Trial Outcomes & Findings for A Study of Luspatercept (ACE-536) to Treat Anemia Due to Very Low, Low, or Intermediate Risk Myelodysplastic Syndromes (NCT NCT02631070)

Last Updated: 2021-12-17

Results Overview

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

Recruitment status

COMPLETED

Study phase

PHASE3

Target enrollment

229 participants

Primary outcome timeframe

From Week 1 through Week 24 of study treatment

Results posted on

2021-12-17

Participant Flow

229 participants were randomized and treated.

Participant milestones

Participant milestones
Measure	Luspatercept Luspatercept 1.0 mg/Kg SC on Day 1 of each 21-day treatment cycle	Placebo Placebo (Volume equivalent to experimental arm) SC on Day 1 of each 21-day treatment cycle
Overall Study STARTED	153	76
Overall Study COMPLETED	4	12
Overall Study NOT COMPLETED	149	64

Reasons for withdrawal

Reasons for withdrawal
Measure	Luspatercept Luspatercept 1.0 mg/Kg SC on Day 1 of each 21-day treatment cycle	Placebo Placebo (Volume equivalent to experimental arm) SC on Day 1 of each 21-day treatment cycle
Overall Study Lost to Follow-up	5	1
Overall Study Withdrawal by Subject	35	13
Overall Study Death	45	24
Overall Study Transition to rollover protocol	52	21
Overall Study Other reasons	12	5

Baseline Characteristics

A Study of Luspatercept (ACE-536) to Treat Anemia Due to Very Low, Low, or Intermediate Risk Myelodysplastic Syndromes

Baseline characteristics by cohort

Baseline characteristics by cohort
Measure	Luspatercept n=153 Participants Luspatercept 1.0 mg/Kg SC on Day 1 of each 21-day treatment cycle	Placebo n=76 Participants Placebo (Volume equivalent to experimental arm) SC on Day 1 of each 21-day treatment cycle	Total n=229 Participants Total of all reporting groups
Age, Continuous	70.5 Years STANDARD_DEVIATION 8.68 • n=5 Participants	70.7 Years STANDARD_DEVIATION 10.88 • n=7 Participants	70.6 Years STANDARD_DEVIATION 9.44 • n=5 Participants
Sex: Female, Male Female	59 Participants n=5 Participants	26 Participants n=7 Participants	85 Participants n=5 Participants
Sex: Female, Male Male	94 Participants n=5 Participants	50 Participants n=7 Participants	144 Participants n=5 Participants
Ethnicity (NIH/OMB) Hispanic or Latino	3 Participants n=5 Participants	4 Participants n=7 Participants	7 Participants n=5 Participants
Ethnicity (NIH/OMB) Not Hispanic or Latino	115 Participants n=5 Participants	52 Participants n=7 Participants	167 Participants n=5 Participants
Ethnicity (NIH/OMB) Unknown or Not Reported	35 Participants n=5 Participants	20 Participants n=7 Participants	55 Participants n=5 Participants
Race/Ethnicity, Customized Black or African American	1 Participants n=5 Participants	0 Participants n=7 Participants	1 Participants n=5 Participants
Race/Ethnicity, Customized White	107 Participants n=5 Participants	51 Participants n=7 Participants	158 Participants n=5 Participants
Race/Ethnicity, Customized Not Collected or Reported	44 Participants n=5 Participants	24 Participants n=7 Participants	68 Participants n=5 Participants
Race/Ethnicity, Customized Other	1 Participants n=5 Participants	1 Participants n=7 Participants	2 Participants n=5 Participants

PRIMARY outcome

Timeframe: From Week 1 through Week 24 of study treatment

Population: All treated participants

Outcome measures

Outcome measures
Measure	Luspatercept n=153 Participants Luspatercept 1.0 mg/Kg SC on Day 1 of each 21-day treatment cycle	Placebo n=76 Participants Placebo (Volume equivalent to experimental arm) SC on Day 1 of each 21-day treatment cycle
Percentage Of Participants Who Achieved Red Blood Cell Transfusion Independence (RBC-TI) ≥ 8 Weeks From Week 1 to Week 24	37.91 Percent of Participants Interval 30.2 to 46.1	13.16 Percent of Participants Interval 6.49 to 22.87

