Trial Outcomes & Findings for A Study to Compare the Efficacy and Safety of Luspatercept (ACE-536) Versus Epoetin Alfa for the Treatment of Anemia Due to IPSS-R Very Low, Low, or Intermediate Risk Myelodysplastic Syndromes (MDS) Participants Who Require Red Blood Cell Transfusions and Are ESA Naïve (NCT NCT03682536)

Last Updated: 2024-11-20

Results Overview

Percentage of participants who are RBC transfusion-free for any 12-week period associated with a concurrent mean hemoglobin (Hgb) increase ≥ 1.5 g/dL compared to baseline. After applying below 14/3-day rule, the baseline Hgb value is defined as the lowest Hgb value from the central, local laboratory, or pre transfusion Hgb from transfusion records that is within 56 days on or prior to the first dose of treatment, or randomization date if participants were not treated. 4/3-day rule: only Hgb values that are at least 14 days after a transfusion may be used unless there is another transfusion within 3 days after the Hgb assessment. If this occurs, that Hgb value will be used despite being \< 14 days after the previous transfusion.

Recruitment status

ACTIVE_NOT_RECRUITING

Study phase

PHASE3

Target enrollment

363 participants

Primary outcome timeframe

Week 1 through Week 24

Results posted on

2024-11-20

Participant Flow

Participant milestones

Participant milestones
Measure	Luspatercept Starting dose of 1.0 mg/kg subcutaneous injection every 3 weeks (21 days; Q3W). Dose levels can be increased in a stepwise manner beyond the starting dose to 1.33 mg/kg, and up to a maximum of 1.75 mg/kg.	Epoetin Alfa Starting dose of 450 IU/kg (maximum total starting dose is 40,000 IU) subcutaneous injection once every week (7 days; QW). Dose levels can be increased in a stepwise manner beyond the starting dose to 787.5 IU/kg, and up to a maximum of 1,050 IU/kg (with a maximum total dose of 80,000 IU).
Randomization STARTED	182	181
Randomization COMPLETED	182	179
Randomization NOT COMPLETED	0	2
Treatment STARTED	182	179
Treatment COMPLETED	78	53
Treatment NOT COMPLETED	104	126

Reasons for withdrawal

Reasons for withdrawal
Measure	Luspatercept Starting dose of 1.0 mg/kg subcutaneous injection every 3 weeks (21 days; Q3W). Dose levels can be increased in a stepwise manner beyond the starting dose to 1.33 mg/kg, and up to a maximum of 1.75 mg/kg.	Epoetin Alfa Starting dose of 450 IU/kg (maximum total starting dose is 40,000 IU) subcutaneous injection once every week (7 days; QW). Dose levels can be increased in a stepwise manner beyond the starting dose to 787.5 IU/kg, and up to a maximum of 1,050 IU/kg (with a maximum total dose of 80,000 IU).
Randomization Withdrawal by Subject	0	2
Treatment Other Reasons	8	7
Treatment Physician Decision	5	5
Treatment Protocol Violation	1	0
Treatment Study Terminated by Sponsor	1	2
Treatment Lost to Follow-up	0	1
Treatment Withdrawal by Subject	16	18
Treatment Lack of Efficacy	41	68
Treatment Disease Progression	9	7
Treatment Adverse Event	9	5
Treatment Death	14	13

Baseline Characteristics

A Study to Compare the Efficacy and Safety of Luspatercept (ACE-536) Versus Epoetin Alfa for the Treatment of Anemia Due to IPSS-R Very Low, Low, or Intermediate Risk Myelodysplastic Syndromes (MDS) Participants Who Require Red Blood Cell Transfusions and Are ESA Naïve

