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

Phase 2

Completed

Conditions: B-Thalassemia

Interventions: Drug: luspatercept

Registration Number: NCT01749540

Lead Sponsor: Acceleron Pharma, Inc., a wholly-owned subsidiary of Merck & Co., Inc., Rahway, NJ USA

Brief Summary: 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.

Detailed Description: Not available

Recruitment & Eligibility

Status: COMPLETED

Sex: All

Target Recruitment: 64

Inclusion Criteria

Men or women ≥18 years of age
For the dose escalation phase of the study: documented diagnosis of β-thalassemia intermedia (transfusion dependent participants must not have begun regular transfusions at age <4.0 years). For the expansion cohort: documented diagnosis of β-thalassemia (including β-thalassemia major or β-thalassemia intermedia)
Prior splenectomy or spleen size <18 cm in the longest diameter by abdominal ultrasound (dose escalation cohorts only)
Anemia, defined as: (1) mean hemoglobin concentration <10.0 g/dL of 2 measurements (one performed within one day prior to Cycle 1 Day 1 and the other performed during the screening period [Day -28 to Day -1]) in non-transfusion dependent participants, defined as having received < 4 units of RBCs within 8 weeks prior to Cycle 1 Day 1, or (2) transfusion dependent participants, defined as requiring ≥ 4 units of RBCs every 8 weeks (confirmed over 6 months prior to Cycle 1 Day 1)
Aspartate aminotransferase (AST) or alanine aminotransferase (ALT) <3 x upper limit of normal (ULN)
Serum creatinine ≤1.5 x ULN
Adequate pregnancy avoidance measures
Participants are able to adhere to the study visit schedule, understand, and comply with all protocol requirements
Understand and able to provide written informed consent

Key

Exclusion Criteria

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 Cycle 1 Day 1
Folate deficiency
Symptomatic splenomegaly
Known positive for human immunodeficiency virus (HIV), active infectious hepatitis B virus (HBV) or active infectious hepatitis C virus (HCV)
Known history of thromboembolic events ≥Grade 3 according to the National Cancer Institute-Common Terminology Criteria for Adverse Events (NCI-CTCAE) version 4.0 (current active minor version)
Ejection fraction <50% by echocardiogram, multi-gated acquisition scan (MUGA), or cardiac magnetic resonance imaging (MRI)
Uncontrolled hypertension defined as systolic blood pressure (BP) ≥150 mm Hg or diastolic BP ≥95 mm Hg
Heart failure class 3 or higher (New York Heart Association [NYHA])
QTc >450 msec on screening electrocardiogram (ECG)
Platelet count <100 x10^9/L or >1,000 x10^9/L
Proteinuria ≥Grade 2
Any active infection requiring parenteral antibiotic therapy within 28 days prior to Cycle 1 Day 1 or oral antibiotics within 14 days of Cycle 1 Day 1
Treatment with another investigational drug or device, or approved therapy for investigational use ≤28 days prior to Cycle 1 Day 1, or if the half-life of the previous investigational product is known, within 5 times the half-life prior to Cycle 1 Day 1, whichever is longer
Transfusion event within 7 days prior to Cycle 1 Day 1
Participants receiving or planning to receive hydroxyurea treatment. Participants must not have had hydroxyurea within 90 days of Cycle 1 Day 1
Splenectomy within 56 days prior to Cycle 1 Day 1
Major surgery (except splenectomy) within 28 days prior to Cycle 1 Day 1. Participants must have completely recovered from any previous surgery prior to Cycle 1 Day 1
Iron chelation therapy initiated within 56 days prior to Cycle 1 Day 1
Cytotoxic agents, systemic corticosteroids, immunosuppressants, or anticoagulant therapy such as warfarin or heparin within 28 days prior to Cycle 1 Day 1 (prophylactic aspirin up to 100 mg/day is permitted)
Pregnant or lactating women
History of severe allergic or anaphylactic reactions or hypersensitivity to recombinant proteins or excipients in the investigational drug
Prior treatment with sotatercept (ACE-011) or luspatercept (ACE-536)