SECONDARY outcome

Timeframe: From Week 1 through Week 24 of study treatment

Population: All treated participants

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

Outcome measures

Outcome measures
Measure	Luspatercept n=153 Participants Luspatercept 1.0 mg/Kg SC on Day 1 of each 21-day treatment cycle	Placebo n=76 Participants Placebo (Volume equivalent to experimental arm) SC on Day 1 of each 21-day treatment cycle
Percentage of Participants Who Achieved Red Blood Cell Transfusion Independence (RBC-TI) ≥ 12 Weeks From Week 1 to Week 24	28.10 Percent of Participants Interval 21.14 to 35.93	7.89 Percent of Participants Interval 2.95 to 16.4

SECONDARY outcome

Timeframe: From Week 1 through Week 48 of study treatment

Population: All treated participants

Outcome measures

Outcome measures
Measure	Luspatercept n=153 Participants Luspatercept 1.0 mg/Kg SC on Day 1 of each 21-day treatment cycle	Placebo n=76 Participants Placebo (Volume equivalent to experimental arm) SC on Day 1 of each 21-day treatment cycle
Percentage of Participants Who Achieved Red Blood Cell Transfusion Independence (RBC-TI) ≥ 12 Weeks From Week 1 to Week 48	33.33 Percent of Participants Interval 25.93 to 41.4	11.84 Percent of Participants Interval 5.56 to 21.29

SECONDARY outcome

Timeframe: From Week 1 through Week 48 of study treatment

Population: All treated participants

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

Outcome measures

Outcome measures
Measure	Luspatercept n=153 Participants Luspatercept 1.0 mg/Kg SC on Day 1 of each 21-day treatment cycle	Placebo n=76 Participants Placebo (Volume equivalent to experimental arm) SC on Day 1 of each 21-day treatment cycle
Percentage of Participants Who Achieved Red Blood Cell Transfusion Independence (RBC-TI) ≥ 8 Weeks From Week 1 Through Week 48	45.10 Percentage of Participants Interval 37.05 to 53.34	15.79 Percentage of Participants Interval 8.43 to 25.96

SECONDARY outcome

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

Population: All treated participants with available measurements at the indicated timepoints

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

Outcome measures

Outcome measures
Measure	Luspatercept n=128 Participants Luspatercept 1.0 mg/Kg SC on Day 1 of each 21-day treatment cycle	Placebo n=68 Participants Placebo (Volume equivalent to experimental arm) SC on Day 1 of each 21-day treatment cycle
Change From Baseline in RBC Units Transfused Over Fixed 16-Week Period Weeks 9 to 24	-3.0 Units Standard Deviation 5.17	0.4 Units Standard Deviation 4.25
Change From Baseline in RBC Units Transfused Over Fixed 16-Week Period Weeks 33 to 48	-4.9 Units Standard Deviation 4.22	-3.9 Units Standard Deviation 7.14

SECONDARY outcome

Timeframe: Week 1 through 24 or Week 1 Through Week 48

Population: All treated participants

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

Outcome measures

Outcome measures
Measure	Luspatercept n=153 Participants Luspatercept 1.0 mg/Kg SC on Day 1 of each 21-day treatment cycle	Placebo n=76 Participants Placebo (Volume equivalent to experimental arm) SC on Day 1 of each 21-day treatment cycle
Percentage of Participants Who Achieved a Modified Hematologic Erythroid Response (mHI-E) Over Any Consecutive 56-Day Period Week 1 Through Week 24	52.9 Percentage of Participants Interval 44.72 to 61.05	11.8 Percentage of Participants Interval 5.56 to 21.29
Percentage of Participants Who Achieved a Modified Hematologic Erythroid Response (mHI-E) Over Any Consecutive 56-Day Period Week 1 Through Week 48	58.8 Percentage of Participants Interval 50.59 to 66.71	17.1 Percentage of Participants Interval 9.43 to 27.47

