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Clinical Trial Results:
AN OPEN-LABEL, RANDOMIZED, PHASE 2, PARALLEL, DOSE-RANGING, MULTICENTER STUDY OF SOTATERCEPT FOR THE TREATMENT OF PATIENTS WITH ANEMIA AND LOW- OR INTERMEDIATE-1 RISK MYELODYSPLASTIC SYNDROMES OR NON-PROLIFERATIVE CHRONIC MYELOMONOCYTIC LEUKEMIA (CMML)

Summary
EudraCT number	2012-002601-22
Trial protocol	FR
Global end of trial date	29 Apr 2018

Results information
Results version number	v1(current)
This version publication date	16 May 2019
First version publication date	16 May 2019
Other versions

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

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Trial information

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Sponsor protocol code

ACE-011-MDS-001

ISRCTN number

US NCT number

NCT01736683

WHO universal trial number (UTN)

Sponsor organisation name

Celgene Corporation

Sponsor organisation address

86 Morris Avenue, Summit, New Jersey, United States, 07901

Public contact

ClinicalTrialDisclosure, Celgene Corporation, +1 888260-1599, ClinicalTrialDisclosure@celgene.com

Scientific contact

ClinicalTrialDisclosure, Celgene Corporation, +1 888260-1599, ClinicalTrialDisclosure@celgene.com

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

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

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

Analysis stage

Final

Date of interim/final analysis

08 Apr 2019

Is this the analysis of the primary completion data?

Global end of trial reached?

Yes

Global end of trial date

29 Apr 2018

Was the trial ended prematurely?

Main objective of the trial

The primary objective of this study is to determine a safe, tolerable and effective dose of sotatercept that results in the greatest frequency of improvement of anemia in patients diagnosed with low- or intermediate-1 risk MDS or non-proliferative chronic myelomonocytic leukemia (CMML).

Protection of trial subjects

The procedures set out in this study protocol pertaining to the conduct, evaluation, and documentation of this study were designed to ensure that Celgene, its authorized representative, and investigator abided by Good Clinical Practice (GCP), as described in the International Council for Harmonisation (ICH) E6 guideline and in accordance with the general ethical principles outlined in the Declaration of Helsinki. The study received approval from an independent review board/ ethics committee (IRB/IEC) prior to commencement. The investigator conducted all aspects of this study in accordance with applicable national, state, and local laws of the pertinent regulatory authorities. An informed consent form (ICF) explaining the procedures of the study, including the potential hazards, was reviewed and approved by the IRB/IEC prior to its use. The investigator obtained informed consent of a subject and/or a subject’s legal representative prior to any study-related procedures. Documentation, including the date, that informed consent occurred prior to the subject’s entry into the study, and of the informed consent process was recorded in the subject’s source documents. The original ICF, signed and dated by the subject and by the person consenting the subject prior to the subject’s entry into the study, was maintained in the investigator’s study files and a copy was given to the subject. In addition, the ICF was revised when the protocol was amended in a way that impacted the content of the informed consent. Subjects participating in the study when the amended protocol was implemented were reconsented with the revised version of the ICF. The revised ICF, signed and dated by the subject and by the person consenting the subject, was maintained in the investigator’s study files, and a copy was given to the subject.

Background therapy

Evidence for comparator

Actual start date of recruitment

27 Nov 2012

Long term follow-up planned

Independent data monitoring committee (IDMC) involvement?

Yes

Number of subjects enrolled per country

Country: Number of subjects enrolled

France: 24

Country: Number of subjects enrolled

United States: 50

Worldwide total number of subjects

EEA total number of subjects

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

85 years and over

Subject disposition

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Recruitment details

Participants were stratified by concentration of serum erythropoietin (EPO) (<500 versus ≥500 IU/L), by number of transfusions within 56 days of study enrollment (<4 versus ≥4 units of red blood cells) and assigned randomly to 0.1 mg/kg and 0.3 mg/kg arms.

Screening details

Enrollment in the other arms (sotatercept 0.5, 1.0 and 2.0 mg/kg arms) commenced after the Steering Committee approved the higher doses based on the safety of preceding doses.

Period 1 title

Overall Trial (overall period)

Is this the baseline period?

Yes

Allocation method

Randomised - controlled

Blinding used

Not blinded

Are arms mutually exclusive

Yes

Sotatercept 0.1 mg/kg

Arm description

Sotatercept 0.1 mg/kg administered via subcutaneous injection every third week (Q3W). Participants were randomized to either the 0.1 mg/kg arm or the 0.3 mg/kg arm. Efficacy and safety data were assessed by a Steering Committee. Based upon the occurrence of dose-limiting toxicity (DLT) in ≤ 1/5 subjects in Cycle 1 in the 0.1 mg/kg and 0.3 mg/kg treatment groups, the 0.5 mg/kg treatment group began inclusion in the randomization scheme.

Arm type

Experimental

Investigational medicinal product name

Sotatercept

Investigational medicinal product code

Other name

ACE-011, ActRIIA-IgG1Fc

Pharmaceutical forms

Powder and solvent for solution for injection

Routes of administration

Subcutaneous use

Dosage and administration details

Sotatercept is supplied as a lyophilized powder that is reconstituted using Water for Injection (WFI) and administered as a subcutaneous (SC) injection by the study staff at the clinical site.

Sotatercept 0.3 mg/kg

Arm description

Sotatercept 0.3 mg/kg administered via subcutaneous injection every third week (Q3W). Participants were randomized to either the 0.1 mg/kg arm or the 0.3 mg/kg arm. Efficacy and safety data were assessed by a Steering Committee. Based upon the occurrence of dose-limiting toxicity (DLT) in ≤ 1/5 subjects in Cycle 1 in the 0.1 mg/kg and 0.3 mg/kg treatment groups, the 0.5 mg/kg treatment group began inclusion in the randomization scheme.

Arm type

Experimental

Investigational medicinal product name

Sotatercept

Investigational medicinal product code

Other name

ACE-011, ActRIIA-IgG1Fc

Pharmaceutical forms

Powder and solvent for solution for injection

Routes of administration

Subcutaneous use

Dosage and administration details

Sotatercept is supplied as a lyophilized powder that is reconstituted using Water for Injection (WFI) and administered as a subcutaneous (SC) injection by the study staff at the clinical site.

Sotatercept 0.5 mg/kg

Arm description

Sotatercept 0.5 mg/kg administered via subcutaneous injection every third week (Q3W). Participants were randomized to one of the active treatment arms. Efficacy and safety data were assessed by a Steering Committee. Based upon the occurrence of dose-limiting toxicity (DLT) in ≤ 1/6 subjects in Cycle 1 in the 0.5 mg/kg treatment group, the 1.0 mg/kg treatment group began inclusion in the randomization scheme.

Arm type

Experimental

Investigational medicinal product name

Sotatercept

Investigational medicinal product code

Other name

ACE-011, ActRIIA-IgG1Fc

Pharmaceutical forms

Powder and solvent for solution for injection

Routes of administration

Subcutaneous use

Dosage and administration details

Sotatercept is supplied as a lyophilized powder that is reconstituted using Water for Injection (WFI) and administered as a subcutaneous (SC) injection by the study staff at the clinical site.

Sotatercept 1.0 mg/kg

Arm description

Sotatercept 1.0 mg/kg administered via subcutaneous injection every third week (Q3W). Participants were randomized to one of the active treatment arms. Efficacy and safety data were assessed by a Steering Committee. Based upon the occurrence of dose-limiting toxicity (DLT) in ≤ 1/6 subjects in Cycle 1 in the 1.0 mg/kg treatment group, the 2.0 mg/kg treatment group began inclusion in the randomization scheme. Following evaluation of all treatment group data by the Steering Committee, enrollment continued only in the 1.0 mg/kg arm because the arm had the greatest frequency of erythroid hematological improvement (HI-E).

Arm type

Experimental

Investigational medicinal product name

Sotatercept

Investigational medicinal product code

Other name

ACE-011, ActRIIA-IgG1Fc

Pharmaceutical forms

Powder and solvent for solution for injection

Routes of administration

Subcutaneous use

Dosage and administration details

Sotatercept is supplied as a lyophilized powder that is reconstituted using Water for Injection (WFI) and administered as a subcutaneous (SC) injection by the study staff at the clinical site.

Sotatercept 2.0 mg/kg

Arm description

Sotatercept 2.0 mg/kg administered via subcutaneous injection every third week (Q3W). Participants were randomized to one of the active treatment arms. Efficacy and safety data were assessed by a Steering Committee. The 2.0 mg/kg sotatercept dose was reduced to 1.5 mg/kg for ongoing and newly enrolled participants by protocol amendment.

Arm type

Experimental

Investigational medicinal product name

Sotatercept

Investigational medicinal product code

Other name

ACE-011, ActRIIA-IgG1Fc

Pharmaceutical forms

Powder and solvent for solution for injection

Routes of administration

Subcutaneous use

Dosage and administration details

Sotatercept is supplied as a lyophilized powder that is reconstituted using Water for Injection (WFI) and administered as a subcutaneous (SC) injection by the study staff at the clinical site.

