placebo.	12.5 ( 10.76 )	99999 ( 99999 )
Extension Phase C55 D1 0 subjects in Placebo.	2.8 ( 17.35 )	99999 ( 99999 )
Extension Phase C57 D1 0 subjects in Placebo.	12.5 ( 5.89 )	99999 ( 99999 )
Extension Phase C59 D1 0 subjects in Placebo.	16.7 ( 99999 )	99999 ( 99999 )
End of Treatment	-9.2 ( 23.97 )	-0.8 ( 23.07 )

No statistical analyses for this end point

Secondary: Percentage of Participants who Achieved a Hematologic Improvement in Neutrophil Response (HI-N) over any Consecutive 56-day Period

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End point title

Percentage of Participants who Achieved a Hematologic Improvement in Neutrophil Response (HI-N) over any Consecutive 56-day Period

End point description

Percentage of participants who achieved a hematologic improvement in neutrophil response (HI-N) per IWG criteria sustained over any consecutive 56-day (8-week) period, during the treatment period (Week 1 to Week 24 and Week 1 to Week 48) HI-N was defined as at least a 100% increase and an absolute increase > 0.5 X 10^9/L.

End point type

Secondary

End point timeframe

Week 1 through Week 24 or Week 1 Through Week 48 of study treatment

End point values	Luspatercept	Placebo
Number of subjects analysed	15	10
Units: Percentage of Participants
number (confidence interval 95%)
Week 1 Through Week 24	13.3 (1.66 to 40.46)	0 (0.00 to 30.85)
Week 1 Through Week 48	20.0 (4.33 to 48.09)	10.0 (0.25 to 44.50)

HI-N_2

Statistical analysis description

Week 1 - 48

Comparison groups

Luspatercept v Placebo

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

P-value

= 0.5127

Method

Cochran-Mantel-Haenszel

Confidence interval

HI-N_1

Statistical analysis description

Week 1 -24

Comparison groups

Luspatercept v Placebo

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

P-value

= 0.2382

Method

Cochran-Mantel-Haenszel

Confidence interval

Secondary: Percentage of Participants who Achieved a Hematologic Improvement in Platelet Response (HI-P) Over any Consecutive 56-day Period

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End point title

Percentage of Participants who Achieved a Hematologic Improvement in Platelet Response (HI-P) Over any Consecutive 56-day Period

End point description

Percentage of participants who achieved a hematologic improvement platelet response (HI-P) was defined as the percentage of participants meeting the HI-P criteria per the IWG sustained over any consecutive 56-day (8-week) period (Week 1 to Week 24 and Week 1 to Week 48) during the treatment period. HI – P reponse was defined as: • Absolute increase of ≥ 30 X 10^9/L in platelets for participants starting with > 20 X 10^9/L platelets • Increase in platelets from < 20 X 10^9/L to > 20 X 10^9/L and by at least 100%

End point type

Secondary

End point timeframe

Week 1 through Week 24 or Week 1 Through Week 48 of study treatment

End point values	Luspatercept	Placebo
Number of subjects analysed	8	6
Units: Percentage of Participants
number (confidence interval 95%)
Week 1 Through Week 24	50.0 (15.70 to 84.30)	33.3 (4.33 to 77.72)
Week 1 Through Week 48	62.5 (24.49 to 91.48)	33.3 (4.33 to 77.72)

HI-P_2

Statistical analysis description

Week 1 - 48

Comparison groups

Luspatercept v Placebo

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

P-value

= 0.298

Method

Cochran-Mantel-Haenszel

Confidence interval

HI-P_1

Statistical analysis description

Week 1 -24

Comparison groups

Luspatercept v Placebo

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

P-value

= 0.5479

Method

Cochran-Mantel-Haenszel

Confidence interval

Secondary: Change from Baseline in Mean Serum Ferritin

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End point title

Change from Baseline in Mean Serum Ferritin

End point description

Mean change from baseline in mean serum ferritin was calculated as the difference of postbaseline mean serum ferritin (averaged over the specified timepoints) and baseline mean serum ferritin.

End point type

Secondary

End point timeframe

Baseline and Week 9 through Week 24 and Week 33 through Week 48

End point values	Luspatercept	Placebo
Number of subjects analysed	148	74
Units: ug/L
least squares mean (standard error)
Weeks 9-24	-2.7 ( 54.05 )	226.5 ( 68.02 )
Weeks 33-48	-72.0 ( 74.76 )	247.4 ( 140.96 )

Ferritin_2

Statistical analysis description

Week 33 Through 48

Comparison groups

Luspatercept v Placebo

Number of subjects included in analysis

222

Analysis specification

Pre-specified

Analysis type

P-value

= 0.0294

Method

ANCOVA

Parameter type

LS Mean Difference

Point estimate

-319.5

Confidence interval

level

95%

sides

2-sided

lower limit

-606.3

upper limit

-32.7

Variability estimate

Standard error of the mean

Dispersion value

144.57

Ferritin_1

Statistical analysis description

Week 9 Through 24

Comparison groups

Luspatercept v Placebo

Number of subjects included in analysis

222

Analysis specification

Pre-specified

Analysis type

P-value

= 0.0024

Method

ANCOVA

Parameter type

LS Mean Difference

Point estimate

-229.1

Confidence interval

level

95%

sides

2-sided

lower limit

-375.8

upper limit

-82.4

Variability estimate

Standard error of the mean

Dispersion value

74.43

Secondary: Change from Baseline in Mean Daily Dose of Iron Chelation Therapy (ICT)

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End point title

Change from Baseline in Mean Daily Dose of Iron Chelation Therapy (ICT)

End point description

Mean change from baseline in mean daily dose of ICT averaged over Week 9 to Week 24 or Week 33 to Week 48. For each participant, the mean change in daily dose of ICT was calculated as the difference of postbaseline mean daily dose and baseline mean daily dose.

