Extension Study to Evaluate the Safety and Efficacy of Luspatercept in Participants With β-Thalassemia Previously Enrolled in A536-04 (A536-06/MK-6143-004)

An Open-Label Extension Study To Evaluate The Long-Term Effects Of ACE-536 In Patients With β-Thalassemia Previously Enrolled In Study A536-04

Study A536-06 (MK-6143-004) is an open-label extension study for participants previously enrolled in study A536-04 (NCT01749540), to evaluate the long-term safety and tolerability of luspatercept in adult participants with beta-thalassemia.

Study Overview

• Status: Completed
• Conditions: β-Thalassemia
• Intervention / Treatment: Drug: luspatercept

Detailed Description

Study A536-06 is an open-label extension study for patients previously enrolled in study A536-04 (ClinicalTrials.gov Identifier NCT01749540), to evaluate the safety,tolerability and pharmacodynamic effects of up to 24 months of ACE-536 treatment in adult patients with beta-thalassemia previously treated with ACE-536 for up to 3 months in study A536-04. The starting dose level in A536-06 will be 0.8 mg/kg by subcutaneous (SC) injection once every 3 weeks. Dose titration/modification rules will be followed for individual patients and will be based upon safety and efficacy data collected during the course of treatment.

• Study Type: Interventional
• Enrollment (Actual): 51
• Phase: Phase 2

Contacts and Locations

Study Locations

• Greece
  • Athens, Greece
    • Acceleron Investigative Site
• Italy
  • Brindisi, Italy
    • Acceleron Investigative Site
  • Catania, Italy
    • Acceleron Investigative Site
  • Ferrara, Italy
    • Acceleron Investigative Site
  • Modena, Italy
    • Acceleron Investigative Site
  • Naples, Italy
    • Acceleron Investigative Site
  • Turin, Italy
    • Acceleron Investigative Site

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Description

The main inclusion and exclusion criteria include but are not limited to the following:

Inclusion Criteria:

• Completion of the treatment period in the base study A536-04.
• Females of child- bearing potential (defined as sexually mature women who have not undergone hysterectomy or bilateral oophorectomy, or are not naturally postmenopausal ≥24 consecutive months) must have negative urine or blood pregnancy test prior to enrollment and use adequate birth control methods (abstinence, oral contraceptives, barrier method with spermicide, or surgical sterilization) during study participation and for 12 weeks following the last dose of study drug
• Males must agree to use a latex condom during any sexual contact with females of child-bearing potential during study participation and for 12 weeks following the last dose of study drug, even if he has undergone a successful vasectomy
• Participants must be counseled concerning measures to be used to prevent pregnancy and potential toxicities prior to the first dose of study drug
• Participants with treatment interruption (defined as participants who complete the end of study visit for study A536-04 and are ≥28 days post end of study visit) must also meet the following criteria:
• Mean hemoglobin concentration <10.0 g/dL of 2 measurements (not influenced by red blood cell [RBC] transfusion) (one performed within one day prior to first dose of study treatment and the other performed during the screening period [Day -28 to Day -1]) in non-transfusion dependent (NTD) participants
• Adequate folate levels or on folate therapy
• Platelet count ≥100 x 10^9/L and ≤1,000 x 10^9/L
• Aspartate aminotransferase (AST) or alanine aminotransferase (ALT) <3 x upper limit of normal (ULN)
• Serum creatinine ≤ 1.5 x ULN
• Ejection fraction ≥50% by echocardiogram (ECHO) or multi-gated acquisition scan (MUGA)

Exclusion Criteria:

• Discontinuation/withdrawal from study A536-04 due to participant request, participant unwillingness or inability to comply with the protocol, pregnancy, use of prohibited medication (e.g., hydroxyurea), medical reason or adverse event, hypersensitivity reaction to the study drug, at the discretion of the sponsor, or loss to follow-up prior to completion of the treatment period
• Any clinically significant pulmonary (including pulmonary hypertension), cardiovascular, endocrine, neurologic, hepatic, gastrointestinal, infectious, immunological (including clinically significant allo- or auto-immunization) or genitourinary disease considered by the investigator as not adequately controlled prior to the first dose of study trearment
• Symptomatic splenomegaly
• Splenectomy within 56 days prior to the first dose of study treatment
• Major surgery (except splenectomy) within 28 days prior to the first dose of study treatment. Participants must have completely recovered from any previous surgery prior to the first dose of study treatment
• Participants receiving or planning to receive hydroxyurea treatment. Participants must not have had hydroxyurea within 90 days of the first dose of study treatment
• For participants with treatment interruption: Iron chelation therapy if initiated within 56 days prior to the first dose of study treatment
• Cytotoxic agents, systemic corticosteroids, immunosuppressants, or anticoagulant therapy such as warfarin or heparin within 28 days prior to the first dose of study treatment (prophylactic aspirin up to 100 mg/day and low molecular weight (LMW) heparin for superficial vein thrombosis (SVT) is permitted)
• Treatment with another investigational drug (including sotatercept [ACE-011]) or device, or approved therapy for investigational use ≤28 days prior to the first dose of study treatment, or if the half-life of the previous investigational product is known, within 5 times the half-life prior to the first dose of study treatment, whichever is longer at any time between the end of treatment of the base study A536-04 and the first dose of study treatment
• Known positive for human immunodeficiency virus (HIV), active infectious hepatitis B virus (HBV) or active infectious hepatitis C virus (HCV)
• Uncontrolled hypertension defined as systolic blood pressure (SBP) ≥150 mm mercury (Hg) or diastolic blood pressure (DBP) ≥100 mm Hg
• Known history of thromboembolic events ≥Grade 3 according to the National Cancer Institute-Common Terminology Criteria for Adverse Events (NCI-CTCAE) Version 4.0
• Pregnant or lactating females
• History of severe allergic or anaphylactic reactions or hypersensitivity to recombinant proteins or excipients in the investigational drug

