A Study to Determine the Efficacy and Safety of Luspatercept in Adults With Non Transfusion Dependent Beta (β)-Thalassemia
Condition: Thalassemia
MeSH terms: Thalassemia
Intervention: Luspatercept; Placebo; Best Supportive Care (BSC)
Intervention description: Subjects will start with luspatercept at 1 mg/kg dose level every 3 weeks and can be dose escalated up to 1.25 mg/kg.; Placebo, Subcutaneous, every 21 days; Best Supportive Care (BSC)
Intervention MeSH terms: Luspatercept
Phase: Phase 2
Study type: Interventional
Primary purpose: Treatment
Allocation: Randomized
Intervention model: Parallel Assignment
Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Enrollment: 145.0
Sex: All
Minimum age: 18 Years
Healthy volunteers: No
Keywords: (β)-Thalassemia; Beta-Thalassemia; Phase 2; Luspatercept; ACE-536; Safety; Efficacy; Placebo; Red Blood Cell Transfusions; Erythrocyte transfusion; Hb increase; NTDT

Summary:

      This is a Phase 2, double-blind, randomized, placebo-controlled, multicenter study to
      determine the efficacy and safety of luspatercept (ACE-536) versus placebo in adults with
      non-transfusion dependent beta (β)-thalassemia. The study is divided into the Screening
      Period, Double-blind Treatment Period (DBTP), Open-label Phase (OLP), and Post-Treatment
      Follow-up Period (PTFP).

      It is planned to randomize approximately 150 subjects at a 2:1 ratio of luspatercept versus
      placebo.
    

Eligibility criteria:

        Inclusion Criteria:

        Subjects must satisfy the following criteria to be enrolled in the study:

          1. Subjects must be ≥ 18 years of age at the time of signing the informed consent
             document (ICF).

          2. Subject must understand and voluntarily sign an ICF prior to any study-related
             assessments/procedures being conducted.

          3. Subject is willing and able to adhere to the study visit schedule (eg, not scheduled
             to receive hematopoietic stem cell transplantation) and other protocol requirements.

          4. Subject must have documented diagnosis of β-thalassemia or hemoglobin E/
             β-thalassemia. Concomitant alpha globin mutation and/or duplication are allowed.

          5. Subject must be non-transfusion dependent, defined as 0 to 5 units of RBCs received
             during the 24-week period prior to randomization. Note: 1 unit defined for this entry
             criterion as approximately 200 to 350 mL of transfused packed RBCs.

          6. Subject must not be on a regular transfusion program and must be RBC transfusion-free
             for at least ≥ 8 weeks prior to randomization

          7. Subject must have mean baseline hemoglobin ≤ 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.

          8. Subject must have performance status: Eastern Cooperative Oncology Group (ECOG)
             performance score of 0 to 1.

          9. A female of childbearing potential (FCBP) for this study is defined as a female who:

        1) has achieved menarche at some point, 2) has not undergone a hysterectomy or bilateral
        oophorectomy or 3) has not been naturally postmenopausal (amenorrhea following cancer
        therapy does not rule out childbearing potential) for at least 24 consecutive months (ie,
        has had menses at any time in the preceding 24 consecutive months). A FCBP participating in
        the study must:

          1. Have 2 negative pregnancy tests as verified by the Investigator prior to starting
             study therapy. She must agree to ongoing pregnancy testing during the course of the
             study, and after end of study treatment. This applies even if the subject practices
             true abstinence* from heterosexual contact.

          2. Either commit to true abstinence* from heterosexual contact (which must be reviewed on
             a monthly basis and source documented). If a FCBP engages in sexual activity that may
             result in a pregnancy, she must agree to use, and be able to comply during the study
             therapy (including dose interruptions), and for 12 weeks (approximately 5 times the
             mean terminal half-life of luspatercept based on multiple dose pharmacokinetics [PK]
             data) after discontinuation of study therapy.