End point type

Secondary

End point timeframe

Baseline and Week 9 through Week 24 and Week 33 through Week 48 of study treatment

End point values	Luspatercept	Placebo
Number of subjects analysed	128	68
Units: mg/day
least squares mean (standard error)
Weeks 9-24	10.0 ( 29.25 )	51.0 ( 35.92 )
Weeks 33-48	-148.8 ( 46.13 )	-123.8 ( 92.19 )

ICT_1

Statistical analysis description

Weeks 9 Through 24

Comparison groups

Luspatercept v Placebo

Number of subjects included in analysis

196

Analysis specification

Pre-specified

Analysis type

P-value

= 0.3087

Method

ANCOVA

Parameter type

LS Mean Difference

Point estimate

-41

Confidence interval

level

95%

sides

2-sided

lower limit

-120.3

upper limit

38.2

Variability estimate

Standard error of the mean

Dispersion value

40.18

ICT_2

Statistical analysis description

Weeks 33 Through 48

Comparison groups

Luspatercept v Placebo

Number of subjects included in analysis

196

Analysis specification

Pre-specified

Analysis type

P-value

= 0.7903

Method

ANCOVA

Parameter type

LS Mean Difference

Point estimate

-24.9

Confidence interval

level

95%

sides

2-sided

lower limit

-210.7

upper limit

160.8

Variability estimate

Standard error of the mean

Dispersion value

93.42

Secondary: Time to Red Blood Cell Transfusion Independence (RBC-TI) - Week 1 Through Week 24

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End point title

Time to Red Blood Cell Transfusion Independence (RBC-TI) - Week 1 Through Week 24

End point description

Time to RBC-TI was defined as the time between first dose date and the date of onset of RBC-TI first observed for participants who achieved RBC-TI of ≥ 8 weeks during Week 1 through Week 24

End point type

Secondary

End point timeframe

From first dose to Week 24 of study treatment

End point values	Luspatercept	Placebo
Number of subjects analysed	58	10
Units: Days
arithmetic mean (standard deviation)	17.2 ( 29.40 )	26.0 ( 31.83 )

No statistical analyses for this end point

Secondary: Time to Red Blood Cell Transfusion Independence (RBC-TI) - Week 1 Through Week 48

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End point title

Time to Red Blood Cell Transfusion Independence (RBC-TI) - Week 1 Through Week 48

End point description

Time to RBC-TI was defined as the time between first dose date and the date of onset of RBC-TI first observed for participants who achieved RBC-TI of ≥ 8 weeks during Week 1 through Week 48

End point type

Secondary

End point timeframe

From first dose to Week 48 of study treatment

End point values	Luspatercept	Placebo
Number of subjects analysed	69	12
Units: Days
arithmetic mean (standard deviation)	40.3 ( 61.03 )	57.2 ( 79.18 )

No statistical analyses for this end point

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

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End point title

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

End point description

Percentage of participants progressing to AML throughout the course of the study

End point type

Secondary

End point timeframe

From randomization to study completion (up to approximately 57 months)

End point values	Luspatercept	Placebo
Number of subjects analysed	153	76
Units: Percentage of Participants
number (not applicable)	2.6	3.9

No statistical analyses for this end point

Secondary: Time to Acute Myeloid Leukemia (AML) Progression

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End point title

Time to Acute Myeloid Leukemia (AML) Progression

End point description

Time to AML progression was defined as the time between randomization date and the first diagnosis of AML as per World Health Organization (WHO) classification of ≥ 20% blasts in peripheral blood or bone marrow. Participants with a diagnosis of AML were considered to have had an event, participants who did not progress to AML at the time of analysis were censored at the last assessment date which did not indicate progression to AML. Median was not reached because of insufficient number of events

End point type

Secondary

End point timeframe

From randomization to study completion (up to approximately 57 months)

End point values	Luspatercept	Placebo
Number of subjects analysed	4 ^[1]	3 ^[2]
Units: Months
median (confidence interval 95%)	99999 (99999 to 99999)	99999 (99999 to 99999)

Notes
[1] - Median was not reached because of insufficient number of events
[2] - Median was not reached because of insufficient number of events

No statistical analyses for this end point

Secondary: Overall Survival

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End point title

Overall Survival

End point description

Overall Survival was defined as the time from the date of study drug randomization to death due to any cause. Overall survival was censored at the last date that the participant was known to be alive for participants who were alive at the time of analysis and for those who discontinued from the study or were lost to follow-up.

End point type

Secondary

End point timeframe

From randomization to study completion (up to approximately 57 months)

End point values	Luspatercept	Placebo
Number of subjects analysed	153	76 ^[3]
Units: Months
median (confidence interval 95%)	46.0 (42.0 to 99999)	99999 (43.1 to 99999)

Notes
[3] - Median not reached because of insufficient number of events

Comparison groups

Luspatercept v Placebo

Number of subjects included in analysis

229

Analysis specification

Pre-specified

Analysis type

P-value

= 0.958

Method

Logrank

Parameter type

Hazard ratio (HR)

Point estimate

0.986

Confidence interval

level

95%

sides

2-sided

lower limit

0.595

upper limit

1.636

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

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End point title

Number of Participants with Treatment Emergent Adverse Events (TEAEs)

End point description

The outcome measure describes the number of participants who experienced different types of Treatment-emergent adverse events (TEAEs). TEAEs were defined as Adverse Events (AEs) that started on or after the day of the first dose and on or before 42 days after the last dose of IP. 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 date of first dose up to 42 days after the last dose (up to approximately 66 weeks)

End point values	Luspatercept	Placebo
Number of subjects analysed	153	76
Units: Participants
≥ 1 TEAE	151	70
≥ 1 Suspected Related TEAE	71	26
≥ 1 Serious TEAE	66	23
≥ 1 Suspected Related Serious TEAE	6	0
≥ 1 TEAE CTCAE Toxicity Grade (GR) 5	8	4
≥ 1 Suspected Related TEAE With CTCAE GR 5	0	0
≥ 1 TEAE with CTCAE GR 3 or 4	86	34
≥ 1 Suspected Related TEAE With CTCAE GR 3 or 4	13	3
≥ 1 TEAE Leading to Dose Interruption	42	4
≥ 1 TEAE Leading to Dose Reduction	9	0
≥ 1 TEAE Leading to Study Drug Discontinuation	22	6

No statistical analyses for this end point

Secondary: Pharmacokinetic (PK) Parameters: Bayesian Estimate of Apparent Clearance (CL/F)

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End point title

Pharmacokinetic (PK) Parameters: Bayesian Estimate of Apparent Clearance (CL/F)

End point description

Apparent total plasma clearance was calculated as Dose/Area Under the Curve to infinity (ꝏ).

End point type

Secondary

End point timeframe

Blood serum samples taken pre-dose at Cycle 1 Day 1 (C1, D1), C1 D8, C1 D15, C2 D1, C4 D1, C5 D8, C6 D1 and Week 25 visit, extension phase C4 D1 and Day 1 of every fourth treatment cycle thereafter.

End point values	Luspatercept	Placebo
Number of subjects analysed	153	0 ^[4]
Units: L/day
geometric mean (geometric coefficient of variation)	0.516 ( 41.2 )	( )

Notes
[4] - Subjects did not receive investigational drug product

No statistical analyses for this end point

Secondary: Pharmacokinetic (PK) Parameters: Bayesian Estimate of Apparent Volume of Distribution of the Central Compartment (V1/F)

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End point title

Pharmacokinetic (PK) Parameters: Bayesian Estimate of Apparent Volume of Distribution of the Central Compartment (V1/F)

End point description

Apparent volume of distribution of luspatercept was calculated according to the equation Vz = (CL)/λ.