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: N/A
• Interventional Model: Single Group Assignment
• Masking: None (Open Label)

Number of Arms

1

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Luspatercept Extension Population; Participants receive luspatercept 0.6, 0.8, 1.0, or 1.25 mg/kg administered by subcutaneous injection on Day 1 of each 21-day cycle for up to 87 cycles (up to approximately 5 years). Participants will receive the highest tolerated dose level of luspatercept that they were assigned in the base study unless a dose modification was required.	Drug: luspatercept; subcutaneous injection; Other Names: ACE-536; MK-6143

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Number of Participants Who Experienced an Adverse Event (AE)	An adverse event (AE) was any untoward medical occurrence in a participant or clinical investigation participant administered a study drug, which did not necessarily have a causal relationship with the treatment. An AE could therefore have been any unfavorable and unintended sign (including an abnormal laboratory finding), symptom, or disease temporally associated with the use of the study drug whether or not it was considered related to the study drug. The number of participants who experienced an AE is reported.	Up to approximately 68 months
Number of Participants Who Discontinued Study Treatment Due To an AE	An adverse event (AE) was any untoward medical occurrence in a participant or clinical investigation participant administered a study drug, which did not necessarily have a causal relationship with the treatment. An AE could therefore have been any unfavorable and unintended sign (including an abnormal laboratory finding), symptom, or disease temporally associated with the use of the study drug whether or not it was considered related to the study drug. The number of participants who discontinued study treatment due to an AE is reported.	Up to approximately 60 months