Study & Design

Study Type: INTERVENTIONAL

Study Design: PARALLEL

Arm && Interventions

Group	Intervention	Description
Luspatercept 0.6 mg/kg	luspatercept	Participants receive luspatercept 0.6 mg/kg as an SC injection Q3W on Day 1 of each cycle for up to 5 cycles (each cycle length = 21 days).
Luspatercept 1.0 mg/kg	luspatercept	Participants receive luspatercept 1.0 mg/kg as an SC injection Q3W on Day 1 of each cycle for up to 5 cycles (each cycle length = 21 days).
Luspatercept 0.2 mg/kg	luspatercept	Participants receive luspatercept 0.2 mg/kg as a subcutaneous (SC) injection every 3 weeks (Q3W) on Day 1 of each cycle for up to 5 cycles (each cycle length = 21 days).
Luspatercept 0.8 mg/kg	luspatercept	Participants receive luspatercept 0.8 mg/kg as an SC injection Q3W on Day 1 of each cycle for up to 5 cycles (each cycle length = 21 days).
Luspatercept 0.4 mg/kg	luspatercept	Participants receive luspatercept 0.4 mg/kg as an SC injection Q3W on Day 1 of each cycle for up to 5 cycles (each cycle length = 21 days).
Luspatercept 1.25 mg/kg	luspatercept	Participants receive luspatercept 1.25 mg/kg as an SC injection Q3W on Day 1 of each cycle for up to 5 cycles (each cycle length = 21 days).
Expansion Cohort	luspatercept	Participants receive an initial dose of luspatercept 0.8 mg/kg as an SC injection on Day 1 of Cycle 1 (Cycle length = 21 days). For each subsequent cycle (up to 5 cycles), the dose was titrated up to a maximum dose of 1.25 mg/kg based on the safety review team (SRT) recommendations.

Primary Outcome Measures

Name	Time	Method
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	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 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.
Percentage of Non-transfusion Dependent (NTD) Participants With a Hemoglobin Increase of ≥1.5 g/dL From Baseline for ≥14 Days	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 increase of ≥1.5 g/dL from baseline for ≥14 days is presented.