Number of subjects in period 1	Sotatercept 0.1 mg/kg	Sotatercept 0.3 mg/kg	Sotatercept 0.5 mg/kg	Sotatercept 1.0 mg/kg	Sotatercept 2.0 mg/kg
Started	7	6	21	35	5
Completed	0	0	0	0	0
Not completed	7	6	21	35	5
Adverse event, serious fatal	-	1	-	-	-
Consent withdrawn by subject	-	-	3	1	1
Adverse event, non-fatal	-	1	2	3	2
Disease relapse	-	-	2	1	-
Lack of therapeutic effect	7	4	13	20	1
Progressive disease	-	-	-	1	-
not specified	-	-	1	9	1

Baseline characteristics

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Reporting group title

Sotatercept 0.1 mg/kg

Reporting group description

Reporting group title

Sotatercept 0.3 mg/kg

Reporting group description

Reporting group title

Sotatercept 0.5 mg/kg

Reporting group description

Reporting group title

Sotatercept 1.0 mg/kg

Reporting group description

Reporting group title

Sotatercept 2.0 mg/kg

Reporting group description

Reporting group values	Sotatercept 0.1 mg/kg	Sotatercept 0.3 mg/kg	Sotatercept 0.5 mg/kg	Sotatercept 1.0 mg/kg	Sotatercept 2.0 mg/kg	Total
Number of subjects	7	6	21	35	5	74
Age categorical
Units: Subjects
<65 years	3	0	7	6	1	17
>=65 to <75 years	2	3	8	17	2	32
>=75 years	2	3	6	12	2	25
Age continuous
Units: years
arithmetic mean (standard deviation)	67 ± 8.3	75 ± 6.9	69 ± 8.0	71 ± 8.2	69 ± 13.0	-
Gender categorical
Units: Subjects
Female	3	0	4	17	4	28
Male	4	6	17	18	1	46
Red Blood Cell (RBC) Transfusion Burden Categories
RBC units transfused during 56 days prior to the start of treatment.
Units: Subjects
<4 units (Low Transfusion Burden)	0	0	3	8	1	12
>=4 units (High Transfusion Burden)	7	6	18	27	4	62
Number of Previous Erythropoiesis-Stimulating Agents (ESA) Therapies for Myelodysplastic Syndromes
Units: Subjects
0 ESA therapies	1	0	1	0	0	2
1 ESA therapy	6	2	11	23	3	45
2 ESA therapies	0	4	8	10	2	24
3 ESA therapies	0	0	1	2	0	3
Race
Units: Subjects
American Indian or Alaska Native	0	0	0	0	0	0
Asian	0	0	0	0	1	1
Native Hawaiian or Other Pacific Islander	0	0	0	0	0	0
Black or African American	0	0	0	1	0	1
White	7	6	14	18	3	48
Unknown or Not Reported	0	0	6	16	1	23
Other	0	0	1	0	0	1
Ethnicity
Units: Subjects
Hispanic or Latino	0	0	2	0	0	2
Not Hispanic or Latino	7	6	13	19	4	49
Missing	0	0	6	16	1	23
Erythropoietin Level
Units: Subjects
<=200 mIU/mL	2	3	6	16	2	29
>200 to <=500 mIU/mL	2	1	6	6	0	15
>500 mIU/mL	3	2	9	9	2	25
Missing	0	0	0	4	1	5
Number of Previous Non-ESA Agents for Myelodysplastic Syndromes
Units: Subjects
0 non-ESA agents	0	0	2	7	2	11
1 non-ESA agent	1	0	7	16	1	25
2 non-ESA agents	2	1	6	7	1	17
3 non-ESA agents	2	1	2	2	1	8
4 non-ESA agents	0	1	2	3	0	6
5 non-ESA agents	1	1	0	0	0	2
>5 non-ESA agents	1	2	2	0	0	5
International Prognostic Scoring System (IPSS)
The International Prognostic Scoring System for MDS (IPSS) assigns a prognostic score (0=good and increasing in risk by half-grades with the top score outlined below) for three prognostic variables: • Marrow blasts (score 0-2.0 • Karyotype (score 0-1.0) • Cytopenias: neutrophil, platelets, and Hg counts (score 0-0.5) The three individual scores are summed resulting in a full range of 0- 3.5 and placed into risk categories • 0 = low risk • 0.5-1.0 = intermediate-1 risk • 1.5-2.0 = intermediate-2 risk • >=2.5 = high risk
Units: Subjects
Low - 0	4	4	5	11	0	24
Intermediate-1: 0.5 to 1.0	3	2	16	24	5	50
Intermediate-2: 1.5 to 2	0	0	0	0	0	0
High: >=2.5	0	0	0	0	0	0
Height
Units: cm
arithmetic mean (standard deviation)	1.70 ± 0.110	1.75 ± 0.054	1.70 ± 0.093	1.68 ± 0.089	1.56 ± 0.043	-
Weight
Units: kg
arithmetic mean (standard deviation)	85.3 ± 21.79	79.5 ± 13.90	77.9 ± 13.97	73.5 ± 15.55	56.4 ± 7.25	-

End points

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Reporting group title

Sotatercept 0.1 mg/kg

Reporting group description

Reporting group title

Sotatercept 0.3 mg/kg

Reporting group description

Reporting group title

Sotatercept 0.5 mg/kg

Reporting group description

Reporting group title

Sotatercept 1.0 mg/kg

Reporting group description

Reporting group title

Sotatercept 2.0 mg/kg

Reporting group description

Primary: Percentage of Participants With Erythroid Hematological Improvement (HI-E) Starting Before the Completion of Five Cycles of Treatment (Responder Rate)

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End point title

Percentage of Participants With Erythroid Hematological Improvement (HI-E) Starting Before the Completion of Five Cycles of Treatment (Responder Rate) ^[1]

End point description

Responder rate includes non-transfusion dependent efficacy (NTDE) participants and transfusion dependent efficacy (TDE) participants. For nontransfusion dependence efficacy (NTDE) participants who required < 4 units of RBCs in the 8 weeks prior to start of therapy, HI-E was defined as an increase of >=1.5 g/dL hemoglobin sustained for 56 days over a period of >=8 weeks. For transfusion dependence efficacy (TDE) participants who required >=4 units of RBCs in the 8 weeks prior to start of therapy, HI-E was defined as a decrease of >= 4 units of RBCs transfused sustained for 56 days over a period of 8 weeks.

End point type

Primary

End point timeframe

Day 2 - 142

Notes
[1] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
Justification: There were no statistical analysis performed.

End point values	Sotatercept 0.1 mg/kg	Sotatercept 0.3 mg/kg	Sotatercept 0.5 mg/kg	Sotatercept 1.0 mg/kg	Sotatercept 2.0 mg/kg
Number of subjects analysed	7 ^[2]	6 ^[3]	21 ^[4]	35 ^[5]	5 ^[6]
Units: percentage of participants
number (not applicable)
All participants	0	66.7	42.9	60.0	40.0
NTDE subpopulation	0	0	33.3	62.5	100
TDE subpopulation	0	66.7	44.4	59.3	25.0

Notes
[2] - All - 7 participants NTDE - 0 participants TDE - 7 participants
[3] - All - 6 participants NTDE - 0 participants TDE - 6 participants
[4] - All - 21 participants NTDE - 3 participants TDE - 18 participants
[5] - All - 35 participants NTDE - 8 participants TDE - 27 participants
[6] - All - 5 participants NTDE - 1 participant TDE - 4 participants

No statistical analyses for this end point

Secondary: Dose Limiting Toxicities (DLTs)

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End point title

Dose Limiting Toxicities (DLTs)

End point description

The following were DLTs if the investigator suspected they were treatment related: 1. Increase to >= 140 mmHg systolic blood pressure 2. Increase to >=90 mmHg diastolic blood pressure 3. Increase to >=140 systolic and increase > 20 mmHg compared to baseline systolic 4. Increase to >=90 mmHg diastolic and increase > 20 mmHg compared to baseline diastolic. 5. Introduction of new anti-hypertension medication during treatment 6. Increase in dose of baseline anti-hypertension medication during treatment 7. >= Grade 2 (moderate severity or worse) hypertension as an adverse event

End point type

Secondary

End point timeframe

Day 1 to 59.2 months

End point values	Sotatercept 0.1 mg/kg	Sotatercept 0.3 mg/kg	Sotatercept 0.5 mg/kg	Sotatercept 1.0 mg/kg	Sotatercept 2.0 mg/kg
Number of subjects analysed	7	6	21	35	5
Units: participants
1. Increase to >= 140 mmHg systolic	1	1	8	19	2
2. Increase to >=90 mmHg diastolic	0	0	2	2	1
3. =140 systolic and increase > 20 mmHg base	0	1	5	10	2
4. >=90 mmHg diastolic and increase > 20 mmHg base	0	0	2	2	1
5. Introduction of new anti-hypertension med	0	0	4	3	1
6. > in dose of baseline anti-hypertension med	0	0	0	0	0
7.>= Grade 2 hypertension TEAE	0	1	2	4	1

No statistical analyses for this end point

Secondary: Time to Erythroid Hematological Improvement (HI-E) Response

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End point title

Time to Erythroid Hematological Improvement (HI-E) Response

End point description

Time to first response = start date of first response (HI-E) - first dose date + 1 day. For NTDE participants (who required < 4 units of RBCs in the 8 weeks prior to start of therapy), HI-E was defined as an increase of >=1.5 g/dL hemoglobin sustained for 56 days over a period of >=8 weeks. For TDE participants (who required >=4 units of RBCs in the 8 weeks prior to start of therapy), HI-E was defined as a decrease of >= 4 units of RBCs transfused sustained for 56 days over a period of 8 weeks. 9999 = not applicable

End point type

Secondary

End point timeframe

Day 1 to Day 87

End point values	Sotatercept 0.1 mg/kg	Sotatercept 0.3 mg/kg	Sotatercept 0.5 mg/kg	Sotatercept 1.0 mg/kg	Sotatercept 2.0 mg/kg
Number of subjects analysed	0 ^[7]	4 ^[8]	9 ^[9]	21 ^[10]	2 ^[11]
Units: days
median (full range (min-max))
All participants	( to )	24.0 (2 to 44)	1.0 (1 to 2)	1.0 (1 to 86)	48.0 (9 to 87)
NTDE subpopulation	( to )	9999 (9999 to 9999)	1.0 (1 to 1)	1.0 (1 to 52)	9.0 (9 to 9)
TDE subpopulation	( to )	24.0 (2 to 44)	1.5 (1 to 2)	1.5 (1 to 86)	87 (87 to 87)

Notes
[7] - Participants who responded
[8] - Participants who responded Total = 4 NTDE = 0 TDE = 4
[9] - Participants who responded Total = 9 NTDE = 1 TDE = 8
[10] - Participants who responded Total = 21 NTDE = 5 TDE = 16
[11] - Participants who responded Total = 2 NTDE = 1 TDE = 1

No statistical analyses for this end point

Secondary: Duration of Erythroid Hematological Improvement (HI-E)

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End point title

Duration of Erythroid Hematological Improvement (HI-E)

End point description

The duration of HI-E response for participants who responded was (the last date of the consecutive hemoglobin [Hgb] measurements of the first >=56 day interval) – (the first date of the consecutive Hgb measurements of the first >=56 day interval) + 1 day. 9999 = not applicable