SECONDARY outcome

Timeframe: Week 1 though Week 24 and Week 1 through 48

Population: All treated participants

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

Outcome measures

Outcome measures
Measure	Luspatercept n=153 Participants Luspatercept 1.0 mg/Kg SC on Day 1 of each 21-day treatment cycle	Placebo n=76 Participants Placebo (Volume equivalent to experimental arm) SC on Day 1 of each 21-day treatment cycle
Percentage of Participants Who Achieved a Mean Hemoglobin (Hgb) Increase of at Least 1.0 g/dL Over Any Consecutive 56-Day Period in Absence of Red Blood Cells (RBC) Transfusions Week 1 Through Week 48	41.2 Percentage of Participants Interval 33.29 to 49.41	10.5 Percentage of Participants Interval 4.66 to 19.69
Percentage of Participants Who Achieved a Mean Hemoglobin (Hgb) Increase of at Least 1.0 g/dL Over Any Consecutive 56-Day Period in Absence of Red Blood Cells (RBC) Transfusions Week 1 Through Week 24	35.3 Percentage of Participants Interval 27.75 to 43.42	7.9 Percentage of Participants Interval 2.95 to 16.4

SECONDARY outcome

Timeframe: From start of study treatment to 16 weeks after last dose, up to approximately 93 weeks

Population: All treated participants who achieved RBC-TI ≥ 8 weeks during Week 1 through Week 24 of study treatment

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

Outcome measures

Outcome measures
Measure	Luspatercept n=58 Participants Luspatercept 1.0 mg/Kg SC on Day 1 of each 21-day treatment cycle	Placebo n=10 Participants Placebo (Volume equivalent to experimental arm) SC on Day 1 of each 21-day treatment cycle
Duration of Red Blood Cell Transfusion Independence (RBC-TI) - Week 1 Through Week 24	30.6 Weeks Interval 20.6 to 40.6	13.6 Weeks Interval 9.1 to 54.9

SECONDARY outcome

Timeframe: From start of study treatment to 16 weeks after last dose, up to approximately 93 weeks

Population: All treated participants who achieved RBC-TI ≥ 8 weeks during Week 1 through Week 48 of study treatment

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

Outcome measures

Outcome measures
Measure	Luspatercept n=69 Participants Luspatercept 1.0 mg/Kg SC on Day 1 of each 21-day treatment cycle	Placebo n=12 Participants Placebo (Volume equivalent to experimental arm) SC on Day 1 of each 21-day treatment cycle
Duration of Red Blood Cell Transfusion Independence (RBC-TI) - Week 1 Through Week 48	30.6 Weeks Interval 20.6 to 50.9	18.6 Weeks Interval 10.9 to Upper limit could not be estimated due to insufficient number of events

SECONDARY outcome

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

Population: All treated participants who completed the EORTC QLQ-C30 assessment at baseline and at least one post-baseline assessment visit.