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Percentage of Non-transfusion Dependent (NTD) Participants With a Hemoglobin Increase of ≥1.0 g/dL From Baseline Over a Rolling 8-week Interval	An erythroid response in NTD participants was defined as a mean hemoglobin increase of ≥1.0 g/dL from baseline over an 8-week interval compared to baseline. Baseline hemoglobin for NTD participants was the average of two or more measurements performed during the screening period of either the base study (A536-04) or the extension study (A536-06). Hemoglobin measurements within 2 weeks following RBC transfusion were excluded from the analysis. NTD participants were participants who had received <4 units of red blood cells (RBCs) within 8 weeks prior to the first dose of study drug. An 8-week interval was defined as any consecutive 8 weeks during the study. The percentage of participants with a hemoglobin increase of ≥1.0 g/dL from baseline is presented.	Any 8-week interval during the study (up to approximately 68 months)
Percentage of Non-transfusion Dependent (NTD) Participants With a Hemoglobin Increase of ≥1.0 g/dL From Baseline Over a Rolling 12-week Interval	An erythroid response in NTD participants was defined as a mean hemoglobin increase of ≥1.0 g/dL from baseline over a 12-week interval compared to baseline. Baseline hemoglobin for NTD participants was the average of two or more measurements performed during the screening period of either the base study (A536-04) or the extension study (A536-06). Hemoglobin measurements within 2 weeks following red blood cell (RBC) transfusion were excluded from the analysis. NTD participants were participants who had received <4 units of RBCs within 8 weeks prior to the first dose of study drug. A 12-week interval was defined as any consecutive 12 weeks during the study. The percentage of participants with a hemoglobin increase of ≥1.0 g/dL from baseline is presented.	Any 12-week interval during the study (up to approximately 68 months)
Percentage of Non-transfusion Dependent (NTD) Participants With a Hemoglobin Increase of ≥1.0 g/dL From Baseline During Weeks 13 to 24	An erythroid response in NTD participants was defined as a mean hemoglobin increase of ≥1.0 g/dL from baseline measured during Weeks 13 to 24. Baseline hemoglobin for NTD participants was the average of two or more measurements performed during the screening period of either the base study (A536-04) or the extension study (A536-06). Hemoglobin measurements within 2 weeks following red blood cell (RBC) transfusion were excluded from the analysis. NTD participants were participants who had received <4 units of RBCs within 8 weeks prior to the first dose of study drug. The percentage of participants with a hemoglobin increase of ≥1.0 g/dL from baseline is presented.	Weeks 13 to 24
Percentage of Non-transfusion Dependent (NTD) Participants With a Hemoglobin Increase of ≥1.0 g/dL From Baseline During Weeks 37 to 48	An erythroid response in NTD participants was defined as a mean hemoglobin increase of ≥1.0 g/dL measured during Weeks 37 to 48. Baseline hemoglobin for NTD participants was the average of two or more measurements performed during the screening period of either the base study (A536-04) or the extension study (A536-06). Hemoglobin measurements within 2 weeks following red blood cell (RBC) transfusion were excluded from the analysis. NTD participants were participants who had received <4 units of RBCs within 8 weeks prior to the first dose of study drug. The percentage of participants with a hemoglobin increase of ≥1.0 g/dL from baseline is presented.	Weeks 37 to 48
Percentage of Non-transfusion Dependent (NTD) Participants With a Hemoglobin Increase of ≥1.5 g/dL From Baseline Over a Rolling 8-week Interval	An erythroid response in NTD participants was defined as a mean hemoglobin increase of ≥1.5 g/dL from baseline over an 8-week interval compared to baseline. Baseline hemoglobin for NTD participants was the average of two or more measurements performed during the screening period of either the base study (A536-04) or the extension study (A536-06). Hemoglobin measurements within 2 weeks following red blood cell (RBC) transfusion were excluded from the analysis. NTD participants were participants who had received <4 units of RBCs within 8 weeks prior to the first dose of study drug. An 8-week interval was defined as any consecutive 8 weeks during the study. The percentage of participants with a hemoglobin increase of ≥1.5 g/dL from baseline will is presented.	Any 8-week interval during the study (up to approximately 68 months)
Percentage of Non-transfusion Dependent (NTD) Participants With a Hemoglobin Increase of ≥1.5 g/dL From Baseline Over a Rolling 12-week Interval	An erythroid response in NTD participants was defined as a mean hemoglobin increase of ≥1.5 g/dL from baseline over a 12-week interval compared to baseline. Baseline hemoglobin for NTD participants was the average of two or more measurements performed during the screening period of either the base study (A536-04) or the extension study (A536-06). Hemoglobin measurements within 2 weeks following red blood cell (RBC) transfusion were excluded from the analysis. NTD participants were participants who had received <4 units of RBCs within 8 weeks prior to the first dose of study drug. A 12-week interval was defined as any consecutive 12 weeks during the study. The percentage of participants with a hemoglobin increase of ≥1.5 g/dL from baseline is presented.	Any 12-week interval during the study (up to approximately 68 months)
Percentage of Non-transfusion Dependent (NTD) Participants With a Hemoglobin Increase of ≥1.5 g/dL From Baseline During Weeks 13 to 24	An erythroid response in NTD participants was defined as a mean hemoglobin increase of ≥1.5 g/dL from baseline measured during Weeks 13 to 24. Baseline hemoglobin for NTD participants was the average of two or more measurements performed during the screening period of either the base study (A536-04) or the extension study (A536-06). Hemoglobin measurements within 2 weeks following red blood cell (RBC) transfusion were excluded from the analysis. NTD participants were participants who had received <4 units of RBCs within 8 weeks prior to the first dose of study drug. The percentage of participants with a hemoglobin increase of ≥1.5 g/dL from baseline is presented.	Weeks 13 to 24
Percentage of Non-transfusion Dependent (NTD) Participants With a Hemoglobin Increase of ≥1.5 g/dL From Baseline During Weeks 37 to 48	An erythroid response in NTD participants was defined as a mean hemoglobin increase of ≥1.5 g/dL from baseline measured during Weeks 37 to 48. Baseline hemoglobin for NTD participants was the average of two or more measurements performed during the screening period of either the base study (A536-04) or the extension study (A536-06). Hemoglobin measurements within 2 weeks following red blood cell (RBC) transfusion were excluded from the analysis. NTD participants were participants who had received <4 units of RBCs within 8 weeks prior to the first dose of study drug. The percentage of participants with a hemoglobin increase of ≥1.5 g/dL from baseline is presented.	Weeks 37 to 48
Percentage of Transfusion Dependent (TD) Participants With a ≥20% Reduction in Red Blood Cell (RBC) Transfusion Burden From Baseline During a Rolling 8-week Interval	Transfusion burden for TD participants was defined as the ratio of RBC transfusion units (or milliliters) transfused during an 8-week interval divided by the duration of that interval compared to the ratio of RBC transfusion units 8 weeks prior to the start of treatment (baseline). TD participants were participants who had received ≥4 units of RBCs every 8 weeks (confirmed over 6 months prior to the first dose of study drug). An 8-week interval was defined as any consecutive 8 weeks during the study. The percentage of participants with a ≥20% reduction in RBC transfusion burden from baseline is presented.	Any 8-week interval during the study (up to approximately 68 months)