End point type

Secondary

End point timeframe

Blood serum samples taken pre-dose at Cycle 1 Day 1 (C1, D1), C1 D8, C1 D15, C2 D1, C4 D1, C5 D8, C6 D1 and Week 25 visit, extension phase C4 D1 and Day 1 of every fourth treatment cycle thereafter.

End point values	Luspatercept	Placebo
Number of subjects analysed	153	0 ^[5]
Units: Liters
geometric mean (geometric coefficient of variation)	9.68 ( 26.5 )	( )

Notes
[5] - Subjects did not receive investigational drug product

No statistical analyses for this end point

Secondary: Pharmacokinetic (PK) Parameters: Bayesian Estimate of Elimination Half-life (t1/2)

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End point title

Pharmacokinetic (PK) Parameters: Bayesian Estimate of Elimination Half-life (t1/2)

End point description

Terminal phase half-life was calculated according to the following equation: t1/2 = 0.693/λz.

End point type

Secondary

End point timeframe

Blood serum samples taken pre-dose at Cycle 1 Day 1 (C1, D1), C1 D8, C1 D15, C2 D1, C4 D1, C5 D8, C6 D1 and Week 25 visit, extension phase C4 D1 and Day 1 of every fourth treatment cycle thereafter.

End point values	Luspatercept	Placebo
Number of subjects analysed	153	0 ^[6]
Units: Day
geometric mean (geometric coefficient of variation)	13.0 ( 31.6 )	( )

Notes
[6] - Subjects did not receive investigational drug product

No statistical analyses for this end point

Secondary: Pharmacokinetic (PK) Parameters: Bayesian Estimate of Time to Reach Maximum Concentration (Tmax)

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End point title

Pharmacokinetic (PK) Parameters: Bayesian Estimate of Time to Reach Maximum Concentration (Tmax)

End point description

Tmax was defined as the observed time to maximum plasma concentration of luspatercept.

End point type

Secondary

End point timeframe

Blood serum samples taken pre-dose at Cycle 1 Day 1 (C1, D1), C1 D8, C1 D15, C2 D1, C4 D1, C5 D8, C6 D1 and Week 25 visit, extension phase C4 D1 and Day 1 of every fourth treatment cycle thereafter.

End point values	Luspatercept	Placebo
Number of subjects analysed	153	0 ^[7]
Units: Day
median (full range (min-max))	5.40 (3.12 to 6.69)	( to )

Notes
[7] - Subjects did not receive investigational drug product

No statistical analyses for this end point

Secondary: Pharmacokinetic (PK) Parameters: Bayesian Estimate of Maximum Concentration for the First Dose (Cmax)

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End point title

Pharmacokinetic (PK) Parameters: Bayesian Estimate of Maximum Concentration for the First Dose (Cmax)

End point description

Cmax was defined as the observed maximum plasma concentration, obtained directly from the observed concentration versus time.

End point type

Secondary

End point timeframe

Blood serum samples taken pre-dose at Cycle 1 Day 1 (C1, D1), C1 D8, C1 D15, C2 D1, C4 D1, C5 D8, C6 D1 and Week 25 visit, extension phase C4 D1 and Day 1 of every fourth treatment cycle thereafter.

End point values	Luspatercept	Placebo
Number of subjects analysed	153	0 ^[8]
Units: μg/mL
geometric mean (geometric coefficient of variation)	5.77 ( 20.5 )	( )

Notes
[8] - Subjects did not receive investigational drug product

No statistical analyses for this end point

Secondary: Pharmacokinetic (PK) Parameters: Bayesian Estimate of Maximum Concentration for the Starting Dose (Cmax) at Steady State

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End point title

Pharmacokinetic (PK) Parameters: Bayesian Estimate of Maximum Concentration for the Starting Dose (Cmax) at Steady State

End point description

Cmax was defined as the observed maximum plasma concentration, obtained directly from the observed concentration at a steady state.

End point type

Secondary

End point timeframe

Blood serum samples taken pre-dose at Cycle 1 Day 1 (C1, D1), C1 D8, C1 D15, C2 D1, C4 D1, C5 D8, C6 D1 and Week 25 visit, extension phase C4 D1 and Day 1 of every fourth treatment cycle thereafter.

End point values	Luspatercept	Placebo
Number of subjects analysed	153	0 ^[9]
Units: μg/mL
geometric mean (geometric coefficient of variation)	9.17 ( 29.9 )	( )

Notes
[9] - Subjects did not receive investigational drug product

No statistical analyses for this end point

Secondary: Pharmacokinetic (PK) Parameters: Bayesian Estimate of Maximum Concentration for the Area Under the Curve at Steady State for Starting Dose (AUC^ss)

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End point title

Pharmacokinetic (PK) Parameters: Bayesian Estimate of Maximum Concentration for the Area Under the Curve at Steady State for Starting Dose (AUC^ss)

End point description

Area under the curve steady state was defined as the area under the plasma concentration-time curve for a steady state. calculated by the linear trapezoidal rule.

End point type

Secondary

End point timeframe

Blood serum samples taken pre-dose at Cycle 1 Day 1 (C1, D1), C1 D8, C1 D15, C2 D1, C4 D1, C5 D8, C6 D1 and Week 25 visit, extension phase C4 D1 and Day 1 of every fourth treatment cycle thereafter.

End point values	Luspatercept	Placebo
Number of subjects analysed	153	0 ^[10]
Units: day/μg/mL
geometric mean (geometric coefficient of variation)	145 ( 38.3 )	( )

Notes
[10] - Subjects did not receive investigational drug product

No statistical analyses for this end point

Secondary: Participants with Pre-Existing and/or Treatment-Emergent Antidrug Antibodies (ADA)

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End point title

Participants with Pre-Existing and/or Treatment-Emergent Antidrug Antibodies (ADA)

End point description

Number of participants with positive ADA prior to taking study drug and/or during study. A participant was counted as “treatment-emergent” if there was a positive post-baseline sample while the baseline sample was ADA negative, or there was a positive post-baseline sample with a titer ≥ 4-fold of the baseline titer while the baseline sample was ADA positive. A participant was counted as “preexisting” if the baseline sample was ADA positive and the participant was not qualified for “treatment-emergent.”