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

Outcome measures

Outcome measures
Measure	Luspatercept n=149 Participants Luspatercept 1.0 mg/Kg SC on Day 1 of each 21-day treatment cycle	Placebo n=76 Participants Placebo (Volume equivalent to experimental arm) SC on Day 1 of each 21-day treatment cycle
Mean Change From Baseline in the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire (EORTC QLQ-C30) Global Quality of Life Score C5 D1	-2.4 Score on a scale Standard Deviation 20.73	2.2 Score on a scale Standard Deviation 17.13
Mean Change From Baseline in the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire (EORTC QLQ-C30) Global Quality of Life Score C7 D1	-2.1 Score on a scale Standard Deviation 23.04	-0.6 Score on a scale Standard Deviation 18.63
Mean Change From Baseline in the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire (EORTC QLQ-C30) Global Quality of Life Score Week 25	-1.8 Score on a scale Standard Deviation 21.75	0.2 Score on a scale Standard Deviation 18.88
Mean Change From Baseline in the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire (EORTC QLQ-C30) Global Quality of Life Score Extension Phase C1 D1	0.0 Score on a scale Standard Deviation 25.32	6.3 Score on a scale Standard Deviation 14.60
Mean Change From Baseline in the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire (EORTC QLQ-C30) Global Quality of Life Score Extension Phase C7 D1	-0.5 Score on a scale Standard Deviation 20.03	3.8 Score on a scale Standard Deviation 20.87
Mean Change From Baseline in the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire (EORTC QLQ-C30) Global Quality of Life Score Extension Phase C9 D1	-2.4 Score on a scale Standard Deviation 18.42	11.9 Score on a scale Standard Deviation 19.75
Mean Change From Baseline in the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire (EORTC QLQ-C30) Global Quality of Life Score Extension Phase C17 D1	-0.6 Score on a scale Standard Deviation 19.03	13.9 Score on a scale Standard Deviation 26.79
Mean Change From Baseline in the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire (EORTC QLQ-C30) Global Quality of Life Score Extension Phase C19 D1	-1.6 Score on a scale Standard Deviation 18.78	-16.7 Score on a scale Standard Deviation 14.43
Mean Change From Baseline in the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire (EORTC QLQ-C30) Global Quality of Life Score Extension Phase C21 D1	3.1 Score on a scale Standard Deviation 18.32	4.2 Score on a scale Standard Deviation 17.68
Mean Change From Baseline in the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire (EORTC QLQ-C30) Global Quality of Life Score Extension Phase C23 D1	0.9 Score on a scale Standard Deviation 17.84	16.7 Score on a scale Standard Deviation NA No standard deviation could be determined because a single participant was analyzed
Mean Change From Baseline in the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire (EORTC QLQ-C30) Global Quality of Life Score Extension Phase C33 D1	-1.5 Score on a scale Standard Deviation 19.41	—
Mean Change From Baseline in the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire (EORTC QLQ-C30) Global Quality of Life Score Extension Phase C47 D1	1.4 Score on a scale Standard Deviation 19.08	—
Mean Change From Baseline in the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire (EORTC QLQ-C30) Global Quality of Life Score Extension Phase C49 D1	-3.8 Score on a scale Standard Deviation 16.40	—
Mean Change From Baseline in the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire (EORTC QLQ-C30) Global Quality of Life Score Extension Phase C51 D1	8.3 Score on a scale Standard Deviation 8.33	—
Mean Change From Baseline in the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire (EORTC QLQ-C30) Global Quality of Life Score Extension Phase C59 D1	16.7 Score on a scale Standard Deviation NA No standard deviation could be determined because a single participant was analyzed	—
Mean Change From Baseline in the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire (EORTC QLQ-C30) Global Quality of Life Score End of Treatment	-9.2 Score on a scale Standard Deviation 23.97	-0.8 Score on a scale Standard Deviation 23.07
Mean Change From Baseline in the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire (EORTC QLQ-C30) Global Quality of Life Score Cycle 3 Day 1 (C3 D1)	-4.1 Score on a scale Standard Deviation 21.01	0.1 Score on a scale Standard Deviation 15.95
Mean Change From Baseline in the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire (EORTC QLQ-C30) Global Quality of Life Score Extension Phase C3 D1	2.0 Score on a scale Standard Deviation 19.68	-3.9 Score on a scale Standard Deviation 26.86
Mean Change From Baseline in the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire (EORTC QLQ-C30) Global Quality of Life Score Extension Phase C5 D1	0.8 Score on a scale Standard Deviation 18.40	0.6 Score on a scale Standard Deviation 20.04
Mean Change From Baseline in the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire (EORTC QLQ-C30) Global Quality of Life Score Extension Phase C11 D1	-1.8 Score on a scale Standard Deviation 19.53	4.8 Score on a scale Standard Deviation 24.47
Mean Change From Baseline in the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire (EORTC QLQ-C30) Global Quality of Life Score Extension Phase C13 D1	-2.6 Score on a scale Standard Deviation 20.84	8.3 Score on a scale Standard Deviation 24.15
Mean Change From Baseline in the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire (EORTC QLQ-C30) Global Quality of Life Score Extension Phase C15 D1	3.1 Score on a scale Standard Deviation 18.27	4.2 Score on a scale Standard Deviation 27.26
Mean Change From Baseline in the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire (EORTC QLQ-C30) Global Quality of Life Score Extension Phase C25 D1	-2.0 Score on a scale Standard Deviation 18.15	16.7 Score on a scale Standard Deviation NA No standard deviation could be determined because a single participant was analyzed
Mean Change From Baseline in the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire (EORTC QLQ-C30) Global Quality of Life Score Extension Phase C27 D1	2.5 Score on a scale Standard Deviation 20.40	—
Mean Change From Baseline in the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire (EORTC QLQ-C30) Global Quality of Life Score Extension Phase C29 D1	2.1 Score on a scale Standard Deviation 21.12	—
Mean Change From Baseline in the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire (EORTC QLQ-C30) Global Quality of Life Score Extension Phase C31 D1	-0.3 Score on a scale Standard Deviation 15.93	—
Mean Change From Baseline in the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire (EORTC QLQ-C30) Global Quality of Life Score Extension Phase C35 D1	3.6 Score on a scale Standard Deviation 23.33	—
Mean Change From Baseline in the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire (EORTC QLQ-C30) Global Quality of Life Score Extension Phase C37 D1	0.5 Score on a scale Standard Deviation 22.04	—
Mean Change From Baseline in the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire (EORTC QLQ-C30) Global Quality of Life Score Extension Phase C39 D1	0.3 Score on a scale Standard Deviation 23.63	—
Mean Change From Baseline in the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire (EORTC QLQ-C30) Global Quality of Life Score Extension Phase C41 D1	6.6 Score on a scale Standard Deviation 20.11	—
Mean Change From Baseline in the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire (EORTC QLQ-C30) Global Quality of Life Score Extension Phase C43 D1	4.8 Score on a scale Standard Deviation 15.29	—
Mean Change From Baseline in the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire (EORTC QLQ-C30) Global Quality of Life Score Extension Phase C45 D1	-2.2 Score on a scale Standard Deviation 21.24	—
Mean Change From Baseline in the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire (EORTC QLQ-C30) Global Quality of Life Score Extension Phase C53 D1	12.5 Score on a scale Standard Deviation 10.76	—
Mean Change From Baseline in the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire (EORTC QLQ-C30) Global Quality of Life Score Extension Phase C55 D1	2.8 Score on a scale Standard Deviation 17.35	—
Mean Change From Baseline in the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire (EORTC QLQ-C30) Global Quality of Life Score Extension Phase C57 D1	12.5 Score on a scale Standard Deviation 5.89	—

