A Phase 2 Study for the Treatment of Anemia with Alpha (α)-Thalassemia to Determine the Efficacy and Safety of Luspatercept (BMS-986346/ACE-536) in Adults and Evaluate the Safety and Pharmacokinetics in Adolescents
- Trial ID
- 2022-502328-35-00
- Protocol
- CA056-015
- Sponsor
- Celgene Corp.
Trial statistics
Diseases & Conditions
Objectives
The primary objective of this Phase 2 study is to evaluate the **erythroid response** of **luspatercept** plus best supportive care (BSC) compared to placebo plus BSC in adult participants with **Alpha (α)-thalassemia** HbH disease. This is clinically relevant as it aims to address anemia, a significant complication in this patient population, potentially improving their quality of life and reducing the need for red blood cell transfusions. Additionally, the study seeks to confirm the recommended safe and tolerable dose of luspatercept in adolescent participants with Alpha (α)-thalassemia, ensuring the treatment's safety profile in a younger demographic.
Secondary objectives include:
- For adult cohorts: Comparing the effect of luspatercept plus BSC versus placebo plus BSC on red blood cell transfusion burden and anemia in participants with Alpha (α)-thalassemia.
- For adolescent cohorts: Evaluating the safety and pharmacokinetics of luspatercept in transfusion-dependent (TD) and non-transfusion-dependent (NTD) adolescent participants with Alpha (α)-thalassemia.
Participants
The clinical trial involves a total of **136 participants** diagnosed with **alpha-thalassemia** HbH disease. The study population includes both male and female subjects, with age ranges spanning from adolescents aged 12 to less than 18 years, and adults aged 18 years and older. Participants were selected based on their documented diagnosis of alpha-thalassemia HbH disease, with specific criteria regarding transfusion dependence. The trial does not include a vulnerable population. Participants' general health status is assessed through performance status scores, with a requirement of a Karnofsky score of 50 or higher for those aged 16 and above, and a Lansky score of 50 or higher for those under 16. Lifestyle considerations such as diet and physical activity are not specified in the available data. The trial aims to evaluate the erythroid response to luspatercept plus best supportive care (BSC) compared to placebo plus BSC in adults, and to confirm the safe and tolerable dose of luspatercept in adolescents.
Plans and Procedures
The clinical trial is designed to evaluate the **efficacy** and safety of **luspatercept** in adults and adolescents with **alpha-thalassemia**. This is a Phase 2, randomized, double-blind, controlled study. The trial will compare the erythroid response of luspatercept plus best supportive care (BSC) versus placebo plus BSC in adult participants, while also confirming the recommended safe and tolerable dose in adolescent participants. The trial is expected to last until July 2026, with recruitment having commenced in January 2023.
Participants will undergo a series of study visits, beginning with an inclusion (screening) visit to assess eligibility based on specific criteria, such as transfusion dependence and hemoglobin levels. Following randomization, participants will attend regular follow-up visits to monitor their response to treatment and any adverse events. The primary endpoints for adult cohorts include a reduction in red blood cell (RBC) transfusion burden and an increase in hemoglobin levels, while adolescent cohorts will be assessed for dose-limiting toxicities and pharmacokinetic parameters. The end-of-study visit will conclude the participant's involvement, summarizing the overall treatment effects and safety profile.
Participant involvement is anticipated to last up to 140 weeks, depending on individual response and adherence to the study protocol. Conditions that may lead to early termination from the study include the occurrence of severe adverse events, non-compliance with study procedures, or withdrawal of consent. The trial aims to provide valuable insights into the management of anemia in individuals with alpha-thalassemia, potentially improving therapeutic strategies for this condition.
Treatment
The clinical trial involves the administration of **Reblozyl**, a pharmaceutical product containing the active substance **luspatercept**. Reblozyl is available in two dosages: 75 mg and 25 mg, both formulated as a **powder for solution for injection**. The active substance, luspatercept, is a fusion protein derived from a synthetic human extracellular domain of the activin receptor type IIB, combined with a synthetic human Fc region. This homo-dimeric protein is classified under the ATC code B03XA, indicating its use as an antianemic preparation. The medication is administered via **subcutaneous injection**. The dosing regimen allows for a maximum daily dose of 1.25 mg/kg, with a total maximum dose of 57 mg/kg over a treatment period of up to 140 days. The trial aims to evaluate the efficacy and safety of luspatercept in treating anemia associated with alpha-thalassemia.