Baseline characteristics by cohort

Baseline characteristics by cohort
Measure	Luspatercept n=182 Participants Starting dose of 1.0 mg/kg subcutaneous injection every 3 weeks (21 days; Q3W). Dose levels can be increased in a stepwise manner beyond the starting dose to 1.33 mg/kg, and up to a maximum of 1.75 mg/kg.	Epoetin Alfa n=181 Participants Starting dose of 450 IU/kg (maximum total starting dose is 40,000 IU) subcutaneous injection once every week (7 days; QW). Dose levels can be increased in a stepwise manner beyond the starting dose to 787.5 IU/kg, and up to a maximum of 1,050 IU/kg (with a maximum total dose of 80,000 IU).	Total n=363 Participants Total of all reporting groups
Age, Continuous	73.5 Years STANDARD_DEVIATION 8.92 • n=5 Participants	73.4 Years STANDARD_DEVIATION 9.66 • n=7 Participants	73.4 Years STANDARD_DEVIATION 9.28 • n=5 Participants
Sex: Female, Male Female	73 Participants n=5 Participants	89 Participants n=7 Participants	162 Participants n=5 Participants
Sex: Female, Male Male	109 Participants n=5 Participants	92 Participants n=7 Participants	201 Participants n=5 Participants
Ethnicity (NIH/OMB) Hispanic or Latino	11 Participants n=5 Participants	12 Participants n=7 Participants	23 Participants n=5 Participants
Ethnicity (NIH/OMB) Not Hispanic or Latino	155 Participants n=5 Participants	156 Participants n=7 Participants	311 Participants n=5 Participants
Ethnicity (NIH/OMB) Unknown or Not Reported	16 Participants n=5 Participants	13 Participants n=7 Participants	29 Participants n=5 Participants
Race (NIH/OMB) American Indian or Alaska Native	0 Participants n=5 Participants	0 Participants n=7 Participants	0 Participants n=5 Participants
Race (NIH/OMB) Asian	19 Participants n=5 Participants	25 Participants n=7 Participants	44 Participants n=5 Participants
Race (NIH/OMB) Native Hawaiian or Other Pacific Islander	0 Participants n=5 Participants	0 Participants n=7 Participants	0 Participants n=5 Participants
Race (NIH/OMB) Black or African American	2 Participants n=5 Participants	0 Participants n=7 Participants	2 Participants n=5 Participants
Race (NIH/OMB) White	146 Participants n=5 Participants	143 Participants n=7 Participants	289 Participants n=5 Participants
Race (NIH/OMB) More than one race	0 Participants n=5 Participants	0 Participants n=7 Participants	0 Participants n=5 Participants
Race (NIH/OMB) Unknown or Not Reported	15 Participants n=5 Participants	13 Participants n=7 Participants	28 Participants n=5 Participants

PRIMARY outcome

Timeframe: Week 1 through Week 24

Population: ITT Population - all randomized participants regardless of whether or not the participant received treatment.

Outcome measures

Outcome measures
Measure	Luspatercept n=182 Participants Starting dose of 1.0 mg/kg subcutaneous injection every 3 weeks (21 days; Q3W). Dose levels can be increased in a stepwise manner beyond the starting dose to 1.33 mg/kg, and up to a maximum of 1.75 mg/kg.	Epoetin Alfa n=181 Participants Starting dose of 450 IU/kg (maximum total starting dose is 40,000 IU) subcutaneous injection once every week (7 days; QW). Dose levels can be increased in a stepwise manner beyond the starting dose to 787.5 IU/kg, and up to a maximum of 1,050 IU/kg (with a maximum total dose of 80,000 IU).
Percentage of Participants With Red Blood Cell Transfusion Independence (RBC-TI) for 12 Weeks (84 Days) With a Mean Hemoglobin Increase ≥ 1.5 g/dL	60.4 Percent of participants Interval 52.9 to 67.6	34.8 Percent of participants Interval 27.9 to 42.2

SECONDARY outcome

Timeframe: Week 1 through Week 24

Population: ITT Population - all randomized participants regardless of whether or not the participant received treatment.

Red blood cell transfusion independence (RBC-TI) for 24 weeks is defined as the percentage of participants who did not receive RBC transfusions from Week 1 through Week 24.

Outcome measures

Outcome measures
Measure	Luspatercept n=182 Participants Starting dose of 1.0 mg/kg subcutaneous injection every 3 weeks (21 days; Q3W). Dose levels can be increased in a stepwise manner beyond the starting dose to 1.33 mg/kg, and up to a maximum of 1.75 mg/kg.	Epoetin Alfa n=181 Participants Starting dose of 450 IU/kg (maximum total starting dose is 40,000 IU) subcutaneous injection once every week (7 days; QW). Dose levels can be increased in a stepwise manner beyond the starting dose to 787.5 IU/kg, and up to a maximum of 1,050 IU/kg (with a maximum total dose of 80,000 IU).
Percentage of Participants With Red Blood Cell Transfusion Independence (RBC-TI) for 24 Weeks	47.8 Percentage of participants Interval 40.4 to 55.3	30.9 Percentage of participants Interval 24.3 to 38.2

SECONDARY outcome

Timeframe: Week 1 through Week 24

Population: ITT Population (all randomized participants regardless of whether or not the participant received treatment) with baseline measurements.

Mean hemoglobin (Hgb) change over the 24-week period of Week 1 through Week 24 compared to baseline. After applying below 14/3-day rule, the baseline Hgb value is defined as the lowest Hgb value from the central, local laboratory, or pre transfusion Hgb from transfusion records that is within 56 days on or prior to the first dose of treatment, or randomization date if participants were not treated. 4/3-day rule: only Hgb values that are at least 14 days after a transfusion may be used unless there is another transfusion within 3 days after the Hgb assessment. If this occurs, that Hgb value will be used despite being \< 14 days after the previous transfusion.

