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Clinical Trial Results:
A Phase 2, Multicenter, Open-Label Study to Evaluate the Efficacy and Safety of Luspatercept (ACE-536) in Subjects With Myeloproliferative Neoplasm-Associated Myelofibrosis and Anemia With and Without Red Blood Cell-Transfusion Dependence

Summary
EudraCT number	2017-000322-35
Trial protocol	GB IT
Global end of trial date	18 Jul 2022

Results information
Results version number	v2(current)
This version publication date	07 Sep 2023
First version publication date	03 Aug 2023
Other versions	v1
Version creation reason

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-536-MF-001

ISRCTN number

US NCT number

NCT03194542

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

06 Sep 2022

Is this the analysis of the primary completion data?

Yes

Primary completion date

18 Jul 2022

Global end of trial reached?

Yes

Global end of trial date

18 Jul 2022

Was the trial ended prematurely?

Main objective of the trial

To evaluate the efficacy and safety of luspatercept for the treatment of anemia in subjects with MPN-associated myelofibrosis with and without RBC-transfusion dependence.

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

15 Nov 2017

Long term follow-up planned

Yes

Long term follow-up rationale

Safety

Long term follow-up duration

3 Years

Independent data monitoring committee (IDMC) involvement?

Number of subjects enrolled per country

Country: Number of subjects enrolled

France: 7

Country: Number of subjects enrolled

Italy: 29

Country: Number of subjects enrolled

United Kingdom: 11

Country: Number of subjects enrolled

United States: 48

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

The target study population included participants with myeloproliferative neoplasm (MPN)-associated myelofibrosis and anemia with and without RBC-transfusion dependence.

Screening details

95 participants were treated in this study.

Period 1 title

Overall Study (overall period)

Is this the baseline period?

Yes

Allocation method

Non-randomised - controlled

Blinding used

Not blinded

Are arms mutually exclusive

Yes

Cohort 1: Anemia Only

Arm description

Participants receive a starting dose level of luspatercept at 1.0 mg/kg subcutaneous injection every 3 weeks (administered on Day 1 of each 21-day treatment cycle). The starting dose can be titrated (increased) during the Treatment Period to 1.33 mg/kg, up to a maximum of 1.75 mg/kg, provided that the participant meets the appropriate criteria. The participant’s dose may also be delayed, reduced, or discontinued, depending on the specific criteria.

Arm type

Experimental

Investigational medicinal product name

Luspatercept

Investigational medicinal product code

Other name

Pharmaceutical forms

Powder for injection

Routes of administration

Subcutaneous use

Dosage and administration details

Administered on Day 1 of every 21-day cycle, at an initial dose level of 1.0 mg/kg. Participants may have the dose level increased in a stepwise manner beyond the starting dose level of 1.0 mg/kg to 1.33 mg/kg, and up to a maximum of 1.75 mg/kg (but no more than 168 mg) during the Treatment Period.

Cohort 2: RBC-Transfusion Dependent

Arm description

Arm type

Experimental

Investigational medicinal product name

Luspatercept

Investigational medicinal product code

Other name

Pharmaceutical forms

Powder for injection

Routes of administration

Subcutaneous use

Dosage and administration details

Cohort 3A: Anemia Only (Stable Dose-Ruxolitinib)

Arm description

Participants receive a starting dose level of luspatercept at 1.0 mg/kg subcutaneous injection every 3 weeks (administered on Day 1 of each 21-day treatment cycle) while being on a stable dose of ruxolitinib for at least 112 days immediately prior to the enrollment date. The starting dose can be titrated (increased) during the Treatment Period to 1.33 mg/kg, up to a maximum of 1.75 mg/kg, provided that the participant meets the appropriate criteria. The participant’s dose may also be delayed, reduced, or discontinued, depending on the specific criteria.

Arm type

Experimental

Investigational medicinal product name

Luspatercept

Investigational medicinal product code

Other name

Pharmaceutical forms

Powder for injection

Routes of administration

Subcutaneous use

Dosage and administration details

Cohort 3B: RBC-Transfusion Dependent (Stable Dose-Ruxolitinib)

Arm description

Arm type

Experimental

Investigational medicinal product name

Luspatercept

Investigational medicinal product code

Other name

Pharmaceutical forms

Powder for injection

Routes of administration

Subcutaneous use

Dosage and administration details

Number of subjects in period 1	Cohort 1: Anemia Only	Cohort 2: RBC-Transfusion Dependent	Cohort 3A: Anemia Only (Stable Dose-Ruxolitinib)	Cohort 3B: RBC-Transfusion Dependent (Stable Dose-Ruxolitinib)
Started	22	21	14	38
Completed	0	0	0	0
Not completed	22	21	14	38
Rollover to Long-term follow-up	1	1	-	5
Adverse event, serious fatal	1	2	-	5
Consent withdrawn by subject	2	1	5	4
Physician decision	-	1	-	-
Adverse event, non-fatal	1	2	-	5
Progressive Disease	1	-	1	1
Participant to Receive Bone Marrow Transplant	1	-	-	-
Per Protocol Repeat Blasts of 10%	1	-	1	-
Did not meet clinical benefit criteria	8	10	2	8
Loss of Response	4	2	3	4
Lack of efficacy	2	2	2	6

Baseline characteristics

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Reporting group title

Cohort 1: Anemia Only

Reporting group description

Reporting group title

Cohort 2: RBC-Transfusion Dependent

Reporting group description

Reporting group title

Cohort 3A: Anemia Only (Stable Dose-Ruxolitinib)

Reporting group description

Reporting group title

Cohort 3B: RBC-Transfusion Dependent (Stable Dose-Ruxolitinib)

Reporting group description

Reporting group values	Cohort 1: Anemia Only	Cohort 2: RBC-Transfusion Dependent	Cohort 3A: Anemia Only (Stable Dose-Ruxolitinib)	Cohort 3B: RBC-Transfusion Dependent (Stable Dose-Ruxolitinib)	Total
Number of subjects	22	21	14	38	95
Age categorical
Units: Subjects
Adults (18-64 years)	5	2	7	5	19
From 65-84 years	16	18	7	33	74
85 years and over	1	1	0	0	2
Age Continuous
Units: Years
arithmetic mean (standard deviation)	69 ( 8.87 )	73.9 ( 5.71 )	65.4 ( 8.45 )	71.3 ( 5.80 )	-
Sex: Female, Male
Units: Participants
Female	9	6	7	15	37
Male	13	15	7	23	58
Race (NIH/OMB)
Units: Subjects
American Indian or Alaska Native	0	0	0	0	0
Asian	2	1	3	1	7
Native Hawaiian or Other Pacific Islander	0	0	0	0	0
Black or African American	0	0	1	2	3
White	16	18	10	30	74
More than one race	0	0	0	0	0
Unknown or Not Reported	4	2	0	5	11
Ethnicity (NIH/OMB)
Units: Subjects
Hispanic or Latino	2	0	0	1	3
Not Hispanic or Latino	16	19	14	32	81
Unknown or Not Reported	4	2	0	5	11

End points

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Reporting group title

Cohort 1: Anemia Only

Reporting group description

Reporting group title

Cohort 2: RBC-Transfusion Dependent

Reporting group description

Reporting group title

Cohort 3A: Anemia Only (Stable Dose-Ruxolitinib)

Reporting group description

Reporting group title

Cohort 3B: RBC-Transfusion Dependent (Stable Dose-Ruxolitinib)

Reporting group description

Primary: The Number of Participants with Anemia Reponses over Any 84-Day Period During the Primary Treatment Period

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End point title

The Number of Participants with Anemia Reponses over Any 84-Day Period During the Primary Treatment Period ^[1]

End point description

The number of participants that achieved anemia response as it relates to hemoglobin (Hgb) increase and red blood cell (RBC)-transfusion independence is defined below: Cohorts 1 (anemia only) and 3A: The number of participants achieving ≥ 1.5 g/dL hemoglobin increase from baseline over any consecutive 84-day period without an RBC transfusion from Day 1 up through and including Day 168. Cohorts 2 (RBC-transfusion dependent) and 3B: The number of participants who become RBC-transfusion free over any consecutive 84-day period from Day 1 up through and including Day 168. Baseline value is defined as the last value (including “unscheduled”) measured on or before the first dose.

End point type

Primary

End point timeframe

Any consecutive “rolling” 84-day period from Day 1 through and including Day 168

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: Only summary statistics planned for this endpoint

End point values	Cohort 1: Anemia Only	Cohort 2: RBC-Transfusion Dependent	Cohort 3A: Anemia Only (Stable Dose-Ruxolitinib)	Cohort 3B: RBC-Transfusion Dependent (Stable Dose-Ruxolitinib)
Number of subjects analysed	22	21	14	38
Units: Participants	3	2	2	10

No statistical analyses for this end point

Secondary: Time to Anemia Response During the Primary Treatment Period

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End point title

Time to Anemia Response During the Primary Treatment Period

End point description

Time to anemia response follows the definitions below: Cohorts 1 (anemia only) and 3A: Time between first administration of luspatercept and the first hemoglobin increase of ≥ 1.5 g/dL from baseline that starts a consecutive 84-day period of consecutive increase ≥ 1.5 g/dL without RBC transfusions. Cohorts 2 (RBC-transfusion dependent) and 3B: Time between first administration of luspatercept and the first day of an RBC transfusion-free period of 84 days. Baseline value is defined as the last value (including “unscheduled”) measured on or before the first dose.