End point type

Secondary

End point timeframe

Day 1 to 183.7 weeks

End point values	Sotatercept 0.1 mg/kg	Sotatercept 0.3 mg/kg	Sotatercept 0.5 mg/kg	Sotatercept 1.0 mg/kg	Sotatercept 2.0 mg/kg
Number of subjects analysed	0 ^[12]	4 ^[13]	9 ^[14]	21 ^[15]	2 ^[16]
Units: days
median (full range (min-max))
All participants	( to )	62.5 (62 to 69)	104.0 (56 to 1794)	133.0 (58 to 1554)	96.0 (58 to 134)
NTDE subpopulation	( to )	9999 (9999 to 9999)	79.0 (79 to 79)	1043.0 (69 to 1554)	134.0 (134 to 134)
TDE subpopulation	( to )	62.5 (62 to 69)	105.5 (56 to 1794)	96.5 (58 to 1033)	58.0 (58 to 58)

Notes
[12] - Efficacy Evaluable Population of participants who responded
[13] - Efficacy Evaluable Population of participants who responded Total = 4 NTDE = 0 TDE = 4
[14] - Efficacy Evaluable Population of participants who responded Total = 9 NTDE = 1 TDE = 8
[15] - Efficacy Evaluable Population of participants who responded Total = 21 NTDE = 5 TDE = 16
[16] - Efficacy Evaluable Population of participants who responded Total = 2 NTDE = 1 TDE = 1

No statistical analyses for this end point

Secondary: Time to Progression to Acute Myeloid Leukemia (AML) for Participants Who Had Progression

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End point title

Time to Progression to Acute Myeloid Leukemia (AML) for Participants Who Had Progression

End point description

Progression to AML used criteria by the International Working Group (IWG) Response Criteria in Myelodysplasia (Cheson, 2006). Progression is considered if any of the following are met: • >=50% increase in blasts • >=50% decrement from maximum remission/response levels in granulocytes or platelets • Reduction in Hgb concentration by >=2 g/dL • Transfusion dependence This outcome was defined as a Kaplan-Meier estimate however few participants progressed so a Kaplan-Meier analysis could not be performed. Disclosed are time to progression values only for participants who did progress to AML.

End point type

Secondary

End point timeframe

Day 1 to 183.7 weeks

End point values	Sotatercept 0.1 mg/kg	Sotatercept 0.3 mg/kg	Sotatercept 0.5 mg/kg	Sotatercept 1.0 mg/kg	Sotatercept 2.0 mg/kg
Number of subjects analysed	0 ^[17]	0 ^[18]	1 ^[19]	1 ^[20]	0 ^[21]
Units: weeks
number (not applicable)			45.6	78.0

Notes
[17] - Efficacy Evaluable Population of participants who progressed to AML
[18] - Efficacy Evaluable Population of participants who progressed to AML
[19] - Efficacy Evaluable Population of participants who progressed to AML
[20] - Efficacy Evaluable Population of participants who progressed to AML
[21] - Efficacy Evaluable Population of participants who progressed to AML

No statistical analyses for this end point

Secondary: Time to Progression to Events of Higher Risk Myelodysplastic Syndromes (MDS) Using the International Prognostic Scoring System (IPSS) For Participants Who Had Progression

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End point title

Time to Progression to Events of Higher Risk Myelodysplastic Syndromes (MDS) Using the International Prognostic Scoring System (IPSS) For Participants Who Had Progression

End point description

Progression to events of higher risk MDS used criteria from the International Prognostic Scoring System for MDS (IPSS) which assigns a prognostic score (0=good and increasing in risk by half-grades with the top score outlined below) for three prognostic variables: • Marrow blasts (score 0-2.0) • Karyotype (score 0-1.0) • Cytopenias: neutrophil, platelets, and Hg counts (score 0-0.5) The three individual scores are summed resulting in a full range of 0- 3.5 and placed into risk categories • 0 = low risk • 0.5-1.0 = intermediate-1 risk • 1.5-2.0 =intermediate-2 risk • >=2.5 = high risk This outcome was defined as a Kaplan-Meier estimate however few participants progressed so a Kaplan-Meier analysis could not be performed. Data reported represent event times (weeks) for participants who did progress to higher risk MDS categories.

End point type

Secondary

End point timeframe

Day 1 to 257.3 weeks

End point values	Sotatercept 0.1 mg/kg	Sotatercept 0.3 mg/kg	Sotatercept 0.5 mg/kg	Sotatercept 1.0 mg/kg	Sotatercept 2.0 mg/kg
Number of subjects analysed	1 ^[22]	0 ^[23]	1 ^[24]	1 ^[25]	0 ^[26]
Units: weeks
number (not applicable)	15.1		24.7	67.4

Notes
[22] - Efficacy Evaluable Population of participants who progressed to high risk MDS categories
[23] - Efficacy Evaluable Population of participants who progressed to high risk MDS categories
[24] - Efficacy Evaluable Population of participants who progressed to high risk MDS categories
[25] - Efficacy Evaluable Population of participants who progressed to high risk MDS categories
[26] - Efficacy Evaluable Population of participants who progressed to high risk MDS categories

No statistical analyses for this end point

Secondary: Kaplan-Meier Estimates for Progression-free Survival

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End point title

Kaplan-Meier Estimates for Progression-free Survival

End point description

Participants who had disease progression were considered to have events. Participants who died without acute myeloid leukemia (AML) were also considered to have events with the event date as the date of death. Those who did not have disease progression and who were lost to follow-up were censored at the last known disease progression assessment date. Participants without disease progression at the last follow-up contact were censored at the date of the last followup contact date. Disease Progression to AML used criteria by the International Working Group (IWG) Response Criteria in Myelodysplasia (Cheson, 2006). Progression is considered if any of the following are met: • >=50% increase in blasts • >=50% decrement from maximum remission/response levels in granulocytes or platelets • Reduction in hemoglobin (Hgb) concentration by >=2 g/dL • Transfusion dependence 9999 = not enough events to allow for calculation

End point type

Secondary

End point timeframe

Day 1 to 257.3 weeks

End point values	Sotatercept 0.1 mg/kg	Sotatercept 0.3 mg/kg	Sotatercept 0.5 mg/kg	Sotatercept 1.0 mg/kg	Sotatercept 2.0 mg/kg
Number of subjects analysed	7 ^[27]	6 ^[28]	21 ^[29]	35 ^[30]	5 ^[31]
Units: weeks
median (confidence interval 95%)	82.7 (15.1 to 82.7)	9999 (91.1 to 9999)	9999 (58.6 to 9999)	9999 (9999 to 9999)	9999 (79.9 to 9999)

Notes
[27] - Efficacy Evaluable Population
[28] - Efficacy Evaluable Population
[29] - Efficacy Evaluable Population
[30] - Efficacy Evaluable Population
[31] - Efficacy Evaluable Population

No statistical analyses for this end point

Secondary: Kaplan-Meier Estimates for Overall Survival (OS)

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End point title

Kaplan-Meier Estimates for Overall Survival (OS)

End point description

OS was defined as the time between start of treatment and the death/censored date. Participants who died (regardless of the cause of death) were considered to have an event. Participants who were alive at the end of the study, and participants who were lost to follow-up, were censored at the last date when subjects were known to be alive. 9999 = not enough events to allow for calculation

End point type

Secondary

End point timeframe

Day 1 to 257.3 weeks

End point values	Sotatercept 0.1 mg/kg	Sotatercept 0.3 mg/kg	Sotatercept 0.5 mg/kg	Sotatercept 1.0 mg/kg	Sotatercept 2.0 mg/kg
Number of subjects analysed	7 ^[32]	6 ^[33]	21 ^[34]	35 ^[35]	5 ^[36]
Units: weeks
median (confidence interval 95%)	82.7 (-9999 to 9999)	9999 (91.0 to 9999)	9999 (58.6 to 9999)	9999 (9999 to 9999)	9999 (79.1 to 9999)

Notes
[32] - Efficacy Evaluable Population
[33] - Efficacy Evaluable Population
[34] - Efficacy Evaluable Population
[35] - Efficacy Evaluable Population
[36] - Efficacy Evaluable Population

No statistical analyses for this end point

Secondary: Participants With Treatment-Emergent Adverse Events (TEAE)

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End point title

Participants With Treatment-Emergent Adverse Events (TEAE)

End point description

An adverse event (AE) is any noxious, unintended, or untoward medical occurrence that may appear or worsen in a subject during the course of a study. Treatment-emergent adverse events (TEAEs) are defined as any AE occurring or worsening on or after the first treatment of the study medication and within 42 days after the last dose. The severity of AEs was graded based on National Cancer Institute Common Terminology Criteria for Adverse Events (CTCAE), Version 4.0 and the scale: Grade 1 = Mild Grade 2 = Moderate Grade 3 = Severe Grade 4 = Life threatening Grade 5 = Death. Relation to study drug was determined by the investigator. A treatment-related TEAE is defined as TEAE which was considered to be related to the study drug and reported as 'Suspected' on the CRF. AEs with a missing relationship were treated as 'treatment-related' in data summaries.

