A Study to Determine the Efficacy and Safety of Luspatercept in Adult Participants With Alpha (α)-Thalassemia

Study Overview
=================
Brief Summary
-----------------
The purpose of the study is to determine the efficacy and safety of luspatercept plus best supportive care (BSC) vs placebo plus BSC on anemia in participants with α-thalassemia hemoglobin H (HbH) disease.

Official Title
-----------------
A Phase 2, Double-blind, Randomized, Placebo-controlled, Multicenter Study to Determine the Efficacy and Safety of Luspatercept (BMS-986346/ACE-536) for the Treatment of Anemia in Adults With Alpha (α)-Thalassemia

Conditions
-----------------
Anemia

Intervention / Treatment
-----------------
* Biological: Luspatercept
* Drug: Placebo
* Other: Best Supportive Care


Participation Criteria
=================
Eligibility Criteria
-----------------
Key Inclusion Criteria: Participant has documented diagnosis of α-thalassemia hemoglobin H (HbH) disease (electrophoresis⎯ or high-performance liquid chromatography [HPLC]⎯based methods for Hb variant analyses are accepted), with or without transfusion dependence; compounded combination with β-thalassemia is allowed if at least 1 non-mutated β-chain gene is present. TD: i) TD participant: (1) ≥ 6 RBC units during the 24 weeks prior to randomization; and (2) No transfusion-free period for > 56 days during the 24 weeks prior to randomization; ii) NTD participant: (1) < 6 Red blood cell (RBC) units during the 24 weeks prior to randomization; and (2) RBC transfusion-free during at least 8 weeks prior to randomization; and (3) Mean baseline Hb ≤ 10 g/dL, based on a minimum of 2 measurements ≥ 1 week apart within 4 weeks prior to randomization; hemoglobin values within 21 days post-transfusion will be excluded. Participant has Eastern Cooperative Oncology Group (ECOG) score of 0 or 1. Investigators shall counsel women of childbearing potential (WOCBP), and male participants who are sexually active with WOCBP, on the importance of pregnancy prevention, the implications of an unexpected pregnancy, and the potential of fetal toxicity occurring due to transmission of study intervention, present in seminal fluid, to a developing fetus, even if the participant has undergone a successful vasectomy or if the partner is pregnant. Key Exclusion Criteria: Any significant medical condition, laboratory abnormality, or psychiatric illness that would prevent the participant from participating in the study. Any condition, including the presence of laboratory abnormalities, which places the participant at unacceptable risk if he/she were to participate in the study History of deep venous thrombosis (DVT) or stroke requiring medical intervention ≤ 24 weeks prior to randomization Diagnosis of α-thalassemia Trait, Hb Bart hydrops, ATRx α-thalassemia, hemoglobin S/β-thalassemia, myelodysplasia subtype anemia, or with HbE homozygous beta gene mutation. Anemia related to nutritional deficiency, anemia of chronic disease, autoimmune hemolytic anemia, or any other hemolytic anemias (for example, severe G6PD deficiency, pyruvate kinase deficiency, etc.). Bleeding disorders manifested by frequent bleeding episodes (e.g., menorrhagia, epistaxis, clotting disorders). Undergone episodes of hemolysis not related to alpha-thalassemia, for example, after use of hemolysis-predisposing drugs (for example, antimalarial, nonsteroidal anti-inflammatory drug [NSAID]), within the 8 weeks prior to randomization. Prior exposure to gene therapy to treat α-thalassemia. Use of an erythropoiesis-stimulating agent (ESA) ≤ 24 weeks prior to randomization. Note: Other protocol-defined inclusion/exclusion criteria apply.

Ages Eligible for Study
-----------------
Minimum Age: 18 Years

Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
No

Study Plan
=================
How is the study designed?
-----------------

Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Transfusion Dependent (TD): Luspatercept + Best supportive care (BSC)<br> | Biological: Luspatercept<br>* Specified dose on specified days<br>* Other names: REBLOZYL;Other: Best Supportive Care<br>* Specified dose on specified days<br>|
| Placebo Comparator: TD: Placebo + BSC<br> | Drug: Placebo<br>* Specified dose on specified days<br>Other: Best Supportive Care<br>* Specified dose on specified days<br>|
| Experimental: Non-transfusion Dependent (NTD): Luspatercept + BSC<br> | Biological: Luspatercept<br>* Specified dose on specified days<br>* Other names: REBLOZYL;Other: Best Supportive Care<br>* Specified dose on specified days<br>|
| Placebo Comparator: NTD: Placebo + BSC<br> | Drug: Placebo<br>* Specified dose on specified days<br>Other: Best Supportive Care<br>* Specified dose on specified days<br>|