End point type

Secondary

End point timeframe

From randomization to 1 year post first dose

End point values	Luspatercept	Placebo
Number of subjects analysed	153	76
Units: Participants
Pre-Existing ADA	7	2
Treatment Emergent ADA	11	3
Treatment Emergent Neutralizing ADA	5	2

No statistical analyses for this end point

Adverse events

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Timeframe for reporting adverse events

All-cause mortality was assessed from first dose to study completion (up to approximately 57 months). SAEs and Other AEs were assessed from first dose to 100 days following last dose (up to approximately 91 weeks)

Assessment type

Systematic

Dictionary name

MedDRA

Dictionary version

23.0

Reporting group title

Placebo

Reporting group description

Placebo (Volume equivalent to experimental arm) SC on Day 1 of each 21-day treatment cycle

Reporting group title

Luspatercept

Reporting group description

Luspatercept 1.0 mg/Kg SC on Day 1 of each 21-day treatment cycle

Serious adverse events	Placebo	Luspatercept
Total subjects affected by serious adverse events
subjects affected / exposed	23 / 76 (30.26%)	66 / 153 (43.14%)
number of deaths (all causes)	4	8
number of deaths resulting from adverse events
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Basal cell carcinoma
subjects affected / exposed	0 / 76 (0.00%)	3 / 153 (1.96%)
occurrences causally related to treatment / all	0 / 0	0 / 4
deaths causally related to treatment / all	0 / 0	0 / 0
Colon adenoma
subjects affected / exposed	0 / 76 (0.00%)	1 / 153 (0.65%)
occurrences causally related to treatment / all	0 / 0	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 1
Intraductal papillary mucinous neoplasm
subjects affected / exposed	0 / 76 (0.00%)	1 / 153 (0.65%)
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	1 / 76 (1.32%)	2 / 153 (1.31%)
occurrences causally related to treatment / all	0 / 1	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 0
Refractory anaemia with an excess of blasts
subjects affected / exposed	0 / 76 (0.00%)	4 / 153 (2.61%)
occurrences causally related to treatment / all	0 / 0	0 / 4
deaths causally related to treatment / all	0 / 0	0 / 0
Transformation to acute myeloid leukaemia
subjects affected / exposed	1 / 76 (1.32%)	3 / 153 (1.96%)
occurrences causally related to treatment / all	0 / 1	1 / 3
deaths causally related to treatment / all	0 / 0	0 / 0
Squamous cell carcinoma of skin
subjects affected / exposed	0 / 76 (0.00%)	3 / 153 (1.96%)
occurrences causally related to treatment / all	0 / 0	0 / 3
deaths causally related to treatment / all	0 / 0	0 / 0
Squamous cell carcinoma
subjects affected / exposed	0 / 76 (0.00%)	1 / 153 (0.65%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Systemic mastocytosis
subjects affected / exposed	0 / 76 (0.00%)	1 / 153 (0.65%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Vascular disorders
Granulomatosis with polyangiitis
subjects affected / exposed	0 / 76 (0.00%)	1 / 153 (0.65%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Orthostatic hypotension
subjects affected / exposed	0 / 76 (0.00%)	1 / 153 (0.65%)
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	0 / 76 (0.00%)	1 / 153 (0.65%)
occurrences causally related to treatment / all	0 / 0	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 1
Aortic stenosis
subjects affected / exposed	0 / 76 (0.00%)	1 / 153 (0.65%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
General disorders and administration site conditions
Asthenia
subjects affected / exposed	0 / 76 (0.00%)	1 / 153 (0.65%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Chest pain
subjects affected / exposed	0 / 76 (0.00%)	1 / 153 (0.65%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Death
subjects affected / exposed	1 / 76 (1.32%)	0 / 153 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 1	0 / 0
Gait disturbance
subjects affected / exposed	0 / 76 (0.00%)	1 / 153 (0.65%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
General physical health deterioration
subjects affected / exposed	1 / 76 (1.32%)	0 / 153 (0.00%)
occurrences causally related to treatment / all	0 / 2	0 / 0
deaths causally related to treatment / all	0 / 1	0 / 0
Generalised oedema
subjects affected / exposed	0 / 76 (0.00%)	1 / 153 (0.65%)
occurrences causally related to treatment / all	0 / 0	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 0
Non-cardiac chest pain
subjects affected / exposed	0 / 76 (0.00%)	1 / 153 (0.65%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Multiple organ dysfunction syndrome
subjects affected / exposed	0 / 76 (0.00%)	1 / 153 (0.65%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 1
Pyrexia
subjects affected / exposed	2 / 76 (2.63%)	3 / 153 (1.96%)
occurrences causally related to treatment / all	0 / 2	1 / 3
deaths causally related to treatment / all	0 / 0	0 / 0
Respiratory, thoracic and mediastinal disorders
Acute respiratory distress syndrome
subjects affected / exposed	0 / 76 (0.00%)	1 / 153 (0.65%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Dyspnoea
subjects affected / exposed	0 / 76 (0.00%)	2 / 153 (1.31%)
occurrences causally related to treatment / all	0 / 0	0 / 3
deaths causally related to treatment / all	0 / 0	0 / 0
Dyspnoea exertional
subjects affected / exposed	0 / 76 (0.00%)	1 / 153 (0.65%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Hypoxia
subjects affected / exposed	1 / 76 (1.32%)	1 / 153 (0.65%)
occurrences causally related to treatment / all	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Epistaxis
subjects affected / exposed	0 / 76 (0.00%)	2 / 153 (1.31%)
occurrences causally related to treatment / all	0 / 0	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 0
Pulmonary fibrosis
subjects affected / exposed	0 / 76 (0.00%)	1 / 153 (0.65%)
occurrences causally related to treatment / all	0 / 0	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Respiratory failure
subjects affected / exposed	1 / 76 (1.32%)	0 / 153 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 1	0 / 0
Psychiatric disorders
Confusional state
subjects affected / exposed	0 / 76 (0.00%)	1 / 153 (0.65%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Delirium
subjects affected / exposed	1 / 76 (1.32%)	0 / 153 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Suicide attempt
subjects affected / exposed	1 / 76 (1.32%)	0 / 153 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Product issues
Thrombosis in device
subjects affected / exposed	0 / 76 (0.00%)	1 / 153 (0.65%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Investigations
General physical condition abnormal
subjects affected / exposed	0 / 76 (0.00%)	1 / 153 (0.65%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Injury, poisoning and procedural complications
Ankle fracture
subjects affected / exposed	1 / 76 (1.32%)	0 / 153 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Clavicle fracture
subjects affected / exposed	0 / 76 (0.00%)	1 / 153 (0.65%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Fall