End point type

Secondary

End point timeframe

From first dose up to first onset of anemia response (calculated from Day 1 through and including Day 168)

End point values	Cohort 1: Anemia Only	Cohort 2: RBC-Transfusion Dependent	Cohort 3A: Anemia Only (Stable Dose-Ruxolitinib)	Cohort 3B: RBC-Transfusion Dependent (Stable Dose-Ruxolitinib)
Number of subjects analysed	3	2	2	10
Units: Days
arithmetic mean (standard deviation)	57.3 ( 14.36 )	2.0 ( 0.00 )	63.5 ( 30.41 )	30.7 ( 27.22 )

No statistical analyses for this end point

Secondary: Duration of Anemia Response

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End point title

Duration of Anemia Response

End point description

The duration of anemia response is defined as the duration of time from first day of longest response to the last day of longest response. Participants who achieved and maintained the anemia response at the time of the analysis are censored at the efficacy cutoff date. For Cohorts 1 and 3A, an anemia responder was defined as a subject with ≥ 1.5 g/dL hemoglobin increase from baseline over any consecutive 84-day period without an RBC transfusion. For Cohorts 2 and 3B, an anemia responder was defined as a subject who becomes RBC transfusion free over any consecutive 84-day period. Baseline value is defined as the last value (including “unscheduled”) measured on or before the first dose.

End point type

Secondary

End point timeframe

From first dose through last day of longest response (calculated from Day 1 through end of treatment, up to approximately 232 weeks)

End point values	Cohort 1: Anemia Only	Cohort 2: RBC-Transfusion Dependent	Cohort 3A: Anemia Only (Stable Dose-Ruxolitinib)	Cohort 3B: RBC-Transfusion Dependent (Stable Dose-Ruxolitinib)
Number of subjects analysed	3	2	2	10
Units: Days
arithmetic mean (standard deviation)	457.7 ( 611.20 )	623.0 ( 29.70 )	88.5 ( 6.36 )	534.7 ( 527.67 )

No statistical analyses for this end point

Secondary: The Number of RBC Units Transfused per Participant per 28 Days (Cohorts 2 and 3B Only)

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End point title

The Number of RBC Units Transfused per Participant per 28 Days (Cohorts 2 and 3B Only) ^[2]

End point description

Frequency of RBC transfusion is defined as the mean number of RBC units transfused per participant every 4 weeks (28 days). The primary treatment period is from Day 1 to and including Day 168. The entire treatment period is from Day 1 through the end of treatment.

End point type

Secondary

End point timeframe

From Day 1 through end of treatment (up to approximately 232 weeks).

Notes
[2] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: Endpoint is specific to certain study arms

End point values	Cohort 2: RBC-Transfusion Dependent	Cohort 3B: RBC-Transfusion Dependent (Stable Dose-Ruxolitinib)
Number of subjects analysed	21	38
Units: RBC Units
arithmetic mean (standard deviation)
Primary Treatment Period	2.76 ( 1.967 )	1.49 ( 1.345 )
Entire Treatment Period	2.70 ( 2.040 )	1.52 ( 1.365 )

No statistical analyses for this end point

Secondary: The Number Participants Achieving >=50% RBC Transfusion Burden Reduction from Baseline Over Any 84-Day Period (Cohorts 2 and 3B Only)

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End point title

The Number Participants Achieving >=50% RBC Transfusion Burden Reduction from Baseline Over Any 84-Day Period (Cohorts 2 and 3B Only) ^[3]

End point description

The number of participants who reduce their transfusion burden by ≥ 50% from baseline over any consecutive 84-day period. Baseline is defined as average number of RBC units per 28 days over the 84 days period on or prior to the C1D1 date. The primary treatment period is from Day 1 to and including Day 168. The entire treatment period is from Day 1 through the end of treatment.

End point type

Secondary

End point timeframe

Baseline and from Day 1 through end of treatment (up to approximately 232 weeks).

Notes
[3] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: Endpoint is specific to certain study arms

End point values	Cohort 2: RBC-Transfusion Dependent	Cohort 3B: RBC-Transfusion Dependent (Stable Dose-Ruxolitinib)
Number of subjects analysed	21	38
Units: Participants
Primary Treatment Period	10	19
Entire Treatment Period	10	20

No statistical analyses for this end point

Secondary: The Number of Participants who Achieve ≥ 50% Reduction in Fatigue Symptom as Measured by the Myeloproliferative Neoplasms Symptom Assessment Form Total Symptom Score (MPN-SAF TSS)

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End point title

The Number of Participants who Achieve ≥ 50% Reduction in Fatigue Symptom as Measured by the Myeloproliferative Neoplasms Symptom Assessment Form Total Symptom Score (MPN-SAF TSS)

End point description

Symptoms response improvement will be assessed using the number of participants who achieve ≥ 50% reduction in fatigue symptoms. Fatigue is 1 out of 10 total symptoms scored on a 0 (absent/as good as it can be) to 10 (worst imaginable/as bad as it can be). The primary treatment period is from Day 1 to and including Day 168. The entire treatment period is from Day 1 through the end of treatment. Baseline is defined as the last value on or before the first dose of study drug. Last Available = Last available assessment on or before the end of the treatment period. Mean = Mean value of the weekly assessments over the treatment period.

End point type

Secondary

End point timeframe

Baseline and from Day 1 through end of treatment (up to approximately 232 weeks)

End point values	Cohort 1: Anemia Only	Cohort 2: RBC-Transfusion Dependent	Cohort 3A: Anemia Only (Stable Dose-Ruxolitinib)	Cohort 3B: RBC-Transfusion Dependent (Stable Dose-Ruxolitinib)
Number of subjects analysed	22	21	14	38
Units: Participants
Primary Treatment Period (Last Available)	4	2	4	10
Entire Treatment Period (Last Available)	4	1	4	7
Primary Treatment Period (Mean)	5	1	3	5
Entire Treatment Period (Mean)	4	0	3	5

No statistical analyses for this end point

Secondary: Mean changes in the Functional Assessment of Cancer Therapy – Anemia (FACT-An) Total Scores Over the Study Compared to Baseline

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End point title

Mean changes in the Functional Assessment of Cancer Therapy – Anemia (FACT-An) Total Scores Over the Study Compared to Baseline

End point description

The Functional Assessment of Cancer Therapy – Anemia (FACT-An) questionnaire includes 47 items rating on a 5-point Likert scale from 0 (not at all) to 4 (very much) on five primary subscales: • Physical well-being (sum of 7 items, score range from 0-28) • Social/Family well-being (sum of 7 items, score range from 0-28) • Emotional well-being (sum of 6 items, score range from 0-24) • Functional well-being (sum of 7 items, score range from 0-28) • Anemia-related symptoms (sum of 20 items, score range from 0-80) A total score for the FACT-An can be calculated by summing the five primary subscales with a score range from 0-188. Higher scores representing better quality of life. Baseline is defined as the last value on or before the first dose of study drug.

End point type

Secondary

End point timeframe

Day 169 and End of treatment (up to approximately 232 weeks)

End point values	Cohort 1: Anemia Only	Cohort 2: RBC-Transfusion Dependent	Cohort 3A: Anemia Only (Stable Dose-Ruxolitinib)	Cohort 3B: RBC-Transfusion Dependent (Stable Dose-Ruxolitinib)
Number of subjects analysed	9 ^[4]	9 ^[5]	8 ^[6]	14 ^[7]
Units: Score on a scale
arithmetic mean (standard deviation)
Day 169	-10.4 ( 13.23 )	-15.7 ( 14.24 )	-9.4 ( 9.24 )	5.0 ( 21.77 )
End of Treatment	-15.9 ( 18.35 )	-16.6 ( 16.80 )	-12.6 ( 10.03 )	-14.2 ( 21.98 )

Notes
[4] - Day 169 (n= 9) End of Treatment (n=9)
[5] - Day 169 (n= 9) End of Treatment (n=8)
[6] - Day 169 (n= 5) End of Treatment (n=8)
[7] - Day 169 (n= 14) End of Treatment (n=14)

No statistical analyses for this end point

Secondary: The Number of Participants who Achieve ≥ 50% Reduction in Total Symptom Score (TSS) as Measured by the Myeloproliferative Neoplasms Symptom Assessment Form Total Symptom Score (MPN-SAF TSS)

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End point title

The Number of Participants who Achieve ≥ 50% Reduction in Total Symptom Score (TSS) as Measured by the Myeloproliferative Neoplasms Symptom Assessment Form Total Symptom Score (MPN-SAF TSS)

End point description

TSS includes 10 items - worst fatigue, concentration, early satiety, inactivity, night sweats, itching, bone pain, abdominal discomfort, weight loss, and fevers, scored on a 0 (absent/as good as it can be) to 10 (worst imaginable/as bad as it can be). For participants who completed at least six of these 10 items, the MPN-SAF TSS was computed as the average of the observed items multiplied by 10 to achieve a 0-to-100 scale. The MPN-SAF TSS thus had a possible range of 0 to 100. The primary treatment period is from Day 1 to and including Day 168. The entire treatment period is from Day 1 through the end of treatment. Baseline is defined as the last value on or before the first dose of study drug. Last Available = Last available assessment on or before the end of the treatment period. Mean = Mean value of the weekly assessments over the treatment period.

