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)

Acceleron Pharma, Inc., a wholly-owned subsidiary of Merck & Co., Inc., Rahway, NJ USA51 enrolled

Overview

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 Type

INTERVENTIONAL

Allocation

Purpose

TREATMENT

Masking

NONE

Enrollment

Conditions

β-Thalassemia

Interventions

luspaterceptDRUG

subcutaneous injection

Eligibility

Sex: ALLMin age: 18 Years

Medical Language ↔ Plain English

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

Locations (7)

Acceleron Investigative Site

Athens, Greece

Acceleron Investigative Site

Brindisi, Italy

Acceleron Investigative Site

Catania, Italy

Acceleron Investigative Site

Ferrara, Italy

Outcomes

Primary Outcomes

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.

Time frame: Up to approximately 68 months

Number of Participants Who Discontinued Study Treatment Due To an AE

Time frame: Up to approximately 60 months

Secondary Outcomes

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.

Data from ClinicalTrials.gov

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Acceleron Investigative Site

Modena, Italy

Acceleron Investigative Site

Naples, Italy

Acceleron Investigative Site

Turin, Italy

Time frame: 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.

Time frame: 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.

Time frame: 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.

Time frame: 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.

Time frame: 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.

Time frame: 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.

Time frame: 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.

Time frame: 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.

Time frame: 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.

Time frame: 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.

Time frame: 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.

Time frame: 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.

Time frame: 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.

Time frame: 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.

Time frame: 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.

Time frame: 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.

Time frame: 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.

Time frame: 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.

Time frame: 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.

Time frame: 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.

Time frame: 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.

Time frame: 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.

Time frame: 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.

Time frame: 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.

Time frame: 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.

Time frame: 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.

Time frame: 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.

Time frame: 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.

Time frame: 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.

Time frame: 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.

Time frame: 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.

Time frame: 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.

Time frame: 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.

Time frame: 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.

Time frame: 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.

Time frame: 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).