subjects affected / exposed	3 / 76 (3.95%)	7 / 153 (4.58%)
occurrences causally related to treatment / all	0 / 3	0 / 7
deaths causally related to treatment / all	0 / 0	0 / 0
Femur fracture
subjects affected / exposed	0 / 76 (0.00%)	6 / 153 (3.92%)
occurrences causally related to treatment / all	0 / 0	0 / 6
deaths causally related to treatment / all	0 / 0	0 / 0
Head injury
subjects affected / exposed	0 / 76 (0.00%)	1 / 153 (0.65%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Hip fracture
subjects affected / exposed	3 / 76 (3.95%)	0 / 153 (0.00%)
occurrences causally related to treatment / all	0 / 3	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Humerus fracture
subjects affected / exposed	1 / 76 (1.32%)	2 / 153 (1.31%)
occurrences causally related to treatment / all	0 / 1	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 0
Joint dislocation
subjects affected / exposed	0 / 76 (0.00%)	1 / 153 (0.65%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Joint injury
subjects affected / exposed	0 / 76 (0.00%)	1 / 153 (0.65%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Rib fracture
subjects affected / exposed	0 / 76 (0.00%)	1 / 153 (0.65%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Road traffic accident
subjects affected / exposed	0 / 76 (0.00%)	1 / 153 (0.65%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 1
Spinal column injury
subjects affected / exposed	0 / 76 (0.00%)	1 / 153 (0.65%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Thoracic vertebral fracture
subjects affected / exposed	1 / 76 (1.32%)	0 / 153 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Pelvic bone injury
subjects affected / exposed	0 / 76 (0.00%)	1 / 153 (0.65%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Spinal fracture
subjects affected / exposed	0 / 76 (0.00%)	1 / 153 (0.65%)
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	0 / 76 (0.00%)	1 / 153 (0.65%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Cardiac disorders
Acute myocardial infarction
subjects affected / exposed	0 / 76 (0.00%)	1 / 153 (0.65%)
occurrences causally related to treatment / all	0 / 0	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Angina pectoris
subjects affected / exposed	0 / 76 (0.00%)	3 / 153 (1.96%)
occurrences causally related to treatment / all	0 / 0	0 / 3
deaths causally related to treatment / all	0 / 0	0 / 0
Aortic valve stenosis
subjects affected / exposed	0 / 76 (0.00%)	1 / 153 (0.65%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Arteriosclerosis coronary artery
subjects affected / exposed	0 / 76 (0.00%)	1 / 153 (0.65%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Atrial fibrillation
subjects affected / exposed	0 / 76 (0.00%)	2 / 153 (1.31%)
occurrences causally related to treatment / all	0 / 0	0 / 3
deaths causally related to treatment / all	0 / 0	0 / 0
Atrioventricular block
subjects affected / exposed	0 / 76 (0.00%)	2 / 153 (1.31%)
occurrences causally related to treatment / all	0 / 0	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 0
Atrioventricular block second degree
subjects affected / exposed	0 / 76 (0.00%)	1 / 153 (0.65%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Bradycardia
subjects affected / exposed	0 / 76 (0.00%)	1 / 153 (0.65%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Cardiac failure
subjects affected / exposed	0 / 76 (0.00%)	2 / 153 (1.31%)
occurrences causally related to treatment / all	0 / 0	0 / 3
deaths causally related to treatment / all	0 / 0	0 / 0
Cardiac failure acute
subjects affected / exposed	0 / 76 (0.00%)	1 / 153 (0.65%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Coronary artery disease
subjects affected / exposed	0 / 76 (0.00%)	1 / 153 (0.65%)
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 / 76 (1.32%)	0 / 153 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Supraventricular tachycardia
subjects affected / exposed	0 / 76 (0.00%)	1 / 153 (0.65%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Nervous system disorders
Cerebral haemorrhage
subjects affected / exposed	0 / 76 (0.00%)	2 / 153 (1.31%)
occurrences causally related to treatment / all	0 / 0	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 1
Cerebral ischaemia
subjects affected / exposed	1 / 76 (1.32%)	0 / 153 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Cerebrospinal fluid leakage
subjects affected / exposed	1 / 76 (1.32%)	0 / 153 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Haemorrhage intracranial
subjects affected / exposed	1 / 76 (1.32%)	0 / 153 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Seizure
subjects affected / exposed	0 / 76 (0.00%)	1 / 153 (0.65%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Syncope
subjects affected / exposed	0 / 76 (0.00%)	3 / 153 (1.96%)
occurrences causally related to treatment / all	0 / 0	0 / 4
deaths causally related to treatment / all	0 / 0	0 / 0
Blood and lymphatic system disorders
Anaemia
subjects affected / exposed	0 / 76 (0.00%)	3 / 153 (1.96%)
occurrences causally related to treatment / all	0 / 0	0 / 4
deaths causally related to treatment / all	0 / 0	0 / 0
Disseminated intravascular coagulation
subjects affected / exposed	0 / 76 (0.00%)	1 / 153 (0.65%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Febrile neutropenia
subjects affected / exposed	0 / 76 (0.00%)	1 / 153 (0.65%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Gastrointestinal disorders
Abdominal pain
subjects affected / exposed	0 / 76 (0.00%)	1 / 153 (0.65%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Abdominal pain upper
subjects affected / exposed	0 / 76 (0.00%)	1 / 153 (0.65%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Ascites
subjects affected / exposed	0 / 76 (0.00%)	1 / 153 (0.65%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Duodenal ulcer
subjects affected / exposed	0 / 76 (0.00%)	1 / 153 (0.65%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Duodenal ulcer haemorrhage
subjects affected / exposed	0 / 76 (0.00%)	1 / 153 (0.65%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Dysphagia
subjects affected / exposed	0 / 76 (0.00%)	1 / 153 (0.65%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Gastrointestinal haemorrhage
subjects affected / exposed	0 / 76 (0.00%)	1 / 153 (0.65%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Nausea
subjects affected / exposed	0 / 76 (0.00%)	1 / 153 (0.65%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Pancreatitis acute
subjects affected / exposed	0 / 76 (0.00%)	1 / 153 (0.65%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Vomiting
subjects affected / exposed	0 / 76 (0.00%)	1 / 153 (0.65%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Constipation
subjects affected / exposed	0 / 76 (0.00%)	1 / 153 (0.65%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Hepatobiliary disorders
Cholangitis
subjects affected / exposed	1 / 76 (1.32%)	0 / 153 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Hyperbilirubinaemia
