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 (COMMANDS)

• ClinicalTrials.gov Identifier: NCT03682536
• Recruitment Status: Active, not recruiting
• First Posted: September 24, 2018
• Last Update Posted: November 21, 2022
• Sponsor: Celgene
• Collaborator: Acceleron Pharma Inc. (a wholly owned subsidiary of Merck Sharp and Dohme, a subsidiary of Merck & Co., Inc.)
• Information provided by (Responsible Party): Celgene

Tracking Information

• First Submitted Date: September 7, 2018
• First Posted Date: September 24, 2018
• Last Update Posted Date: November 21, 2022
• Actual Study Start Date: January 2, 2019
• Estimated Primary Completion Date: February 9, 2023 (Final data collection date for primary outcome measure)
• Current Primary Outcome Measures (submitted: February 25, 2022): Red blood cell transfusion independence (RBC-TI) for 12 weeks (84 days) with a mean hemoglobin increase ≥ 1.5 g/dL [ Time Frame: Week 1 through Week 24 ]

Original Primary Outcome Measures (submitted: September 20, 2018)

Red Blood Cell Transfusion Independence (RBCTI) for 24 weeks [ Time Frame: Randomization through Week 24 ]

Proportion of subjects who are RBC transfusion free over the first 24 weeks from randomization

Current Secondary Outcome Measures (submitted: February 25, 2022)

• RBC-TI for 24 weeks [ Time Frame: Week 1 through Week 24 ]
• Mean hemoglobin change over 24 weeks [ Time Frame: Week 1 through Week 24 ]
• Hematologic improvement - erythroid response (HI-E) per International Working Group (IWG) [ Time Frame: Week 1 through Week 24 ]
• Time to HI-E [ Time Frame: Week 1 through Week 24 ]
• RBC-TI for ≥ 12 weeks (84 days) [ Time Frame: Week 1 through Week 24 ]
• Duration of RBC-TI ≥ 12 weeks (84 days) [ Time Frame: Week 1 through End of Treatment (EOT), up to approximately 60 months ]
• Time to RBC-TI ≥ 12 weeks (84 days) [ Time Frame: Week 1 through Week 24 ]
• Time to first red blood cell (RBC) transfusion [ Time Frame: Week 1 through EOT, up to approximately 60 months ]
• RBC transfusion burden on treatment [ Time Frame: Week 1 through Week 24 ]
• RBC-TI for ≥ 56 days (8 weeks) [ Time Frame: Week 1 through Week 24 ]
• RBC-TI for a consecutive 24-week period [ Time Frame: Week 1 through Week 48 ]
• The European Organization for Research and Treatment of Cancer Quality-of-Life questionnaire (EORTC QLQ-C30) [ Time Frame: Screening through Week 24 ]
• The Functional Assessment of Cancer Therapy-Anemia Version 4 (FACT-An) questionnaire [ Time Frame: Screening through Week 24 ]
• Number of participants with Adverse Events (AEs) [ Time Frame: Week 1 through 42 days post last dose ]
• Pharmacokinetic - area under the concentration-time curve (AUC) [ Time Frame: Randomization through 1-year post first dose ]
• Pharmacokinetic - maximum plasma concentration of drug (Cmax) [ Time Frame: Randomization through 1-year post first dose ]
• Frequency of antidrug antibodies (ADA) [ Time Frame: Randomization through 1-year post first dose ]
• Number of participants progressing to acute myeloid leukemia (AML) [ Time Frame: Randomization through up to 60 months ]
• Percentage of participants progressing to AML [ Time Frame: Randomization through up to 60 months ]
• Time to AML progression [ Time Frame: Randomization through up to 60 months ]
• Overall survival [ Time Frame: Randomization through up to 60 months ]

Original Secondary Outcome Measures (submitted: September 20, 2018)