End point type

Secondary

End point timeframe

Day 1 up to 59.2 months

End point values	Sotatercept 0.1 mg/kg	Sotatercept 0.3 mg/kg	Sotatercept 0.5 mg/kg	Sotatercept 1.0 mg/kg	Sotatercept 2.0 mg/kg
Number of subjects analysed	7 ^[37]	6 ^[38]	21 ^[39]	35 ^[40]	5 ^[41]
Units: participants
>= 1 Treatment-emergent adverse event (TEAE)	6	4	20	34	5
>=1 Treatment-related TEAE	2	3	7	18	4
>=1 Serious TEAE	1	2	6	10	2
>=1 Serious TEAE related to treatment	0	0	0	0	1
>=1 TEAE severity 3 or 4	1	2	9	13	2
>=1 TEAE severity grade 3/4 related to treatment	0	0	1	0	1
>=1 TEAE leading to death	0	1	0	0	0
>=1 TEAE leading to dose reduction	0	0	0	0	0
>=1 TEAE leading to dose interruption	0	1	2	9	1
>=1 TEAE leading to dose interruption + reduction	0	0	0	1	0
>= 1 TEAE leading to drug discontinuation	0	2	2	3	2

Notes
[37] - Safety population
[38] - Safety population
[39] - Safety population
[40] - Safety population
[41] - Safety population

No statistical analyses for this end point

Secondary: Percentage of Participants Who Achieved Red Blood Cell (RBC)-Transfusion Independence During the Erythroid Hematological Improvement (HI-E) Interval

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End point title

Percentage of Participants Who Achieved Red Blood Cell (RBC)-Transfusion Independence During the Erythroid Hematological Improvement (HI-E) Interval

End point description

Percentage of participants who achieved RBC-independence was defined as participants who required no RBC transfusions during a 56-day interval of erythroid hematological improvement (HI-E). NTDE = nonntransfusion dependence efficacy participants who required < 4 units of RBCs in the 8 weeks prior to start of therapy TDE = transfusion dependence efficacy participants who required >=4 units of RBCs in the 8 weeks prior to start of therapy

End point type

Secondary

End point timeframe

Day 2 - 142

End point values	Sotatercept 0.1 mg/kg	Sotatercept 0.3 mg/kg	Sotatercept 0.5 mg/kg	Sotatercept 1.0 mg/kg	Sotatercept 2.0 mg/kg
Number of subjects analysed	7 ^[42]	6 ^[43]	21 ^[44]	35 ^[45]	5 ^[46]
Units: percent of participants
number (not applicable)
All subjects	0	1	3	15	1
NTDE subpopulation	0	0	1	6	1
TDE subpopulation	0	1	2	9	0

Notes
[42] - All = 7 participants NTDE = 0 participants TDE = 7 participants
[43] - All = 6 participants NTDE = 0 participants TDE = 6 participants
[44] - All = 21 participants NTDE = 3 participants TDE = 18 participants
[45] - All = 35 participants NTDE = 8 participants TDE = 27 participants
[46] - All = 5 participants NTDE = 1 participants TDE = 4 participants

No statistical analyses for this end point

Adverse events

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Timeframe for reporting adverse events

Day 1 up to 60.7 months

Assessment type

Systematic

Dictionary name

MedDRA

Dictionary version

21.0

Reporting group title

Sotatercept 0.1 mg/kg

Reporting group description

Reporting group title

Sotatercept 0.3 mg/kg

Reporting group description

Reporting group title

Sotatercept 0.5 mg/kg

Reporting group description

Sotatercept 0.5 mg/kg administered via subcutaneous injection every third week (Q3W). Participants were randomized to one of the active treatment arms. Efficacy and safety data were assessed by a Steering Committee. Based upon the occurrence of dose-limiting toxicity (DLT) in ≤ 1/6 subjects in Cycle 1 in the 0.5 mg/ kg treatment group, the 1.0 mg/kg treatment group began inclusion in the randomization scheme.

Reporting group title

Sotatercept 1.0 mg/kg

Reporting group description

Sotatercept 1.0 mg/kg administered via subcutaneous injection every third week (Q3W). Participants were randomized to one of the active treatment arms. Efficacy and safety data were assessed by a Steering Committee. Based upon the occurrence of dose-limiting toxicity (DLT) in ≤ 1/6 subjects in Cycle 1 in the 1.0 mg/ kg treatment group, the 2.0 mg/kg treatment group began inclusion in the randomization scheme. Following evaluation of all treatment group data by the Steering Committee, enrollment continued only in the 1.0 mg/kg arm because the arm had the greatest frequency of erythroid hematological improvement (HI-E).

Reporting group title

Sotatercept 2.0 mg/kg

Reporting group description

Serious adverse events	Sotatercept 0.1 mg/kg	Sotatercept 0.3 mg/kg	Sotatercept 0.5 mg/kg	Sotatercept 1.0 mg/kg	Sotatercept 2.0 mg/kg
Total subjects affected by serious adverse events
subjects affected / exposed	1 / 7 (14.29%)	2 / 6 (33.33%)	6 / 21 (28.57%)	10 / 35 (28.57%)	2 / 5 (40.00%)
number of deaths (all causes)	0	1	0	0	0
number of deaths resulting from adverse events	0	0	0	0	0
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Basal cell carcinoma
subjects affected / exposed	0 / 7 (0.00%)	0 / 6 (0.00%)	1 / 21 (4.76%)	0 / 35 (0.00%)	0 / 5 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Vascular disorders
Aortic stenosis
subjects affected / exposed	0 / 7 (0.00%)	1 / 6 (16.67%)	0 / 21 (0.00%)	0 / 35 (0.00%)	0 / 5 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Hypotension
subjects affected / exposed	0 / 7 (0.00%)	0 / 6 (0.00%)	1 / 21 (4.76%)	0 / 35 (0.00%)	0 / 5 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
General disorders and administration site conditions
Mass
subjects affected / exposed	0 / 7 (0.00%)	0 / 6 (0.00%)	1 / 21 (4.76%)	0 / 35 (0.00%)	0 / 5 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Non-cardiac chest pain
subjects affected / exposed	0 / 7 (0.00%)	0 / 6 (0.00%)	1 / 21 (4.76%)	0 / 35 (0.00%)	0 / 5 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Pyrexia
subjects affected / exposed	0 / 7 (0.00%)	0 / 6 (0.00%)	1 / 21 (4.76%)	0 / 35 (0.00%)	0 / 5 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Respiratory, thoracic and mediastinal disorders
Hypoxia
subjects affected / exposed	0 / 7 (0.00%)	0 / 6 (0.00%)	0 / 21 (0.00%)	1 / 35 (2.86%)	0 / 5 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Psychiatric disorders
Delirium
subjects affected / exposed	0 / 7 (0.00%)	0 / 6 (0.00%)	1 / 21 (4.76%)	0 / 35 (0.00%)	0 / 5 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Investigations
Blood pressure increased
subjects affected / exposed	0 / 7 (0.00%)	0 / 6 (0.00%)	0 / 21 (0.00%)	0 / 35 (0.00%)	1 / 5 (20.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
International normalised ratio increased
subjects affected / exposed	0 / 7 (0.00%)	0 / 6 (0.00%)	1 / 21 (4.76%)	0 / 35 (0.00%)	0 / 5 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Injury, poisoning and procedural complications
Hip fracture
subjects affected / exposed	0 / 7 (0.00%)	0 / 6 (0.00%)	2 / 21 (9.52%)	0 / 35 (0.00%)	0 / 5 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 2	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Spinal compression fracture
subjects affected / exposed	0 / 7 (0.00%)	0 / 6 (0.00%)	0 / 21 (0.00%)	1 / 35 (2.86%)	0 / 5 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Spinal fracture
subjects affected / exposed	0 / 7 (0.00%)	0 / 6 (0.00%)	0 / 21 (0.00%)	1 / 35 (2.86%)	0 / 5 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 2	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Subdural haematoma
subjects affected / exposed	0 / 7 (0.00%)	1 / 6 (16.67%)	0 / 21 (0.00%)	0 / 35 (0.00%)	0 / 5 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 2	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0
Transfusion reaction
subjects affected / exposed	0 / 7 (0.00%)	0 / 6 (0.00%)	0 / 21 (0.00%)	0 / 35 (0.00%)	1 / 5 (20.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Cardiac disorders
Angina pectoris
subjects affected / exposed	0 / 7 (0.00%)	0 / 6 (0.00%)	0 / 21 (0.00%)	1 / 35 (2.86%)	0 / 5 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Nervous system disorders
Cerebrovascular accident
subjects affected / exposed	0 / 7 (0.00%)	0 / 6 (0.00%)	1 / 21 (4.76%)	0 / 35 (0.00%)	0 / 5 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Hemiparesis
subjects affected / exposed	0 / 7 (0.00%)	0 / 6 (0.00%)	1 / 21 (4.76%)	0 / 35 (0.00%)	0 / 5 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Blood and lymphatic system disorders
Anaemia
subjects affected / exposed	0 / 7 (0.00%)	0 / 6 (0.00%)	1 / 21 (4.76%)	0 / 35 (0.00%)	1 / 5 (20.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Gastrointestinal disorders
Colitis
subjects affected / exposed	0 / 7 (0.00%)	0 / 6 (0.00%)	0 / 21 (0.00%)	3 / 35 (8.57%)	0 / 5 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 3	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Large intestine perforation
subjects affected / exposed	0 / 7 (0.00%)	0 / 6 (0.00%)	0 / 21 (0.00%)	1 / 35 (2.86%)	0 / 5 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Hepatobiliary disorders
Cholangitis
subjects affected / exposed	0 / 7 (0.00%)	0 / 6 (0.00%)	0 / 21 (0.00%)	1 / 35 (2.86%)	0 / 5 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Cholelithiasis
subjects affected / exposed	0 / 7 (0.00%)	0 / 6 (0.00%)	1 / 21 (4.76%)	0 / 35 (0.00%)	0 / 5 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Skin and subcutaneous tissue disorders
Diabetic foot
subjects affected / exposed	0 / 7 (0.00%)	0 / 6 (0.00%)	0 / 21 (0.00%)	1 / 35 (2.86%)	0 / 5 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Renal and urinary disorders
Haematuria
subjects affected / exposed	0 / 7 (0.00%)	0 / 6 (0.00%)	0 / 21 (0.00%)	1 / 35 (2.86%)	0 / 5 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Musculoskeletal and connective tissue disorders
Osteoarthritis
subjects affected / exposed	0 / 7 (0.00%)	0 / 6 (0.00%)	1 / 21 (4.76%)	0 / 35 (0.00%)	0 / 5 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 3	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Infections and infestations
Bronchitis
subjects affected / exposed	1 / 7 (14.29%)	0 / 6 (0.00%)	0 / 21 (0.00%)	0 / 35 (0.00%)	0 / 5 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Clostridium difficile colitis
subjects affected / exposed	0 / 7 (0.00%)	0 / 6 (0.00%)	0 / 21 (0.00%)	1 / 35 (2.86%)	0 / 5 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Escherichia pyelonephritis
subjects affected / exposed	0 / 7 (0.00%)	0 / 6 (0.00%)	0 / 21 (0.00%)	1 / 35 (2.86%)	0 / 5 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Influenza
subjects affected / exposed	1 / 7 (14.29%)	0 / 6 (0.00%)	0 / 21 (0.00%)	0 / 35 (0.00%)	0 / 5 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Lung infection
subjects affected / exposed	0 / 7 (0.00%)	0 / 6 (0.00%)	0 / 21 (0.00%)	1 / 35 (2.86%)	0 / 5 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Peritoneal abscess
subjects affected / exposed	0 / 7 (0.00%)	0 / 6 (0.00%)	0 / 21 (0.00%)	1 / 35 (2.86%)	0 / 5 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Pneumonia
subjects affected / exposed	0 / 7 (0.00%)	1 / 6 (16.67%)	1 / 21 (4.76%)	0 / 35 (0.00%)	0 / 5 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 2	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0