End point type

Secondary

End point timeframe

Baseline and from Day 1 through end of treatment (up to approximately 232 weeks)

End point values	Cohort 1: Anemia Only	Cohort 2: RBC-Transfusion Dependent	Cohort 3A: Anemia Only (Stable Dose-Ruxolitinib)	Cohort 3B: RBC-Transfusion Dependent (Stable Dose-Ruxolitinib)
Number of subjects analysed	22	21	14	38
Units: Participants
Primary Treatment Period (Last Available)	2	2	2	9
Entire Treatment Period (Last Available)	2	1	2	7
Primary Treatment Period (Mean)	2	2	3	6
Entire Treatment Period (Mean)	2	2	3	6

No statistical analyses for this end point

Secondary: Mean change in EQ-5D-5L Utility Score Compared to Baseline

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End point title

Mean change in EQ-5D-5L Utility Score Compared to Baseline

End point description

The European Quality of Life 5D-5L Scale (EQ-5D-5L) assesses general health-related quality of life. Health is defined in 5 dimensions: mobility, self-care, usual activities, pain/discomfort, and anxiety/depression. Each dimension has 5 levels: no problems, slight problems, moderate problems, severe problems, and extreme problems. Responses are coded so that a '1' indicates no problem, and '5' indicates the most serious problem. The responses for the 5 dimensions are combined in a 5-digit number. The EQ-5D-5L health utility index for this analysis will be derived using the United Kingdom (UK) value sets based on UK time trade-off (TTO) valuation techniques and will use the Decision Support Unit (DSU) model to cross-walk to the EQ-5D-3L value set from the UK to derive a single index value. The EQ-5D-3L health utility index based on the UK population weights range from -0.594 to 1.0 with higher scores indicating higher health utility.

End point type

Secondary

End point timeframe

Day 169 and End of treatment (up to approximately 232 weeks)

End point values	Cohort 1: Anemia Only	Cohort 2: RBC-Transfusion Dependent	Cohort 3A: Anemia Only (Stable Dose-Ruxolitinib)	Cohort 3B: RBC-Transfusion Dependent (Stable Dose-Ruxolitinib)
Number of subjects analysed	11 ^[8]	9 ^[9]	8 ^[10]	14 ^[11]
Units: Score on a scale
arithmetic mean (standard deviation)
Day 169	-0.043 ( 0.1466 )	-0.063 ( 0.1152 )	-0.126 ( 0.1246 )	0.005 ( 0.1084 )
End of Treatment	-0.029 ( 0.1029 )	-0.120 ( 0.1740 )	-0.129 ( 0.1812 )	-0.103 ( 0.2055 )

Notes
[8] - Day 169 (n= 11) End of Treatment (n=10)
[9] - Day 169 (n= 9) End of Treatment (n=9)
[10] - Day 169 (n= 6) End of Treatment (n=8)
[11] - Day 169 (n= 14) End of Treatment (n=12)

No statistical analyses for this end point

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

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End point title

The Number of Participants Treatment-Emergent Adverse Events (TEAE)

End point description

TEAE is defined as any AEs that begin or worsen on or after the day of the first dose. An AE is any noxious, unintended, or untoward medical occurrence that may appear or worsen in a subject during the course of a study. An SAE is any AE occurring at any dose that: results in death, is life-threatening, requires inpatient hospitalization or prolongation of existing hospitalization, results in persistent or significant disability/incapacity, is a congenital anomaly/birth defect, or constitutes an important medical event. The severity/intensity of AEs will be graded based on the Common Terminology Criteria for Adverse Events (CTCAE, version 4.03) where Grade 3 = Severe, Grade 4 = Life-threatening, and Grade 5 = Death.

End point type

Secondary

End point timeframe

From first dose through 42 days after the last dose (up to approximately 238 weeks)

End point values	Cohort 1: Anemia Only	Cohort 2: RBC-Transfusion Dependent	Cohort 3A: Anemia Only (Stable Dose-Ruxolitinib)	Cohort 3B: RBC-Transfusion Dependent (Stable Dose-Ruxolitinib)
Number of subjects analysed	22	21	14	38
Units: Participants
TEAE	21	19	13	36
Treatment-Related TEAE	14	5	7	19
Serious TEAE	8	8	4	17
Treatment-Related Serious TEAE	1	0	0	2
TEAE Grade >=3	9	11	4	24
Treatment-Related TEAE Grade >=3	0	1	2	7
TEAE Leading to Dose Interruption	2	2	3	12
Treatment-Related TEAE to Dose Interruption	1	1	1	4
TEAE Leading to Dose Reduction	1	0	2	2
Treatment-Related TEAE Leading to Dose Reduction	1	0	2	2
TEAE Leading to Study Drug Withdrawn	1	2	1	5
Treatment-Related TEAE to Study Drug Withdrawn	0	0	0	1
TEAE Leading to Death	1	2	0	5
Treatment-Related TEAE Leading to Death	0	0	0	0

No statistical analyses for this end point

Secondary: V1/F (L)

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End point title

V1/F (L)

End point description

Apparent volume of distribution of the central compartment

End point type

Secondary

End point timeframe

C1D1 (pre-dose), C1D8, C1D15, C2D1, C4D1, C5D1, C5D8, C6D1, and C8D1, day 169, Day 1 of every 4th Extension Phase treatment cycle for up to 1 year post the date of first dose of luspatercept, and end of treatment.

End point values	Cohort 1: Anemia Only	Cohort 2: RBC-Transfusion Dependent	Cohort 3A: Anemia Only (Stable Dose-Ruxolitinib)	Cohort 3B: RBC-Transfusion Dependent (Stable Dose-Ruxolitinib)
Number of subjects analysed	22	21	14	38
Units: Liter
geometric mean (geometric coefficient of variation)	11.65 ( 53 )	10.15 ( 31 )	11.36 ( 34 )	10.84 ( 39 )

No statistical analyses for this end point

Secondary: CL/F (L/day)

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End point title

CL/F (L/day)

End point description

Apparent clearance

End point type

Secondary

End point timeframe

End point values	Cohort 1: Anemia Only	Cohort 2: RBC-Transfusion Dependent	Cohort 3A: Anemia Only (Stable Dose-Ruxolitinib)	Cohort 3B: RBC-Transfusion Dependent (Stable Dose-Ruxolitinib)
Number of subjects analysed	22	21	14	38
Units: L/day
geometric mean (geometric coefficient of variation)	0.61 ( 51 )	0.53 ( 31 )	0.46 ( 34 )	0.44 ( 38 )

No statistical analyses for this end point

Secondary: Ka (day-1)

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End point title

Ka (day-1)

End point description

First-order rate constant of absorption

End point type

Secondary

End point timeframe

End point values	Cohort 1: Anemia Only	Cohort 2: RBC-Transfusion Dependent	Cohort 3A: Anemia Only (Stable Dose-Ruxolitinib)	Cohort 3B: RBC-Transfusion Dependent (Stable Dose-Ruxolitinib)
Number of subjects analysed	22	21	14	38
Units: Day-1
geometric mean (geometric coefficient of variation)	0.3 ( 37 )	0.28 ( 19 )	0.29 ( 21 )	0.28 ( 28 )

No statistical analyses for this end point

Secondary: T1/2 (day)

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End point title

T1/2 (day)

End point description

Elimination half-life

End point type

Secondary

End point timeframe

End point values	Cohort 1: Anemia Only	Cohort 2: RBC-Transfusion Dependent	Cohort 3A: Anemia Only (Stable Dose-Ruxolitinib)	Cohort 3B: RBC-Transfusion Dependent (Stable Dose-Ruxolitinib)
Number of subjects analysed	22	21	14	38
Units: Day
geometric mean (geometric coefficient of variation)	13.28 ( 2.4 )	13.3 ( 1.4 )	16.96 ( 2.1 )	16.98 ( 2.2 )

No statistical analyses for this end point

Secondary: Tmax (day)

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End point title

Tmax (day)

End point description

Time to reach the maximum concentration for the first dose (Cmax)

End point type

Secondary

End point timeframe

End point values	Cohort 1: Anemia Only	Cohort 2: RBC-Transfusion Dependent	Cohort 3A: Anemia Only (Stable Dose-Ruxolitinib)	Cohort 3B: RBC-Transfusion Dependent (Stable Dose-Ruxolitinib)
Number of subjects analysed	22	21	14	38
Units: Day
median (full range (min-max))	6.72 (4.84 to 10.01)	7.38 (5.75 to 9.14)	7.85 (6.17 to 9.54)	7.96 (5.24 to 11.34)