SECONDARY outcome

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

Population: All treated participants with available measurements

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

Outcome measures

Outcome measures
Measure	Luspatercept n=15 Participants Luspatercept 1.0 mg/Kg SC on Day 1 of each 21-day treatment cycle	Placebo n=10 Participants Placebo (Volume equivalent to experimental arm) SC on Day 1 of each 21-day treatment cycle
Percentage of Participants Who Achieved a Hematologic Improvement in Neutrophil Response (HI-N) Over Any Consecutive 56-day Period Week 1 Through Week 24	13.3 Percentage of Participants Interval 1.66 to 40.46	0 Percentage of Participants Interval 0.0 to 30.85
Percentage of Participants Who Achieved a Hematologic Improvement in Neutrophil Response (HI-N) Over Any Consecutive 56-day Period Week 1 Through Week 48	20.0 Percentage of Participants Interval 4.33 to 48.09	10.0 Percentage of Participants Interval 0.25 to 44.5

SECONDARY outcome

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

Population: All treated participants with available measurements

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

Outcome measures

Outcome measures
Measure	Luspatercept n=8 Participants Luspatercept 1.0 mg/Kg SC on Day 1 of each 21-day treatment cycle	Placebo n=6 Participants Placebo (Volume equivalent to experimental arm) SC on Day 1 of each 21-day treatment cycle
Percentage of Participants Who Achieved a Hematologic Improvement in Platelet Response (HI-P) Over Any Consecutive 56-day Period Week 1 Through Week 24	50.0 Percentage of Participants Interval 15.7 to 84.3	33.3 Percentage of Participants Interval 4.33 to 77.72
Percentage of Participants Who Achieved a Hematologic Improvement in Platelet Response (HI-P) Over Any Consecutive 56-day Period Week 1 Through Week 48	62.5 Percentage of Participants Interval 24.49 to 91.48	33.3 Percentage of Participants Interval 4.33 to 77.72

