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NCT01749540

Study to Evaluate the Safety and Efficacy of Luspatercept (ACE-536) in Participants With Beta-thalassemia (A536-04/MK-6143-002)

Completed Phase 2 Results posted Last updated 18 July 2024
What this trial tests

Phase 2 trial testing luspatercept in B-Thalassemia in 64 participants. Completed in 11 November 2015.

Timeline
28 February 2013
Primary endpoint
11 November 2015
11 November 2015

Quick facts

Lead sponsorAcceleron Pharma, Inc., a wholly-owned subsidiary of Merck & Co., Inc., Rahway, NJ USA
PhasePhase 2
StatusCompleted
Study typeINTERVENTIONAL
Allocationnon randomized
Designparallel
Maskingnone
Primary purposetreatment
Enrollment64
Start date28 February 2013
Primary completion11 November 2015
Estimated completion11 November 2015
Sites8 locations across Italy, Greece

Drugs / interventions tested

Conditions studied

Sponsor

Acceleron Pharma, Inc., a wholly-owned subsidiary of Merck & Co., Inc., Rahway, NJ USA — full company profile →

Who can join

18 and older, any sex, with B-Thalassemia. Patients with the condition only — healthy volunteers not accepted.

Results — posted to ClinicalTrials.gov

Per-arm endpoint measurements with 95% confidence intervals where reported. Source: trial results section.

Percentage of Non-transfusion Dependent (NTD) Participants With a Hemoglobin Increase of ≥1.5 g/dL From Baseline for ≥14 Days Primary · Up to approximately 20 weeks

An erythroid response in NTD participants was defined as a mean hemoglobin increase of ≥1.5 g/dL from baseline for ≥14 days in the absence of blood transfusion. Baseline hemoglobin for NTD participants was the average of two or more measurements performed during the screening period. Hemoglobin measurements within 2 weeks following red blood cell (RBC) transfusion or 56 days after the last dose were excluded from 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

GroupValue95% CI
Luspatercept 0.2 mg/kg0.00.0 – 45.9
Luspatercept 0.4 mg/kg0.00.0 – 45.9
Luspatercept 0.6 mg/kg0.00.0 – 52.2
Luspatercept 0.8 mg/kg66.79.4 – 99.2
Luspatercept 1.0 mg/kg50.01.3 – 98.7
Luspatercept 1.25 mg/kg0.00.0 – 97.5
Expansion Cohort60.026.2 – 87.8
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 Primary · Any 12-week interval during the study (up to approximately 20 weeks)

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 interval during the pretreatment period was defined as the 12 weeks prior to the first dose of study drug. An interval during the treatment plus follow-up period was defined as any 12-week interval after the first dose of study drug. TD participants were participants who had received ≥4 units of RBCs every 8 we

GroupValue95% CI
Luspatercept 0.6 mg/kg1002.5 – 100
Luspatercept 0.8 mg/kg66.79.4 – 99.2
Luspatercept 1.0 mg/kg10039.8 – 100
Luspatercept 1.25 mg/kg75.019.4 – 99.4
Expansion Cohort78.954.4 – 93.9
Number of Participants Who Experienced an Adverse Event (AE) Secondary · Up to approximately 20 weeks

An AE was any untoward medical occurrence in a participant or clinical investigation participant administered a study drug, which does not necessarily have a causal relationship with this treatment. An AE could therefore be 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 is considered related to the study drug. The number of participants who experienced an AE is presented.

GroupValue95% CI
Luspatercept 0.2 mg/kg5
Luspatercept 0.4 mg/kg6
Luspatercept 0.6 mg/kg5
Luspatercept 0.8 mg/kg6
Luspatercept 1.0 mg/kg6
Luspatercept 1.25 mg/kg5
Expansion Cohort26
Number of Participants Who Experienced a Serious Adverse Event (SAE) Secondary · Up to approximately 20 weeks

An SAE was any adverse event, occurring at any dose level/regimen and regardless of causality that: resulted in death; was life-threatening; required inpatient hospitalization or prolongation of existing hospitalization; resulted in persistent or significant disability/incapacity; was a congenital anomaly/birth defect; or was an important medical event. The number of participants who experienced an SAE is presented.