Secondary Outcome Measures

Name	Time	Method
Number of Participants Who Experienced an Adverse Event (AE)	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.
Number of Participants Who Experienced a Dose-Limiting Toxicity (DLT)	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 hematologic AE ≥ Grade 4. The number of participants who experienced a DLT is presented.
Percentage of Non-transfusion Dependent (NTD) Participants With a Hemoglobin Increase of ≥1.5 g/dL From Baseline During a Rolling 8-week Interval	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 defined as any consecutive 8 weeks during the study. The percentage of participants with a hemoglobin increase of ≥1.5 g/dL from baseline is presented.
Percentage of Non-transfusion Dependent (NTD) Participants With a Hemoglobin Increase of ≥1.0 g/dL From Baseline During a Rolling 12-week Interval	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 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.
Duration of Erythroid Response for Non-transfusion Dependent (NTD) Participants Who Achieved a Hemoglobin Increase ≥1.0 g/dL During a Rolling 12-week Interval	Any 12-week interval during the study (up to approximately 20 weeks)	Duration of erythroid response was defined as the time from the first rolling 12-week window achieving a hemoglobin increase of ≥1.0 g/dL to the 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 analysis cutoff were censored. The duration of response for participants achieving a hemoglobin increase ≥1.0 g/dL is presented.
Number of Participants Who Experienced a Serious Adverse Event (SAE)	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.
Number of Participants Who Experienced an Adverse Event (AE) of Grade 3 or Greater	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 (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 of ≥Grade 3 is presented.
Number of Participants Who Discontinued Study Treatment Due To an Adverse Event (AE)	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.
Percentage of Non-transfusion Dependent (NTD) Participants With a Hemoglobin Increase of ≥1.0 g/dL From Baseline During a Rolling 8-week Interval	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 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.
Percentage of Non-transfusion Dependent (NTD) Participants With a Hemoglobin Increase of ≥1.5 g/dL From Baseline During a Rolling 12-week Interval	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 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.
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	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 is presented.
Percentage of Transfusion Dependent (TD) Participants Who Maintained Red Blood Cell (RBC) Transfusion Independence For ≥8 Weeks	Any 8-week interval during the study (up to approximately 20 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.
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	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). 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.
Percent Change From Baseline to End of Treatment in Mean Bone-specific Alkaline Phosphatase (BSAP)	Baseline (prior to first dose of study drug) and End of Treatment (up to Day 113)	Blood samples were collected at pre-specified time intervals to determine BSAP. The percent change from baseline in BSAP was measured. Baseline was the last measurement prior to the first dose of study drug.
Percent Change From Baseline to End of Treatment in Mean C-telopeptide of Type I Collagen (CTX)	Baseline (prior to first dose of study drug) and End of Treatment (up to Day 113)	Blood samples were collected at pre-specified time intervals to determine CTX. The percent change from baseline in CTX was measured. Baseline was the last measurement prior to the first dose of study drug.
Percent Change From Baseline to End of Treatment in Serum Iron	Baseline (prior to first dose of study drug) and End of Treatment (up to Day 113)	Blood samples were collected at pre-specified time intervals to determine serum iron. The percent change from baseline in serum iron was measured. Baseline was the last measurement prior to the first dose of study drug.
Percent Change From Baseline to End of Treatment in Soluble Transferrin Receptor	Baseline (prior to first dose of study drug) and End of Treatment (up to Day 113)	Blood samples were collected at pre-specified time intervals to determine soluble transferrin receptor. The percent change from baseline in soluble transferrin receptor was measured. Baseline was the last measurement prior to the first dose of study drug.
Percent Change From Baseline to Day 113 in Calculated Transferrin Saturation	Baseline (prior to first dose of study drug) and Day 113	The calculated transferrin saturation is the ratio of the serum iron concentration and the total iron binding capacity (TIBC) expressed as a percentage. Blood samples were to be collected at pre-specified time intervals for serum iron and TIBC to determine the calculated transferrin saturation. Baseline was pre-specified to be the last measurement prior to the first dose of study drug.