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| TD Cohort: Number of participants with ≥ 50% reduction from baseline in RBC transfusion burden with a reduction of at least 2 units during any continuous 12 weeks during Week 13-48 compared to 12-week interval immediately prior to date of first dose |  | Up to Week 48 | 
| NTD Cohort: Number of participants with an increase from baseline of ≥ 1.0 grams (g)/decilitre (dL) in mean hemoglobin (Hb) values over the continuous 12-week interval from Week 13 to Week 24 in the absence of transfusion |  | Up to Week 24 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| TD Cohort: Number of participants with ≥ 33% reduction from baseline in RBC transfusion burden with a reduction of at least 2 units during any continuous 24-week interval on treatment compared to 24-week interval immediately prior to date of first dose |  | Up to Week 108 | 
| TD Cohort: The longest duration with ≥ 50% reduction from baseline in RBC transfusion burden with a reduction of at least 2 units |  | Up to Week 48 | 
| TD Cohort: Number of RBC transfusion units from week 1 to week 48 |  | Up to Week 48 | 
| NTD Cohort: Change from baseline in hemoglobin in the absence of transfusion at Week 24 |  | Baseline, Week 24 | 
| NTD Cohort: The longest duration of an increase from baseline of ≥ 1.0 g/dL in mean hemoglobin values starting from Week 13 in the absence of transfusion |  | From Week 13 up to Week 48 | 
| NTD Cohort: Time Duration with an increase from baseline of ≥ 1.0 g/dL in hemoglobin values in the absence of transfusion within 48 weeks |  | Up to Week 48 | 
| NTD Cohort: Number of participants with an increase from baseline of ≥1.0 g/dL in mean Hb values over the continuous 12- week interval in the absence of transfusion |  | Up to Week 24 | 
| NTD Cohort: ≥ 3 Increase from Baseline in Functional Assessment of Cancer Therapy Anemia Fatigue Subscale (FACT-An FS) Score from Baseline to Week 13 to Week 24 |  | Baseline, Up to Week 24 | 
| TD and NTD Cohorts: Number of participants with adverse events (AEs) |  | Up to 5 years | 
| TD and NTD Cohorts: Number of participants with serious AEs (SAEs) |  | Up to 5 years | 
| TD and NTD Cohorts: Number of participants with antidrug antibody (ADA) (positive or negative) |  | Up to Week 48 | 
| TD Cohort: Number of participants with ≥ 50% reduction from baseline in RBC transfusion burden during any continuous 24-week interval within 48 weeks compared to the 24-week interval immediately prior to the date of first dose |  | Up to Week 48 | 
| TD Cohort: Number of participants with ≥ 33% reduction from baseline in RBC transfusion burden during any continuous 12-week interval compared to the 12-week interval immediately prior to the date of first dose |  | Up to Week 48 | 
| TD Cohort: Number of participants with ≥ 33% reduction from baseline in RBC transfusion burden from Week 13 to Week 24 and Week 37 to Week 48 compared to the 12-week interval immediately prior to the date of first dose |  | Up to Week 48 | 
| TD Cohort: Number of participants with ≥ 33% reduction from baseline in RBC transfusion burden from Week 1 to Week 24 and Week 25 to Week 48 compared to the 24-week interval immediately prior to the date of first dose |  | Up to Week 48 | 
| TD Cohort: Number of participants with ≥ 50% reduction from baseline in RBC transfusion burden from Week 13 to Week 24 and Week 37 to Week 48 compared to the 12-week interval immediately prior to the date of first dose |  | Up to Week 48 | 
| TD Cohort: Number of participants with ≥ 50% reduction from baseline in RBC transfusion burden from Week 1 to Week 24 and Week 25 to Week 48 compared to the 24-week interval immediately prior to the date of first dose |  | Up to Week 48 | 
| TD Cohort: Change from baseline in total RBC units transfused from Week 1 to Week 24, Week 25 to Week 48, and Week 1 to Week 48 |  | Baseline, Up to Week 48 | 
| TD Cohort: The longest duration of RBC transfusion-free period for participants who achieve transfusion-free period of ≥ 12 weeks |  | Up to Week 48 | 
| TD Cohort: The longest duration of reduction in transfusion burden for participants who achieve a response (rolling 12-week and 24-week response, both for ≥ 33% and ≥ 50% reduction) |  | Up to Week 48 | 
| TD Cohort: Time from first dose to first day of response (rolling 12-week and 24-week response, both for ≥ 33% and ≥ 50% reduction) |  | Up to Week 48 | 