GroupValue95% CI
Luspatercept 0.2 mg/kg0
Luspatercept 0.4 mg/kg1
Luspatercept 0.6 mg/kg0
Luspatercept 0.8 mg/kg0
Luspatercept 1.0 mg/kg0
Luspatercept 1.25 mg/kg0
Expansion Cohort0
Number of Participants Who Experienced an Adverse Event (AE) of Grade 3 or Greater Secondary · Up to approximately 20 weeks

AEs were graded using the National Cancer Institute Common Toxicity Criteria for Adverse Events, Version 4.0 (NCI-CTCAE v4.0) and graded as follows: Grade 1=mild; Grade 2=moderate; Grade 3=severe or medically significant but not immediately life-threatening; Grade 4=life-threatening consequences; and Grade 5=death related to AE. An AE was any untoward medical occurrence in a participant or clinical investigation participant administered a study drug, which does not necessarily have a causal relationship with this treatment. An AE could therefore be any unfavorable and unintended sign (includin

GroupValue95% CI
Luspatercept 0.2 mg/kg0
Luspatercept 0.4 mg/kg1
Luspatercept 0.6 mg/kg0
Luspatercept 0.8 mg/kg1
Luspatercept 1.0 mg/kg2
Luspatercept 1.25 mg/kg0
Expansion Cohort4
Number of Participants Who Discontinued Study Treatment Due To an Adverse Event (AE) Secondary · Up to approximately 12 weeks

An AE was any untoward medical occurrence in a participant or clinical investigation participant administered a study drug, which does not necessarily have a causal relationship with this treatment. An AE could therefore be 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 is considered related to the study drug. The number of participants who discontinued study treatment due to an AE is presented.

GroupValue95% CI
Luspatercept 0.2 mg/kg0
Luspatercept 0.4 mg/kg0
Luspatercept 0.6 mg/kg1
Luspatercept 0.8 mg/kg2
Luspatercept 1.0 mg/kg0
Luspatercept 1.25 mg/kg0
Expansion Cohort2
Number of Participants Who Experienced a Dose-Limiting Toxicity (DLT) Secondary · Up to 28 days

DLTs were determined using the National Cancer Institute Common Toxicity Criteria for Adverse Events, Version 4.0 (NCI-CTCAE v4.0) and graded as follows: Grade 1=mild; Grade 2=moderate; Grade 3=severe or medically significant but not immediately life-threatening; Grade 4=life-threatening consequences; and Grade 5=death related to AE. The occurrence of any of the following toxicities occurring up to 28 days after the first dose was considered a DLT: treatment-related serious adverse event (SAE) ≥ Grade 3; treatment related non-hematologic adverse event (AE) ≥ Grade 3; and treatment related hema

GroupValue95% CI
Luspatercept 0.2 mg/kg0
Luspatercept 0.4 mg/kg0
Luspatercept 0.6 mg/kg0
Luspatercept 0.8 mg/kg1
Luspatercept 1.0 mg/kg0
Luspatercept 1.25 mg/kg0
Expansion Cohort0
Percentage of Non-transfusion Dependent (NTD) Participants With a Hemoglobin Increase of ≥1.0 g/dL From Baseline During a Rolling 8-week Interval Secondary · Any 8-week interval during the study (up to approximately 20 Weeks)

A modified erythroid response in NTD participants was defined as a mean hemoglobin increase of ≥1.0 g/dL from baseline during 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. Hemoglobin measurements within 2 weeks following red blood cell (RBC) transfusion or 56 days after the last dose were excluded from 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 de

GroupValue95% CI
Luspatercept 0.2 mg/kg16.70.4 – 64.1
Luspatercept 0.4 mg/kg16.70.4 – 64.1
Luspatercept 0.6 mg/kg80.028.4 – 99.5
Luspatercept 0.8 mg/kg66.79.4 – 99.2
Luspatercept 1.0 mg/kg50.01.3 – 98.7
Luspatercept 1.25 mg/kg0.00.0 – 97.5
Expansion Cohort70.034.8 – 93.3
Percentage of Non-transfusion Dependent (NTD) Participants With a Hemoglobin Increase of ≥1.5 g/dL From Baseline During a Rolling 8-week Interval Secondary · Any 8-week interval during the study (up to approximately 20 Weeks)

A modified erythroid response in NTD participants was defined as a mean hemoglobin increase of ≥1.5 g/dL from baseline during 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. Hemoglobin measurements within 2 weeks following red blood cell (RBC) transfusion or 56 days after the last dose were excluded from 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 de