Percent Change From Baseline to End of Treatment in Hemoglobin C (Hb C)	Baseline (prior to first dose of study drug) and End of Treatment (up to Day 113)	Blood samples were collected at pre-specified time intervals to determine Hb C. The percent change from baseline in Hb C was measured. Baseline was the last measurement prior to the first dose of study drug.
Percent Change From Baseline to End of Treatment in Beta Globin Gene	Baseline (prior to first dose of study drug) and End of Treatment (up to Day 113)	Blood samples were collected at pre-specified time intervals to determine beta globin gene. The percent change from baseline in beta globin gene was measured. Baseline was the last measurement prior to the first dose of study drug.
Percent Change From Baseline to End of Treatment in Gamma Globin Gene	Baseline (prior to first dose of study drug) and End of Treatment (up to Day 113)	Blood samples were collected at pre-specified time intervals to determine gamma globin gene. The percent change from baseline in gamma globin gene was measured. Baseline was the last measurement prior to the first dose of study drug.
Percent Change From Baseline to End of Treatment in Indirect Bilirubin	Baseline (prior to first dose of study drug) and End of Treatment (up to Day 113)	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.
Time To Erythroid Response for Non-transfusion Dependent (NTD) Participants Who Achieved a Hemoglobin Increase ≥1.0 g/dL During a Rolling 12-week Interval by Pooled Dose Groups	Any 12-week interval during the study (up to approximately 20 weeks)	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 analysis cutoff were censored. The time to the first date of any rolling 12-week window achieving a hemoglobin increase ≥1.0 g/dL is presented.
Time To Erythroid Response for Transfusion Dependent (TD) Participants Who Achieved a Transfusion Burden Reduction of ≥50% During a Rolling 12-week Interval	Any 12-week interval during the study (up to approximately 20 weeks)	Time to erythroid response was defined as the time from the first dose to the first date of any rolling 12-week window achieving a red blood cell (RBC) transfusion burden reduction of ≥50% compared to pretreatment. When there were multiple disjointed intervals with response, the longest interval was used. Participants with response ongoing by analysis cutoff were censored. The time to the first date of any rolling 12-week window achieving a red blood cell transfusion burden reduction of ≥50% compared to pretreatment is presented.
Percent Change From Baseline to End of Treatment in Total Iron Binding Capacity (TIBC)	Baseline (prior to first dose of study drug) and End of Treatment (up to Day 113)	Blood samples were collected at pre-specified time intervals to determine TIBC. The percent change from baseline in TIBC was measured. Baseline was the last measurement prior to the first dose of study drug.
Duration of Erythroid Response for Transfusion Dependent (TD) Participants Who Achieved a Transfusion Burden Reduction of ≥50% During a Rolling 12-week Interval	Any 12-week interval during the study (up to approximately 20 weeks)	Duration of erythroid response was defined as the time from the first rolling 12-week window achieving a red blood cell (RBC) transfusion burden reduction of ≥50% compared to pretreatment to the last consecutive rolling 12-week window achieving a RBC transfusion burden reduction of ≥50% compared to pretreatment. When there were multiple disjointed intervals with response, the longest interval was used. Participants with response ongoing by analysis cutoff were censored. The duration of response for participants achieving a RBC transfusion burden reduction of ≥50% compared to pretreatment is presented.
Percent Change From Baseline to Day 113 in Serum Non-transferrin Bound Iron (NTBI)	Baseline (prior to first dose of study drug) and Day 113	Blood samples were to be collected at pre-specified time intervals to determine NTBI. Baseline was pre-specified to be the last measurement prior to the first dose of study drug.
Percent Change From Baseline to End of Treatment in Transferrin	Baseline (prior to first dose of study drug) and End of Treatment (up to Day 113)	Blood samples were collected at pre-specified time intervals to determine transferrin. The percent change from baseline in transferrin was measured. Baseline was the last measurement prior to the first dose of study drug.
Percent Change From Baseline to End of Treatment in Ferritin	Baseline (prior to first dose of study drug) and End of Treatment (up to Day 113)	Blood samples were collected at pre-specified time intervals to determine ferritin. The percent change from baseline in ferritin was measured. Baseline was the last measurement prior to the first dose of study drug.