• Hematologic improvement - erythroid response (HI-E) per International Working Group (IWG) within 24 weeks [ Time Frame: Randomization through Week 24 ]
  Proportion of subjects achieving HI-E over any consecutive 56-day period
• Mean hemoglobin increase ≥ 1.5 g/dL [ Time Frame: Randomization through Week 24 ]
  Proportion of subjects achieving ≥ 1.5 g/dL mean increase in hemoglobin over the first 24 weeks from randomization compared to baseline in the absence of RBC transfusions
• Time to Hematologic improvement - erythroid response (HI-E) [ Time Frame: Randomization through Week 48 ]
  Time from first dose to first onset of achieving ≥ 1.5 g/dL increase in hemoglobin over any consecutive 56-day period in the absence of RBC transfusions
• Duration of HI-E [ Time Frame: Randomization through Week 48 ]
  Maximum duration of achieving ≥ 1.5 g/dL increase in hemoglobin for subjects who achieve mean hemoglobin increase ≥ 56 days in the absence of RBC transfusions
• Duration of Red blood cell transfusion independence (RBC-TI) ≥ 24 weeks [ Time Frame: Randomization through Week 48 ]
  Maximum duration of RBC transfusion independence for subjects who achieve RBC TI ≥ 24 weeks
• RBC-TI for ≥ 84 days [ Time Frame: Randomization through Week 24 ]
  Proportion of subjects who are RBC transfusion free over a consecutive 84-day period
• Duration of RBC-TI ≥ 84 days [ Time Frame: Randomization through Week 48 ]
  Maximum duration of RBC transfusion independence for subjects who achieve RBC TI ≥ 84 days
• Time to RBC-TI ≥ 84 days [ Time Frame: Randomization through Week 24 ]
  Time from randomization to first onset of transfusion independence ≥ 84 days
• Time to first Red blood cell (RBC) transfusion [ Time Frame: Randomization through Week 48 ]
  Time from randomization to first transfusion on treatment
• RBC transfusion burden on treatment [ Time Frame: Randomization through Week 24 ]
  Total number of RBC units transfused on treatment
• For subjects with RBC transfusion burden of ≥4 units/8 weeks at baseline: [ Time Frame: Randomization through Week 48 ]
  Mean change in total Packed red blood cells (pRBC) units transfused over a rolling 8-week period
• RBC-TI during Weeks 4-24 [ Time Frame: Week 4 through Week 24 ]
  Proportion of subjects who are RBC transfusion independent during Weeks 4-24
• RBC-TI for a consecutive 24-week period [ Time Frame: Randomization through Week 48 ]
  Proportion of subjects who are RBC transfusion free for a consecutive 24-week period in the first 48 weeks from Randomization
• The European Organization for Research and Treatment of Cancer Quality-of-Life questionnaire (EORTC QLQ-C30) [ Time Frame: Screening through Week 48 ]
  Is a validated HRQoL measure applicable to subjects with any cancer diagnosis. It is composed of 30 items that address general physical symptoms, physical functioning, fatigue and malaise, and social and emotional functioning.
• The Functional Assessment of Cancer Therapy-Anemia Version 4 (FACT-An) questionnaire [ Time Frame: Screening through Week 48 ]
  Is a validated instrument specific in measuring HRQoL related anemia. The 47-item FACT-An scale measures cancer-related symptoms with 13 items that measure fatigue (the FACIT-Fatigue subscale) and an additional 7 items that measure items pertinent to anemia.
• Adverse Event (AE) [ Time Frame: Randomization through Week 48 ]
  Type, frequency, severity of AEs and relationship of AEs to luspatercept/epoetin alfa
• Pharmacokinetic - AUC [ Time Frame: Randomization through 1-year post first dose. ]
  Area under the concentration-time curve
• Pharmacokinetic - Cmax [ Time Frame: Randomization through 1-year post first dose. ]
  Maximum plasma concentration of drug
• Antidrug antibodies (ADA) [ Time Frame: Randomization through 1-year post first dose. ]
  Frequency of antidrug antibodies and effects on efficacy, safety or PK
• Progression to AML [ Time Frame: Randomization through at least 5 years post last dose ]
  Number and percentage of subjects progressing to AML
• Time to AML [ Time Frame: Randomization through at least 5 years post last dose ]
  Time between randomization and first diagnosis of AML
• Overall survival [ Time Frame: Randomization through at least 5 years post last dose; ]
  Time from date of randomization to death due to any cause

• Current Other Pre-specified Outcome Measures: Not Provided
• Original Other Pre-specified Outcome Measures: Not Provided