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

Non-serious adverse events	Sotatercept 0.1 mg/kg	Sotatercept 0.3 mg/kg	Sotatercept 0.5 mg/kg	Sotatercept 1.0 mg/kg	Sotatercept 2.0 mg/kg
Total subjects affected by non serious adverse events
subjects affected / exposed	6 / 7 (85.71%)	4 / 6 (66.67%)	18 / 21 (85.71%)	32 / 35 (91.43%)	5 / 5 (100.00%)
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Basal cell carcinoma
subjects affected / exposed	0 / 7 (0.00%)	1 / 6 (16.67%)	0 / 21 (0.00%)	0 / 35 (0.00%)	0 / 5 (0.00%)
occurrences all number	0	1	0	0	0
Vascular disorders
Hypertension
subjects affected / exposed	0 / 7 (0.00%)	1 / 6 (16.67%)	2 / 21 (9.52%)	4 / 35 (11.43%)	1 / 5 (20.00%)
occurrences all number	0	1	3	6	1
Hypotension
subjects affected / exposed	0 / 7 (0.00%)	0 / 6 (0.00%)	1 / 21 (4.76%)	3 / 35 (8.57%)	0 / 5 (0.00%)
occurrences all number	0	0	1	4	0
General disorders and administration site conditions
Asthenia
subjects affected / exposed	0 / 7 (0.00%)	1 / 6 (16.67%)	3 / 21 (14.29%)	7 / 35 (20.00%)	0 / 5 (0.00%)
occurrences all number	0	1	6	28	0
Chest discomfort
subjects affected / exposed	1 / 7 (14.29%)	0 / 6 (0.00%)	0 / 21 (0.00%)	0 / 35 (0.00%)	0 / 5 (0.00%)
occurrences all number	1	0	0	0	0
Face oedema
subjects affected / exposed	0 / 7 (0.00%)	0 / 6 (0.00%)	0 / 21 (0.00%)	3 / 35 (8.57%)	0 / 5 (0.00%)
occurrences all number	0	0	0	4	0
Fatigue
subjects affected / exposed	0 / 7 (0.00%)	1 / 6 (16.67%)	6 / 21 (28.57%)	11 / 35 (31.43%)	1 / 5 (20.00%)
occurrences all number	0	9	13	16	1
Gait disturbance
subjects affected / exposed	0 / 7 (0.00%)	1 / 6 (16.67%)	0 / 21 (0.00%)	1 / 35 (2.86%)	0 / 5 (0.00%)
occurrences all number	0	1	0	1	0
Influenza like illness
subjects affected / exposed	0 / 7 (0.00%)	1 / 6 (16.67%)	0 / 21 (0.00%)	3 / 35 (8.57%)	0 / 5 (0.00%)
occurrences all number	0	1	0	4	0
Injection site reaction
subjects affected / exposed	0 / 7 (0.00%)	0 / 6 (0.00%)	0 / 21 (0.00%)	2 / 35 (5.71%)	0 / 5 (0.00%)
occurrences all number	0	0	0	2	0
Oedema
subjects affected / exposed	0 / 7 (0.00%)	0 / 6 (0.00%)	0 / 21 (0.00%)	1 / 35 (2.86%)	1 / 5 (20.00%)
occurrences all number	0	0	0	1	1
Oedema peripheral
subjects affected / exposed	2 / 7 (28.57%)	2 / 6 (33.33%)	6 / 21 (28.57%)	11 / 35 (31.43%)	0 / 5 (0.00%)
occurrences all number	2	3	10	19	0
Peripheral swelling
subjects affected / exposed	0 / 7 (0.00%)	0 / 6 (0.00%)	0 / 21 (0.00%)	1 / 35 (2.86%)	1 / 5 (20.00%)
occurrences all number	0	0	0	1	1
Pyrexia
subjects affected / exposed	0 / 7 (0.00%)	1 / 6 (16.67%)	4 / 21 (19.05%)	1 / 35 (2.86%)	1 / 5 (20.00%)
occurrences all number	0	1	4	1	1
Vessel puncture site swelling
subjects affected / exposed	0 / 7 (0.00%)	1 / 6 (16.67%)	0 / 21 (0.00%)	0 / 35 (0.00%)	0 / 5 (0.00%)
occurrences all number	0	1	0	0	0
Immune system disorders
Anaphylactic reaction
subjects affected / exposed	0 / 7 (0.00%)	1 / 6 (16.67%)	0 / 21 (0.00%)	0 / 35 (0.00%)	0 / 5 (0.00%)
occurrences all number	0	1	0	0	0
Reproductive system and breast disorders
Gynaecomastia
subjects affected / exposed	0 / 7 (0.00%)	1 / 6 (16.67%)	0 / 21 (0.00%)	0 / 35 (0.00%)	0 / 5 (0.00%)
occurrences all number	0	1	0	0	0
Respiratory, thoracic and mediastinal disorders
Cough
subjects affected / exposed	1 / 7 (14.29%)	1 / 6 (16.67%)	2 / 21 (9.52%)	6 / 35 (17.14%)	1 / 5 (20.00%)
occurrences all number	1	3	3	6	1
Dyspnoea
subjects affected / exposed	0 / 7 (0.00%)	1 / 6 (16.67%)	6 / 21 (28.57%)	2 / 35 (5.71%)	1 / 5 (20.00%)
occurrences all number	0	1	7	5	1
Dyspnoea exertional
subjects affected / exposed	0 / 7 (0.00%)	1 / 6 (16.67%)	1 / 21 (4.76%)	3 / 35 (8.57%)	0 / 5 (0.00%)
occurrences all number	0	2	1	8	0
Epistaxis
subjects affected / exposed	0 / 7 (0.00%)	0 / 6 (0.00%)	0 / 21 (0.00%)	8 / 35 (22.86%)	1 / 5 (20.00%)
occurrences all number	0	0	0	11	1
Hypoxia
subjects affected / exposed	0 / 7 (0.00%)	1 / 6 (16.67%)	0 / 21 (0.00%)	0 / 35 (0.00%)	0 / 5 (0.00%)
occurrences all number	0	1	0	0	0
Nasal congestion
subjects affected / exposed	0 / 7 (0.00%)	0 / 6 (0.00%)	1 / 21 (4.76%)	2 / 35 (5.71%)	0 / 5 (0.00%)
occurrences all number	0	0	1	2	0
Rhinorrhoea
subjects affected / exposed	0 / 7 (0.00%)	0 / 6 (0.00%)	0 / 21 (0.00%)	0 / 35 (0.00%)	1 / 5 (20.00%)
occurrences all number	0	0	0	0	1
Upper-airway cough syndrome
subjects affected / exposed	0 / 7 (0.00%)	0 / 6 (0.00%)	2 / 21 (9.52%)	1 / 35 (2.86%)	0 / 5 (0.00%)
occurrences all number	0	0	2	1	0
Psychiatric disorders
Anxiety
subjects affected / exposed	0 / 7 (0.00%)	0 / 6 (0.00%)	1 / 21 (4.76%)	4 / 35 (11.43%)	0 / 5 (0.00%)
occurrences all number	0	0	1	4	0
Confusional state
subjects affected / exposed	0 / 7 (0.00%)	1 / 6 (16.67%)	1 / 21 (4.76%)	0 / 35 (0.00%)	0 / 5 (0.00%)
occurrences all number	0	1	2	0	0
Depression
subjects affected / exposed	0 / 7 (0.00%)	0 / 6 (0.00%)	1 / 21 (4.76%)	3 / 35 (8.57%)	0 / 5 (0.00%)
occurrences all number	0	0	1	3	0
Insomnia
subjects affected / exposed	0 / 7 (0.00%)	0 / 6 (0.00%)	1 / 21 (4.76%)	3 / 35 (8.57%)	0 / 5 (0.00%)
occurrences all number	0	0	1	4	0
Investigations
Alanine aminotransferase increased
subjects affected / exposed	0 / 7 (0.00%)	0 / 6 (0.00%)	3 / 21 (14.29%)	3 / 35 (8.57%)	0 / 5 (0.00%)
occurrences all number	0	0	3	3	0
Aspartate aminotransferase increased
subjects affected / exposed	0 / 7 (0.00%)	0 / 6 (0.00%)	4 / 21 (19.05%)	5 / 35 (14.29%)	0 / 5 (0.00%)
occurrences all number	0	0	4	5	0
Blood alkaline phosphatase increased
subjects affected / exposed	0 / 7 (0.00%)	0 / 6 (0.00%)	1 / 21 (4.76%)	2 / 35 (5.71%)	0 / 5 (0.00%)
occurrences all number	0	0	1	2	0
Blood bilirubin increased
subjects affected / exposed	0 / 7 (0.00%)	0 / 6 (0.00%)	0 / 21 (0.00%)	2 / 35 (5.71%)	0 / 5 (0.00%)
occurrences all number	0	0	0	3	0
Blood creatinine increased
subjects affected / exposed	0 / 7 (0.00%)	1 / 6 (16.67%)	0 / 21 (0.00%)	3 / 35 (8.57%)	1 / 5 (20.00%)
occurrences all number	0	1	0	5	1
Creatinine renal clearance decreased
subjects affected / exposed	0 / 7 (0.00%)	1 / 6 (16.67%)	0 / 21 (0.00%)	0 / 35 (0.00%)	0 / 5 (0.00%)
occurrences all number	0	1	0	0	0
Lipase increased
subjects affected / exposed	0 / 7 (0.00%)	0 / 6 (0.00%)	2 / 21 (9.52%)	1 / 35 (2.86%)	0 / 5 (0.00%)
occurrences all number	0	0	2	1	0
Neutrophil count decreased
subjects affected / exposed	0 / 7 (0.00%)	0 / 6 (0.00%)	0 / 21 (0.00%)	0 / 35 (0.00%)	1 / 5 (20.00%)
occurrences all number	0	0	0	0	2
Platelet count decreased
subjects affected / exposed	0 / 7 (0.00%)	0 / 6 (0.00%)	2 / 21 (9.52%)	0 / 35 (0.00%)	1 / 5 (20.00%)
occurrences all number	0	0	7	0	1
Injury, poisoning and procedural complications
Contusion
subjects affected / exposed	0 / 7 (0.00%)	0 / 6 (0.00%)	0 / 21 (0.00%)	2 / 35 (5.71%)	0 / 5 (0.00%)
occurrences all number	0	0	0	2	0
Fall
subjects affected / exposed	0 / 7 (0.00%)	2 / 6 (33.33%)	1 / 21 (4.76%)	1 / 35 (2.86%)	0 / 5 (0.00%)
occurrences all number	0	3	1	5	0
Muscle strain
subjects affected / exposed	0 / 7 (0.00%)	1 / 6 (16.67%)	0 / 21 (0.00%)	0 / 35 (0.00%)	0 / 5 (0.00%)
occurrences all number	0	1	0	0	0
Skin abrasion
subjects affected / exposed	0 / 7 (0.00%)	1 / 6 (16.67%)	0 / 21 (0.00%)	0 / 35 (0.00%)	0 / 5 (0.00%)
occurrences all number	0	1	0	0	0
Spinal compression fracture
subjects affected / exposed	0 / 7 (0.00%)	0 / 6 (0.00%)	0 / 21 (0.00%)	2 / 35 (5.71%)	0 / 5 (0.00%)
occurrences all number	0	0	0	2	0
Tooth fracture
subjects affected / exposed	0 / 7 (0.00%)	0 / 6 (0.00%)	0 / 21 (0.00%)	2 / 35 (5.71%)	0 / 5 (0.00%)
occurrences all number	0	0	0	2	0
Cardiac disorders
Sinus tachycardia
subjects affected / exposed	0 / 7 (0.00%)	0 / 6 (0.00%)	0 / 21 (0.00%)	1 / 35 (2.86%)	1 / 5 (20.00%)
occurrences all number	0	0	0	1	1
Nervous system disorders
Ataxia
subjects affected / exposed	1 / 7 (14.29%)	0 / 6 (0.00%)	0 / 21 (0.00%)	0 / 35 (0.00%)	0 / 5 (0.00%)
occurrences all number	1	0	0	0	0
Dizziness
subjects affected / exposed	1 / 7 (14.29%)	2 / 6 (33.33%)	1 / 21 (4.76%)	6 / 35 (17.14%)	2 / 5 (40.00%)
occurrences all number	1	3	1	7	2
Dysgeusia
subjects affected / exposed	0 / 7 (0.00%)	0 / 6 (0.00%)	1 / 21 (4.76%)	3 / 35 (8.57%)	0 / 5 (0.00%)
occurrences all number	0	0	1	3	0
Headache
subjects affected / exposed	3 / 7 (42.86%)	1 / 6 (16.67%)	4 / 21 (19.05%)	5 / 35 (14.29%)	1 / 5 (20.00%)
occurrences all number	3	2	4	8	1
Paraesthesia
subjects affected / exposed	0 / 7 (0.00%)	0 / 6 (0.00%)	0 / 21 (0.00%)	2 / 35 (5.71%)	0 / 5 (0.00%)
occurrences all number	0	0	0	2	0
Blood and lymphatic system disorders
Anaemia
subjects affected / exposed	0 / 7 (0.00%)	0 / 6 (0.00%)	0 / 21 (0.00%)	2 / 35 (5.71%)	0 / 5 (0.00%)
occurrences all number	0	0	0	5	0
Haemolytic anaemia
subjects affected / exposed	0 / 7 (0.00%)	1 / 6 (16.67%)	0 / 21 (0.00%)	0 / 35 (0.00%)	0 / 5 (0.00%)
occurrences all number	0	1	0	0	0
Leukocytosis
subjects affected / exposed	0 / 7 (0.00%)	1 / 6 (16.67%)	0 / 21 (0.00%)	0 / 35 (0.00%)	0 / 5 (0.00%)