SECONDARY outcome

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

Population: All treated participants with available measurements

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

Outcome measures

Outcome measures
Measure	Luspatercept n=148 Participants Luspatercept 1.0 mg/Kg SC on Day 1 of each 21-day treatment cycle	Placebo n=74 Participants Placebo (Volume equivalent to experimental arm) SC on Day 1 of each 21-day treatment cycle
Change From Baseline in Mean Serum Ferritin Weeks 33-48	-72.0 ug/L Standard Error 74.76	247.4 ug/L Standard Error 140.96
Change From Baseline in Mean Serum Ferritin Weeks 9-24	-2.7 ug/L Standard Error 54.05	226.5 ug/L Standard Error 68.02

SECONDARY outcome

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

Population: All treated participants with available measurements

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

Outcome measures

Outcome measures
Measure	Luspatercept n=128 Participants Luspatercept 1.0 mg/Kg SC on Day 1 of each 21-day treatment cycle	Placebo n=68 Participants Placebo (Volume equivalent to experimental arm) SC on Day 1 of each 21-day treatment cycle
Change From Baseline in Mean Daily Dose of Iron Chelation Therapy (ICT) Weeks 9-24	10.0 mg/day Standard Error 29.25	51.0 mg/day Standard Error 35.92
Change From Baseline in Mean Daily Dose of Iron Chelation Therapy (ICT) Weeks 33-48	-148.8 mg/day Standard Error 46.13	-123.8 mg/day Standard Error 92.19

SECONDARY outcome

Timeframe: From first dose to Week 24 of study treatment

Population: All participants who achieved RBC-TI ≥ 8 weeks during Week 1 through Week 24

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

Outcome measures

Outcome measures
Measure	Luspatercept n=58 Participants Luspatercept 1.0 mg/Kg SC on Day 1 of each 21-day treatment cycle	Placebo n=10 Participants Placebo (Volume equivalent to experimental arm) SC on Day 1 of each 21-day treatment cycle
Time to Red Blood Cell Transfusion Independence (RBC-TI) - Week 1 Through Week 24	17.2 Days Standard Deviation 29.40	26.0 Days Standard Deviation 31.83

SECONDARY outcome

Timeframe: From first dose to Week 48 of study treatment

Population: All participants who achieved RBC-TI ≥ 8 weeks during Week 1 through Week 48

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

Outcome measures

Outcome measures
Measure	Luspatercept n=69 Participants Luspatercept 1.0 mg/Kg SC on Day 1 of each 21-day treatment cycle	Placebo n=12 Participants Placebo (Volume equivalent to experimental arm) SC on Day 1 of each 21-day treatment cycle
Time to Red Blood Cell Transfusion Independence (RBC-TI) - Week 1 Through Week 48	40.3 Days Standard Deviation 61.03	57.2 Days Standard Deviation 79.18

SECONDARY outcome

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

Population: All treated participants

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

Outcome measures

Outcome measures
Measure	Luspatercept n=153 Participants Luspatercept 1.0 mg/Kg SC on Day 1 of each 21-day treatment cycle	Placebo n=76 Participants Placebo (Volume equivalent to experimental arm) SC on Day 1 of each 21-day treatment cycle
Percentage of Participants Who Progressed to Acute Myeloid Leukemia (AML)	2.6 Percentage of Participants	3.9 Percentage of Participants

SECONDARY outcome

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

Population: All treated participants who progressed to AML

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

Outcome measures

Outcome measures
Measure	Luspatercept n=4 Participants Luspatercept 1.0 mg/Kg SC on Day 1 of each 21-day treatment cycle	Placebo n=3 Participants Placebo (Volume equivalent to experimental arm) SC on Day 1 of each 21-day treatment cycle
Time to Acute Myeloid Leukemia (AML) Progression	NA Months Median was not estimable due to the insufficient number of events	NA Months Median was not estimable due to the insufficient number of events

SECONDARY outcome

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

Population: All treated participants

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

Outcome measures

Outcome measures
Measure	Luspatercept n=153 Participants Luspatercept 1.0 mg/Kg SC on Day 1 of each 21-day treatment cycle	Placebo n=76 Participants Placebo (Volume equivalent to experimental arm) SC on Day 1 of each 21-day treatment cycle
Overall Survival	46.0 Months Interval 42.0 to Upper limit could not be estimated because of the insufficient number of events	NA Months Interval 43.1 to Median and Upper limit could not be estimated because of the insufficient number of events