Outcome measures

Outcome measures
Measure	Luspatercept n=181 Participants Starting dose of 1.0 mg/kg subcutaneous injection every 3 weeks (21 days; Q3W). Dose levels can be increased in a stepwise manner beyond the starting dose to 1.33 mg/kg, and up to a maximum of 1.75 mg/kg.	Epoetin Alfa n=176 Participants Starting dose of 450 IU/kg (maximum total starting dose is 40,000 IU) subcutaneous injection once every week (7 days; QW). Dose levels can be increased in a stepwise manner beyond the starting dose to 787.5 IU/kg, and up to a maximum of 1,050 IU/kg (with a maximum total dose of 80,000 IU).
Mean Hemoglobin Change Over 24 Weeks	2.0 g/dL Standard Deviation 1.14	1.5 g/dL Standard Deviation 1.12

SECONDARY outcome

Timeframe: Week 1 through Week 24

Population: ITT Population - all randomized participants regardless of whether or not the participant received treatment.

The percentage of participants meeting the modified HI-E criteria per the International Working Group (IWG) sustained over any consecutive 56-day period in Week 1-24: For participants with baseline red blood cell (RBC) transfusion burden of \>= 4 units/8 weeks, a reduction of at least 4 units RBC transfusion; for participants with baseline RBC transfusion burden of \< 4 units/8 weeks, mean increase of hemoglobin of at least 1.5 g/dL in the absence of transfusions.

Outcome measures

Outcome measures
Measure	Luspatercept n=182 Participants Starting dose of 1.0 mg/kg subcutaneous injection every 3 weeks (21 days; Q3W). Dose levels can be increased in a stepwise manner beyond the starting dose to 1.33 mg/kg, and up to a maximum of 1.75 mg/kg.	Epoetin Alfa n=181 Participants Starting dose of 450 IU/kg (maximum total starting dose is 40,000 IU) subcutaneous injection once every week (7 days; QW). Dose levels can be increased in a stepwise manner beyond the starting dose to 787.5 IU/kg, and up to a maximum of 1,050 IU/kg (with a maximum total dose of 80,000 IU).
Percentage of Participants Achieving Hematologic Improvement - Erythroid Response (HI-E) Per IWG	74.2 Percentage of participants Interval 67.2 to 80.4	53.0 Percentage of participants Interval 45.5 to 60.5

SECONDARY outcome

Timeframe: Week 1 through Week 24

Population: ITT Population (all randomized participants regardless of whether or not the participant received treatment) who achieve HI-E response (Week 1-24)

Time from first dose to first onset of achieving modified HI-E. The modified HI-E criteria per the International Working Group (IWG) sustained over any consecutive 56-day period in Week 1-24: For participants with baseline red blood cell (RBC) transfusion burden of \>= 4 units/8 weeks, a reduction of at least 4 units RBC transfusion; for participants with baseline RBC transfusion burden of \< 4 units/8 weeks, mean increase of hemoglobin of at least 1.5 g/dL in the absence of transfusions.

Outcome measures

Outcome measures
Measure	Luspatercept n=135 Participants Starting dose of 1.0 mg/kg subcutaneous injection every 3 weeks (21 days; Q3W). Dose levels can be increased in a stepwise manner beyond the starting dose to 1.33 mg/kg, and up to a maximum of 1.75 mg/kg.	Epoetin Alfa n=96 Participants Starting dose of 450 IU/kg (maximum total starting dose is 40,000 IU) subcutaneous injection once every week (7 days; QW). Dose levels can be increased in a stepwise manner beyond the starting dose to 787.5 IU/kg, and up to a maximum of 1,050 IU/kg (with a maximum total dose of 80,000 IU).
Time to Hematologic Improvement - Erythroid Response (HI-E)	1.0 Days Interval 1.0 to 113.0	6.0 Days Interval 1.0 to 108.0

SECONDARY outcome

Timeframe: Week 1 through Week 24

Population: ITT Population - all randomized participants regardless of whether or not the participant received treatment.

Percentage of participants who are RBC transfusion-free over a consecutive 84-day period.

Outcome measures

Outcome measures
Measure	Luspatercept n=182 Participants Starting dose of 1.0 mg/kg subcutaneous injection every 3 weeks (21 days; Q3W). Dose levels can be increased in a stepwise manner beyond the starting dose to 1.33 mg/kg, and up to a maximum of 1.75 mg/kg.	Epoetin Alfa n=181 Participants Starting dose of 450 IU/kg (maximum total starting dose is 40,000 IU) subcutaneous injection once every week (7 days; QW). Dose levels can be increased in a stepwise manner beyond the starting dose to 787.5 IU/kg, and up to a maximum of 1,050 IU/kg (with a maximum total dose of 80,000 IU).
Percentage of Participants Achieving Red Blood Cell Transfusion Independence (RBC-TI) for ≥ 12 Weeks (84 Days)	68.1 Percent of participants Interval 60.8 to 74.8	48.6 Percent of participants Interval 41.1 to 56.1

SECONDARY outcome

Timeframe: Week 1 through End of Treatment (Up to approximately an average of 66 weeks and a maximum of 202 weeks)

Population: ITT Population (all randomized participants regardless of whether or not the participant received treatment) who were RBC-TI \>= 12 Weeks (Week 1-24) responders

Maximum duration of RBC transfusion independence for participants who achieve RBC-TI ≥ 84 days.