No statistical analyses for this end point

Secondary: Cmax (µg/mL)

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End point title

Cmax (µg/mL)

End point description

Maximum concentration for the first dose

End point type

Secondary

End point timeframe

End point values	Cohort 1: Anemia Only	Cohort 2: RBC-Transfusion Dependent	Cohort 3A: Anemia Only (Stable Dose-Ruxolitinib)	Cohort 3B: RBC-Transfusion Dependent (Stable Dose-Ruxolitinib)
Number of subjects analysed	22	21	14	38
Units: µg/mL
geometric mean (geometric coefficient of variation)	4.41 ( 39 )	4.68 ( 20 )	4.96 ( 23 )	5.01 ( 30 )

No statistical analyses for this end point

Secondary: Cmax.ss (µg/mL)

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End point title

Cmax.ss (µg/mL)

End point description

Maximum concentration for the first dose (Cmax) at steady state for the starting dose

End point type

Secondary

End point timeframe

End point values	Cohort 1: Anemia Only	Cohort 2: RBC-Transfusion Dependent	Cohort 3A: Anemia Only (Stable Dose-Ruxolitinib)	Cohort 3B: RBC-Transfusion Dependent (Stable Dose-Ruxolitinib)
Number of subjects analysed	22	21	14	38
Units: µg/mL
geometric mean (geometric coefficient of variation)	7.28 ( 42 )	7.72 ( 21 )	9.45 ( 24 )	9.6 ( 32 )

No statistical analyses for this end point

Secondary: AUCss (day* µg/mL)

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End point title

AUCss (day* µg/mL)

End point description

Area under the concentration-time curve at the steady state for the starting dose

End point type

Secondary

End point timeframe

End point values	Cohort 1: Anemia Only	Cohort 2: RBC-Transfusion Dependent	Cohort 3A: Anemia Only (Stable Dose-Ruxolitinib)	Cohort 3B: RBC-Transfusion Dependent (Stable Dose-Ruxolitinib)
Number of subjects analysed	22	21	14	38
Units: day* µg/mL
geometric mean (geometric coefficient of variation)	123 ( 47 )	132 ( 24 )	168 ( 26 )	171 ( 35 )

No statistical analyses for this end point

Secondary: Mean Changes in Hemoglobin over the study compared to baseline in the absence of RBC transfusions (Cohorts 1 and 3A)

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End point title

Mean Changes in Hemoglobin over the study compared to baseline in the absence of RBC transfusions (Cohorts 1 and 3A) ^[12]

End point description

Calculated based on average hemoglobin measurements collected during the treatment period.The primary treatment period is from Day 1 to and including Day 168. The entire treatment period is from Day 1 through the end of treatment. The baseline RBC transfusion is defined as average number of RBC units/28 days over the 84 days period immediately prior to the C1D1 date.

End point type

Secondary

End point timeframe

Baseline and Day 1 through end of treatment (up to approximately 232 weeks)

Notes
[12] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: Endpoint is specific to certain study arms

End point values	Cohort 1: Anemia Only	Cohort 3A: Anemia Only (Stable Dose-Ruxolitinib)
Number of subjects analysed	22	14
Units: g/dL
arithmetic mean (standard deviation)
Primary Treatment Period	0.795 ( 0.7697 )	1.157 ( 0.5178 )
Entire Treatment Period	0.824 ( 0.8613 )	1.172 ( 0.5992 )

No statistical analyses for this end point

Secondary: The Number of Participants with Antidrug Antibody (ADA) Measurements

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End point title

The Number of Participants with Antidrug Antibody (ADA) Measurements

End point description

The ADA status of a participant during treatment is determined based on the longitudinal ADA results as follows: Negative: All samples (baseline and post-baseline) are negative. Positive to treatment-emergent ADA: At least one post-baseline sample is positive if the baseline sample is negative, or at least one post-baseline sample is positive with a titer ≥ 4-fold of the baseline titer if the baseline sample is positive

End point type

Secondary

End point timeframe

C1D1 (pre- dose), C2D1, C4D1, C6D1, C8D1, Day 1 of every 4th Extension Phase treatment cycle for up to 1 year post the date of first dose of luspatercept, and end of treatment.

End point values	Cohort 1: Anemia Only	Cohort 2: RBC-Transfusion Dependent	Cohort 3A: Anemia Only (Stable Dose-Ruxolitinib)	Cohort 3B: RBC-Transfusion Dependent (Stable Dose-Ruxolitinib)
Number of subjects analysed	22	21	14	38
Units: Participants
Positive	1	2	2	2
Negative	21	19	12	36

No statistical analyses for this end point

Secondary: The Number of Participants with a Mean Hemoglobin Increase >= 1.5 g/dL from Baseline Over any Consecutive 84-day Period (Cohorts 1 and 3A)

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End point title

The Number of Participants with a Mean Hemoglobin Increase >= 1.5 g/dL from Baseline Over any Consecutive 84-day Period (Cohorts 1 and 3A) ^[13]

End point description

The number of participants with a Mean hemoglobin increase of ≥ 1.5 g/dL from baseline over any consecutive 84-day period without an RBC transfusion. The primary treatment period is from Day 1 to and including Day 168. The entire treatment period is from Day 1 through the end of treatment. Baseline is defined as all non-missing Hgb records within 28 days on or prior to date of first dose (or date of enrollment if not treated).

End point type

Secondary

End point timeframe

Baseline and Day 1 through end of treatment (up to approximately 232 weeks)

Notes
[13] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: Endpoint is specific to certain study arms

End point values	Cohort 1: Anemia Only	Cohort 3A: Anemia Only (Stable Dose-Ruxolitinib)
Number of subjects analysed	22	14
Units: Participants
Primary Treatment Period	5	6
Entire Treatment Period	6	7

No statistical analyses for this end point

Adverse events

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Timeframe for reporting adverse events

SAEs and NSAEs were assessed from first dose through 42 days after the last dose (up to approximately 238 weeks)

Assessment type

Systematic

Dictionary name

MedDRA

Dictionary version

25.0

Reporting group title

Cohort 1: Anemia Only

Reporting group description

Reporting group title

Cohort 2: RBC-Transfusion Dependent

Reporting group description

Reporting group title

Cohort 3B: RBC-Transfusion Dependent (Stable Dose-Ruxolitinib)

Reporting group description

Reporting group title

Cohort 3A: Anemia Only (Stable Dose-Ruxolitinib)