Percent Change From Baseline to End of Treatment in Hepcidin	Baseline (prior to first dose of study drug) and End of Treatment (up to Day 113)	Blood samples were collected at pre-specified time intervals to determine hepcidin. The percent change from baseline in hepcidin was measured. Baseline was the last measurement prior to the first dose of study drug.
Percent Change From Baseline to End of Treatment in Reticulocytes	Baseline (prior to first dose of study drug) and End of Treatment (up to Day 113)	Blood samples were collected at pre-specified time intervals to determine reticulocytes. The percent change from baseline in reticulocytes was measured. Baseline was the last measurement prior to the first dose of study drug.
Percent Change From Baseline to End of Treatment in Hemoglobin A (Hb A)	Baseline (prior to first dose of study drug) and End of Treatment (up to Day 113)	Blood samples were collected at pre-specified time intervals to determine Hb A. The percent change from baseline in Hb A was measured. Baseline was the last measurement prior to the first dose of study drug.
Percent Change From Baseline to End of Treatment in Hemoglobin D (Hb D)	Baseline (prior to first dose of study drug) and End of Treatment (up to Day 113)	Blood samples were collected at pre-specified time intervals to determine Hb D. The percent change from baseline in Hb D was measured. Baseline was the last measurement prior to the first dose of study drug.
Percent Change From Baseline to End of Treatment in Erythropoietin	Baseline (prior to first dose of study drug) and End of Treatment (up to Day 113)	Blood samples were collected at pre-specified time intervals to determine erythropoietin. The percent change from baseline in erythropoietin was measured. Baseline was the last measurement prior to the first dose of study drug.
Percent Change From Baseline to End of Treatment in Nucleated Red Blood Cell (nRBC) Count	Baseline (prior to first dose of study drug) and End of Treatment (up to Day 113)	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.
Percent Change From Baseline to End of Treatment in Hemoglobin A2 (Hb A2)	Baseline (prior to first dose of study drug) and End of Treatment (up to Day 113)	Blood samples were collected at pre-specified time intervals to determine Hb A2. The percent change from baseline in Hb A2 was measured. Baseline was the last measurement prior to the first dose of study drug.
Percent Change From Baseline to End of Treatment in Hemoglobin F (Hb F)	Baseline (prior to first dose of study drug) and End of Treatment (up to Day 113)	Blood samples were collected at pre-specified time intervals to determine Hb F. The percent change from baseline in Hb F was measured. Baseline was the last measurement prior to the first dose of study drug.
Percent Change From Baseline to End of Treatment in Hemoglobin S (Hb S)	Baseline (prior to first dose of study drug) and End of Treatment (up to Day 113)	Blood samples were collected at pre-specified time intervals to determine Hb S. The percent change from baseline in Hb S was measured. Baseline was the last measurement prior to the first dose of study drug.
Percent Change From Baseline to End of Treatment in Alpha Globin Gene	Baseline (prior to first dose of study drug) and End of Treatment (up to Day 113)	Blood samples were collected at pre-specified time intervals to determine alpha globin gene. The percent change from baseline in alpha globin gene was measured. Baseline was the last measurement prior to the first dose of study drug.
Percent Change From Baseline to End of Treatment in Haptoglobin	Baseline (prior to first dose of study drug) and End of Treatment (up to Day 113)	Blood samples were collected at pre-specified time intervals to determine haptoglobin. The percent change from baseline in haptoglobin was measured. Baseline was the last measurement prior to the first dose of study drug.
Percentage of Non-transfusion Dependent (NTD) Participants With Baseline Liver Iron Concentration (LIC) of ≥3 mg/g Dry Weight Who Have Demonstrated an LIC Response at End of Treatment	End of Treatment (up to Day 113)	LIC response was defined as a demonstrated LIC reduction of ≥1 mg/g dry weight. Blood samples were collected at pre-specified time intervals to determine LIC in NTD participants with a baseline LIC of ≥3 mg/g dry weight. LIC was measured using magnetic resonance imaging (MRI). Baseline was the last measurement prior to the first dose of study drug. 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 NTD participants with baseline LIC ≥3 mg/g dry weight who have demonstrated an LIC response is presented.