GroupValue95% CI
Luspatercept 0.2 mg/kg0.00.0 – 45.9
Luspatercept 0.4 mg/kg0.00.0 – 45.9
Luspatercept 0.6 mg/kg0.00.0 – 52.2
Luspatercept 0.8 mg/kg33.30.8 – 90.6
Luspatercept 1.0 mg/kg50.01.3 – 98.7
Luspatercept 1.25 mg/kg0.00.0 – 97.5
Expansion Cohort60.026.2 – 87.8
Percentage of Non-transfusion Dependent (NTD) Participants With a Hemoglobin Increase of ≥1.0 g/dL From Baseline During a Rolling 12-week Interval Secondary · Any 12-week interval during the study (up to approximately 20 Weeks)

A modified erythroid response in NTD participants was defined as a mean hemoglobin increase of ≥1.0 g/dL from baseline during 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. Hemoglobin measurements within 2 weeks following red blood cell (RBC) transfusion or 56 days after the last dose were excluded from 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. A 12-week interval was de

GroupValue95% CI
Luspatercept 0.2 mg/kg16.70.4 – 64.1
Luspatercept 0.4 mg/kg0.00.0 – 45.9
Luspatercept 0.6 mg/kg80.028.4 – 99.5
Luspatercept 0.8 mg/kg66.79.4 – 99.2
Luspatercept 1.0 mg/kg50.01.3 – 98.7
Luspatercept 1.25 mg/kg0.00.0 – 97.5
Expansion Cohort60.026.2 – 87.8
Percentage of Non-transfusion Dependent (NTD) Participants With a Hemoglobin Increase of ≥1.5 g/dL From Baseline During a Rolling 12-week Interval Secondary · Any 12-week interval during the study (up to approximately 20 Weeks)

A modified erythroid response in NTD participants was defined as a mean hemoglobin increase of ≥1.5 g/dL from baseline during 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. Hemoglobin measurements within 2 weeks following red blood cell (RBC) transfusion or 56 days after the last dose were excluded from 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. A 12-week interval was de

GroupValue95% CI
Luspatercept 0.2 mg/kg0.00.0 – 45.9
Luspatercept 0.4 mg/kg0.00.0 – 45.9
Luspatercept 0.6 mg/kg0.00.0 – 52.2
Luspatercept 0.8 mg/kg33.30.8 – 90.6
Luspatercept 1.0 mg/kg50.01.3 – 98.7
Luspatercept 1.25 mg/kg0.00.0 – 97.5
Expansion Cohort50.018.7 – 81.3
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 Secondary · Any 8-week interval during the study (up to approximately 20 weeks)

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 i

GroupValue95% CI
Luspatercept 0.6 mg/kg1002.5 – 100
Luspatercept 0.8 mg/kg10029.2 – 100
Luspatercept 1.0 mg/kg10039.8 – 100
Luspatercept 1.25 mg/kg75.019.4 – 99.4
Expansion Cohort78.954.4 – 93.9

Adverse events — posted to ClinicalTrials.gov

Time frame: Up to approximately 20 weeks. Reporting threshold: 5%. Adverse-event reports describe events observed during the trial — not all are caused by the drug.

Luspatercept 0.2 mg/kg
Serious: 0/6 (0%)
Deaths: 0/6
Luspatercept 0.4 mg/kg
Serious: 1/6 (17%)
Deaths: 0/6
Luspatercept 0.6 mg/kg
Serious: 0/6 (0%)
Deaths: 0/6
Luspatercept 0.8 mg/kg
Serious: 0/6 (0%)
Deaths: 0/6
Luspatercept 1.0 mg/kg
Serious: 0/6 (0%)
Deaths: 0/6
Luspatercept 1.25 mg/kg
Serious: 0/5 (0%)
Deaths: 0/5
Expansion Cohort
Serious: 0/29 (0%)
Deaths: 0/29

Serious adverse events (1 terms)

ReactionSystemLuspatercept 0.2 mg/kgLuspatercept 0.4 mg/kgLuspatercept 0.6 mg/kgLuspatercept 0.8 mg/kgLuspatercept 1.0 mg/kgLuspatercept 1.25 mg/kgExpansion Cohort
Bone marrow failureBlood and lymphatic system disorders
Other adverse events (91 terms — click to expand)