occurrences all number	0	1	0	0	0
Neutropenia
subjects affected / exposed	0 / 7 (0.00%)	0 / 6 (0.00%)	2 / 21 (9.52%)	1 / 35 (2.86%)	1 / 5 (20.00%)
occurrences all number	0	0	5	4	4
Thrombocytopenia
subjects affected / exposed	1 / 7 (14.29%)	0 / 6 (0.00%)	2 / 21 (9.52%)	1 / 35 (2.86%)	1 / 5 (20.00%)
occurrences all number	1	0	8	1	1
Ear and labyrinth disorders
Ear pain
subjects affected / exposed	0 / 7 (0.00%)	0 / 6 (0.00%)	0 / 21 (0.00%)	2 / 35 (5.71%)	0 / 5 (0.00%)
occurrences all number	0	0	0	2	0
Vertigo
subjects affected / exposed	0 / 7 (0.00%)	0 / 6 (0.00%)	1 / 21 (4.76%)	2 / 35 (5.71%)	0 / 5 (0.00%)
occurrences all number	0	0	1	2	0
Eye disorders
Eye haemorrhage
subjects affected / exposed	0 / 7 (0.00%)	1 / 6 (16.67%)	0 / 21 (0.00%)	0 / 35 (0.00%)	0 / 5 (0.00%)
occurrences all number	0	1	0	0	0
Eye inflammation
subjects affected / exposed	0 / 7 (0.00%)	0 / 6 (0.00%)	0 / 21 (0.00%)	0 / 35 (0.00%)	1 / 5 (20.00%)
occurrences all number	0	0	0	0	1
Eyelid oedema
subjects affected / exposed	0 / 7 (0.00%)	0 / 6 (0.00%)	0 / 21 (0.00%)	2 / 35 (5.71%)	0 / 5 (0.00%)
occurrences all number	0	0	0	2	0
Lacrimation increased
subjects affected / exposed	0 / 7 (0.00%)	1 / 6 (16.67%)	2 / 21 (9.52%)	0 / 35 (0.00%)	0 / 5 (0.00%)
occurrences all number	0	1	2	0	0
Vitreous floaters
subjects affected / exposed	1 / 7 (14.29%)	0 / 6 (0.00%)	0 / 21 (0.00%)	0 / 35 (0.00%)	0 / 5 (0.00%)
occurrences all number	1	0	0	0	0
Gastrointestinal disorders
Abdominal discomfort
subjects affected / exposed	0 / 7 (0.00%)	1 / 6 (16.67%)	0 / 21 (0.00%)	0 / 35 (0.00%)	0 / 5 (0.00%)
occurrences all number	0	1	0	0	0
Abdominal pain
subjects affected / exposed	0 / 7 (0.00%)	0 / 6 (0.00%)	2 / 21 (9.52%)	5 / 35 (14.29%)	0 / 5 (0.00%)
occurrences all number	0	0	2	9	0
Abdominal pain upper
subjects affected / exposed	1 / 7 (14.29%)	0 / 6 (0.00%)	0 / 21 (0.00%)	4 / 35 (11.43%)	0 / 5 (0.00%)
occurrences all number	1	0	0	4	0
Constipation
subjects affected / exposed	0 / 7 (0.00%)	1 / 6 (16.67%)	6 / 21 (28.57%)	3 / 35 (8.57%)	0 / 5 (0.00%)
occurrences all number	0	1	7	4	0
Diarrhoea
subjects affected / exposed	0 / 7 (0.00%)	2 / 6 (33.33%)	7 / 21 (33.33%)	9 / 35 (25.71%)	2 / 5 (40.00%)
occurrences all number	0	5	7	17	3
Dry mouth
subjects affected / exposed	0 / 7 (0.00%)	0 / 6 (0.00%)	0 / 21 (0.00%)	2 / 35 (5.71%)	1 / 5 (20.00%)
occurrences all number	0	0	0	2	1
Dyspepsia
subjects affected / exposed	0 / 7 (0.00%)	0 / 6 (0.00%)	0 / 21 (0.00%)	2 / 35 (5.71%)	0 / 5 (0.00%)
occurrences all number	0	0	0	3	0
Nausea
subjects affected / exposed	0 / 7 (0.00%)	1 / 6 (16.67%)	4 / 21 (19.05%)	8 / 35 (22.86%)	2 / 5 (40.00%)
occurrences all number	0	2	4	15	2
Salivary gland enlargement
subjects affected / exposed	0 / 7 (0.00%)	1 / 6 (16.67%)	0 / 21 (0.00%)	0 / 35 (0.00%)	0 / 5 (0.00%)
occurrences all number	0	1	0	0	0
Stomatitis
subjects affected / exposed	1 / 7 (14.29%)	1 / 6 (16.67%)	1 / 21 (4.76%)	0 / 35 (0.00%)	0 / 5 (0.00%)
occurrences all number	1	1	1	0	0
Toothache
subjects affected / exposed	1 / 7 (14.29%)	0 / 6 (0.00%)	0 / 21 (0.00%)	1 / 35 (2.86%)	0 / 5 (0.00%)
occurrences all number	1	0	0	1	0
Vomiting
subjects affected / exposed	0 / 7 (0.00%)	1 / 6 (16.67%)	3 / 21 (14.29%)	9 / 35 (25.71%)	1 / 5 (20.00%)
occurrences all number	0	1	4	14	4
Skin and subcutaneous tissue disorders
Dry skin
subjects affected / exposed	0 / 7 (0.00%)	0 / 6 (0.00%)	0 / 21 (0.00%)	0 / 35 (0.00%)	1 / 5 (20.00%)
occurrences all number	0	0	0	0	1
Ecchymosis
subjects affected / exposed	0 / 7 (0.00%)	1 / 6 (16.67%)	0 / 21 (0.00%)	1 / 35 (2.86%)	0 / 5 (0.00%)
occurrences all number	0	1	0	1	0
Pruritus
subjects affected / exposed	1 / 7 (14.29%)	1 / 6 (16.67%)	1 / 21 (4.76%)	4 / 35 (11.43%)	0 / 5 (0.00%)
occurrences all number	1	1	1	4	0
Pruritus generalised
subjects affected / exposed	0 / 7 (0.00%)	0 / 6 (0.00%)	0 / 21 (0.00%)	2 / 35 (5.71%)	0 / 5 (0.00%)
occurrences all number	0	0	0	2	0
Rash
subjects affected / exposed	0 / 7 (0.00%)	0 / 6 (0.00%)	2 / 21 (9.52%)	3 / 35 (8.57%)	0 / 5 (0.00%)
occurrences all number	0	0	2	3	0
Skin lesion
subjects affected / exposed	0 / 7 (0.00%)	1 / 6 (16.67%)	0 / 21 (0.00%)	1 / 35 (2.86%)	0 / 5 (0.00%)
occurrences all number	0	1	0	1	0
Renal and urinary disorders
Pollakiuria
subjects affected / exposed	0 / 7 (0.00%)	0 / 6 (0.00%)	2 / 21 (9.52%)	0 / 35 (0.00%)	0 / 5 (0.00%)
occurrences all number	0	0	2	0	0
Proteinuria
subjects affected / exposed	0 / 7 (0.00%)	0 / 6 (0.00%)	0 / 21 (0.00%)	2 / 35 (5.71%)	0 / 5 (0.00%)
occurrences all number	0	0	0	3	0
Musculoskeletal and connective tissue disorders
Arthralgia
subjects affected / exposed	0 / 7 (0.00%)	0 / 6 (0.00%)	2 / 21 (9.52%)	4 / 35 (11.43%)	0 / 5 (0.00%)
occurrences all number	0	0	2	8	0
Arthritis
subjects affected / exposed	0 / 7 (0.00%)	0 / 6 (0.00%)	1 / 21 (4.76%)	0 / 35 (0.00%)	1 / 5 (20.00%)
occurrences all number	0	0	1	0	1
Back pain
subjects affected / exposed	1 / 7 (14.29%)	1 / 6 (16.67%)	1 / 21 (4.76%)	4 / 35 (11.43%)	1 / 5 (20.00%)
occurrences all number	1	2	1	7	2
Muscle spasms
subjects affected / exposed	0 / 7 (0.00%)	0 / 6 (0.00%)	2 / 21 (9.52%)	2 / 35 (5.71%)	0 / 5 (0.00%)
occurrences all number	0	0	3	2	0
Muscular weakness
subjects affected / exposed	0 / 7 (0.00%)	0 / 6 (0.00%)	1 / 21 (4.76%)	3 / 35 (8.57%)	0 / 5 (0.00%)
occurrences all number	0	0	1	3	0
Musculoskeletal chest pain
subjects affected / exposed	0 / 7 (0.00%)	0 / 6 (0.00%)	1 / 21 (4.76%)	2 / 35 (5.71%)	0 / 5 (0.00%)
occurrences all number	0	0	2	2	0
Myalgia
subjects affected / exposed	0 / 7 (0.00%)	1 / 6 (16.67%)	2 / 21 (9.52%)	2 / 35 (5.71%)	0 / 5 (0.00%)
occurrences all number	0	1	2	2	0
Neck pain
subjects affected / exposed	0 / 7 (0.00%)	0 / 6 (0.00%)	0 / 21 (0.00%)	1 / 35 (2.86%)	1 / 5 (20.00%)
occurrences all number	0	0	0	1	1
Osteoarthritis
subjects affected / exposed	0 / 7 (0.00%)	0 / 6 (0.00%)	1 / 21 (4.76%)	2 / 35 (5.71%)	0 / 5 (0.00%)
occurrences all number	0	0	2	7	0
Osteopenia
subjects affected / exposed	0 / 7 (0.00%)	1 / 6 (16.67%)	0 / 21 (0.00%)	1 / 35 (2.86%)	0 / 5 (0.00%)
occurrences all number	0	1	0	1	0
Pain in extremity
subjects affected / exposed	0 / 7 (0.00%)	1 / 6 (16.67%)	3 / 21 (14.29%)	4 / 35 (11.43%)	1 / 5 (20.00%)
occurrences all number	0	1	3	16	2
Infections and infestations
Bronchitis
subjects affected / exposed	0 / 7 (0.00%)	0 / 6 (0.00%)	1 / 21 (4.76%)	3 / 35 (8.57%)	0 / 5 (0.00%)
occurrences all number	0	0	2	3	0
Laryngitis
subjects affected / exposed	0 / 7 (0.00%)	0 / 6 (0.00%)	0 / 21 (0.00%)	0 / 35 (0.00%)	1 / 5 (20.00%)
occurrences all number	0	0	0	0	1
Nasopharyngitis
subjects affected / exposed	0 / 7 (0.00%)	1 / 6 (16.67%)	0 / 21 (0.00%)	0 / 35 (0.00%)	0 / 5 (0.00%)
occurrences all number	0	1	0	0	0
Pharyngitis
subjects affected / exposed	0 / 7 (0.00%)	0 / 6 (0.00%)	0 / 21 (0.00%)	2 / 35 (5.71%)	0 / 5 (0.00%)
occurrences all number	0	0	0	2	0
Pneumonia
subjects affected / exposed	0 / 7 (0.00%)	0 / 6 (0.00%)	2 / 21 (9.52%)	2 / 35 (5.71%)	0 / 5 (0.00%)
occurrences all number	0	0	2	2	0
Sinusitis
subjects affected / exposed	0 / 7 (0.00%)	0 / 6 (0.00%)	2 / 21 (9.52%)	4 / 35 (11.43%)	0 / 5 (0.00%)
occurrences all number	0	0	2	6	0
Tooth infection
subjects affected / exposed	0 / 7 (0.00%)	0 / 6 (0.00%)	0 / 21 (0.00%)	2 / 35 (5.71%)	0 / 5 (0.00%)
occurrences all number	0	0	0	2	0
Upper respiratory tract infection
subjects affected / exposed	0 / 7 (0.00%)	0 / 6 (0.00%)	1 / 21 (4.76%)	5 / 35 (14.29%)	0 / 5 (0.00%)
occurrences all number	0	0	1	9	0
Urinary tract infection
subjects affected / exposed	1 / 7 (14.29%)	0 / 6 (0.00%)	0 / 21 (0.00%)	4 / 35 (11.43%)	2 / 5 (40.00%)
occurrences all number	1	0	0	7	2
Metabolism and nutrition disorders
Decreased appetite
subjects affected / exposed	0 / 7 (0.00%)	0 / 6 (0.00%)	4 / 21 (19.05%)	8 / 35 (22.86%)	1 / 5 (20.00%)
occurrences all number	0	0	5	10	1
Dehydration
subjects affected / exposed	0 / 7 (0.00%)	0 / 6 (0.00%)	2 / 21 (9.52%)	3 / 35 (8.57%)	0 / 5 (0.00%)
occurrences all number	0	0	2	3	0
Hypercalcaemia
subjects affected / exposed	0 / 7 (0.00%)	0 / 6 (0.00%)	0 / 21 (0.00%)	2 / 35 (5.71%)	0 / 5 (0.00%)
occurrences all number	0	0	0	2	0
Hyperglycaemia
subjects affected / exposed	0 / 7 (0.00%)	0 / 6 (0.00%)	0 / 21 (0.00%)	2 / 35 (5.71%)	0 / 5 (0.00%)
occurrences all number	0	0	0	4	0
Hyperkalaemia
subjects affected / exposed	0 / 7 (0.00%)	1 / 6 (16.67%)	2 / 21 (9.52%)	2 / 35 (5.71%)	1 / 5 (20.00%)
occurrences all number	0	1	2	2	1
Hyperuricaemia
subjects affected / exposed	0 / 7 (0.00%)	0 / 6 (0.00%)	1 / 21 (4.76%)	2 / 35 (5.71%)	0 / 5 (0.00%)
occurrences all number	0	0	1	2	0
Hypoglycaemia
subjects affected / exposed	0 / 7 (0.00%)	1 / 6 (16.67%)	0 / 21 (0.00%)	0 / 35 (0.00%)	0 / 5 (0.00%)
occurrences all number	0	1	0	0	0
Iron overload
subjects affected / exposed	0 / 7 (0.00%)	0 / 6 (0.00%)	1 / 21 (4.76%)	2 / 35 (5.71%)	1 / 5 (20.00%)
occurrences all number	0	0	1	2	1