Outcome measures

Outcome measures
Measure	Luspatercept n=124 Participants Starting dose of 1.0 mg/kg subcutaneous injection every 3 weeks (21 days; Q3W). Dose levels can be increased in a stepwise manner beyond the starting dose to 1.33 mg/kg, and up to a maximum of 1.75 mg/kg.	Epoetin Alfa n=88 Participants Starting dose of 450 IU/kg (maximum total starting dose is 40,000 IU) subcutaneous injection once every week (7 days; QW). Dose levels can be increased in a stepwise manner beyond the starting dose to 787.5 IU/kg, and up to a maximum of 1,050 IU/kg (with a maximum total dose of 80,000 IU).
Duration of Red Blood Cell Transfusion Independence (RBC-TI) ≥ 12 Weeks (84 Days)	128.1 Weeks Interval 108.3 to Insufficient number of participants with events	89.7 Weeks Interval 55.9 to 157.3

SECONDARY outcome

Timeframe: Week 1 through Week 24

Population: ITT Population (all randomized participants regardless of whether or not the participant received treatment) who were RBC-TI \>= 12 Weeks (Week 1-24) responders

Time from first dose to first onset of transfusion independence ≥ 84 days.

Outcome measures

Outcome measures
Measure	Luspatercept n=124 Participants Starting dose of 1.0 mg/kg subcutaneous injection every 3 weeks (21 days; Q3W). Dose levels can be increased in a stepwise manner beyond the starting dose to 1.33 mg/kg, and up to a maximum of 1.75 mg/kg.	Epoetin Alfa n=88 Participants Starting dose of 450 IU/kg (maximum total starting dose is 40,000 IU) subcutaneous injection once every week (7 days; QW). Dose levels can be increased in a stepwise manner beyond the starting dose to 787.5 IU/kg, and up to a maximum of 1,050 IU/kg (with a maximum total dose of 80,000 IU).
Time to Red Blood Cell Transfusion Independence (RBC-TI) ≥ 12 Weeks (84 Days)	1.0 Days Interval 1.0 to 75.0	1.0 Days Interval 1.0 to 85.0

SECONDARY outcome

Timeframe: Week 1 through End of Treatment (Up to approximately an average of 66 weeks and a maximum of 202 weeks)

Population: ITT Population - all randomized participants regardless of whether or not the participant received treatment.

Time to first RBC transfusion is defined as time from Week 1 to first RBC transfusion on treatment. Participants who maintain RBC-TI through the end of the Treatment Period or time of analysis will be censored at EOT visit date, subsequent MDS therapy start date, study discontinuation date, analysis cutoff date or death, whichever occurs first. Median is from un-stratified Kaplan-Meier method.

Outcome measures

Outcome measures
Measure	Luspatercept n=182 Participants Starting dose of 1.0 mg/kg subcutaneous injection every 3 weeks (21 days; Q3W). Dose levels can be increased in a stepwise manner beyond the starting dose to 1.33 mg/kg, and up to a maximum of 1.75 mg/kg.	Epoetin Alfa n=181 Participants Starting dose of 450 IU/kg (maximum total starting dose is 40,000 IU) subcutaneous injection once every week (7 days; QW). Dose levels can be increased in a stepwise manner beyond the starting dose to 787.5 IU/kg, and up to a maximum of 1,050 IU/kg (with a maximum total dose of 80,000 IU).
Time to First Red Blood Cell (RBC) Transfusion	155.0 Days Interval 80.0 to 266.0	42.0 Days Interval 23.0 to 55.0

SECONDARY outcome

Timeframe: Week 1 through Week 24

Population: All participants who were randomized and received at least one dose.

RBC transfusion burden on treatment is defined as total number of packed red blood cell (pRBC) units transfused within the first 24 weeks of treatment since Week 1.

Outcome measures

Outcome measures
Measure	Luspatercept n=182 Participants Starting dose of 1.0 mg/kg subcutaneous injection every 3 weeks (21 days; Q3W). Dose levels can be increased in a stepwise manner beyond the starting dose to 1.33 mg/kg, and up to a maximum of 1.75 mg/kg.	Epoetin Alfa n=179 Participants Starting dose of 450 IU/kg (maximum total starting dose is 40,000 IU) subcutaneous injection once every week (7 days; QW). Dose levels can be increased in a stepwise manner beyond the starting dose to 787.5 IU/kg, and up to a maximum of 1,050 IU/kg (with a maximum total dose of 80,000 IU).
The Number of Red Blood Cell (RBC) Units Transfused Within the First 24 Weeks of Treatment	3.8 RBC units Standard Deviation 5.90	5.2 RBC units Standard Deviation 6.36

SECONDARY outcome

Timeframe: Week 1 through Week 24

Population: ITT Population - all randomized participants regardless of whether or not the participant received treatment.