Reporting group description

Serious adverse events	Cohort 1: Anemia Only	Cohort 2: RBC-Transfusion Dependent	Cohort 3B: RBC-Transfusion Dependent (Stable Dose-Ruxolitinib)	Cohort 3A: Anemia Only (Stable Dose-Ruxolitinib)
Total subjects affected by serious adverse events
subjects affected / exposed	8 / 22 (36.36%)	8 / 21 (38.10%)	17 / 38 (44.74%)	4 / 14 (28.57%)
number of deaths (all causes)	6	12	13	2
number of deaths resulting from adverse events
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Skin squamous cell carcinoma recurrent
subjects affected / exposed	0 / 22 (0.00%)	0 / 21 (0.00%)	1 / 38 (2.63%)	0 / 14 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Acute leukaemia
subjects affected / exposed	0 / 22 (0.00%)	1 / 21 (4.76%)	0 / 38 (0.00%)	0 / 14 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Basal cell carcinoma
subjects affected / exposed	0 / 22 (0.00%)	0 / 21 (0.00%)	2 / 38 (5.26%)	2 / 14 (14.29%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 3	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Bowen's disease
subjects affected / exposed	0 / 22 (0.00%)	0 / 21 (0.00%)	1 / 38 (2.63%)	0 / 14 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Chloroma
subjects affected / exposed	0 / 22 (0.00%)	1 / 21 (4.76%)	0 / 38 (0.00%)	0 / 14 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Squamous cell carcinoma of skin
subjects affected / exposed	0 / 22 (0.00%)	0 / 21 (0.00%)	1 / 38 (2.63%)	0 / 14 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Squamous cell carcinoma
subjects affected / exposed	0 / 22 (0.00%)	0 / 21 (0.00%)	1 / 38 (2.63%)	0 / 14 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Vascular disorders
Aortic embolus
subjects affected / exposed	1 / 22 (4.55%)	0 / 21 (0.00%)	0 / 38 (0.00%)	0 / 14 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
General disorders and administration site conditions
Fatigue
subjects affected / exposed	0 / 22 (0.00%)	1 / 21 (4.76%)	0 / 38 (0.00%)	0 / 14 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Asthenia
subjects affected / exposed	0 / 22 (0.00%)	0 / 21 (0.00%)	0 / 38 (0.00%)	1 / 14 (7.14%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Gait disturbance
subjects affected / exposed	1 / 22 (4.55%)	0 / 21 (0.00%)	0 / 38 (0.00%)	0 / 14 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Multiple organ dysfunction syndrome
subjects affected / exposed	0 / 22 (0.00%)	0 / 21 (0.00%)	1 / 38 (2.63%)	0 / 14 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0
Non-cardiac chest pain
subjects affected / exposed	0 / 22 (0.00%)	1 / 21 (4.76%)	0 / 38 (0.00%)	0 / 14 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Systemic inflammatory response syndrome
subjects affected / exposed	1 / 22 (4.55%)	0 / 21 (0.00%)	0 / 38 (0.00%)	0 / 14 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Respiratory, thoracic and mediastinal disorders
Respiratory failure
subjects affected / exposed	1 / 22 (4.55%)	0 / 21 (0.00%)	1 / 38 (2.63%)	0 / 14 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Pulmonary embolism
subjects affected / exposed	0 / 22 (0.00%)	0 / 21 (0.00%)	0 / 38 (0.00%)	1 / 14 (7.14%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Epistaxis
subjects affected / exposed	0 / 22 (0.00%)	0 / 21 (0.00%)	1 / 38 (2.63%)	0 / 14 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Dyspnoea
subjects affected / exposed	1 / 22 (4.55%)	0 / 21 (0.00%)	1 / 38 (2.63%)	0 / 14 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Acute respiratory failure
subjects affected / exposed	0 / 22 (0.00%)	0 / 21 (0.00%)	1 / 38 (2.63%)	0 / 14 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Pneumonitis
subjects affected / exposed	0 / 22 (0.00%)	0 / 21 (0.00%)	1 / 38 (2.63%)	0 / 14 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0
Psychiatric disorders
Confusional state
subjects affected / exposed	0 / 22 (0.00%)	0 / 21 (0.00%)	1 / 38 (2.63%)	0 / 14 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Investigations
Troponin T increased
subjects affected / exposed	0 / 22 (0.00%)	0 / 21 (0.00%)	1 / 38 (2.63%)	0 / 14 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Ejection fraction decreased
subjects affected / exposed	0 / 22 (0.00%)	0 / 21 (0.00%)	1 / 38 (2.63%)	0 / 14 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Injury, poisoning and procedural complications
Ankle fracture
subjects affected / exposed	0 / 22 (0.00%)	0 / 21 (0.00%)	1 / 38 (2.63%)	0 / 14 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Humerus fracture
subjects affected / exposed	0 / 22 (0.00%)	1 / 21 (4.76%)	0 / 38 (0.00%)	0 / 14 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Subdural haematoma
subjects affected / exposed	1 / 22 (4.55%)	1 / 21 (4.76%)	0 / 38 (0.00%)	0 / 14 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0
Post procedural haemorrhage
subjects affected / exposed	1 / 22 (4.55%)	0 / 21 (0.00%)	0 / 38 (0.00%)	0 / 14 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0
Cardiac disorders
Cardiac failure congestive
subjects affected / exposed	0 / 22 (0.00%)	0 / 21 (0.00%)	1 / 38 (2.63%)	0 / 14 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Cardiac failure
subjects affected / exposed	0 / 22 (0.00%)	0 / 21 (0.00%)	1 / 38 (2.63%)	0 / 14 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Nervous system disorders
Disturbance in attention
subjects affected / exposed	0 / 22 (0.00%)	0 / 21 (0.00%)	1 / 38 (2.63%)	0 / 14 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Cerebrovascular accident
subjects affected / exposed	0 / 22 (0.00%)	0 / 21 (0.00%)	1 / 38 (2.63%)	0 / 14 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Haemorrhage intracranial
subjects affected / exposed	0 / 22 (0.00%)	1 / 21 (4.76%)	0 / 38 (0.00%)	0 / 14 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Syncope
subjects affected / exposed	0 / 22 (0.00%)	2 / 21 (9.52%)	1 / 38 (2.63%)	0 / 14 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 3	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Subarachnoid haemorrhage
subjects affected / exposed	0 / 22 (0.00%)	0 / 21 (0.00%)	1 / 38 (2.63%)	0 / 14 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Somnolence
subjects affected / exposed	0 / 22 (0.00%)	1 / 21 (4.76%)	0 / 38 (0.00%)	0 / 14 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Ischaemic stroke
subjects affected / exposed	0 / 22 (0.00%)	0 / 21 (0.00%)	1 / 38 (2.63%)	0 / 14 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0
Blood and lymphatic system disorders
Leukopenia
subjects affected / exposed	0 / 22 (0.00%)	0 / 21 (0.00%)	1 / 38 (2.63%)	0 / 14 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Anaemia
subjects affected / exposed	0 / 22 (0.00%)	2 / 21 (9.52%)	0 / 38 (0.00%)	0 / 14 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 2	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Gastrointestinal disorders
Diarrhoea
subjects affected / exposed	0 / 22 (0.00%)	1 / 21 (4.76%)	1 / 38 (2.63%)	0 / 14 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	1 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Abdominal pain
subjects affected / exposed	1 / 22 (4.55%)	0 / 21 (0.00%)	0 / 38 (0.00%)	0 / 14 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Diverticular perforation
subjects affected / exposed	1 / 22 (4.55%)	0 / 21 (0.00%)	1 / 38 (2.63%)	0 / 14 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Small intestinal haemorrhage
subjects affected / exposed	0 / 22 (0.00%)	0 / 21 (0.00%)	1 / 38 (2.63%)	0 / 14 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Enteritis
subjects affected / exposed	0 / 22 (0.00%)	0 / 21 (0.00%)	1 / 38 (2.63%)	0 / 14 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Stomatitis
subjects affected / exposed	1 / 22 (4.55%)	0 / 21 (0.00%)	0 / 38 (0.00%)	0 / 14 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Hepatobiliary disorders
Hepatic failure
subjects affected / exposed	0 / 22 (0.00%)	0 / 21 (0.00%)	1 / 38 (2.63%)	0 / 14 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Renal and urinary disorders
Acute kidney injury
subjects affected / exposed	0 / 22 (0.00%)	0 / 21 (0.00%)	1 / 38 (2.63%)	0 / 14 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Haematuria
subjects affected / exposed	0 / 22 (0.00%)	1 / 21 (4.76%)	0 / 38 (0.00%)	0 / 14 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Renal failure
subjects affected / exposed	1 / 22 (4.55%)	0 / 21 (0.00%)	1 / 38 (2.63%)	0 / 14 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0
Musculoskeletal and connective tissue disorders
Chest wall haematoma
subjects affected / exposed	0 / 22 (0.00%)	0 / 21 (0.00%)	1 / 38 (2.63%)	0 / 14 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Infections and infestations
Gastroenteritis
subjects affected / exposed	0 / 22 (0.00%)	1 / 21 (4.76%)	0 / 38 (0.00%)	0 / 14 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Biliary tract infection
subjects affected / exposed	0 / 22 (0.00%)	0 / 21 (0.00%)	1 / 38 (2.63%)	0 / 14 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 2	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Escherichia bacteraemia
subjects affected / exposed	1 / 22 (4.55%)	0 / 21 (0.00%)	0 / 38 (0.00%)	0 / 14 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Diverticulitis
subjects affected / exposed	1 / 22 (4.55%)	0 / 21 (0.00%)	0 / 38 (0.00%)	0 / 14 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Cerebral toxoplasmosis
subjects affected / exposed	0 / 22 (0.00%)	0 / 21 (0.00%)	1 / 38 (2.63%)	0 / 14 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	1 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Urosepsis
subjects affected / exposed	0 / 22 (0.00%)	0 / 21 (0.00%)	0 / 38 (0.00%)	1 / 14 (7.14%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Urinary tract infection
subjects affected / exposed	2 / 22 (9.09%)	1 / 21 (4.76%)	0 / 38 (0.00%)	0 / 14 (0.00%)
occurrences causally related to treatment / all	1 / 2	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Septic shock
subjects affected / exposed	0 / 22 (0.00%)	0 / 21 (0.00%)	1 / 38 (2.63%)	0 / 14 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0
Sepsis
subjects affected / exposed	1 / 22 (4.55%)	0 / 21 (0.00%)	1 / 38 (2.63%)	0 / 14 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Pyelonephritis
subjects affected / exposed	0 / 22 (0.00%)	0 / 21 (0.00%)	1 / 38 (2.63%)	0 / 14 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Pulmonary sepsis
subjects affected / exposed	0 / 22 (0.00%)	0 / 21 (0.00%)	1 / 38 (2.63%)	0 / 14 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Pneumonia
subjects affected / exposed	1 / 22 (4.55%)	1 / 21 (4.76%)	1 / 38 (2.63%)	0 / 14 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 1	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0
Kidney infection
subjects affected / exposed	0 / 22 (0.00%)	0 / 21 (0.00%)	1 / 38 (2.63%)	0 / 14 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 2	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Influenza
subjects affected / exposed	1 / 22 (4.55%)	0 / 21 (0.00%)	0 / 38 (0.00%)	1 / 14 (7.14%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0