Percentage of Transfusion Dependent (TD) Participants With a ≥33% Reduction in Red Blood Cell (RBC) Transfusion Burden From Baseline During a Rolling 8-Week Interval	Transfusion burden for TD participants was defined as the ratio of RBC transfusion units (or milliliters) transfused during an 8-week interval divided by the duration of that interval compared to the ratio of RBC transfusion units 8 weeks prior to the start of treatment (baseline). TD participants were participants who had received ≥4 units of RBCs every 8 weeks (confirmed over 6 months prior to the first dose of study drug). An 8-week interval was defined as any consecutive 8 weeks during the study. The percentage of participants with a ≥33% reduction in RBC transfusion burden from baseline is presented.	Any 8-week interval during the study (up to approximately 68 months)
Percentage of Transfusion Dependent (TD) Participants With a ≥50% Reduction in Red Blood Cell (RBC) Transfusion Burden From Baseline During a Rolling 8-week Interval	Transfusion burden for TD participants was defined as the ratio of RBC transfusion units (or milliliters) transfused during an 8-week interval divided by the duration of that interval compared to the ratio of RBC transfusion units 8 weeks prior to the start of treatment (baseline). TD participants were participants who had received ≥4 units of RBCs every 8 weeks (confirmed over 6 months prior to the first dose of study drug). An 8-week interval was defined as any consecutive 8 weeks during the study. The percentage of participants with a ≥50% reduction in RBC transfusion burden from baseline is presented.	Any 8-week interval during the study (up to approximately 68 months)
Percentage of Transfusion Dependent (TD) Participants With a ≥20% Reduction in Red Blood Cell (RBC) Transfusion Burden From Baseline During a Rolling 12-week Interval	Transfusion burden for TD participants was defined as the ratio of RBC transfusion units (or milliliters) transfused during a 12-week interval divided by the duration of that interval compared to the ratio of RBC transfusion units 12 weeks prior to the start of treatment (baseline). TD participants were participants who had received ≥4 units of RBCs every 8 weeks (confirmed over 6 months prior to the first dose of study drug). A 12-week interval was defined as any consecutive 12 weeks during the study. The percentage of participants with a ≥20% reduction in RBC transfusion burden from baseline is presented.	Any 12-week interval during the study (up to approximately 68 months)
Percentage of Transfusion Dependent (TD) Participants With a ≥33% Reduction in Red Blood Cell (RBC) Transfusion Burden From Baseline During a Rolling 12-Week Interval	Transfusion burden for TD participants was defined as the ratio of RBC transfusion units (or milliliters) transfused during a 12-week interval divided by the duration of that interval compared to the ratio of RBC transfusion units 8 weeks prior to the start of treatment (baseline). TD participants were participants who had received ≥4 units of RBCs every 8 weeks (confirmed over 6 months prior to the first dose of study drug). A 12-week interval was defined as any consecutive 12 weeks during the study. The percentage of participants with a ≥33% reduction in RBC transfusion burden from baseline is presented.	Any 12-week interval during the study (up to approximately 68 months)
Percentage of Transfusion Dependent (TD) Participants With a ≥50% Reduction in Red Blood Cell (RBC) Transfusion Burden From Baseline During a Rolling 12-week Interval	Transfusion burden for TD participants was defined as the ratio of RBC transfusion units (or milliliters) transfused during a 12-week interval divided by the duration of that interval compared to the ratio of RBC transfusion units 12 weeks prior to the start of treatment (baseline). TD participants were participants who had received ≥4 units of RBCs every 8 weeks (confirmed over 6 months prior to the first dose of study drug). A 12-week interval was defined as any consecutive 12 weeks during the study. The percentage of participants with a ≥50% reduction in RBC transfusion burden from baseline is presented.	Any 12-week interval during the study (up to approximately 68 months)
Percentage of Transfusion Dependent (TD) Participants With a ≥20% Reduction in Red Blood Cell (RBC) Transfusion Burden From Baseline During Weeks 13 to 24	Transfusion burden for TD participants was defined as the ratio of RBC transfusion units (or milliliters) transfused during a Weeks 13 to 24 divided by the duration of that interval compared to the ratio of RBC transfusion units 12 weeks prior to the start of treatment (baseline). TD participants were participants who had received ≥4 units of RBCs every 8 weeks (confirmed over 6 months prior to the first dose of study drug). The percentage of participants with a ≥20% reduction in RBC transfusion burden from baseline is presented.	Weeks 13 to 24
Percentage of Transfusion Dependent (TD) Participants With a ≥33% Reduction in Red Blood Cell (RBC) Transfusion Burden From Baseline During Weeks 13 to 24	Transfusion burden for TD participants was defined as the ratio of RBC transfusion units (or milliliters) transfused during a Weeks 13 to 24 divided by the duration of that interval compared to the ratio of RBC transfusion units 12 weeks prior to the start of treatment (baseline). TD participants were participants who had received ≥4 units of RBCs every 8 weeks (confirmed over 6 months prior to the first dose of study drug). The percentage of participants with a ≥33% reduction in RBC transfusion burden from baseline is presented.	Weeks 13 to 24
Percentage of Transfusion Dependent (TD) Participants With a ≥50% Reduction in Red Blood Cell (RBC) Transfusion Burden From Baseline During Weeks 13 to 24	Transfusion burden for TD participants was defined as the ratio of RBC transfusion units (or milliliters) transfused during Weeks 13 to 24 divided by the duration of that interval compared to the ratio of RBC transfusion units 12 weeks prior to the start of treatment (baseline). TD participants were participants who had received ≥4 units of RBCs every 8 weeks (confirmed over 6 months prior to the first dose of study drug). The percentage of participants with a ≥50% reduction in RBC transfusion burden from baseline is presented.	Weeks 13 to 24
Percentage of Transfusion Dependent (TD) Participants With a ≥20% Reduction in Red Blood Cell (RBC) Transfusion Burden From Baseline During Weeks 37 to 48	Transfusion burden for TD participants was defined as the ratio of RBC transfusion units (or milliliters) transfused during Weeks 37 to 48 divided by the duration of that interval compared to the ratio of RBC transfusion units 12 weeks prior to the start of treatment (baseline). TD participants were participants who had received ≥4 units of RBCs every 8 weeks (confirmed over 6 months prior to the first dose of study drug). The percentage of participants with a ≥20% reduction in RBC transfusion burden from baseline is presented.	Weeks 37 to 48
Percentage of Transfusion Dependent (TD) Participants With a ≥33% Reduction in Red Blood Cell (RBC) Transfusion Burden From Baseline During Weeks 37 to 48	Transfusion burden for TD participants was defined as the ratio of RBC transfusion units (or milliliters) transfused during Weeks 37 to 48 divided by the duration of that interval compared to the ratio of RBC transfusion units 12 weeks prior to the start of treatment (baseline). TD participants were participants who had received ≥4 units of RBCs every 8 weeks (confirmed over 6 months prior to the first dose of study drug). The percentage of participants with a ≥33% reduction in RBC transfusion burden from baseline is presented.	Weeks 37 to 48
Percentage of Transfusion Dependent (TD) Participants With a ≥50% Reduction in Red Blood Cell (RBC) Transfusion Burden From Baseline During Weeks 37 to 48	Transfusion burden for TD participants was defined as the ratio of RBC transfusion units (or milliliters) transfused during Weeks 37 to 48 divided by the duration of that interval compared to the ratio of RBC transfusion units 12 weeks prior to the start of treatment (baseline). TD participants were participants who had received ≥4 units of RBCs every 8 weeks (confirmed over 6 months prior to the first dose of study drug). The percentage of participants with a ≥50% reduction in RBC transfusion burden from baseline is presented.	Weeks 37 to 48