Defined as percentage of participants achieving RBC-TI for \>= 56 days during any consecutive 56-day period from Week 1 through Week 24.

Outcome measures

Outcome measures
Measure	Luspatercept n=182 Participants Starting dose of 1.0 mg/kg subcutaneous injection every 3 weeks (21 days; Q3W). Dose levels can be increased in a stepwise manner beyond the starting dose to 1.33 mg/kg, and up to a maximum of 1.75 mg/kg.	Epoetin Alfa n=181 Participants Starting dose of 450 IU/kg (maximum total starting dose is 40,000 IU) subcutaneous injection once every week (7 days; QW). Dose levels can be increased in a stepwise manner beyond the starting dose to 787.5 IU/kg, and up to a maximum of 1,050 IU/kg (with a maximum total dose of 80,000 IU).
Percentage of Participants Achieving Red Blood Cell Transfusion Independence (RBC-TI) for ≥ 56 Days (8 Weeks)	79.1 Percent of Participants Interval 72.5 to 84.8	64.6 Percent of Participants Interval 57.2 to 71.6

SECONDARY outcome

Timeframe: Week 1 through Week 48

Population: ITT Population (all randomized participants regardless of whether or not the participant received treatment) whose first dose date is at least 337 days from the cutoff date or discontinued early are included in this analysis.

Defined as percentage of participants achieving RBC-TI for \>= 168 days during any consecutive 168-day period from Week 1 through Week 48.

Outcome measures

Outcome measures
Measure	Luspatercept n=163 Participants Starting dose of 1.0 mg/kg subcutaneous injection every 3 weeks (21 days; Q3W). Dose levels can be increased in a stepwise manner beyond the starting dose to 1.33 mg/kg, and up to a maximum of 1.75 mg/kg.	Epoetin Alfa n=167 Participants Starting dose of 450 IU/kg (maximum total starting dose is 40,000 IU) subcutaneous injection once every week (7 days; QW). Dose levels can be increased in a stepwise manner beyond the starting dose to 787.5 IU/kg, and up to a maximum of 1,050 IU/kg (with a maximum total dose of 80,000 IU).
Percentage of Participants Achieving Red Blood Cell Transfusion Independence (RBC-TI) for a Consecutive 24-week Period	60.7 Percent of participants Interval 52.8 to 68.3	39.5 Percent of participants Interval 32.1 to 47.4

SECONDARY outcome

Timeframe: From randomization to 5 years from first dose or 3 years from last dose (whichever occurs later), unless the participant withdraws consent from the study, dies or is lost to follow-up. (Up to approximately 221 weeks)

Population: ITT Population - all randomized participants regardless of whether or not the participant received treatment.

Progression to AML is defined as a diagnosis of AML as per WHO classification of ≥ 20% blasts in peripheral blood or bone marrow.

Outcome measures

Outcome measures
Measure	Luspatercept n=182 Participants Starting dose of 1.0 mg/kg subcutaneous injection every 3 weeks (21 days; Q3W). Dose levels can be increased in a stepwise manner beyond the starting dose to 1.33 mg/kg, and up to a maximum of 1.75 mg/kg.	Epoetin Alfa n=181 Participants Starting dose of 450 IU/kg (maximum total starting dose is 40,000 IU) subcutaneous injection once every week (7 days; QW). Dose levels can be increased in a stepwise manner beyond the starting dose to 787.5 IU/kg, and up to a maximum of 1,050 IU/kg (with a maximum total dose of 80,000 IU).
The Number of Participants With Acute Myeloid Leukemia (AML) Progression	5 Participants	6 Participants

SECONDARY outcome

Timeframe: From randomization to first diagnosis of AML up to 5 years from first dose or 3 years from last dose (whichever occurs later), unless the participant withdraws consent from the study, dies or is lost to follow-up. (Up to approximately 221 weeks)

Population: ITT Population: all randomized participants regardless of whether or not the participant received treatment

Time to AML progression is defined as the time between randomization and first diagnosis of AML as per WHO classification of ≥ 20% blasts in peripheral blood or bone marrow. Participants with diagnosis of AML will be considered to have had an event. Participants who have not progressed to AML at the time of analysis will be censored at the last assessment date which does not indicate progression to AML estimated by Kaplan-Meier method.