SECONDARY outcome

Timeframe: From date of first dose up to 42 days after the last dose (up to approximately 83 weeks)

Population: All treated participants

The outcome measure describes the number of participants who experienced different types of Treatment-emergent adverse events (TEAEs). TEAEs were defined as Adverse Events (AEs) that started on or after the day of the first dose and on or before 42 days after the last dose of IP. The investigator determined the relationship of an AE to study drug based on the timing of the AE relative to drug administration and whether or not other drugs, therapeutic interventions, or underlying conditions could provide a sufficient explanation for the event. The severity of an AE was evaluated by the investigator according to National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE) (Version 4.0) where Grade 1 = Mild, Grade 2 = Moderate, Grade 3 = Severe, Grade 4 = Life-threatening and Grade 5 = Death.

Outcome measures

Outcome measures
Measure	Luspatercept n=153 Participants Luspatercept 1.0 mg/Kg SC on Day 1 of each 21-day treatment cycle	Placebo n=76 Participants Placebo (Volume equivalent to experimental arm) SC on Day 1 of each 21-day treatment cycle
Number of Participants With Treatment Emergent Adverse Events (TEAEs) ≥ 1 TEAE	151 Participants	70 Participants
Number of Participants With Treatment Emergent Adverse Events (TEAEs) ≥ 1 Suspected Related TEAE	71 Participants	26 Participants
Number of Participants With Treatment Emergent Adverse Events (TEAEs) ≥ 1 Suspected Related Serious TEAE	6 Participants	0 Participants
Number of Participants With Treatment Emergent Adverse Events (TEAEs) ≥ 1 TEAE CTCAE Toxicity Grade (GR) 5	8 Participants	4 Participants
Number of Participants With Treatment Emergent Adverse Events (TEAEs) ≥ 1 TEAE with CTCAE GR 3 or 4	86 Participants	34 Participants
Number of Participants With Treatment Emergent Adverse Events (TEAEs) ≥ 1 TEAE Leading to Dose Reduction	9 Participants	0 Participants
Number of Participants With Treatment Emergent Adverse Events (TEAEs) ≥ 1 TEAE Leading to Study Drug Discontinuation	22 Participants	6 Participants
Number of Participants With Treatment Emergent Adverse Events (TEAEs) ≥ 1 Serious TEAE	66 Participants	23 Participants
Number of Participants With Treatment Emergent Adverse Events (TEAEs) ≥ 1 Suspected Related TEAE With CTCAE GR 5	0 Participants	0 Participants
Number of Participants With Treatment Emergent Adverse Events (TEAEs) ≥ 1 Suspected Related TEAE With CTCAE GR 3 or 4	13 Participants	3 Participants
Number of Participants With Treatment Emergent Adverse Events (TEAEs) ≥ 1 TEAE Leading to Dose Interruption	42 Participants	4 Participants

SECONDARY outcome

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

Population: Pharmacokinetic (PK) population included all participants who received at least 1 dose of luspatercept and had measurable luspatercept serum concentrations.

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

Outcome measures

Outcome measures
Measure	Luspatercept n=153 Participants Luspatercept 1.0 mg/Kg SC on Day 1 of each 21-day treatment cycle	Placebo Placebo (Volume equivalent to experimental arm) SC on Day 1 of each 21-day treatment cycle
Pharmacokinetic (PK) Parameters: Bayesian Estimate of Apparent Clearance (CL/F)	0.516 L/day Geometric Coefficient of Variation 41.2	—

SECONDARY outcome

Population: Pharmacokinetic population included all participants who received at least 1 dose of luspatercept and had measurable luspatercept serum concentrations.

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

Outcome measures

Outcome measures
Measure	Luspatercept n=153 Participants Luspatercept 1.0 mg/Kg SC on Day 1 of each 21-day treatment cycle	Placebo Placebo (Volume equivalent to experimental arm) SC on Day 1 of each 21-day treatment cycle
Pharmacokinetic (PK) Parameters: Bayesian Estimate of Apparent Volume of Distribution of the Central Compartment (V1/F)	9.68 L Geometric Coefficient of Variation 26.5	—

SECONDARY outcome

Population: Pharmacokinetic population Included all participants who received at least 1 dose of luspatercept and had measurable luspatercept serum concentrations.