subjects affected / exposed	0 / 76 (0.00%)	1 / 153 (0.65%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Cholelithiasis
subjects affected / exposed	0 / 76 (0.00%)	1 / 153 (0.65%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Renal and urinary disorders
Acute kidney injury
subjects affected / exposed	0 / 76 (0.00%)	2 / 153 (1.31%)
occurrences causally related to treatment / all	0 / 0	1 / 2
deaths causally related to treatment / all	0 / 0	0 / 0
Renal colic
subjects affected / exposed	0 / 76 (0.00%)	1 / 153 (0.65%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Renal failure
subjects affected / exposed	1 / 76 (1.32%)	1 / 153 (0.65%)
occurrences causally related to treatment / all	0 / 1	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 1
Urinary retention
subjects affected / exposed	1 / 76 (1.32%)	1 / 153 (0.65%)
occurrences causally related to treatment / all	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Urethral stenosis
subjects affected / exposed	0 / 76 (0.00%)	1 / 153 (0.65%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Musculoskeletal and connective tissue disorders
Back pain
subjects affected / exposed	0 / 76 (0.00%)	3 / 153 (1.96%)
occurrences causally related to treatment / all	0 / 0	1 / 3
deaths causally related to treatment / all	0 / 0	0 / 0
Chondritis
subjects affected / exposed	0 / 76 (0.00%)	1 / 153 (0.65%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Flank pain
subjects affected / exposed	0 / 76 (0.00%)	1 / 153 (0.65%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Gouty arthritis
subjects affected / exposed	0 / 76 (0.00%)	1 / 153 (0.65%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Muscle haemorrhage
subjects affected / exposed	0 / 76 (0.00%)	1 / 153 (0.65%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Muscular weakness
subjects affected / exposed	0 / 76 (0.00%)	1 / 153 (0.65%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Myositis
subjects affected / exposed	0 / 76 (0.00%)	1 / 153 (0.65%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Polymyalgia rheumatica
subjects affected / exposed	0 / 76 (0.00%)	1 / 153 (0.65%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Rheumatoid arthritis
subjects affected / exposed	0 / 76 (0.00%)	1 / 153 (0.65%)
occurrences causally related to treatment / all	0 / 0	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 0
Infections and infestations
Abdominal infection
subjects affected / exposed	0 / 76 (0.00%)	1 / 153 (0.65%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Bacteraemia
subjects affected / exposed	1 / 76 (1.32%)	0 / 153 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Bronchitis
subjects affected / exposed	0 / 76 (0.00%)	2 / 153 (1.31%)
occurrences causally related to treatment / all	0 / 0	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 0
Cellulitis
subjects affected / exposed	1 / 76 (1.32%)	1 / 153 (0.65%)
occurrences causally related to treatment / all	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Endocarditis
subjects affected / exposed	0 / 76 (0.00%)	1 / 153 (0.65%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Diverticulitis
subjects affected / exposed	1 / 76 (1.32%)	0 / 153 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Enterocolitis infectious
subjects affected / exposed	1 / 76 (1.32%)	0 / 153 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Epididymitis
subjects affected / exposed	0 / 76 (0.00%)	1 / 153 (0.65%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Escherichia urinary tract infection
subjects affected / exposed	0 / 76 (0.00%)	1 / 153 (0.65%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Gastroenteritis
subjects affected / exposed	0 / 76 (0.00%)	1 / 153 (0.65%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Localised infection
subjects affected / exposed	0 / 76 (0.00%)	1 / 153 (0.65%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Lower respiratory tract infection
subjects affected / exposed	0 / 76 (0.00%)	2 / 153 (1.31%)
occurrences causally related to treatment / all	0 / 0	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 0
Metapneumovirus infection
subjects affected / exposed	1 / 76 (1.32%)	0 / 153 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Orchitis
subjects affected / exposed	0 / 76 (0.00%)	1 / 153 (0.65%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Parainfluenzae virus infection
subjects affected / exposed	0 / 76 (0.00%)	1 / 153 (0.65%)
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 / 76 (0.00%)	1 / 153 (0.65%)
occurrences causally related to treatment / all	0 / 0	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 0
Pneumonia
subjects affected / exposed	2 / 76 (2.63%)	8 / 153 (5.23%)
occurrences causally related to treatment / all	0 / 2	0 / 14
deaths causally related to treatment / all	0 / 0	0 / 0
Pneumonia staphylococcal
subjects affected / exposed	0 / 76 (0.00%)	1 / 153 (0.65%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Septic shock
subjects affected / exposed	1 / 76 (1.32%)	1 / 153 (0.65%)
occurrences causally related to treatment / all	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Sepsis
subjects affected / exposed	1 / 76 (1.32%)	4 / 153 (2.61%)
occurrences causally related to treatment / all	0 / 1	0 / 6
deaths causally related to treatment / all	0 / 0	0 / 2
Soft tissue infection
subjects affected / exposed	0 / 76 (0.00%)	1 / 153 (0.65%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Staphylococcal infection
subjects affected / exposed	0 / 76 (0.00%)	1 / 153 (0.65%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Streptococcal infection
subjects affected / exposed	1 / 76 (1.32%)	0 / 153 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Upper respiratory tract infection
subjects affected / exposed	0 / 76 (0.00%)	1 / 153 (0.65%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Urinary tract infection bacterial
subjects affected / exposed	1 / 76 (1.32%)	0 / 153 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Urinary tract infection
subjects affected / exposed	1 / 76 (1.32%)	4 / 153 (2.61%)
occurrences causally related to treatment / all	0 / 2	0 / 4
deaths causally related to treatment / all	0 / 0	0 / 0
Urosepsis
subjects affected / exposed	1 / 76 (1.32%)	1 / 153 (0.65%)
occurrences causally related to treatment / all	0 / 2	0 / 1
deaths causally related to treatment / all	0 / 1	0 / 0
Pneumonia moraxella
subjects affected / exposed	0 / 76 (0.00%)	1 / 153 (0.65%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Metabolism and nutrition disorders
Dehydration
subjects affected / exposed	0 / 76 (0.00%)	1 / 153 (0.65%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Hypoglycaemia
subjects affected / exposed	0 / 76 (0.00%)	1 / 153 (0.65%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Lactic acidosis
subjects affected / exposed	0 / 76 (0.00%)	1 / 153 (0.65%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Type 2 diabetes mellitus
subjects affected / exposed	0 / 76 (0.00%)	1 / 153 (0.65%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0