Outcome measures

Outcome measures
Measure	Luspatercept n=182 Participants Starting dose of 1.0 mg/kg subcutaneous injection every 3 weeks (21 days; Q3W). Dose levels can be increased in a stepwise manner beyond the starting dose to 1.33 mg/kg, and up to a maximum of 1.75 mg/kg.	Epoetin Alfa n=181 Participants Starting dose of 450 IU/kg (maximum total starting dose is 40,000 IU) subcutaneous injection once every week (7 days; QW). Dose levels can be increased in a stepwise manner beyond the starting dose to 787.5 IU/kg, and up to a maximum of 1,050 IU/kg (with a maximum total dose of 80,000 IU).
Median Time to Acute Myeloid Leukemia (AML) Progression	NA Months Insufficient number of participants with events	NA Months Insufficient number of participants with events

SECONDARY outcome

Timeframe: Randomization to death due to any cause up to 5 years from first dose or 3 years from last dose (whichever occurs later), unless the participant withdraws consent from the study, dies or is lost to follow-up. (Up to approximately 221 weeks)

Population: ITT Population - all randomized participants regardless of whether or not the participant received treatment.

Time from date of randomization to death due to any cause

Outcome measures

Outcome measures
Measure	Luspatercept n=182 Participants Starting dose of 1.0 mg/kg subcutaneous injection every 3 weeks (21 days; Q3W). Dose levels can be increased in a stepwise manner beyond the starting dose to 1.33 mg/kg, and up to a maximum of 1.75 mg/kg.	Epoetin Alfa n=181 Participants Starting dose of 450 IU/kg (maximum total starting dose is 40,000 IU) subcutaneous injection once every week (7 days; QW). Dose levels can be increased in a stepwise manner beyond the starting dose to 787.5 IU/kg, and up to a maximum of 1,050 IU/kg (with a maximum total dose of 80,000 IU).
Overall Survival (OS)	NA Months Interval 35.3 to Insufficient number of participants with events	42.8 Months Interval 42.8 to Insufficient number of participants with events

SECONDARY outcome

Timeframe: From first dose to 42 days post last dose (Up to approximately an average of 72 weeks and a maximum of 208 weeks)

Population: Safety Population - all participants who were randomized and received at least one dose of treatment.

Treatment-emergent adverse events include adverse events that started on or after the first dose of treatment until 42 days after the last dose of treatment, as well as those serious adverse events (SAEs) made known to the investigator at any time thereafter that are suspected of being related to treatment. The severity/intensity of AEs were graded according to the National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE, Version 4.0). Grade 3 = Severe, Grade 4 = Life-threatening, and Grade 5 = Death.

Outcome measures

Outcome measures
Measure	Luspatercept n=182 Participants Starting dose of 1.0 mg/kg subcutaneous injection every 3 weeks (21 days; Q3W). Dose levels can be increased in a stepwise manner beyond the starting dose to 1.33 mg/kg, and up to a maximum of 1.75 mg/kg.	Epoetin Alfa n=179 Participants Starting dose of 450 IU/kg (maximum total starting dose is 40,000 IU) subcutaneous injection once every week (7 days; QW). Dose levels can be increased in a stepwise manner beyond the starting dose to 787.5 IU/kg, and up to a maximum of 1,050 IU/kg (with a maximum total dose of 80,000 IU).
The Number of Participants With Adverse Events (AEs) One Suspected Related Serious TEAE	1 Participants	3 Participants
The Number of Participants With Adverse Events (AEs) NCI CTCAE Grade 3 or 4 TEAEs	107 Participants	88 Participants
The Number of Participants With Adverse Events (AEs) Suspected Related NCI CTCAE Grade 3 or 4 TEAEs	14 Participants	4 Participants
The Number of Participants With Adverse Events (AEs) One TEAE Leading to Dose Withdrawn	21 Participants	13 Participants
The Number of Participants With Adverse Events (AEs) One TEAE	178 Participants	165 Participants
The Number of Participants With Adverse Events (AEs) One Suspected Related TEAE	61 Participants	36 Participants
The Number of Participants With Adverse Events (AEs) One Serious TEAE	82 Participants	71 Participants
The Number of Participants With Adverse Events (AEs) NCI CTCAE Grade 5 TEAE	15 Participants	14 Participants
The Number of Participants With Adverse Events (AEs) Suspected Related NCI CTCAE Grade 5 TEAE	1 Participants	0 Participants
The Number of Participants With Adverse Events (AEs) One TEAE Leading to Dose Interruption	61 Participants	51 Participants
The Number of Participants With Adverse Events (AEs) One TEAE Leading to Dose Reduction	7 Participants	6 Participants

SECONDARY outcome

Timeframe: Day 1 on week 4, 10, 16, 22, and every 12 weeks (±14 days) from the 24-Week MDS Assessment visit for up to one year from the first dose

Population: Safety Population (all participants who were randomized and received at least one dose of treatment) with baseline and at least one post-baseline immunogenicity assessment result. - Luspatercept Arm Only.

Number of participants under each ADA positive category. A participant is counted as 'Treatment-Emergent' if there is a positive post-baseline sample while the baseline sample is ADA negative, or there is a positive post-baseline sample with a titer \>= 4-fold of the baseline titer while the baseline sample is ADA positive. A participant is counted as 'Preexisting' if the baseline sample is ADA positive and the participant is not qualified for 'Treatment-Emergent'. If the participant was discontinued from study treatment earlier than one year from the first dose, additional samples will be collected if last ADA is positive. Baseline is defined as the last value on or before the first dose of study drug.