ReactionSystemLuspatercept 0.2 mg/kgLuspatercept 0.4 mg/kgLuspatercept 0.6 mg/kgLuspatercept 0.8 mg/kgLuspatercept 1.0 mg/kgLuspatercept 1.25 mg/kgExpansion Cohort
Bone painMusculoskeletal and connective tissue disorders
AstheniaGeneral disorders
HeadacheNervous system disorders
ArthralgiaMusculoskeletal and connective tissue disorders
Musculoskeletal painMusculoskeletal and connective tissue disorders
MyalgiaMusculoskeletal and connective tissue disorders
Back painMusculoskeletal and connective tissue disorders
DiarrhoeaGastrointestinal disorders
NauseaGastrointestinal disorders
PyrexiaGeneral disorders
Oedema peripheralGeneral disorders
Oropharyngeal painRespiratory, thoracic and mediastinal disorders
Bone marrow failureBlood and lymphatic system disorders
VertigoEar and labyrinth disorders
Abdominal pain upperGastrointestinal disorders
Influenza like illnessGeneral disorders
InfluenzaInfections and infestations
NasopharyngitisInfections and infestations
RhinitisInfections and infestations
Post-traumatic painInjury, poisoning and procedural complications
Musculoskeletal chest painMusculoskeletal and connective tissue disorders
DizzinessNervous system disorders
ParaesthesiaNervous system disorders
CoughRespiratory, thoracic and mediastinal disorders
MaculeSkin and subcutaneous tissue disorders
ErythroblastosisBlood and lymphatic system disorders
ThrombocytosisBlood and lymphatic system disorders
Supraventricular tachycardiaCardiac disorders
Ear painEar and labyrinth disorders
MyopiaEye disorders
Abdominal painGastrointestinal disorders
Abdominal pain lowerGastrointestinal disorders
ConstipationGastrointestinal disorders
Gastrooesophageal reflux diseaseGastrointestinal disorders
Gingival painGastrointestinal disorders
Gingival swellingGastrointestinal disorders
ToothacheGastrointestinal disorders
VomitingGastrointestinal disorders
FatigueGeneral disorders
Injection site erythemaGeneral disorders

Most-reported serious reactions: Bone marrow failure.

Data from ClinicalTrials.gov NCT01749540 adverse events section.

Sponsor's own description

The purpose of this study is to evaluate the efficacy, safety, and pharmacokinetics, of ascending doses of luspatercept in participants with β-thalassemia. The primary objective of this study is to evaluate erythroid response, defined as: 1. a hemoglobin increase of ≥ 1.5 g/dL from baseline for ≥ 14 days (in the absence of red blood cell \[RBC\] transfusions) in non-transfusion dependent participants, or 2. a ≥ 20% reduction in RBC transfusion burden compared to pretreatment in transfusion dependent participants.

Publications & conference data

8 peer-reviewed publications reference this trial (live from Europe PMC):

  1. Clinical development of galunisertib (LY2157299 monohydrate), a small molecule inhibitor of transforming growth factor-beta signaling pathway.
    Herbertz S, Sawyer JS, Stauber AJ, Gueorguieva I, et al · · 2015 · cited 424× · PMID 26309397 · DOI 10.2147/dddt.s86621
  2. TGF-beta signal transduction: biology, function and therapy for diseases.
    Tie Y, Tang F, Peng D, Zhang Y, et al · · 2022 · cited 97× · PMID 36534225 · DOI 10.1186/s43556-022-00109-9
  3. Luspatercept improves hemoglobin levels and blood transfusion requirements in a study of patients with β-thalassemia.
    Piga A, Perrotta S, Gamberini MR, Voskaridou E, et al · · 2019 · cited 76× · PMID 30617198 · DOI 10.1182/blood-2018-10-879247
  4. The role of TGFβ in hematopoiesis and myeloid disorders.
    Bataller A, Montalban-Bravo G, Soltysiak KA, Garcia-Manero G. · · 2019 · cited 57× · PMID 30816330 · DOI 10.1038/s41375-019-0420-1
  5. Beta Thalassemia: New Therapeutic Options Beyond Transfusion and Iron Chelation.
    Motta I, Bou-Fakhredin R, Taher AT, Cappellini MD. · · 2020 · cited 54× · PMID 32557398 · DOI 10.1007/s40265-020-01341-9
  6. New therapeutic targets in transfusion-dependent and -independent thalassemia.
    Cappellini MD, Motta I. · · 2017 · cited 35× · PMID 29222267 · DOI 10.1182/asheducation-2017.1.278
  7. The use of luspatercept for thalassemia in adults.
    Cappellini MD, Taher AT. · · 2021 · cited 33× · PMID 33570654 · DOI 10.1182/bloodadvances.2020002725
  8. Novel Therapeutic Advances in β-Thalassemia.
    Makis A, Voskaridou E, Papassotiriou I, Hatzimichael E. · · 2021 · cited 28× · PMID 34207028 · DOI 10.3390/biology10060546

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