Descriptive Information

• Brief Title: 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
• Official Title: A Phase 3, Open-label, Randomized Study to Compare the Efficacy and Safety of Luspatercept (ACE-536) Versus Epoetin Alpha for the Treatment of Anemia Due to IPSS-R Very Low, Low or Intermediate Risk Due to Myelodysplastic Syndrome (MDS) ESA in Native Subjects Who Require Red Blood Cell Transfusions
• Brief Summary: The purpose of this study is to determine the effectiveness of luspatercept (ACE-536) compared to epoetin alfa on red blood cell (RBC) transfusion independence (for at least 12 weeks) with a concurrent hemoglobin increase of at least 1.5 g/dL in participants with anemia due to revised international prognostic scoring system (IPSS-R) very low, low, or intermediate risk myelodysplastic syndromes (MDS) who require RBC transfusions and have never been exposed to erythropoiesis stimulating agent (ESA).
• Detailed Description: Not Provided
• Study Type: Interventional
• Study Phase: Phase 3
• Study Design: Allocation: Randomized; Intervention Model: Parallel Assignment; Masking: None (Open Label); Primary Purpose: Treatment
• Condition: Myelodysplastic Syndromes

Intervention

• Drug: Luspatercept
  Specified dose on specified days
  Other Name: ACE-536
• Drug: Epoetin alfa
  Specified dose on specified days
  Other Names:

  • EPREX®
  • ERYPO®
  • PROCRIT®

Study Arms

• Experimental: Luspatercept
  Intervention: Drug: Luspatercept
• Active Comparator: Epoetin alfa
  Intervention: Drug: Epoetin alfa

• Publications *: Not Provided

Recruitment Information

• Recruitment Status: Active, not recruiting
• Actual Enrollment (submitted: September 14, 2022): 347
• Original Estimated Enrollment (submitted: September 20, 2018): 350
• Estimated Study Completion Date: February 14, 2028
• Estimated Primary Completion Date: February 9, 2023 (Final data collection date for primary outcome measure)

Eligibility Criteria

Inclusion Criteria:

• Documented diagnosis of Myelodysplastic syndromes (MDS) according to WHO 2016 classification that meets revised international prognostic scoring system (IPSS-R) classification of very low, low, or intermediate risk disease, and have < 5% blasts in bone marrow
• Endogenous serum erythropoietin (sEPO) level of < 500 U/L
• Requires Red blood cell (RBC) transfusions, as documented by the criteria: Average transfusion requirement of 2 - 6 units/8 weeks of packed red blood cells (pRBCs) confirmed for a minimum of 8 weeks immediately preceding randomization
• Eastern Cooperative Oncology Group (ECOG) score of 0, 1, or 2

Exclusion Criteria:

• Clinically significant anemia due to iron, vitamin B12, or folate deficiencies, or autoimmune or hereditary hemolytic anemia, or hypothyroidism, or any type of known clinically significant bleeding or sequestration or drug induced anemia
• Known history of diagnosis of Acute myeloid leukemia (AML)
• Uncontrolled hypertension, defined as repeated elevations of systolic blood pressure (SBP) of ≥ 150 mmHg and/or diastolic blood pressure (DBP) ≥ 100 mmHg despite adequate treatment

Other protocol-defined inclusion/exclusion criteria apply

Sex/Gender

• Sexes Eligible for Study: All

• Ages: 18 Years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Contacts: Contact information is only displayed when the study is recruiting subjects
• Listed Location Countries: Australia, Austria, Belgium, Canada, Czechia, France, Germany, Greece, Hungary, Israel, Italy, Japan, Korea, Republic of, Lithuania, Netherlands, Poland, Portugal, Russian Federation, Spain, Sweden, Switzerland, Taiwan, Turkey, Ukraine, United Kingdom, United States

Administrative Information

• NCT Number: NCT03682536
• Other Study ID Numbers: ACE-536-MDS-002; U1111-1218-1810 ( Registry Identifier: WHO ); 2017-003190-34 ( EudraCT Number )
• Has Data Monitoring Committee: Yes

U.S. FDA-regulated Product

• Studies a U.S. FDA-regulated Drug Product: Yes
• Studies a U.S. FDA-regulated Device Product: No

• IPD Sharing Statement: Not Provided
• Current Responsible Party: Celgene
• Original Responsible Party: Same as current
• Current Study Sponsor: Celgene
• Original Study Sponsor: Same as current
• Collaborators: Acceleron Pharma Inc. (a wholly owned subsidiary of Merck Sharp and Dohme, a subsidiary of Merck & Co., Inc.)

Investigators

• Study Director: Bristol-Myers Squibb; Bristol-Myers Squibb

• PRS Account: Celgene
• Verification Date: November 2022