Percentage of Transfusion Dependent (TD) Participants Who Maintained Red Blood Cell (RBC) Transfusion Independence For ≥8 Weeks	Transfusion independence for TD participants was defined as the percentage of participants who did not require RBC transfusion units (or milliliters) transfused for ≥8 weeks in the study after start of treatment. TD participants were participants who had received ≥4 units of RBCs every 8 weeks (confirmed over 6 months prior to the first dose of study drug). The percentage of participants who maintained transfusion independence for ≥8 weeks is presented.	Any 8-week interval during the study (up to approximately 68 months)
Maximum Percent Change From Baseline in Red Blood Cell (RBC) Transfusions in Transfusion Dependent (TD) Participants Over 8 Weeks	The reduction from baseline in red blood cell transfusions for TD participants was defined as the ratio of RBC transfusion units (or milliliters) transfused during an 8-week interval divided by the duration of that interval compared to the ratio of RBC transfusion units 8 weeks prior to the start of treatment (baseline). TD participants were participants who had received ≥4 units of RBCs every 8 weeks (confirmed over 6 months prior to the first dose of study drug). An 8-week interval was defined as any consecutive 8 weeks during the study. The percentage change from baseline in RBC transfusions in TD participants is presented.	Any 8-week interval during the study (up to approximately 68 months)
Maximum Percent Change From Baseline in Red Blood Cell (RBC) Transfusions in Transfusion Dependent (TD) Participants Over 12 Weeks	The change from baseline in red blood cell transfusions for TD participants was defined as the ratio of RBC transfusion units (or milliliters) transfused during a 12-week interval divided by the duration of that interval compared to the ratio of RBC transfusion units 12 weeks prior to the start of treatment (baseline). TD participants were participants who had received ≥4 units of RBCs every 8 weeks (confirmed over 6 months prior to the first dose of study drug). A 12-week interval was defined as any consecutive 12 weeks during the study. The percentage change from baseline in RBC transfusions in TD participants is presented.	Any 12-week interval during the study (up to approximately 68 months)
Time To Erythroid Response for Non-transfusion Dependent (NTD) Participants Who Achieved a Hemoglobin Increase ≥1.0 g/dL Over a Rolling 12-week Interval	Time to erythroid response was defined as the time from first dose to the first date of any rolling 12-week window achieving a hemoglobin increase ≥1.0 g/dL. When there were multiple disjointed intervals with response, the longest interval was used. Participants with response ongoing by the analysis cutoff day were censored. The time to the first date of any rolling 12-week window achieving a hemoglobin increase ≥1.0 g/dL is presented.	Any 12-week interval during the study (up to approximately 68 months)
Time To Erythroid Response for Non-transfusion Dependent (NTD) Participants Who Achieved a Hemoglobin Increase ≥1.5 g/dL Over a Rolling 12-week Interval	Time to erythroid response was defined as the time from first dose to the first date of any rolling 12-week window achieving a hemoglobin increase ≥1.5 g/dL. When there were multiple disjointed intervals with response, the longest interval was used. Participants with response ongoing by the analysis cutoff day were censored. The time to the first date of any rolling 12-week window achieving a hemoglobin increase ≥1.5 g/dL is presented.	Any 12-week interval during the study (up to approximately 68 months)
Time To Erythroid Response for Transfusion Dependent (TD) Participants Who Achieved a Transfusion Burden Reduction of ≥33% Over a Rolling 12-week Interval	Time to erythroid response was defined as the time from first dose to the first date of any rolling 12-week window achieving a red blood cell (RBC) transfusion burden reduction compared to pretreatment of ≥33%. When there were multiple disjointed intervals with response, the longest interval was used. Participants with response ongoing by the analysis cutoff day were censored. The time to the first date of any rolling 12-week window achieving a red blood cell transfusion burden reduction compared to pretreatment of ≥33% is presented.	Any 12-week interval during the study (up to approximately 68 months)
Time To Erythroid Response for Transfusion Dependent (TD) Participants Who Achieved a Transfusion Burden Reduction of ≥50% Over a Rolling 12-week Interval	Time to erythroid response was defined as the time from first dose to the first date of any rolling 12-week window achieving a red blood cell (RBC) transfusion burden reduction compared to pretreatment of ≥50%. When there were multiple disjointed intervals with response, the longest interval was used. Participants with response ongoing by the analysis cutoff day were censored. The time to the first date of any rolling 12-week window achieving a red blood cell transfusion burden reduction compared to pretreatment of ≥50% is presented.	Any 12-week interval during the study (up to approximately 68 months)
Duration of Erythroid Response for Non-transfusion Dependent (NTD) Participants Who Achieved a Hemoglobin Increase ≥1.0 g/dL Over a Rolling 12-week Interval	Duration of erythroid response was defined as the time from the starting date of the first rolling 12-week window achieving a hemoglobin increase of ≥1.0 g/dL to the last date of the last consecutive rolling 12-week window achieving a hemoglobin increase of ≥1.0 g/dL. When there were multiple disjointed intervals with response, the longest interval was used. Participants with response ongoing by the analysis cutoff day were censored. The duration of response for participants achieving a hemoglobin increase ≥1.0 g/dL is presented.	Any 12-week interval during the study (up to approximately 68 months)
Duration of Erythroid Response for Non-transfusion Dependent (NTD) Participants Who Achieved a Hemoglobin Increase ≥1.5 g/dL Over a Rolling 12-week Interval	Duration of erythroid response was defined as the time from the starting date of the first rolling 12-week window achieving a hemoglobin increase of ≥1.5 g/dL to the last date of the last consecutive rolling 12-week window achieving a hemoglobin increase of ≥1.5 g/dL. When there were multiple disjointed intervals with response, the longest interval was used. Participants with response ongoing by the analysis cutoff day were censored. The duration of response for participants achieving a hemoglobin increase ≥1.5 g/dL is presented.	Any 12-week interval during the study (up to approximately 68 months)
Duration of Erythroid Response for Transfusion Dependent (TD) Participants Who Achieved a Transfusion Burden Reduction of ≥33% Over a Rolling 12-week Interval	Duration of erythroid response was defined as the time from the starting date of the first rolling 12-week window achieving a red blood cell (RBC) transfusion burden reduction compared to pretreatment of ≥33% to the last date of the last consecutive rolling 12-week window achieving a RBC transfusion burden reduction compared to pretreatment of ≥33%. When there were multiple disjointed intervals with response, the longest interval was used. Participants with response ongoing by the analysis cutoff day were censored. The duration of response for participants achieving a RBC transfusion burden reduction compared to pretreatment of ≥33% is presented.	Any 12-week interval during the study (up to approximately 68 months)
Duration of Erythroid Response for Transfusion Dependent (TD) Participants Who Achieved a Transfusion Burden Reduction of ≥50% Over a Rolling 12-week Interval	Duration of erythroid response was defined as the time from the starting date of the first rolling 12-week window achieving a red blood cell (RBC) transfusion burden reduction compared to pretreatment of ≥50% to the last date of the last consecutive rolling 12-week window achieving a RBC transfusion burden reduction compared to pretreatment of ≥50%. When there were multiple disjointed intervals with response, the longest interval was used. Participants with response ongoing by the analysis cutoff day were censored. The duration of response for participants achieving a RBC transfusion burden reduction compared to pretreatment of ≥50% is presented.	Any 12-week interval during the study (up to approximately 68 months)