Percent Change From Baseline to End of Treatment in Lactate Dehydrogenase (LDH)	Baseline (prior to first dose of study drug) and End of Treatment (up to Day 113)	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.
Change From Baseline to End of Treatment in Liver Iron Concentration (LIC) For Non-transfusion Dependent (NTD) Participants With Baseline LIC <3 mg/g Dry Weight	Baseline (prior to first dose of study drug) and End of Treatment (up to Day 113)	Blood samples were collected at pre-specified time intervals to determine LIC. The change from baseline in mean LIC for NTD 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. NTD participants were participants who had received \<4 units of RBCs within 8 weeks prior to the first dose of study drug. The change from baseline to Day 113 in mean LIC for NTD participants with baseline LIC \<3 mg/g dry weight is presented.
Change From Baseline to End of Treatment in Liver Iron Concentration (LIC) For Non-transfusion Dependent (NTD) Participants With Baseline LIC ≥3 mg/g Dry Weight	Baseline (prior to first dose of study drug) and End of Treatment (up to Day 113)	Blood samples were collected at pre-specified time intervals to determine LIC. The change from baseline in mean LIC for NTD 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. NTD participants were participants who had received \<4 units of RBCs within 8 weeks prior to the first dose of study drug. The change from baseline to Day 113 in mean LIC for NTD participants with baseline LIC ≥3 mg/g dry weight is presented.
Percentage of Non-transfusion Dependent (NTD) Participants With Baseline Liver Iron Concentration (LIC) of ≥3 mg/g Dry Weight, Who Have Used Iron Chelation Therapy (ICT), and Who Have Demonstrated an LIC Response at End of Treatment	End of Treatment (up to Day 113)	LIC response was defined as a demonstrated LIC reduction of ≥1 mg/g dry weight. Blood samples were collected at pre-specified time intervals to determine LIC in NTD participants with a baseline LIC of ≥3 mg/g dry weight and who have used ICT. LIC was measured using magnetic resonance imaging (MRI). Baseline was the last measurement prior to the first dose of study drug. 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 NTD participants with baseline LIC ≥3 mg/g dry weight, who have used ICT, and who have demonstrated an LIC response is presented.
Percentage of Non-transfusion Dependent (NTD) Participants With Baseline Liver Iron Concentration (LIC) of ≥3 mg/g Dry Weight, Who Have Not Used Iron Chelation Therapy (ICT), and Who Have Demonstrated an LIC Response at End of Treatment	End of Treatment (up to Day 113)	LIC response was defined as a demonstrated LIC reduction of ≥1 mg/g dry weight. Blood samples were collected at pre-specified time intervals to determine LIC in NTD participants with a baseline LIC of ≥3 mg/g dry weight and who have not used ICT. LIC was measured using magnetic resonance imaging (MRI). Baseline was the last measurement prior to the first dose of study drug. 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 NTD participants with baseline LIC ≥3 mg/g dry weight, who have not used ICT, and who have demonstrated an LIC response is presented.
Change From Baseline to End of Treatment in Liver Iron Concentration (LIC) For Transfusion Dependent (TD) Participants With Baseline LIC ≥3 mg/g Dry Weight	Baseline (prior to first dose of study drug) and End of Treatment (up to Day 113)	Blood samples were collected at pre-specified time intervals to determine LIC. The change from baseline in mean LIC for TD 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. 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 change from baseline to Day 113 in mean LIC for TD participants with baseline LIC ≥3 mg/g dry weight is presented.
Change From Baseline to End of Treatment in Liver Iron Concentration (LIC) For Transfusion Dependent (TD) Participants With Baseline LIC <3 mg/g Dry Weight	Baseline (prior to first dose of study drug) and End of Treatment (up to Day 113)	Blood samples were collected at pre-specified time intervals to determine LIC. The change from baseline in mean LIC for TD 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. 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 change from baseline to Day 113 in mean LIC for TD participants with baseline LIC \<3 mg/g dry weight is presented.
Percentage of Transfusion Dependent (TD) Participants With Baseline Liver Iron Concentration (LIC) of ≥3 mg/g Dry Weight Who Have Demonstrated an LIC Response at End of Treatment	End of Treatment (up to Day 113)	LIC response was defined as a demonstrated LIC reduction of ≥1 mg/g dry weight. Blood samples were collected at pre-specified time intervals to determine LIC in TD participants with a baseline LIC of ≥3 mg/g dry weight. LIC was measured using magnetic resonance imaging (MRI). Baseline was the last measurement prior to the first dose of study drug. 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 TD participants with baseline LIC ≥3 mg/g dry weight who have demonstrated an LIC response is presented.