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

Non-serious adverse events	Cohort 1: Anemia Only	Cohort 2: RBC-Transfusion Dependent	Cohort 3B: RBC-Transfusion Dependent (Stable Dose-Ruxolitinib)	Cohort 3A: Anemia Only (Stable Dose-Ruxolitinib)
Total subjects affected by non serious adverse events
subjects affected / exposed	21 / 22 (95.45%)	19 / 21 (90.48%)	33 / 38 (86.84%)	13 / 14 (92.86%)
Vascular disorders
Hypertension
subjects affected / exposed	5 / 22 (22.73%)	3 / 21 (14.29%)	9 / 38 (23.68%)	6 / 14 (42.86%)
occurrences all number	6	3	16	6
Hypotension
subjects affected / exposed	0 / 22 (0.00%)	0 / 21 (0.00%)	4 / 38 (10.53%)	1 / 14 (7.14%)
occurrences all number	0	0	6	1
General disorders and administration site conditions
Asthenia
subjects affected / exposed	1 / 22 (4.55%)	3 / 21 (14.29%)	5 / 38 (13.16%)	0 / 14 (0.00%)
occurrences all number	1	3	7	0
Chills
subjects affected / exposed	0 / 22 (0.00%)	1 / 21 (4.76%)	1 / 38 (2.63%)	1 / 14 (7.14%)
occurrences all number	0	1	1	1
Fatigue
subjects affected / exposed	4 / 22 (18.18%)	5 / 21 (23.81%)	6 / 38 (15.79%)	2 / 14 (14.29%)
occurrences all number	4	5	12	2
Influenza like illness
subjects affected / exposed	1 / 22 (4.55%)	1 / 21 (4.76%)	1 / 38 (2.63%)	3 / 14 (21.43%)
occurrences all number	1	1	1	3
Injection site pain
subjects affected / exposed	0 / 22 (0.00%)	0 / 21 (0.00%)	0 / 38 (0.00%)	1 / 14 (7.14%)
occurrences all number	0	0	0	1
Non-cardiac chest pain
subjects affected / exposed	2 / 22 (9.09%)	0 / 21 (0.00%)	1 / 38 (2.63%)	0 / 14 (0.00%)
occurrences all number	2	0	1	0
Oedema peripheral
subjects affected / exposed	3 / 22 (13.64%)	0 / 21 (0.00%)	5 / 38 (13.16%)	1 / 14 (7.14%)
occurrences all number	3	0	5	1
Pain
subjects affected / exposed	0 / 22 (0.00%)	0 / 21 (0.00%)	0 / 38 (0.00%)	1 / 14 (7.14%)
occurrences all number	0	0	0	1
Peripheral swelling
subjects affected / exposed	0 / 22 (0.00%)	1 / 21 (4.76%)	0 / 38 (0.00%)	1 / 14 (7.14%)
occurrences all number	0	1	0	1
Pyrexia
subjects affected / exposed	5 / 22 (22.73%)	1 / 21 (4.76%)	7 / 38 (18.42%)	1 / 14 (7.14%)
occurrences all number	7	1	10	1
Early satiety
subjects affected / exposed	0 / 22 (0.00%)	0 / 21 (0.00%)	2 / 38 (5.26%)	2 / 14 (14.29%)
occurrences all number	0	0	3	2
Respiratory, thoracic and mediastinal disorders
Cough
subjects affected / exposed	3 / 22 (13.64%)	5 / 21 (23.81%)	4 / 38 (10.53%)	0 / 14 (0.00%)
occurrences all number	5	6	7	0
Dyspnoea
subjects affected / exposed	4 / 22 (18.18%)	5 / 21 (23.81%)	9 / 38 (23.68%)	2 / 14 (14.29%)
occurrences all number	4	5	10	3
Epistaxis
subjects affected / exposed	1 / 22 (4.55%)	2 / 21 (9.52%)	4 / 38 (10.53%)	3 / 14 (21.43%)
occurrences all number	1	2	4	3
Sleep apnoea syndrome
subjects affected / exposed	2 / 22 (9.09%)	0 / 21 (0.00%)	0 / 38 (0.00%)	0 / 14 (0.00%)
occurrences all number	2	0	0	0
Oropharyngeal pain
subjects affected / exposed	0 / 22 (0.00%)	1 / 21 (4.76%)	1 / 38 (2.63%)	1 / 14 (7.14%)
occurrences all number	0	1	1	1
Nasal congestion
subjects affected / exposed	0 / 22 (0.00%)	0 / 21 (0.00%)	1 / 38 (2.63%)	1 / 14 (7.14%)
occurrences all number	0	0	1	1
Psychiatric disorders
Insomnia
subjects affected / exposed	1 / 22 (4.55%)	2 / 21 (9.52%)	1 / 38 (2.63%)	0 / 14 (0.00%)
occurrences all number	1	2	1	0
Depression
subjects affected / exposed	2 / 22 (9.09%)	0 / 21 (0.00%)	0 / 38 (0.00%)	0 / 14 (0.00%)
occurrences all number	2	0	0	0
Confusional state
subjects affected / exposed	0 / 22 (0.00%)	0 / 21 (0.00%)	2 / 38 (5.26%)	0 / 14 (0.00%)
occurrences all number	0	0	3	0
Investigations
Alanine aminotransferase increased
subjects affected / exposed	0 / 22 (0.00%)	2 / 21 (9.52%)	7 / 38 (18.42%)	1 / 14 (7.14%)
occurrences all number	0	2	10	2
Aspartate aminotransferase increased
subjects affected / exposed	0 / 22 (0.00%)	1 / 21 (4.76%)	2 / 38 (5.26%)	1 / 14 (7.14%)
occurrences all number	0	1	2	1
Blood alkaline phosphatase increased
subjects affected / exposed	1 / 22 (4.55%)	1 / 21 (4.76%)	1 / 38 (2.63%)	1 / 14 (7.14%)
occurrences all number	1	1	1	1
Blood bilirubin increased
subjects affected / exposed	0 / 22 (0.00%)	1 / 21 (4.76%)	2 / 38 (5.26%)	0 / 14 (0.00%)
occurrences all number	0	1	3	0
Blood creatine phosphokinase increased
subjects affected / exposed	0 / 22 (0.00%)	0 / 21 (0.00%)	0 / 38 (0.00%)	1 / 14 (7.14%)
occurrences all number	0	0	0	1
Blood creatinine increased
subjects affected / exposed	1 / 22 (4.55%)	0 / 21 (0.00%)	0 / 38 (0.00%)	2 / 14 (14.29%)
occurrences all number	1	0	0	2
Blood glucose increased
subjects affected / exposed	0 / 22 (0.00%)	0 / 21 (0.00%)	0 / 38 (0.00%)	1 / 14 (7.14%)
occurrences all number	0	0	0	1
Weight decreased
subjects affected / exposed	1 / 22 (4.55%)	2 / 21 (9.52%)	1 / 38 (2.63%)	0 / 14 (0.00%)
occurrences all number	1	2	1	0
White blood cell count increased
subjects affected / exposed	0 / 22 (0.00%)	0 / 21 (0.00%)	2 / 38 (5.26%)	0 / 14 (0.00%)
occurrences all number	0	0	2	0
Injury, poisoning and procedural complications
Contusion
subjects affected / exposed	0 / 22 (0.00%)	2 / 21 (9.52%)	4 / 38 (10.53%)	0 / 14 (0.00%)
occurrences all number	0	2	4	0
Fall
subjects affected / exposed	1 / 22 (4.55%)	2 / 21 (9.52%)	3 / 38 (7.89%)	1 / 14 (7.14%)
occurrences all number	2	4	10	3
Lower limb fracture
subjects affected / exposed	0 / 22 (0.00%)	0 / 21 (0.00%)	0 / 38 (0.00%)	1 / 14 (7.14%)
occurrences all number	0	0	0	1
Nervous system disorders
Disturbance in attention
subjects affected / exposed	0 / 22 (0.00%)	0 / 21 (0.00%)	2 / 38 (5.26%)	1 / 14 (7.14%)
occurrences all number	0	0	2	1
Memory impairment
subjects affected / exposed	0 / 22 (0.00%)	1 / 21 (4.76%)	0 / 38 (0.00%)	1 / 14 (7.14%)
occurrences all number	0	1	0	1
Headache
subjects affected / exposed	3 / 22 (13.64%)	1 / 21 (4.76%)	3 / 38 (7.89%)	1 / 14 (7.14%)
occurrences all number	3	1	3	2
Dizziness
subjects affected / exposed	2 / 22 (9.09%)	2 / 21 (9.52%)	7 / 38 (18.42%)	3 / 14 (21.43%)
occurrences all number	2	2	11	4
Blood and lymphatic system disorders
Thrombocytopenia
subjects affected / exposed	3 / 22 (13.64%)	3 / 21 (14.29%)	11 / 38 (28.95%)	1 / 14 (7.14%)
occurrences all number	3	3	17	1
Splenomegaly
subjects affected / exposed	0 / 22 (0.00%)	1 / 21 (4.76%)	0 / 38 (0.00%)	2 / 14 (14.29%)
occurrences all number	0	1	0	2
Neutropenia
subjects affected / exposed	0 / 22 (0.00%)	1 / 21 (4.76%)	2 / 38 (5.26%)	0 / 14 (0.00%)
occurrences all number	0	1	2	0
Anaemia
subjects affected / exposed	3 / 22 (13.64%)	1 / 21 (4.76%)	1 / 38 (2.63%)	0 / 14 (0.00%)
occurrences all number	3	1	1	0
Eye disorders
Glaucoma
subjects affected / exposed	0 / 22 (0.00%)	0 / 21 (0.00%)	0 / 38 (0.00%)	1 / 14 (7.14%)
occurrences all number	0	0	0	1
Gastrointestinal disorders
Abdominal distension
subjects affected / exposed	1 / 22 (4.55%)	0 / 21 (0.00%)	2 / 38 (5.26%)	1 / 14 (7.14%)
occurrences all number	1	0	2	1