Mean Change From Baseline in Pre-transfusion Hemoglobin Levels in Transfusion Dependent (TD) Participants	Pre-transfusion hemoglobin levels were calculated in TD participants. TD participants were participants who had received ≥4 units of red blood cells (RBC) every 8 weeks (confirmed over 6 months prior to the first dose of study drug). The baseline pre-transfusion hemoglobin level was an average of all hemoglobin values measured before the first dose of study drug given. The post-baseline pre-transfusion hemoglobin levels were calculated using the average of all hemoglobin values recorded before each transfusion that was required after the first dose of study drug was given. All hemoglobin levels measured within the 2 weeks following a red blood cell transfusion were excluded from the analysis. The change from baseline in pre-transfusion hemoglobin levels is presented.	Any 8 or 12-week interval during the study (up to approximately 68 months)
Mean Change From Baseline in Hemoglobin Level Over Multiple Rolling 8-Week Intervals in Non-transfusion Dependent (NTD) Participants	Mean change from baseline in hemoglobin levels was calculated for multiple rolling 8-week intervals in NTD participants. NTD participants were participants who had received <4 units of red blood cells (RBC) within 8 weeks prior to the first dose of study treatment. The baseline pre-transfusion hemoglobin level was an average of all hemoglobin values measured before the first dose of study drug given. The post-baseline hemoglobin level was taken after every rolling 8-week interval producing multiple values for the mean change from baseline in hemoglobin. The maximum change from baseline in hemoglobin level among the multiple rolling 8-week intervals is presented.	Baseline (prior to first dose of study drug) and multiple 8-week intervals during the study (up to approximately 68 months)
Mean Change From Baseline in Hemoglobin Level Over Multiple Rolling 12-Week Intervals in Non-transfusion Dependent (NTD) Participants	Mean change from baseline in hemoglobin levels was calculated for multiple rolling 12-week intervals in NTD participants. NTD participants were participants who had received <4 units of red blood cells (RBC) within 8 weeks prior to the first dose of study treatment. The baseline pre-transfusion hemoglobin level was an average of all hemoglobin values measured before the first dose of study drug given. The post-baseline hemoglobin level was taken after every rolling 12-week interval producing multiple values for the mean change from baseline in hemoglobin. The maximum change from baseline in hemoglobin level among the multiple rolling 12-week intervals is presented.	Baseline (prior to first dose of study drug) and multiple 12-week intervals during the study (up to approximately 68 months)
Percent Change From Baseline in Transfusion Burden Over Multiple Rolling 8-Week Intervals in Transfusion Dependent (TD) Participants	Percent change from baseline in transfusion burden was calculated for multiple rolling 8-week intervals in TD participants. TD participants were participants who had received ≥4 units of red blood cells (RBC) every 8 weeks (confirmed over 6 months prior to the first dose of study drug). Transfusion burden for TD participants was defined as the ratio of RBC transfusion units (or milliliters) transfused during an 8-week interval divided by the duration of that interval compared to the ratio of RBC transfusion units 8 weeks prior to the start of treatment (baseline). The post-baseline transfusion burden was calculated after every rolling 8-week interval producing multiple values for the percent change from baseline in transfusion burden. The maximum percent change from baseline in transfusion burden among the multiple rolling 8-week intervals is presented.	Baseline (prior to first dose of study drug) and multiple 8-week intervals during the study (up to approximately 68 months)
Percent Change From Baseline in Transfusion Burden Over Multiple Rolling 12-Week Intervals in Transfusion Dependent (TD) Participants	Percent change from baseline in transfusion burden was calculated for multiple rolling 12-week intervals in TD participants. TD participants were participants who had received ≥4 units of red blood cells (RBC) every 8 weeks (confirmed over 6 months prior to the first dose of study drug). Transfusion burden for TD participants was defined as the ratio of RBC transfusion units (or milliliters) transfused during a 12-week interval divided by the duration of that interval compared to the ratio of RBC transfusion units 12 weeks prior to the start of treatment (baseline). The post-baseline transfusion burden was calculated after every rolling 12-week interval producing multiple values for the percent change from baseline in transfusion burden. The maximum percent change from baseline in transfusion burden among the multiple rolling 12-week intervals is presented.	Baseline (prior to first dose of study drug) and multiple 12-week intervals during the study (up to approximately 68 months)
Percent Change From Baseline to End of Treatment in Erythropoietin	Blood samples were collected at pre-specified time intervals to determine erythropoietin. The percent change from baseline in mean concentration of erythropoietin was measured. Baseline was the last measurement prior to the first dose of study drug. Per protocol, the analysis was presented by transfusion status (non-transfusion and transfusion dependent).	Baseline (prior to first dose of study drug) and End of Treatment (up to Day 1807)
Percent Change From Baseline to End of Treatment in Reticulocyte Count	Blood samples were collected at pre-specified time intervals to determine reticulocyte count. The percent change from baseline in reticulocyte count was measured. Baseline was the last measurement prior to the first dose of study drug. Per protocol, the analysis was presented by transfusion status (non-transfusion and transfusion dependent).	Baseline (prior to first dose of study drug) and End of Treatment (up to Day 1807)
Percent Change From Baseline to End of Treatment in Nucleated Red Blood Cell (nRBC) Count	Blood samples were collected at pre-specified time intervals to determine nRBC count. The percent change from baseline in nRBC count was measured. Baseline was the last measurement prior to the first dose of study drug. Per protocol, the analysis was presented by transfusion status (non-transfusion and transfusion dependent).	Baseline (prior to first dose of study drug) and End of Treatment (up to Day 1807)
Percent Change From Baseline to End of Treatment in Soluble Transferrin Receptor	Blood samples were collected at pre-specified time intervals to determine soluble transferrin receptor. The percent change from baseline in mean concentration of soluble transferrin receptor was measured. Baseline was the last measurement prior to the first dose of study drug. Per protocol, the analysis was presented by transfusion status (non-transfusion and transfusion dependent).	Baseline (prior to first dose of study drug) and End of Treatment (up to Day 1807)
Percent Change From Baseline to End of Treatment in Serum Ferritin	Blood samples were collected at pre-specified time intervals to determine serum ferritin. The percent change from baseline in mean concentration of serum ferritin was measured. Baseline was the last measurement prior to the first dose of study drug. Per protocol, the analysis was presented by transfusion status (non-transfusion and transfusion dependent).	Baseline (prior to first dose of study drug) and End of Treatment (up to Day 1807)
Percent Change From Baseline to End of Treatment in Percent Transferrin (Iron) Saturation	Blood samples were collected at pre-specified time intervals to determine percent transferrin (iron) saturation. The percent change from baseline in mean concentration of percent transferrin (iron) saturation was measured. Baseline was the last measurement prior to the first dose of study drug. Per protocol, the analysis was presented by transfusion status (non-transfusion and transfusion dependent).	Baseline (prior to first dose of study drug) and End of Treatment (up to Day 1807)
Percent Change From Baseline to End of Treatment in Serum Transferrin	Blood samples were to be collected at pre-specified time intervals to determine serum transferrin. Baseline was pre-specified to be the last measurement prior to the first dose of study drug. Per protocol, the analysis was planned to be presented by transfusion status (non-transfusion and transfusion dependent).	Baseline (prior to first dose of study drug) and End of Treatment (up to Day 1807)