             10. Male subjects must:

        a. Practice true abstinence (which must be reviewed on a monthly basis) or agree to use a
        condom during sexual contact with a pregnant female or a female of childbearing potential
        while participating in the study, during dose interruptions and for at least 12 weeks
        (approximately 5 times the mean terminal half-life of luspatercept based on multiple-dose
        PK data) following IP discontinuation, even if he has undergone a successful vasectomy

        Exclusion Criteria:

        The presence of any of the following will exclude a subject from enrollment:

          1. Any significant medical condition, laboratory abnormality, or psychiatric illness that
             would prevent the subject from participating in the study.

          2. Any condition including the presence of laboratory abnormalities, which places the
             subject at unacceptable risk if he/she were to participate in the study.

          3. Any condition that confounds the ability to interpret data from the study.

          4. Diagnosis of hemoglobin S/β-thalassemia or alpha (α)-thalassemia (eg,Hemoglobin H).

          5. Active hepatitis C (HCV) infection

          6. Deep vein thrombosis (DVT) or stroke requiring medical intervention ≤ 24 weeks prior
             to randomization.

          7. Subjects on chronic anticoagulant therapy are excluded, unless they stopped the
             treatment at least 28 days prior to randomization. Anticoagulant therapies for
             prophylaxis and for surgery or high-risk procedures as well as low molecular weight
             (LMW) heparin for superficial vein thrombosis (SVT) and chronic aspirin are allowed
             before and during the study.

          8. Treatment with another investigational drug or device ≤ 28 days prior to
             randomization.

          9. Prior exposure to sotatercept (ACE-011) or luspatercept (ACE-536).

         10. Platelet count > 1000 x 109/L.

         11. Subjects on iron chelation therapy (ICT) at the time of ICF signature must have
             initiated the treatment with ICT at least 24 weeks before the predicted randomization
             date. ICT can be initiated at any time during treatment and should be used according
             to the label.

         12. Subject had Hydroxyurea and ESA treatment ≤ 24 weeks prior to randomization, and no
             prior gene therapy.

         13. Subject is pregnant or a lactating female.

         14. Uncontrolled hypertension. Controlled hypertension for this protocol is considered ≤
             Grade 1 according to National Cancer Institute Common Terminology for Adverse Events
             (NCI CTCAE) version 4.0 (current active minor version).

         15. Subject has major organ damage, including:

               1. Liver disease with alanine aminotransferase (ALT) > 3 x upper limit of normal
                  (ULN) or history/evidence of cirrhosis, as well as presence of masses/tumor
                  detected by ultrasound at screening.

               2. Heart disease, heart failure as classified by the New York Heart Association
                  (NYHA) classification 3 or higher, or significant arrhythmia requiring treatment,
                  or recent myocardial infarction (MI) within 6 months of randomization.

               3. Severe lung disease, including pulmonary fibrosis or pulmonary hypertension, ie,
                  ≥G3 NCI CTCAE version 4.0 (current active minor version).

               4. Estimated glomerular filtration rate (eGFR) < 60 ml/min/1.73 m2 (per Modification
                  of Diet in Renal Disease [MDRD] formula).

         16. Subject has received chronic systemic glucocorticoids ≤ 12 weeks prior to
             randomization (physiologic replacement therapy for adrenal insufficiency is allowed).

         17. Major surgery ≤ 12 weeks prior to randomization (subjects must have completely
             recovered from any previous surgery prior to randomization).

         18. History of severe allergic or anaphylactic reactions or hypersensitivity to
             recombinant proteins or excipients in the investigational product (see Investigator
             Brochure).

         19. Subject has received immunosuppressants ≤ 28 days prior to randomization.

         20. History or current malignancies (solid tumors and hematological malignancies) unless
             the subject has been free of the disease (including completion of any active or
             adjuvant treatment for prior malignancy) for ≥ 5 years. However, subjects with the
             following history/concurrent conditions are allowed:

               -  Basal or squamous cell carcinoma of the skin

               -  Carcinoma in situ of the cervix

               -  Carcinoma in situ of the breast

               -  Incidental histologic finding of prostate cancer (T1a or T1b using the tumor,
                  nodes, metastasis [TNM] clinical staging system)