In addition to the experimental treatment, the study utilizes a **0.9% sodium chloride injection** as a placebo. This solution for injection serves as a comparator to assess the efficacy of Reblozyl in the trial. The sodium chloride injection does not contain any active pharmaceutical ingredients and is used to maintain blinding in the study. The administration route and frequency for the placebo are consistent with those of the experimental treatment to ensure the integrity of the trial design.
Efficacy
Efficacy in this clinical trial will be assessed using specific primary endpoints tailored to both adult and adolescent cohorts. For adult participants with **alpha-thalassemia HbH disease**, the primary endpoints include the achievement of a ≥ 50% reduction from baseline in red blood cell (RBC) transfusion burden, with a reduction of at least 2 units during any continuous 12 weeks from Weeks 13 to 48, compared to the 12-week interval immediately prior to the first dose. Additionally, for non-transfusion-dependent (NTD) adults, efficacy will be measured by an increase from baseline of ≥ 1.0 g/dL in mean hemoglobin values over a continuous 12-week interval from Week 13 to Week 24, in the absence of RBC transfusion.
For adolescent cohorts, the primary endpoints focus on safety and pharmacokinetics, including the observation of dose-limiting toxicities (DLTs) defined as ≥ Grade 3-related hemolytic crises or ≥ Grade 3-related events outside of the known safety profile occurring within 21 days from the first dose of study therapy. Additionally, pharmacokinetic parameters and the frequency, severity, and seriousness of adverse events (AEs) will be evaluated. These endpoints will be measured and analyzed at specified intervals throughout the trial to determine the efficacy and safety of **luspatercept** in treating anemia associated with alpha-thalassemia.
Inclusion and Exclusion Criteria
Inclusion Criteria
- Adult participant ≥ 18 years with documented diagnosis of α-thalassemia HbH disease with Transfusion dependence defined as: - TD participant: ≥ 6 RBC units during the 24 weeks prior to randomization and no transfusion-free period for > 56 days during the 24 weeks prior to randomization - NTD participant: < 6 RBC units during the 24 weeks prior to randomization and, RBC transfusion-free during at least 8 weeks prior to randomization and, 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. Adolescent participant 12 years to < 18 years with documented diagnosis of α- thalassemia HbH disease with transfusion dependence defined as: - TD participant: ≥ 4 RBC events during the 24 weeks prior to enrollment and, no transfusion-free period for > 56 days during the 24 weeks prior to enrollment. Participants must have a history of regular transfusions for at least 2 years - NTD participant: < 4 RBC events during the 24 weeks prior to enrollment and RBC transfusion-free during at least 8 weeks prior to enrollment and, mean baseline Hb ≤ 10 g/dL, based on a minimum of 2 measurements ≥ 1 week apart within 4 weeks prior to enrollment, hemoglobin values within 21 days post-transfusion will be excluded. - Participant has Karnofsky (age ≥16 years) or Lansky (age < 16 years) performance status score ≥ 50 at screening.
Exclusion Criteria
- Key Exclusion Criteria - Adult and Adolescent participants: - Medical Conditions: 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. Bleeding disorders manifested by frequent bleeding episodes. Undergone episodes of hemolysis not related to α-thalassemia within the 8 weeks prior to randomization. - Reproductive Status: Women who are pregnant, plan to get pregnant during the study, or who are breastfeeding. - Prior/Concomitant Therapy: Prior exposure to gene therapy to treat α-thalassemia. Undergone hematopoietic stem cell transplantation (HSCT)
Trial Status by Country
| Country | Status | Start of Recruitment | Planned Patients |
|---|---|---|---|
 Greece | Recruiting | 12 Jan 2023 | 21 |
 Italy | Recruiting | 12 Jan 2023 | 20 |
Sites & Investigators
Investigational Products
Details about the medicinal products being studied in this clinical trial.
| Product Name | Role in Trial | Formulation | Administration | Max Daily Dose | Treatment Duration | EU MP Number |
|---|---|---|---|---|---|---|
Reblozyl 75 mg powder for solution for injection | Test | POWDER FOR SOLUTION FOR INJECTION | SUBCUTANEOUS USE | 1.25 | 140 | PRD9257437 |
Reblozyl 25 mg powder for solution for injection | Test | POWDER FOR SOLUTION FOR INJECTION | SUBCUTANEOUS USE | 1.25 | 140 | PRD9257430 |
0.9% sodium chloride injection, solution for injection | Placebo | N/A | — | — | — | N/A |