Percent Change From Baseline to End of Treatment in Serum Iron	Blood samples were to be collected at pre-specified time intervals to determine serum iron. Baseline was pre-specified to be the last measurement prior to the first dose of study drug. Per protocol, the analysis was planned to be presented by transfusion status (non-transfusion and transfusion dependent).	Baseline (prior to first dose of study drug) and End of Treatment (up to Day 1807)
Percent Change From Baseline to End of Treatment in Serum Hepcidin	Blood samples were to be collected at pre-specified time intervals to determine serum hepcidin. Baseline was pre-specified to be the last measurement prior to the first dose of study drug. Per protocol, the analysis was planned to be presented by transfusion status (non-transfusion and transfusion dependent).	Baseline (prior to first dose of study drug) and End of Treatment (up to Day 1807)
Percent Change From Baseline to End of Treatment in Serum Total Iron Binding Capacity (TIBC)	Blood samples were to be collected at pre-specified time intervals to determine serum total iron binding capacity. Baseline was pre-specified to be the last measurement prior to the first dose of study drug. Per protocol, the analysis was planned to be presented by transfusion status (non-transfusion and transfusion dependent).	Baseline (prior to first dose of study drug) and End of Treatment (up to Day 1807)
Percent Change From Baseline to End of Treatment in Non-transferrin Bound Iron (NTBI)	Blood samples were to be collected at pre-specified time intervals to determine serum non-transferrin bound iron. Baseline was pre-specified to be the last measurement prior to the first dose of study drug. Per protocol, the analysis was planned to be presented by transfusion status (non-transfusion and transfusion dependent).	Baseline (prior to first dose of study drug) and End of Treatment (up to Day 1807)
Percent Change From Baseline to End of Treatment in Total Bilirubin	Blood samples were collected at pre-specified time intervals to determine total bilirubin. The percent change from baseline in total bilirubin was measured. Baseline was the last measurement prior to the first dose of study drug.	Baseline (prior to first dose of study drug) and End of Treatment (up to Day 1807)
Percent Change From Baseline to End of Treatment in Indirect Bilirubin	Blood samples were collected at pre-specified time intervals to determine indirect bilirubin. The percent change from baseline in indirect bilirubin was measured. Baseline was the last measurement prior to the first dose of study drug.	Baseline (prior to first dose of study drug) and End of Treatment (up to Day 1807)
Percent Change From Baseline to End of Treatment in Lactate Dehydrogenase (LDH)	Blood samples were collected at pre-specified time intervals to determine LDH. The percent change from baseline in LDH was measured. Baseline was the last measurement prior to the first dose of study drug.	Baseline (prior to first dose of study drug) and End of Treatment (up to Day 1807)
Change From Baseline in Liver Iron Concentration (LIC) For Participants With Baseline LIC <3 mg/g Dry Weight Measured After 18 Months and Up to 60 Months of Treatment	Blood samples were collected at pre-specified time intervals to determine LIC. The change from baseline in mean LIC for participants with baseline LIC <3 mg/g dry weight was measured using magnetic resonance imaging (MRI). Baseline was the last measurement prior to the first dose of study drug. Per protocol, the analysis was presented by transfusion status (non-transfusion and transfusion dependent).	Baseline (prior to first dose of study drug) and up to approximately 60 Months
Change From Baseline in Liver Iron Concentration (LIC) For Participants With Baseline LIC ≥3 mg/g Dry Weight Measured After 18 Months and Up to 60 Months of Treatment	Blood samples were collected at pre-specified time intervals to determine LIC. The change from baseline in mean LIC for participants with baseline LIC ≥3 mg/g dry weight was measured using magnetic resonance imaging (MRI). Baseline was the last measurement prior to the first dose of study drug. Per protocol, the analysis was presented by transfusion status (non-transfusion and transfusion dependent).	Baseline (prior to first dose of study drug) and up to approximately 60 Months
Change From Baseline in Liver Iron Concentration (LIC) For Participants With Baseline LIC <3 mg/g Dry Weight, Who Have Used Iron Chelation Therapy (ICT), Measured After 18 Months and Up to 60 Months of Treatment	Blood samples were collected at pre-specified time intervals to determine LIC. The change from baseline in mean LIC for participants with baseline LIC <3 mg/g dry weight and who have used ICT within 84 days prior to the first dose of study drug or during the study treatment period was measured using magnetic resonance imaging (MRI). Baseline was the last measurement prior to the first dose of study drug. Per protocol, the analysis was presented by transfusion status (non-transfusion and transfusion dependent).	Baseline (prior to first dose of study drug) and up to approximately 60 Months
Change From Baseline in Liver Iron Concentration (LIC) For Participants With Baseline LIC ≥3 mg/g Dry Weight, Who Have Used Iron Chelation Therapy (ICT), Measured After 18 Months and Up to 60 Months of Treatment	Blood samples were collected at pre-specified time intervals to determine LIC. The change from baseline in mean LIC for participants with baseline LIC ≥3 mg/g dry weight and who have used ICT within 84 days prior to the first dose of study drug or during the study treatment period was measured using magnetic resonance imaging (MRI). Baseline was the last measurement prior to the first dose of study drug. Per protocol, the analysis was presented by transfusion status (non-transfusion and transfusion dependent).	Baseline (prior to first dose of study drug) and up to approximately 60 Months
Change From Baseline in Liver Iron Concentration (LIC) For Participants With Baseline LIC <3 mg/g Dry Weight, Who Have Not Used Iron Chelation Therapy (ICT), Measured After 18 Months and Up to 60 Months of Treatment	Blood samples were collected at pre-specified time intervals to determine LIC. The change from baseline in mean LIC for participants with baseline LIC <3 mg/g dry weight and who have not used ICT within 84 days prior to the first dose of study drug or during the study treatment period was measured using magnetic resonance imaging (MRI). Baseline was the last measurement prior to the first dose of study drug. Per protocol, the analysis was presented by transfusion status (non-transfusion and transfusion dependent).	Baseline (prior to first dose of study drug) and up to approximately 60 Months
Change From Baseline in Liver Iron Concentration (LIC) For Participants With Baseline LIC ≥3 mg/g Dry Weight, Who Have Not Used Iron Chelation Therapy (ICT), Measured After 18 Months and Up to 60 Months of Treatment	Blood samples were collected at pre-specified time intervals to determine LIC. The change from baseline in mean LIC for participants with baseline LIC ≥3 mg/g dry weight and who have not used ICT within 84 days prior to the first dose of study drug or during the study treatment period was measured using magnetic resonance imaging (MRI). Baseline was the last measurement prior to the first dose of study drug. Per protocol, the analysis was presented by transfusion status (non-transfusion and transfusion dependent).	Baseline (prior to first dose of study drug) and up to approximately 60 Months
Serum Concentration of Luspatercept	Blood samples were collected at multiple time points to determine the serum concentration of luspatercept. Serum concentrations that were below the limit of quantitation (LOQ) of the assay prior to the first dose were assigned a numerical value of zero. Post-treatment serum concentrations that were below the LOQ of the assay were treated as missing. Serum concentrations assigned a value of missing were omitted from the analysis. The LOQ of the assay was 50 ng/mL.	Predose and Postdose Days 1, 8, 22, 169, 176, 190, 337, and 344