Percentage of Transfusion Dependent (TD) Participants With Baseline Liver Iron Concentration (LIC) of ≥3 mg/g Dry Weight, Who Have Used Iron Chelation Therapy (ICT), and Who Have Demonstrated an LIC Response at End of Treatment	End of Treatment (up to Day 113)	LIC response was defined as a demonstrated LIC reduction of ≥1 mg/g dry weight. Blood samples were collected at pre-specified time intervals to determine LIC in TD participants with a baseline LIC of ≥3 mg/g dry weight and who have used ICT. LIC was measured using magnetic resonance imaging (MRI). Baseline was the last measurement prior to the first dose of study drug. 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 TD participants with baseline LIC ≥3 mg/g dry weight, who have used ICT, and who have demonstrated an LIC response is presented.
Percentage of Transfusion Dependent (TD) Participants With Baseline Liver Iron Concentration (LIC) of ≥3 mg/g Dry Weight, Who Have Not Used Iron Chelation Therapy (ICT), and Who Have Demonstrated an LIC Response at End of Treatment	End of Treatment (up to Day 113)	LIC response was defined as a demonstrated LIC reduction of ≥1 mg/g dry weight. Blood samples were collected at pre-specified time intervals to determine LIC in TD participants with a baseline LIC of ≥3 mg/g dry weight and who have not used ICT. LIC was measured using magnetic resonance imaging (MRI). Baseline was the last measurement prior to the first dose of study drug. 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 TD participants with baseline LIC ≥3 mg/g dry weight, who have not used ICT, and who have demonstrated an LIC response is presented.
Maximum Concentration (Cmax) of Luspatercept	Cycle 1 (21-day cycle): Days 1, 8, 11, and 15; Cycle 2 (21-day cycle): Day 1	Blood samples were collected at specified intervals for the determination of Cmax. Cmax was defined as the maximum concentration of luspatercept observed after administration. Cmax was based on non-compartmental analysis.
Apparent Terminal Rate Constant (Lambda z) of Luspatercept	Cycle 1 (21-day cycle): Days 1, 8, 11, and 15; Cycle 2 (21-day cycle): Days 1 and 8; Cycles 4 and 5 (21-day cycles): Days 1, 8, and 15; study follow-up on Days 113, 141, and 169	Blood samples were collected at specified intervals for the determination of apparent terminal rate constant. Apparent terminal rate constant was defined as the amount of luspatercept that was eliminated from the body during a given period of time and was calculated by linear regression of the terminal portion of the log-concentration-time curve in serum. Apparent terminal rate constant was based on non-compartmental analysis.
Time to Maximum Concentration (Tmax) of Luspatercept	Cycle 1 (21-day cycle): Days 1, 8, 11, and 15; Cycle 2 (21-day cycle): Day 1	Blood samples were collected at specified intervals for the determination of Tmax. Tmax was defined as the time to maximum concentration of luspatercept observed after administration. Tmax was based on non-compartmental analysis.
Area Under the Concentration Time Curve of Luspatercept From Time Zero to Day 21 (AUC0-21)	Cycle 1: Days 1, 8, 11, and 15; Day 22 (Cycle 2 Day 1). Cycles 1 and 2 are 21-day cycles	Blood samples were collected at specified intervals for the determination of AUC0-21. AUC0-21 was defined as the area under the concentration time curve of luspatercept from time zero to Day 21. AUC0-21 was based on non-compartmental analysis and calculated by the linear trapezoidal method.
Terminal Elimination Half Life (t½) of Luspatercept	Cycle 1 (21-day cycle): Days 1, 8, 11, and 15; Cycle 2 (21-day cycle): Days 1 and 8; Cycles 4 and 5 (21-day cycles): Days 1, 8, and 15; study follow-up on Days 113, 141, and 169	Blood samples were collected at specified intervals for the determination of t½. t½ was defined as the time required to divide the serum concentration of luspatercept by two after reaching pseudo-equilibrium. t½ was based on non-compartmental analysis.

Trial Locations

Locations (8): AORN A. Cardarelli
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Napoli, Italy
CEMEF Medicina 2
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Modena, Italy
ARNAS Garibaldi - P.O. Garibaldi Centro
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Catania, Italy
A.O.U. Arcispedale S. Anna
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Ferrara, Italy
A.O.U. Seconda Università degli Studi di Napoli
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Napoli, Italy
A.O.U. San Luigi Gonzaga
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Orbassano, Italy
Laiko General Hospital, Ampelokipi
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Athens, Greece
Ospedale "A. Perriino" U.O Ematologia
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Brindisi, Italy