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

Outcome measures

Outcome measures
Measure	Luspatercept n=153 Participants Luspatercept 1.0 mg/Kg SC on Day 1 of each 21-day treatment cycle	Placebo Placebo (Volume equivalent to experimental arm) SC on Day 1 of each 21-day treatment cycle
Pharmacokinetic (PK) Parameters: Bayesian Estimate of Elimination Half-life (t1/2)	13.0 Day Geometric Coefficient of Variation 31.6	—

SECONDARY outcome

Population: Pharmacokinetic population Included all participants who received at least 1 dose of luspatercept and had measurable luspatercept serum concentrations.

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

Outcome measures

Outcome measures
Measure	Luspatercept n=153 Participants Luspatercept 1.0 mg/Kg SC on Day 1 of each 21-day treatment cycle	Placebo Placebo (Volume equivalent to experimental arm) SC on Day 1 of each 21-day treatment cycle
Pharmacokinetic (PK) Parameters: Bayesian Estimate of Time to Reach Maximum Concentration (Tmax)	5.40 Day Interval 3.12 to 6.69	—

SECONDARY outcome

Population: Pharmacokinetic population Included all participants who received at least 1 dose of luspatercept and had measurable luspatercept serum concentrations.

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

Outcome measures

Outcome measures
Measure	Luspatercept n=153 Participants Luspatercept 1.0 mg/Kg SC on Day 1 of each 21-day treatment cycle	Placebo Placebo (Volume equivalent to experimental arm) SC on Day 1 of each 21-day treatment cycle
Pharmacokinetic (PK) Parameters: Bayesian Estimate of Maximum Concentration for the First Dose (Cmax)	5.77 μg/mL Geometric Coefficient of Variation 20.5	—

SECONDARY outcome

Population: Pharmacokinetic population included all participants who received at least 1 dose of luspatercept and had measurable luspatercept serum concentrations.

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

Outcome measures

Outcome measures
Measure	Luspatercept n=153 Participants Luspatercept 1.0 mg/Kg SC on Day 1 of each 21-day treatment cycle	Placebo Placebo (Volume equivalent to experimental arm) SC on Day 1 of each 21-day treatment cycle
Pharmacokinetic (PK) Parameters: Bayesian Estimate of Maximum Concentration for the Starting Dose (Cmax) at Steady State	9.17 μg/mL Geometric Coefficient of Variation 29.9	—

SECONDARY outcome

Population: Pharmacokinetic population included all participants who received at least 1 dose of luspatercept and had measurable luspatercept serum concentrations.

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

Outcome measures

Outcome measures
Measure	Luspatercept n=153 Participants Luspatercept 1.0 mg/Kg SC on Day 1 of each 21-day treatment cycle	Placebo Placebo (Volume equivalent to experimental arm) SC on Day 1 of each 21-day treatment cycle
Pharmacokinetic (PK) Parameters: Bayesian Estimate of Maximum Concentration for the Area Under the Curve at Steady State for Starting Dose (AUC^ss)	145 day/μg/mL Geometric Coefficient of Variation 38.3	—

SECONDARY outcome

Timeframe: From randomization to 1 year post first dose

Population: Safety population of participants with ADA samples collected.

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

Outcome measures

Outcome measures
Measure	Luspatercept n=153 Participants Luspatercept 1.0 mg/Kg SC on Day 1 of each 21-day treatment cycle	Placebo n=76 Participants Placebo (Volume equivalent to experimental arm) SC on Day 1 of each 21-day treatment cycle
Participants With Pre-Existing and/or Treatment-Emergent Antidrug Antibodies (ADA) Pre-Existing ADA	7 Participants	2 Participants
Participants With Pre-Existing and/or Treatment-Emergent Antidrug Antibodies (ADA) Treatment Emergent Neutralizing ADA	5 Participants	2 Participants
Participants With Pre-Existing and/or Treatment-Emergent Antidrug Antibodies (ADA) Treatment Emergent ADA	11 Participants	3 Participants

Adverse Events

Luspatercept

Serious events: 66 serious events

Other events: 145 other events

Deaths: 45 deaths

Placebo

Serious events: 23 serious events

Other events: 63 other events

Deaths: 24 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