More information

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Were there any global substantial amendments to the protocol? Yes

12 Sep 2012

- Revision of protocol title and inclusion criteria to reflect the inclusion of CMML as a subclassification of the MDS/ myeloproliferative neoplasms subgroup as outlined in protocol Appendix A. -Revision of the DLT criteria, including Rules for Delay, Reduction and Discontinuation of Treatment (protocol Table 8) and Reasons for Discontinuation for: a. Hemoglobin > 12 g/dL, sustained for ≥ 7 days, confirmed by 2 assessments ≥ 1 week apart. b. Hypertension Grade ≥ 2 according to NCI-CTCAE version 4.0 (current active minor version), BP values must be confirmed by 2 readings obtained 5 minutes apart. c. Treatment-related (suspected) toxicity Grade ≥ 3. - Clarification of definition of favorable safety profile as a safe, tolerable, and effective dose of sotatercept that results in the greatest frequency of HI-E in subjects with anemia and low- or int-1 risk MDS. - Addition of specific early stopping criteria for an excess number of DLTs or the absence of efficacy within a dose cohort - Revision of inclusion criteria to: a. Only allow subjects requiring RBC transfusions to be eligible for the study b. Add language that females of child-bearing potential must agree to use effective contraception while participating in this study c. Add pregnancy prevention language for males participating in this study - Revision of exclusion criteria to exclude subjects with uncontrolled hypertension (SBP > 140 mm Hg or DBP ≥ 90 mm Hg). Controlled hypertension for this protocol was considered Grade ≤ 1 according to NCI-CTCAE version 4.0 (current active minor version) - Revision of Rules for Delay, Reduction and Discontinuation of Treatment Section to: a. Clarify discontinuation due to treatment-related (suspected) toxicity Grade ≥ 3 b. Clarify discontinuation due to treatment-related (suspected) toxicity Grade ≤ 2 that delays treatment by more than 3 months c. Provide dose reduction guidance for subjects who experience a rapid rise in Hgb .........