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

Non-serious adverse events	Placebo	Luspatercept
Total subjects affected by non serious adverse events
subjects affected / exposed	63 / 76 (82.89%)	145 / 153 (94.77%)
Vascular disorders
Hypertension
subjects affected / exposed	6 / 76 (7.89%)	16 / 153 (10.46%)
occurrences all number	8	53
General disorders and administration site conditions
Asthenia
subjects affected / exposed	9 / 76 (11.84%)	40 / 153 (26.14%)
occurrences all number	9	74
Fatigue
subjects affected / exposed	11 / 76 (14.47%)	46 / 153 (30.07%)
occurrences all number	14	70
Influenza like illness
subjects affected / exposed	3 / 76 (3.95%)	9 / 153 (5.88%)
occurrences all number	4	11
Malaise
subjects affected / exposed	3 / 76 (3.95%)	8 / 153 (5.23%)
occurrences all number	3	11
Oedema peripheral
subjects affected / exposed	13 / 76 (17.11%)	37 / 153 (24.18%)
occurrences all number	14	45
Pyrexia
subjects affected / exposed	6 / 76 (7.89%)	19 / 153 (12.42%)
occurrences all number	7	24
Reproductive system and breast disorders
Benign prostatic hyperplasia
subjects affected / exposed	0 / 76 (0.00%)	8 / 153 (5.23%)
occurrences all number	0	8
Respiratory, thoracic and mediastinal disorders
Dyspnoea
subjects affected / exposed	5 / 76 (6.58%)	30 / 153 (19.61%)
occurrences all number	6	39
Cough
subjects affected / exposed	10 / 76 (13.16%)	35 / 153 (22.88%)
occurrences all number	13	50
Epistaxis
subjects affected / exposed	3 / 76 (3.95%)	12 / 153 (7.84%)
occurrences all number	3	13
Oropharyngeal pain
subjects affected / exposed	6 / 76 (7.89%)	6 / 153 (3.92%)
occurrences all number	6	6
Psychiatric disorders
Confusional state
subjects affected / exposed	0 / 76 (0.00%)	9 / 153 (5.88%)
occurrences all number	0	10
Depression
subjects affected / exposed	5 / 76 (6.58%)	9 / 153 (5.88%)
occurrences all number	5	10
Insomnia
subjects affected / exposed	4 / 76 (5.26%)	13 / 153 (8.50%)
occurrences all number	4	14
Anxiety
subjects affected / exposed	1 / 76 (1.32%)	9 / 153 (5.88%)
occurrences all number	1	9
Investigations
Alanine aminotransferase increased
subjects affected / exposed	3 / 76 (3.95%)	9 / 153 (5.88%)
occurrences all number	7	17
Aspartate aminotransferase increased
subjects affected / exposed	1 / 76 (1.32%)	10 / 153 (6.54%)
occurrences all number	3	22
Weight decreased
subjects affected / exposed	5 / 76 (6.58%)	9 / 153 (5.88%)
occurrences all number	5	16
Injury, poisoning and procedural complications
Fall
subjects affected / exposed	7 / 76 (9.21%)	25 / 153 (16.34%)
occurrences all number	8	34
Cardiac disorders
Palpitations
subjects affected / exposed	5 / 76 (6.58%)	11 / 153 (7.19%)
occurrences all number	5	12
Tachycardia
subjects affected / exposed	0 / 76 (0.00%)	8 / 153 (5.23%)
occurrences all number	0	9
Nervous system disorders
Headache
subjects affected / exposed	5 / 76 (6.58%)	27 / 153 (17.65%)
occurrences all number	7	32
Dizziness
subjects affected / exposed	4 / 76 (5.26%)	35 / 153 (22.88%)
occurrences all number	4	52
Syncope
subjects affected / exposed	1 / 76 (1.32%)	10 / 153 (6.54%)
occurrences all number	1	11
Blood and lymphatic system disorders
Anaemia
subjects affected / exposed	6 / 76 (7.89%)	14 / 153 (9.15%)
occurrences all number	9	36
Neutropenia
subjects affected / exposed	7 / 76 (9.21%)	8 / 153 (5.23%)
occurrences all number	13	15
Ear and labyrinth disorders
Vertigo
subjects affected / exposed	0 / 76 (0.00%)	12 / 153 (7.84%)
occurrences all number	0	14
Gastrointestinal disorders
Abdominal pain
subjects affected / exposed	4 / 76 (5.26%)	11 / 153 (7.19%)
occurrences all number	5	14
Abdominal pain upper
subjects affected / exposed	2 / 76 (2.63%)	11 / 153 (7.19%)
occurrences all number	2	12
Constipation
subjects affected / exposed	7 / 76 (9.21%)	21 / 153 (13.73%)
occurrences all number	11	28
Diarrhoea
subjects affected / exposed	8 / 76 (10.53%)	44 / 153 (28.76%)
occurrences all number	9	63
Nausea
subjects affected / exposed	6 / 76 (7.89%)	35 / 153 (22.88%)
occurrences all number	7	53
Vomiting
subjects affected / exposed	5 / 76 (6.58%)	14 / 153 (9.15%)
occurrences all number	5	21
Skin and subcutaneous tissue disorders
Erythema
subjects affected / exposed	4 / 76 (5.26%)	2 / 153 (1.31%)
occurrences all number	4	2
Pruritus
subjects affected / exposed	3 / 76 (3.95%)	11 / 153 (7.19%)
occurrences all number	3	14
Musculoskeletal and connective tissue disorders
Arthralgia
subjects affected / exposed	9 / 76 (11.84%)	13 / 153 (8.50%)
occurrences all number	14	14
Back pain
subjects affected / exposed	6 / 76 (7.89%)	32 / 153 (20.92%)
occurrences all number	8	47
Myalgia
subjects affected / exposed	5 / 76 (6.58%)	13 / 153 (8.50%)
occurrences all number	6	14
Infections and infestations
Bronchitis
subjects affected / exposed	1 / 76 (1.32%)	19 / 153 (12.42%)
occurrences all number	1	29
Upper respiratory tract infection
subjects affected / exposed	4 / 76 (5.26%)	19 / 153 (12.42%)
occurrences all number	5	27
Influenza
subjects affected / exposed	0 / 76 (0.00%)	11 / 153 (7.19%)
occurrences all number	0	17
Urinary tract infection
subjects affected / exposed	4 / 76 (5.26%)	21 / 153 (13.73%)
occurrences all number	7	37
Nasopharyngitis
subjects affected / exposed	4 / 76 (5.26%)	18 / 153 (11.76%)
occurrences all number	5	26
Metabolism and nutrition disorders
Decreased appetite
subjects affected / exposed	3 / 76 (3.95%)	14 / 153 (9.15%)
occurrences all number	4	14
Hyperglycaemia
subjects affected / exposed	3 / 76 (3.95%)	12 / 153 (7.84%)
occurrences all number	3	14
Hyperkalaemia
subjects affected / exposed	1 / 76 (1.32%)	10 / 153 (6.54%)
occurrences all number	1	19
Hyperuricaemia
subjects affected / exposed	2 / 76 (2.63%)	12 / 153 (7.84%)
occurrences all number	2	22
Iron overload
subjects affected / exposed	3 / 76 (3.95%)	9 / 153 (5.88%)
occurrences all number	3	9

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Were there any global substantial amendments to the protocol? Yes

21 Sep 2016

- Updates to criteria related to contraception measures - Added sites guidance for sample collection - Added language to exploratory markers - Updates to eligibility criteria - Updates to benefits/risk section

09 May 2017

- Updates to discontinuation criteria and dose modification - Clarification on sample collection modalities - Follow up period extension