| TD Cohort: Change from baseline in number of transfusion events at Week 48 |  | Baseline, Up to Week 48 | 
| TD Cohort: Number of participants who achieve RBC transfusion-free period of any continuous ≥ 12 weeks during treatment |  | Up to Week 48 | 
| NTD Cohort: Number of participants who achieve RBC transfusion-free period of any continuous ≥ 24 weeks during treatment |  | Up to Week 48 | 
| NTD Cohort: Time to first transfusion |  | Up to Week 48 | 
| NTD Cohort: Number of transfusions |  | Up to Week 48 | 
| NTD Cohort: Number of transfusion visits/units |  | Up to Week 48 | 
| TD and NTD Cohorts: Change from baseline in mean of hemoglobin values over the continuous 12-week interval from Week 13 to Week 24 and Week 37 to Week 48 in the absence of transfusions |  | Baseline, Up to Week 48 | 
| NTD Cohort: Number of participants achieving an increase from baseline of ≥1.0g/dL or ≥1.5g/dL in mean Hb values in absence of transfusions from Week 13 to Week 24, Week 37 to Week 48 and during any continuous 12-week window within 24 weeks and 48 weeks |  | Up to Week 48 | 
| NTD Cohort: Time from first to last Hb measurement with increase from baseline by ≥ 1.0 g/dL |  | Up to Week 48 | 
| NTD Cohort: Number of participants who achieve an increase in mean Hb of >10g/dL values during any continuous 12-week and 24-week interval within 48 weeks in the absence of transfusions |  | Up to Week 48 | 
| TD and NTD Cohorts: Change from baseline in self-reported health-related quality of life (HRQoL) assessed by physical component summary (PCS) and mental component summary (MCS) of 36-item short-form health survey version2 (SF-36v2) at Week 24 and Week 48 |  | Baseline, Up to Week 48 | 
| NTD Cohort: Change from baseline in non-transfusion dependent β-thalassemia patient-reported outcome (NTDT-PRO) Tiredness/weakness (T/W) and shortness of breath (SoB) domain scores from Week 13 to Week 24 and from Week 37 to Week 48 |  | Baseline, Up to Week 48 | 
| NTD Cohort: Change from baseline in FACT-An FS Score at Week 24 and Week 48 |  | Baseline, Up to Week 48 | 
| NTD Cohort: Change from baseline in Functional Assessment of Cancer Therapy Anemia Anemia Subscale (FACT-An AS) at Week 24 and Week 48 |  | Baseline, Up to Week 48 | 
| TD and NTD Cohorts: Number of participants with at least one hemolytic crisis |  | Up to Week 48 | 
| TD and NTD Cohorts: Rate of hemolytic crises |  | Up to Week 48 | 
| TD and NTD Cohorts: Time to first hemolytic crisis |  | Up to Week 48 | 
| TD and NTD Cohorts: Time to second hemolytic crisis |  | Up to Week 48 | 
| TD and NTD Cohorts: Change from baseline in hemolysis markers at Week 24 and Week 48 |  | Baseline, Up to Week 48 | 
| NTD Cohort: Change from baseline in the 6-minute walk test (6MWT) distance at Week 24 and Week 48 |  | Baseline, Up to Week 48 | 
| TD and NTD Cohorts: Pharmacokinetics (PK): Serum concentration of Luspatercept |  | Predose and post dose Day 1 through Day 48 | 
| TD and NTD Cohorts: Percent Change from Baseline in Biomarkers for Erythropoiesis at Week 84 | The biomarkers for erythropoiesis to be evaluated include Hb variants including hemoglobin H (HbH), sTfR1, erythropoietin (EPO), growth differentiation factor (GDF11), GDF8, GDF15. The change will be measured as a percentage of change from baseline for all the biomarkers. | Baseline, Week 84 | 
| TD and NTD Cohorts: Percent Change from Baseline in Biomarkers and Parameters for Iron Homeostasis at Week 84 | The biomarkers and parameters for iron homeostasis to be evaluated include hepcidin, erythroferrone (ERFE), serum ferritin, liver iron concentration (LIC), myocardial iron, iron chelation therapy (ICT). The change will be measured as a percentage of change from baseline for all the biomarkers. | Baseline, Week 84 | 
| TD and NTD Cohorts: Change in mean corpuscular volume (MCV) at Week 48 |  | Baseline, Week 48 | 
| TD and NTD Cohorts: Change in mean corpuscular hemoglobin (MCH) at Week 48 |  | Baseline, Week 48 | 
| TD and NTD Cohorts: Change in nucleated red blood cells (nRBC) at Week 48 |  | Baseline, Week 48 | 
| TD and NTD Cohorts: Change in red blood cells (RBC) at Week 48 |  | Baseline, Week 48 | 

 Terms related to the study
=================
Keywords Provided by Centre Hospitalier Valida
-----------------
RBC transfusion dependent, Luspatercept, BMS-986346, ACE-536, α-thalassemia, Alpha Thalassemia, Reblozyl, Transfusions, Non-transfusion dependent