Outcome measures

Outcome measures
Measure	Luspatercept n=176 Participants Starting dose of 1.0 mg/kg subcutaneous injection every 3 weeks (21 days; Q3W). Dose levels can be increased in a stepwise manner beyond the starting dose to 1.33 mg/kg, and up to a maximum of 1.75 mg/kg.	Epoetin Alfa Starting dose of 450 IU/kg (maximum total starting dose is 40,000 IU) subcutaneous injection once every week (7 days; QW). Dose levels can be increased in a stepwise manner beyond the starting dose to 787.5 IU/kg, and up to a maximum of 1,050 IU/kg (with a maximum total dose of 80,000 IU).
Number of Participants With a Positive Anti-drug Antibody (ADA) Test Preexisting	4 Participants	—
Number of Participants With a Positive Anti-drug Antibody (ADA) Test Treatment-emergent	11 Participants	—

SECONDARY outcome

Timeframe: Baseline and week 24.

Population: All randomized participants who completed the EORTC QLQ-C30 assessment at baseline and post-baseline assessment at the respective visit.

The EORTC QLQ-C30 is composed of 30 items that includes a global health status score ranging from: 1-7 as well as scores for 5 functional scales (physical, role, emotional, cognitive and social), 3 symptom scales (fatigue, nausea/vomiting, and pain) and 6 single items (dyspnea, insomnia, appetite loss, constipation, diarrhea, and financial difficulties) all ranging from 1-4. Subscale scores are transformed to a 0 to 100 scale. A high score for a functional scale represents a high or healthy level of functioning; a high score for the global health status/health related quality of life (HRQoL) represents a high overall HRQoL; but a high score for a symptom scale represents a high level of symptomatology or problems. Baseline is defined as the last value on or before the first dose of study drug.

Outcome measures

Outcome measures
Measure	Luspatercept n=125 Participants Starting dose of 1.0 mg/kg subcutaneous injection every 3 weeks (21 days; Q3W). Dose levels can be increased in a stepwise manner beyond the starting dose to 1.33 mg/kg, and up to a maximum of 1.75 mg/kg.	Epoetin Alfa n=110 Participants Starting dose of 450 IU/kg (maximum total starting dose is 40,000 IU) subcutaneous injection once every week (7 days; QW). Dose levels can be increased in a stepwise manner beyond the starting dose to 787.5 IU/kg, and up to a maximum of 1,050 IU/kg (with a maximum total dose of 80,000 IU).
Change From Baseline in the European Organization for Research and Treatment of Cancer Quality-of-Life Questionnaire (EORTC QLQ-C30) Global Health Status / QoL	1.7 Score on a scale Standard Deviation 16.70	2.7 Score on a scale Standard Deviation 20.99
Change From Baseline in the European Organization for Research and Treatment of Cancer Quality-of-Life Questionnaire (EORTC QLQ-C30) Physical Functioning	0.1 Score on a scale Standard Deviation 16.32	4.4 Score on a scale Standard Deviation 18.30
Change From Baseline in the European Organization for Research and Treatment of Cancer Quality-of-Life Questionnaire (EORTC QLQ-C30) Role Functioning	-1.9 Score on a scale Standard Deviation 25.59	-2.6 Score on a scale Standard Deviation 26.92
Change From Baseline in the European Organization for Research and Treatment of Cancer Quality-of-Life Questionnaire (EORTC QLQ-C30) Emotional Functioning	2.5 Score on a scale Standard Deviation 17.17	3.4 Score on a scale Standard Deviation 18.32
Change From Baseline in the European Organization for Research and Treatment of Cancer Quality-of-Life Questionnaire (EORTC QLQ-C30) Cognitive Functioning	2.0 Score on a scale Standard Deviation 17.79	0.2 Score on a scale Standard Deviation 20.75
Change From Baseline in the European Organization for Research and Treatment of Cancer Quality-of-Life Questionnaire (EORTC QLQ-C30) Social Functioning	-2.9 Score on a scale Standard Deviation 20.64	-0.9 Score on a scale Standard Deviation 24.09
Change From Baseline in the European Organization for Research and Treatment of Cancer Quality-of-Life Questionnaire (EORTC QLQ-C30) Fatigue	-1.9 Score on a scale Standard Deviation 19.84	-9.0 Score on a scale Standard Deviation 23.77
Change From Baseline in the European Organization for Research and Treatment of Cancer Quality-of-Life Questionnaire (EORTC QLQ-C30) Nausea and Vomiting	2.1 Score on a scale Standard Deviation 12.34	-1.2 Score on a scale Standard Deviation 13.11
Change From Baseline in the European Organization for Research and Treatment of Cancer Quality-of-Life Questionnaire (EORTC QLQ-C30) Pain	-2.1 Score on a scale Standard Deviation 25.40	-1.7 Score on a scale Standard Deviation 21.77
Change From Baseline in the European Organization for Research and Treatment of Cancer Quality-of-Life Questionnaire (EORTC QLQ-C30) Dyspnea	-1.6 Score on a scale Standard Deviation 22.34	-8.8 Score on a scale Standard Deviation 26.59
Change From Baseline in the European Organization for Research and Treatment of Cancer Quality-of-Life Questionnaire (EORTC QLQ-C30) Insomnia	-4.0 Score on a scale Standard Deviation 26.30	-3.0 Score on a scale Standard Deviation 33.95
Change From Baseline in the European Organization for Research and Treatment of Cancer Quality-of-Life Questionnaire (EORTC QLQ-C30) Appetite Loss	-1.1 Score on a scale Standard Deviation 23.55	-0.0 Score on a scale Standard Deviation 25.14
Change From Baseline in the European Organization for Research and Treatment of Cancer Quality-of-Life Questionnaire (EORTC QLQ-C30) Constipation	-0.8 Score on a scale Standard Deviation 21.36	0.9 Score on a scale Standard Deviation 23.23
Change From Baseline in the European Organization for Research and Treatment of Cancer Quality-of-Life Questionnaire (EORTC QLQ-C30) Diarrhea	1.6 Score on a scale Standard Deviation 14.58	1.2 Score on a scale Standard Deviation 18.58
Change From Baseline in the European Organization for Research and Treatment of Cancer Quality-of-Life Questionnaire (EORTC QLQ-C30) Financial difficulties	-0.8 Score on a scale Standard Deviation 19.15	-1.5 Score on a scale Standard Deviation 22.75