Abdominal discomfort
subjects affected / exposed	1 / 22 (4.55%)	1 / 21 (4.76%)	1 / 38 (2.63%)	1 / 14 (7.14%)
occurrences all number	1	1	1	1
Vomiting
subjects affected / exposed	2 / 22 (9.09%)	0 / 21 (0.00%)	2 / 38 (5.26%)	2 / 14 (14.29%)
occurrences all number	2	0	2	3
Nausea
subjects affected / exposed	2 / 22 (9.09%)	3 / 21 (14.29%)	6 / 38 (15.79%)	2 / 14 (14.29%)
occurrences all number	4	3	8	2
Mouth haemorrhage
subjects affected / exposed	2 / 22 (9.09%)	0 / 21 (0.00%)	0 / 38 (0.00%)	0 / 14 (0.00%)
occurrences all number	2	0	0	0
Dysphagia
subjects affected / exposed	0 / 22 (0.00%)	2 / 21 (9.52%)	0 / 38 (0.00%)	0 / 14 (0.00%)
occurrences all number	0	2	0	0
Dyspepsia
subjects affected / exposed	1 / 22 (4.55%)	0 / 21 (0.00%)	0 / 38 (0.00%)	1 / 14 (7.14%)
occurrences all number	1	0	0	1
Diarrhoea
subjects affected / exposed	3 / 22 (13.64%)	4 / 21 (19.05%)	11 / 38 (28.95%)	4 / 14 (28.57%)
occurrences all number	4	10	17	5
Constipation
subjects affected / exposed	2 / 22 (9.09%)	2 / 21 (9.52%)	1 / 38 (2.63%)	1 / 14 (7.14%)
occurrences all number	2	2	1	1
Abdominal pain
subjects affected / exposed	5 / 22 (22.73%)	2 / 21 (9.52%)	4 / 38 (10.53%)	2 / 14 (14.29%)
occurrences all number	6	2	5	2
Skin and subcutaneous tissue disorders
Seborrhoeic dermatitis
subjects affected / exposed	0 / 22 (0.00%)	0 / 21 (0.00%)	0 / 38 (0.00%)	1 / 14 (7.14%)
occurrences all number	0	0	0	1
Pruritus
subjects affected / exposed	3 / 22 (13.64%)	2 / 21 (9.52%)	3 / 38 (7.89%)	3 / 14 (21.43%)
occurrences all number	3	3	3	3
Erythema
subjects affected / exposed	2 / 22 (9.09%)	0 / 21 (0.00%)	1 / 38 (2.63%)	0 / 14 (0.00%)
occurrences all number	2	0	1	0
Ecchymosis
subjects affected / exposed	0 / 22 (0.00%)	0 / 21 (0.00%)	0 / 38 (0.00%)	1 / 14 (7.14%)
occurrences all number	0	0	0	1
Night sweats
subjects affected / exposed	2 / 22 (9.09%)	2 / 21 (9.52%)	2 / 38 (5.26%)	3 / 14 (21.43%)
occurrences all number	3	2	3	3
Renal and urinary disorders
Pollakiuria
subjects affected / exposed	1 / 22 (4.55%)	0 / 21 (0.00%)	2 / 38 (5.26%)	0 / 14 (0.00%)
occurrences all number	1	0	3	0
Chronic kidney disease
subjects affected / exposed	0 / 22 (0.00%)	0 / 21 (0.00%)	3 / 38 (7.89%)	0 / 14 (0.00%)
occurrences all number	0	0	3	0
Acute kidney injury
subjects affected / exposed	2 / 22 (9.09%)	0 / 21 (0.00%)	0 / 38 (0.00%)	0 / 14 (0.00%)
occurrences all number	2	0	0	0
Endocrine disorders
Hypothyroidism
subjects affected / exposed	2 / 22 (9.09%)	0 / 21 (0.00%)	2 / 38 (5.26%)	0 / 14 (0.00%)
occurrences all number	2	0	2	0
Musculoskeletal and connective tissue disorders
Muscle spasms
subjects affected / exposed	0 / 22 (0.00%)	0 / 21 (0.00%)	1 / 38 (2.63%)	1 / 14 (7.14%)
occurrences all number	0	0	1	1
Arthralgia
subjects affected / exposed	2 / 22 (9.09%)	0 / 21 (0.00%)	6 / 38 (15.79%)	3 / 14 (21.43%)
occurrences all number	2	0	6	3
Back pain
subjects affected / exposed	3 / 22 (13.64%)	1 / 21 (4.76%)	2 / 38 (5.26%)	2 / 14 (14.29%)
occurrences all number	4	1	2	2
Bone pain
subjects affected / exposed	4 / 22 (18.18%)	2 / 21 (9.52%)	4 / 38 (10.53%)	3 / 14 (21.43%)
occurrences all number	5	2	5	4
Bursitis
subjects affected / exposed	0 / 22 (0.00%)	0 / 21 (0.00%)	0 / 38 (0.00%)	1 / 14 (7.14%)
occurrences all number	0	0	0	1
Spinal pain
subjects affected / exposed	0 / 22 (0.00%)	0 / 21 (0.00%)	2 / 38 (5.26%)	0 / 14 (0.00%)
occurrences all number	0	0	2	0
Pain in extremity
subjects affected / exposed	1 / 22 (4.55%)	1 / 21 (4.76%)	3 / 38 (7.89%)	0 / 14 (0.00%)
occurrences all number	1	1	4	0
Neck pain
subjects affected / exposed	1 / 22 (4.55%)	1 / 21 (4.76%)	2 / 38 (5.26%)	0 / 14 (0.00%)
occurrences all number	1	1	2	0
Neck mass
subjects affected / exposed	0 / 22 (0.00%)	0 / 21 (0.00%)	0 / 38 (0.00%)	1 / 14 (7.14%)
occurrences all number	0	0	0	1
Myalgia
subjects affected / exposed	3 / 22 (13.64%)	0 / 21 (0.00%)	4 / 38 (10.53%)	1 / 14 (7.14%)
occurrences all number	3	0	4	1
Musculoskeletal chest pain
subjects affected / exposed	0 / 22 (0.00%)	0 / 21 (0.00%)	2 / 38 (5.26%)	0 / 14 (0.00%)
occurrences all number	0	0	2	0
Infections and infestations
Sinusitis
subjects affected / exposed	0 / 22 (0.00%)	1 / 21 (4.76%)	1 / 38 (2.63%)	1 / 14 (7.14%)
occurrences all number	0	1	1	2
Abscess limb
subjects affected / exposed	0 / 22 (0.00%)	0 / 21 (0.00%)	1 / 38 (2.63%)	1 / 14 (7.14%)
occurrences all number	0	0	1	1
Cellulitis
subjects affected / exposed	0 / 22 (0.00%)	0 / 21 (0.00%)	2 / 38 (5.26%)	0 / 14 (0.00%)
occurrences all number	0	0	2	0
Cystitis
subjects affected / exposed	1 / 22 (4.55%)	0 / 21 (0.00%)	1 / 38 (2.63%)	1 / 14 (7.14%)
occurrences all number	5	0	2	1
Nasopharyngitis
subjects affected / exposed	1 / 22 (4.55%)	0 / 21 (0.00%)	2 / 38 (5.26%)	0 / 14 (0.00%)
occurrences all number	1	0	2	0
Pyelonephritis
subjects affected / exposed	0 / 22 (0.00%)	0 / 21 (0.00%)	0 / 38 (0.00%)	1 / 14 (7.14%)
occurrences all number	0	0	0	1
Tooth infection
subjects affected / exposed	0 / 22 (0.00%)	0 / 21 (0.00%)	0 / 38 (0.00%)	1 / 14 (7.14%)
occurrences all number	0	0	0	1
Upper respiratory tract infection
subjects affected / exposed	2 / 22 (9.09%)	2 / 21 (9.52%)	2 / 38 (5.26%)	2 / 14 (14.29%)
occurrences all number	2	2	2	2
Urinary tract infection
subjects affected / exposed	2 / 22 (9.09%)	4 / 21 (19.05%)	3 / 38 (7.89%)	1 / 14 (7.14%)
occurrences all number	2	6	3	1
Metabolism and nutrition disorders
Decreased appetite
subjects affected / exposed	1 / 22 (4.55%)	1 / 21 (4.76%)	2 / 38 (5.26%)	0 / 14 (0.00%)
occurrences all number	1	1	2	0
Hyperuricaemia
subjects affected / exposed	2 / 22 (9.09%)	2 / 21 (9.52%)	3 / 38 (7.89%)	0 / 14 (0.00%)
occurrences all number	2	2	4	0
Hyperkalaemia
subjects affected / exposed	2 / 22 (9.09%)	1 / 21 (4.76%)	3 / 38 (7.89%)	1 / 14 (7.14%)
occurrences all number	3	1	4	1
Hyperglycaemia
subjects affected / exposed	1 / 22 (4.55%)	0 / 21 (0.00%)	1 / 38 (2.63%)	1 / 14 (7.14%)
occurrences all number	1	0	2	1
Gout
subjects affected / exposed	0 / 22 (0.00%)	2 / 21 (9.52%)	0 / 38 (0.00%)	0 / 14 (0.00%)
occurrences all number	0	2	0	0
Dehydration
subjects affected / exposed	2 / 22 (9.09%)	0 / 21 (0.00%)	2 / 38 (5.26%)	0 / 14 (0.00%)
occurrences all number	2	0	3	0
Hypocalcaemia
subjects affected / exposed	0 / 22 (0.00%)	0 / 21 (0.00%)	3 / 38 (7.89%)	1 / 14 (7.14%)
occurrences all number	0	0	3	1
Hypokalaemia
subjects affected / exposed	1 / 22 (4.55%)	0 / 21 (0.00%)	2 / 38 (5.26%)	1 / 14 (7.14%)
occurrences all number	1	0	5	1
Hypomagnesaemia
subjects affected / exposed	2 / 22 (9.09%)	1 / 21 (4.76%)	1 / 38 (2.63%)	0 / 14 (0.00%)
occurrences all number	2	2	2	0
Hyponatraemia
subjects affected / exposed	0 / 22 (0.00%)	0 / 21 (0.00%)	0 / 38 (0.00%)	1 / 14 (7.14%)
occurrences all number	0	0	0	1
Hypernatraemia
subjects affected / exposed	0 / 22 (0.00%)	0 / 21 (0.00%)	0 / 38 (0.00%)	1 / 14 (7.14%)
occurrences all number	0	0	0	1