12 Feb 2013

- Added clarification related to the hypertension DLT definition to ensure harmonization of DLT assessment for hypertension across all study sites due to unique attributes of the study population - Provided clear parameters for Extension Period eligibility to offer flexibility for those subjects who do not meet protocol-defined HI-E to enter the Extension Period, at the investigator’s discretion, if clinical benefit was seen at the conclusion of the Treatment Period - Removed the Cycle 3 Day 1 mandatory MDS response assessment as it was deemed too soon after initiation of treatment of study drug - Continued to follow efficacy parameters (ie, Hgb and transfusions) for up to 3 months after the last dose of study drug or start of next treatment to assess potential late response after study drug discontinuation as was sometimes observed with ESAs - Modified the AE reporting period to 42 days after the last dose was administered. Beyond 42 days, all SAEs deemed suspected related to study drug will still be reported - Included chromosome del (5q) MDS patients who have failed on lenalidomide, intolerable to lenalidomide, or have other cytopenia precluding use of lenalidomide, as these patients could potentially benefit from treatment with sotatercept Increased the frequency of BP monitoring from once per cycle to weekly during the first 5 cycles of treatment, with the added flexibility of home monitoring - Addition of an Independent Cardiologist to the Steering Committee to focus on potential cardiovascular effects of the study drug - Increased the contraception use requirement for males after the last administration of study drug from 112 days to 7 months/210 days to account for the limited data on the study drug’s effect on spermatogenesis - Agreement on additional language related to clarification of the hypertension DLT definition ....

04 Aug 2013

- Additional dose levels were added beyond 0.5 mg/kg cohort (ie, 1.0 mg/kg SC Q3W and 2.0 mg/kg SQ Q3W), as 0.5 mg/kg may be subtherapeutic in study population - Additional safety measure was added to ensure adequate data were available and reviewed by the Steering Committee prior to all future dose escalation - Additional safety measure was added to allow potential exploration of intermediate dose levels (eg, 0.75 mg/kg and 1.5 mg/kg) at time of dose escalation to 1.0 mg/kg and 2.0 mg/kg respectively upon Steering Committee review of safety and efficacy data - Additional dose reduction levels were added to account for additional dose levels added beyond 0.5 mg/kg - New text was added to provide guidance to sites when total volume of calculated dose exceeds what was typically administered in 1 SC injection - New text consistent with previous rationale added to “Rationale for Study Design” section to account for addition of dose levels beyond 0.5 mg/kg - New text added related to timing of Steering Committee meetings to account for additional dose levels beyond 0.5 mg/kg - Additional guidance related to predose Hgb level prior to Cycle 1 Day 1 treatment administration for subjects who were deemed NTDE per protocol was provided - New text was added related to Steering Committee guidance on closure of treatment group to further enrollment due to lack of efficacy to minimize number of patients enrolled at subtherapeutic doses after their review of safety and efficacy data - New text was added to account for varying operational logistics at study sites related to timing of availability of predose Hgb result - Clarification on HI-E definition for subjects who were classified as NTDE per protocol - Clarification was added that hypertension DLT was confirmed by study investigator/clinical site at the clinical site and not based solely on a measurement taken at home by the subject or caretaker ....

03 Aug 2015

- Subjects in the sotatercept 2.0 mg/kg dosing group were dose reduced to sotatercept 1.5 mg/kg. Subsequent enrollment into this dosing group was at sotatercept 1.5 mg/kg; however, no subjects were enrolled at the 1.5 mg/kg starting dose level. - Enrollment into Part 2 (expansion) commenced without delay at a sotatercept dose level of 1.0 mg/kg - Language was added to include the availability of a roll-over protocol for subjects that remained on study following the analysis of all key endpoints and objectives of the study - A request for historic MDS molecular mutational analysis data, if available, was added - Recently published preclinical data was added - Addition of references related to recently published preclinical data - Updated data from the completed ACE-011-NSCL-001 study was added - Updated incidence of antisotatercept antibody data was added

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

http://www.ncbi.nlm.nih.gov/pubmed/29331635

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Clinical trials

Clinical Trial Results:
AN OPEN-LABEL, RANDOMIZED, PHASE 2, PARALLEL, DOSE-RANGING, MULTICENTER STUDY OF SOTATERCEPT FOR THE TREATMENT OF PATIENTS WITH ANEMIA AND LOW- OR INTERMEDIATE-1 RISK MYELODYSPLASTIC SYNDROMES OR NON-PROLIFERATIVE CHRONIC MYELOMONOCYTIC LEUKEMIA (CMML)

Trial information

Trial information

Subject disposition

Subject disposition

Baseline characteristics

Baseline characteristics

End points

End points

Primary: Percentage of Participants With Erythroid Hematological Improvement (HI-E) Starting Before the Completion of Five Cycles of Treatment (Responder Rate)

Primary: Percentage of Participants With Erythroid Hematological Improvement (HI-E) Starting Before the Completion of Five Cycles of Treatment (Responder Rate)

Secondary: Dose Limiting Toxicities (DLTs)

Secondary: Dose Limiting Toxicities (DLTs)

Secondary: Time to Erythroid Hematological Improvement (HI-E) Response

Secondary: Time to Erythroid Hematological Improvement (HI-E) Response

Secondary: Duration of Erythroid Hematological Improvement (HI-E)

Secondary: Duration of Erythroid Hematological Improvement (HI-E)

Secondary: Time to Progression to Acute Myeloid Leukemia (AML) for Participants Who Had Progression

Secondary: Time to Progression to Acute Myeloid Leukemia (AML) for Participants Who Had Progression

Secondary: Time to Progression to Events of Higher Risk Myelodysplastic Syndromes (MDS) Using the International Prognostic Scoring System (IPSS) For Participants Who Had Progression

Secondary: Time to Progression to Events of Higher Risk Myelodysplastic Syndromes (MDS) Using the International Prognostic Scoring System (IPSS) For Participants Who Had Progression

Secondary: Kaplan-Meier Estimates for Progression-free Survival

Secondary: Kaplan-Meier Estimates for Progression-free Survival

Secondary: Kaplan-Meier Estimates for Overall Survival (OS)

Secondary: Kaplan-Meier Estimates for Overall Survival (OS)

Secondary: Participants With Treatment-Emergent Adverse Events (TEAE)

Secondary: Participants With Treatment-Emergent Adverse Events (TEAE)

Secondary: Percentage of Participants Who Achieved Red Blood Cell (RBC)-Transfusion Independence During the Erythroid Hematological Improvement (HI-E) Interval

Secondary: Percentage of Participants Who Achieved Red Blood Cell (RBC)-Transfusion Independence During the Erythroid Hematological Improvement (HI-E) Interval

Adverse events

Adverse events

More information

Substantial protocol amendments (globally)

Interruptions (globally)

Limitations and caveats

Online references

More information

Austria
Belgium
Bulgaria
Croatia
Cyprus
Czechia
Denmark
Estonia
Finland
France
Germany
Greece
Hungary
Iceland
Ireland
Italy
Latvia
Liechtenstein
Lithuania
Luxembourg
Malta
Netherlands
Norway
Poland
Portugal
Romania
Slovakia
Slovenia
Spain
Sweden
United Kingdom
Outside EU/EEA

Clinical trials

Clinical Trial Results: AN OPEN-LABEL, RANDOMIZED, PHASE 2, PARALLEL, DOSE-RANGING, MULTICENTER STUDY OF SOTATERCEPT FOR THE TREATMENT OF PATIENTS WITH ANEMIA AND LOW- OR INTERMEDIATE-1 RISK MYELODYSPLASTIC SYNDROMES OR NON-PROLIFERATIVE CHRONIC MYELOMONOCYTIC LEUKEMIA (CMML)

Trial information

Trial information

Subject disposition

Subject disposition

Baseline characteristics

Baseline characteristics

End points

End points

Primary: Percentage of Participants With Erythroid Hematological Improvement (HI-E) Starting Before the Completion of Five Cycles of Treatment (Responder Rate)

Primary: Percentage of Participants With Erythroid Hematological Improvement (HI-E) Starting Before the Completion of Five Cycles of Treatment (Responder Rate)

Secondary: Dose Limiting Toxicities (DLTs)

Secondary: Dose Limiting Toxicities (DLTs)

Secondary: Time to Erythroid Hematological Improvement (HI-E) Response

Secondary: Time to Erythroid Hematological Improvement (HI-E) Response

Secondary: Duration of Erythroid Hematological Improvement (HI-E)

Secondary: Duration of Erythroid Hematological Improvement (HI-E)

Secondary: Time to Progression to Acute Myeloid Leukemia (AML) for Participants Who Had Progression

Secondary: Time to Progression to Acute Myeloid Leukemia (AML) for Participants Who Had Progression

Secondary: Time to Progression to Events of Higher Risk Myelodysplastic Syndromes (MDS) Using the International Prognostic Scoring System (IPSS) For Participants Who Had Progression

Secondary: Time to Progression to Events of Higher Risk Myelodysplastic Syndromes (MDS) Using the International Prognostic Scoring System (IPSS) For Participants Who Had Progression

Secondary: Kaplan-Meier Estimates for Progression-free Survival

Secondary: Kaplan-Meier Estimates for Progression-free Survival

Secondary: Kaplan-Meier Estimates for Overall Survival (OS)

Secondary: Kaplan-Meier Estimates for Overall Survival (OS)

Secondary: Participants With Treatment-Emergent Adverse Events (TEAE)

Secondary: Participants With Treatment-Emergent Adverse Events (TEAE)

Secondary: Percentage of Participants Who Achieved Red Blood Cell (RBC)-Transfusion Independence During the Erythroid Hematological Improvement (HI-E) Interval

Secondary: Percentage of Participants Who Achieved Red Blood Cell (RBC)-Transfusion Independence During the Erythroid Hematological Improvement (HI-E) Interval

Adverse events

Adverse events

More information

Substantial protocol amendments (globally)

Interruptions (globally)

Limitations and caveats

Online references

More information

Clinical Trial Results:
AN OPEN-LABEL, RANDOMIZED, PHASE 2, PARALLEL, DOSE-RANGING, MULTICENTER STUDY OF SOTATERCEPT FOR THE TREATMENT OF PATIENTS WITH ANEMIA AND LOW- OR INTERMEDIATE-1 RISK MYELODYSPLASTIC SYNDROMES OR NON-PROLIFERATIVE CHRONIC MYELOMONOCYTIC LEUKEMIA (CMML)