SECONDARY outcome

Timeframe: Baseline, Day 1 on weeks 7,13,19, and 24.

Population: All randomized participants who completed the Fact-An assessment at baseline and post-baseline assessment at the respective visit.

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) (so that 0 is considered worse quality of life and 4 is good response) 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.

Outcome measures

Outcome measures
Measure	Luspatercept n=145 Participants Starting dose of 1.0 mg/kg subcutaneous injection every 3 weeks (21 days; Q3W). Dose levels can be increased in a stepwise manner beyond the starting dose to 1.33 mg/kg, and up to a maximum of 1.75 mg/kg.	Epoetin Alfa n=133 Participants Starting dose of 450 IU/kg (maximum total starting dose is 40,000 IU) subcutaneous injection once every week (7 days; QW). Dose levels can be increased in a stepwise manner beyond the starting dose to 787.5 IU/kg, and up to a maximum of 1,050 IU/kg (with a maximum total dose of 80,000 IU).
Change From Baseline in the Functional Assessment of Cancer Therapy-Anemia Version 4 (FACT-An) W7D1	2.1 Score on a scale Standard Deviation 17.41	3.7 Score on a scale Standard Deviation 16.43
Change From Baseline in the Functional Assessment of Cancer Therapy-Anemia Version 4 (FACT-An) W13D1	1.8 Score on a scale Standard Deviation 20.58	4.5 Score on a scale Standard Deviation 20.36
Change From Baseline in the Functional Assessment of Cancer Therapy-Anemia Version 4 (FACT-An) W19D1	-0.2 Score on a scale Standard Deviation 19.30	3.1 Score on a scale Standard Deviation 23.07
Change From Baseline in the Functional Assessment of Cancer Therapy-Anemia Version 4 (FACT-An) Week 24 (D169)	1.5 Score on a scale Standard Deviation 21.39	2.8 Score on a scale Standard Deviation 22.18

SECONDARY outcome

Timeframe: Day 1 on week 4, 10, 16, 22, and every 12 weeks (±14 days) from the 24-Week MDS Assessment visit for up to one year from the first dose

Outcome measures

Outcome data not reported

SECONDARY outcome

Timeframe: Day 1 on week 4, 10, 16, 22, and every 12 weeks (±14 days) from the 24-Week MDS Assessment visit for up to one year from the first dose

Outcome measures

Outcome data not reported

Adverse Events

Luspatercept

Serious events: 82 serious events

Other events: 153 other events

Deaths: 39 deaths

Epoetin Alfa

Serious events: 71 serious events

Other events: 134 other events

Deaths: 38 deaths

Serious adverse events

Other adverse events

Additional Information

Bristol-Myers Squibb Study Director

Bristol-Myers Squibb

Phone: Please email

Email: [email protected]

Results disclosure agreements

Principal investigator is a sponsor employee Bristol-Myers Squibb Co. agreements with investigators vary; constant is our right to embargo communications regarding trial results prior to public release for a period ≤60 days from submittal for review. We will not prohibit investigators from publishing, but will prohibit the disclosure of previously undisclosed confidential information other than study results, and request postponement of single-center publications until after disclosure of the clinical trial's primary publication.
Publication restrictions are in place

Restriction type: OTHER