More information

Top of page

Were there any global substantial amendments to the protocol? Yes

21 Mar 2018

Addition of exclusion criterion for a white blood count threshold. Addition of exclusion criterion for a platelet count threshold. Addition of exclusion criterion for subjects on anticoagulant therapy who are not under appropriate control or not on a stable dose of anticoagulant therapy for ≥ 8 weeks up to the enrollment date. Addition of exclusion criterion for subjects on anagrelide within 28 days immediately up to the enrollment date. Addition of exclusion criterion for subjects with a major bleeding event in the last 6 months prior to enrollment. Addition of secondary endpoint to capture changes in hemoglobin over the study compared to baseline in the absence of red blood cell (RBC) transfusions. Addition of minimum number of days between hemoglobin assessments as outlined within Inclusion Criterion 3A. Modified protocol criteria related to dose modification (dose delay, dose reductions, and discontinuation) measures to account for elevated white blood counts at the day of dosing.

18 Dec 2018

Clarification to collection of exploratory biomarkers in Section 1.4.4, Section 2 (Table 2) and Section 5 (Table 3)

01 Aug 2019

Expansion of Cohort 3 enrollment. Modifying Cohorts 2 and 3B inclusion criterion. Statistical considerations supporting Cohort 3 expansion. Addition of secondary endpoint to assess mean hemoglobin increase. Modifying dose titration criteria. Adapting clinical benefit criteria to allow subjects to continue in the Extension Phase. Addition of language supporting the ACE-536-LTFU-001 roll-over study. New starting dose level of 1.33 mg/kg. Amended Exclusion Criterion #3 for ruxolitinib dosing in Cohort 3. Added Section 10.9 Monitoring of Toxicity and Study Stopping Rules.

19 Feb 2020

Prolongation of Extension Phase of the Treatment Period.

Were there any global interruptions to the trial? No

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

None reported

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Clinical trials

Clinical Trial Results: A Phase 2, Multicenter, Open-Label Study to Evaluate the Efficacy and Safety of Luspatercept (ACE-536) in Subjects With Myeloproliferative Neoplasm-Associated Myelofibrosis and Anemia With and Without Red Blood Cell-Transfusion Dependence

Trial information

Trial information

Subject disposition

Subject disposition

Baseline characteristics

Baseline characteristics

End points

End points

Primary: The Number of Participants with Anemia Reponses over Any 84-Day Period During the Primary Treatment Period

Primary: The Number of Participants with Anemia Reponses over Any 84-Day Period During the Primary Treatment Period

Secondary: Time to Anemia Response During the Primary Treatment Period

Secondary: Time to Anemia Response During the Primary Treatment Period

Secondary: Duration of Anemia Response

Secondary: Duration of Anemia Response

Secondary: The Number of RBC Units Transfused per Participant per 28 Days (Cohorts 2 and 3B Only)

Secondary: The Number of RBC Units Transfused per Participant per 28 Days (Cohorts 2 and 3B Only)

Secondary: The Number Participants Achieving >=50% RBC Transfusion Burden Reduction from Baseline Over Any 84-Day Period (Cohorts 2 and 3B Only)

Secondary: The Number Participants Achieving >=50% RBC Transfusion Burden Reduction from Baseline Over Any 84-Day Period (Cohorts 2 and 3B Only)

Secondary: The Number of Participants who Achieve ≥ 50% Reduction in Fatigue Symptom as Measured by the Myeloproliferative Neoplasms Symptom Assessment Form Total Symptom Score (MPN-SAF TSS)

Secondary: The Number of Participants who Achieve ≥ 50% Reduction in Fatigue Symptom as Measured by the Myeloproliferative Neoplasms Symptom Assessment Form Total Symptom Score (MPN-SAF TSS)

Secondary: Mean changes in the Functional Assessment of Cancer Therapy – Anemia (FACT-An) Total Scores Over the Study Compared to Baseline

Secondary: Mean changes in the Functional Assessment of Cancer Therapy – Anemia (FACT-An) Total Scores Over the Study Compared to Baseline

Secondary: The Number of Participants who Achieve ≥ 50% Reduction in Total Symptom Score (TSS) as Measured by the Myeloproliferative Neoplasms Symptom Assessment Form Total Symptom Score (MPN-SAF TSS)

Secondary: The Number of Participants who Achieve ≥ 50% Reduction in Total Symptom Score (TSS) as Measured by the Myeloproliferative Neoplasms Symptom Assessment Form Total Symptom Score (MPN-SAF TSS)

Secondary: Mean change in EQ-5D-5L Utility Score Compared to Baseline

Secondary: Mean change in EQ-5D-5L Utility Score Compared to Baseline

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

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

Secondary: V1/F (L)

Secondary: V1/F (L)

Secondary: CL/F (L/day)

Secondary: CL/F (L/day)

Secondary: Ka (day-1)

Secondary: Ka (day-1)

Secondary: T1/2 (day)

Secondary: T1/2 (day)

Secondary: Tmax (day)

Secondary: Tmax (day)

Secondary: Cmax (µg/mL)

Secondary: Cmax (µg/mL)

Secondary: Cmax.ss (µg/mL)

Secondary: Cmax.ss (µg/mL)

Secondary: AUCss (day* µg/mL)

Secondary: AUCss (day* µg/mL)

Secondary: Mean Changes in Hemoglobin over the study compared to baseline in the absence of RBC transfusions (Cohorts 1 and 3A)

Secondary: Mean Changes in Hemoglobin over the study compared to baseline in the absence of RBC transfusions (Cohorts 1 and 3A)

Secondary: The Number of Participants with Antidrug Antibody (ADA) Measurements

Secondary: The Number of Participants with Antidrug Antibody (ADA) Measurements

Secondary: The Number of Participants with a Mean Hemoglobin Increase >= 1.5 g/dL from Baseline Over any Consecutive 84-day Period (Cohorts 1 and 3A)

Secondary: The Number of Participants with a Mean Hemoglobin Increase >= 1.5 g/dL from Baseline Over any Consecutive 84-day Period (Cohorts 1 and 3A)

Adverse events

Adverse events

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Substantial protocol amendments (globally)

Interruptions (globally)

Limitations and caveats

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Clinical Trial Results:
A Phase 2, Multicenter, Open-Label Study to Evaluate the Efficacy and Safety of Luspatercept (ACE-536) in Subjects With Myeloproliferative Neoplasm-Associated Myelofibrosis and Anemia With and Without Red Blood Cell-Transfusion Dependence