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 Transfusion Independence (RBC-TI) ≥ 8 Weeks From Week 1 to Week 24

Primary: Percentage Of Participants Who Achieved Red Blood Cell Transfusion Independence (RBC-TI) ≥ 8 Weeks From Week 1 to Week 24

Secondary: Percentage of Participants Who Achieved Red Blood Cell Transfusion Independence (RBC-TI) ≥ 12 Weeks From Week 1 to Week 24

Secondary: Percentage of Participants Who Achieved Red Blood Cell Transfusion Independence (RBC-TI) ≥ 12 Weeks From Week 1 to Week 24

Secondary: Percentage of Participants Who Achieved Red Blood Cell Transfusion Independence (RBC-TI) ≥ 12 Weeks From Week 1 to Week 48

Secondary: Percentage of Participants Who Achieved Red Blood Cell Transfusion Independence (RBC-TI) ≥ 12 Weeks From Week 1 to Week 48

Secondary: Percentage of Participants Who Achieved Red Blood Cell Transfusion Independence (RBC-TI) ≥ 8 Weeks From Week 1 Through Week 48

Secondary: Percentage of Participants Who Achieved Red Blood Cell Transfusion Independence (RBC-TI) ≥ 8 Weeks From Week 1 Through Week 48

Secondary: Change From Baseline in RBC Units Transfused Over Fixed 16-Week Period

Secondary: Change From Baseline in RBC Units Transfused Over Fixed 16-Week Period

Secondary: Percentage of Participants who Achieved a Modified Hematologic Erythroid Response (mHI-E) Over any Consecutive 56-Day Period

Secondary: Percentage of Participants who Achieved a Modified Hematologic Erythroid Response (mHI-E) Over any Consecutive 56-Day Period

Secondary: Percentage of Participants Who Achieved a Mean Hemoglobin (Hgb) Increase of at Least 1.0 g/dL Over any Consecutive 56-Day Period in Absence of Red Blood Cells (RBC) Transfusions

Secondary: Percentage of Participants Who Achieved a Mean Hemoglobin (Hgb) Increase of at Least 1.0 g/dL Over any Consecutive 56-Day Period in Absence of Red Blood Cells (RBC) Transfusions

Secondary: Duration of Red Blood Cell Transfusion Independence (RBC-TI) - Week 1 through Week 24

Secondary: Duration of Red Blood Cell Transfusion Independence (RBC-TI) - Week 1 through Week 24

Secondary: Duration of Red Blood Cell Transfusion Independence (RBC-TI) - Week 1 through Week 48

Secondary: Duration of Red Blood Cell Transfusion Independence (RBC-TI) - Week 1 through Week 48

Secondary: Mean Change From Baseline in the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire (EORTC QLQ-C30) Global Quality of Life Score

Secondary: Mean Change From Baseline in the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire (EORTC QLQ-C30) Global Quality of Life Score

Secondary: Percentage of Participants who Achieved a Hematologic Improvement in Neutrophil Response (HI-N) over any Consecutive 56-day Period

Secondary: Percentage of Participants who Achieved a Hematologic Improvement in Neutrophil Response (HI-N) over any Consecutive 56-day Period

Secondary: Percentage of Participants who Achieved a Hematologic Improvement in Platelet Response (HI-P) Over any Consecutive 56-day Period

Secondary: Percentage of Participants who Achieved a Hematologic Improvement in Platelet Response (HI-P) Over any Consecutive 56-day Period

Secondary: Change from Baseline in Mean Serum Ferritin

Secondary: Change from Baseline in Mean Serum Ferritin

Secondary: Change from Baseline in Mean Daily Dose of Iron Chelation Therapy (ICT)

Secondary: Change from Baseline in Mean Daily Dose of Iron Chelation Therapy (ICT)

Secondary: Time to Red Blood Cell Transfusion Independence (RBC-TI) - Week 1 Through Week 24

Secondary: Time to Red Blood Cell Transfusion Independence (RBC-TI) - Week 1 Through Week 24

Secondary: Time to Red Blood Cell Transfusion Independence (RBC-TI) - Week 1 Through Week 48

Secondary: Time to Red Blood Cell Transfusion Independence (RBC-TI) - Week 1 Through Week 48

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 Acute Myeloid Leukemia (AML) Progression

Secondary: Time to Acute Myeloid Leukemia (AML) Progression

Secondary: Overall Survival

Secondary: Overall Survival

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

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

Secondary: Pharmacokinetic (PK) Parameters: Bayesian Estimate of Apparent Clearance (CL/F)

Secondary: Pharmacokinetic (PK) Parameters: Bayesian Estimate of Apparent Clearance (CL/F)

Secondary: Pharmacokinetic (PK) Parameters: Bayesian Estimate of Apparent Volume of Distribution of the Central Compartment (V1/F)

Secondary: Pharmacokinetic (PK) Parameters: Bayesian Estimate of Apparent Volume of Distribution of the Central Compartment (V1/F)

Secondary: Pharmacokinetic (PK) Parameters: Bayesian Estimate of Elimination Half-life (t1/2)

Secondary: Pharmacokinetic (PK) Parameters: Bayesian Estimate of Elimination Half-life (t1/2)

Secondary: Pharmacokinetic (PK) Parameters: Bayesian Estimate of Time to Reach Maximum Concentration (Tmax)

Secondary: Pharmacokinetic (PK) Parameters: Bayesian Estimate of Time to Reach Maximum Concentration (Tmax)

Secondary: Pharmacokinetic (PK) Parameters: Bayesian Estimate of Maximum Concentration for the First Dose (Cmax)

Secondary: Pharmacokinetic (PK) Parameters: Bayesian Estimate of Maximum Concentration for the First Dose (Cmax)

Secondary: Pharmacokinetic (PK) Parameters: Bayesian Estimate of Maximum Concentration for the Starting Dose (Cmax) at Steady State

Secondary: Pharmacokinetic (PK) Parameters: Bayesian Estimate of Maximum Concentration for the Starting Dose (Cmax) at Steady State

Secondary: Pharmacokinetic (PK) Parameters: Bayesian Estimate of Maximum Concentration for the Area Under the Curve at Steady State for Starting Dose (AUC^ss)

Secondary: Pharmacokinetic (PK) Parameters: Bayesian Estimate of Maximum Concentration for the Area Under the Curve at Steady State for Starting Dose (AUC^ss)

Secondary: Participants with Pre-Existing and/or Treatment-Emergent Antidrug Antibodies (ADA)

Secondary: Participants with Pre-Existing and/or Treatment-Emergent Antidrug Antibodies (ADA)

Adverse events

Adverse events

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Substantial protocol amendments (globally)

Interruptions (globally)

Limitations and caveats

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