Collaborators and Investigators

• Sponsor: Acceleron Pharma, Inc., a wholly-owned subsidiary of Merck & Co., Inc., Rahway, NJ USA
• Investigators: Study Director: Medical Director, Merck Sharp & Dohme LLC

Publications and helpful links

General Publications

• Piga A, Perrotta S, Gamberini MR, Voskaridou E, Melpignano A, Filosa A, Caruso V, Pietrangelo A, Longo F, Tartaglione I, Borgna-Pignatti C, Zhang X, Laadem A, Sherman ML, Attie KM. Luspatercept improves hemoglobin levels and blood transfusion requirements in a study of patients with beta-thalassemia. Blood. 2019 Mar 21;133(12):1279-1289. doi: 10.1182/blood-2018-10-879247. Epub 2019 Jan 7.

Helpful Links

• A536-06 Results Posting

Study record dates

Study Major Dates

• Study Start (Actual): October 20, 2014
• Primary Completion (Actual): June 18, 2020
• Study Completion (Actual): June 18, 2020

Study Registration Dates

• First Submitted: October 6, 2014
• First Submitted That Met QC Criteria: October 16, 2014
• First Posted (Estimated): October 20, 2014

Study Record Updates

• Last Update Posted (Actual): July 18, 2024
• Last Update Submitted That Met QC Criteria: February 6, 2024
• Last Verified: February 1, 2024

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Hematologic Diseases; Genetic Diseases, Inborn; Anemia; Anemia, Hemolytic, Congenital; Anemia, Hemolytic; Hemoglobinopathies; Thalassemia; beta-Thalassemia; Hematinics; Luspatercept
• Other Study ID Numbers: A536-06 (Other Identifier: Acceleron); MK-6143-004 (Other Identifier: Merck); 2014-001281-94 (EudraCT Number)