Non transfusion dependent ß-thalassemia MedDRA version: 20.0 Level: LLT Classification code 10074356 Term: Non-transfusion dependent thalassemia System Organ Class: 100000004850
Conditions
Sponsors
Celgene Corporation
Eligibility
Sex/Gender
All
Inclusion criteria
Inclusion criteria: 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 ß-thalassemia or hemoglobin E/ ß-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: a. Have 2 negative pregnancy tests as verified by the Investigator prior to starting study therapy. She must agree to ongoing pregnancy testing during the study, and after end of study treatment. This applies even if the subject practices true abstinence from heterosexual contact. b. 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 with, effective contraception without interruption, 28 days prior to starting IP, 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 Are the trial subjects under 18? no Number of subjects for this age range: F.1.2 Adults (18-64 years) yes F.1.2.1 Number of subjects for this age range 148 F.1.3 Elderly (>=65 years) yes F.1.3.1 Number of subjects for this age range 2
Exclusion criteria
Exclusion criteria: 1. Subject has any significant medical condition, laboratory abnormality, or psychiatric illness that would prevent the subject from participating in the study. 2. Subject has 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. Subject has any condition that confounds the ability to interpret data from the study. 4. Subject has a diagnosis of hemoglobin S/ß-thalassemia or alpha (a)-thalassemia (eg, Hemoglobin H). 5. Subject has active hepatitis C (HCV) infection as demonstrated by a positive HCV-RNA test of sufficient sensitivity, or active infectious hepatitis B as demonstrated by the presence of hepatitis B surface antigen (HBsAG) and/or hepatitis B virus DNA (HBV-DNA) positive, or known positive human immunodeficiency virus (HIV). Note: Subjects receiving antiviral therapies should have 2 negative HCV-RNA test 3 months apart before ICF signature, ie, one test at the end of the anti-viral therapy and second test 3 months following the first test. 6. Subject had 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. Subject has received treatment with another investigational drug or device = 28 days prior to randomization. 9. Subject had prior exposure to sotatercept (ACE-011) or luspatercept (ACE-536). 10. Subject has platelet count > 1000 x 10^9/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. Subject has 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: a. 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. b. 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. c. Severe lung disease, including pulmonary fibrosis or pulmonary hypertension, ie, =G3 NCI CTCAE version 4.0 (current active minor version). d. 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. Subject had major surgery = 12 weeks prior to randomization (subjects must have completely recovered fr
Design outcomes
Primary
| Measure | Time frame |
|---|---|
| Main Objective: To evaluate the effect of luspatercept versus placebo on anemia, as measured by mean hemoglobin concentration in the absence of transfusions over a continuous 12-week interval, from Week 13 to Week 24, compared to baseline;Secondary Objective: To evaluate the effect of luspatercept versus placebo in anemia-related symptoms in patients with ß-thalassemia, as measured by nontransfusion dependent ß-thalassemia-patient reported outcome (NTDTPRO) over continuous 12-week intervals To evaluate the effect of luspatercept versus placebo on functional and health-related QoL as measured by the Medical Outcomes Study SF-36 and FACIT-F questionnaires To evaluate the long-term effect of luspatercept versus placebo on anemia, as measured by mean hemoglobin concentration in the absence of transfusions over a continuous 12-week interval from Week 37 to Week 48, compared to baseline To evaluate the effect of luspatercept versus placebo on iron overload, as measured by LIC and ICT daily dose To evaluate the effect of luspatercept versus placebo on iron overload, as measured by serum ferritin To evaluate the duration of erythroid response To evaluate the effect of luspatercept versus placebo on physical activity measured by 6MWT;Primary end point(s): Proportion of subjects who have an increase from baseline =1.0 g/dL in mean of hemoglobin values over a continuous 12-week interval from Week 13 to Week 24 in the absence of transfusions;Timepoint(s) of evaluation of this end point: Week 24 | — |
Secondary
| Measure | Time frame |
|---|---|
| Secondary end point(s): 1. Mean change from baseline in non transfusion dependent ß-thalassemia-patient reported outcome (NTDT-PRO) Tiredness and Weakness (T/W) domain score over a continuous 12-week interval from Week 13 to Week 24 2. Mean change from baseline in mean of hemoglobin values over a continuous 12-week interval from Week 13 to Week 24 in the absence of transfusions 3. Proportion of subjects who have an increase from baseline =1.0 g/dL in mean of hemoglobin values over a continuous 12-week interval from Week 37 to Week 48 in the absence of transfusions 4. Mean change from baseline in mean Functional Assessment of Chronic Illness Therapy-Fatigue (FACIT-F) Fatigue subscale score over a continuous 12-week interval from Week 13 to Week 24 5. Mean change from baseline in mean NTDT-PRO Shortness of Breath (SoB) domain over a continuous 12-week interval from Week 13 to Week 24 6. Mean change from baseline in mean hemoglobin values over a continuous 12-week interval from Week 37 to Week 48 in the absence of transfusions 7. Mean change from baseline in mean FACIT-F, mean NTDT-PRO TW domain and mean NTDT-PRO total score over a continuous 12-week interval from Week 37 to Week 48 8. Proportion of subjects with an increase from baseline = 3 in mean FACIT-F score over a continuous 12-week interval from Week 13 to Week 24 9. Proportion of subjects with an increase from baseline = 3 in mean FACIT-F score over a continuous 12-week interval from Week 37 to Week 48 10. Mean change from baseline in the physical component summary (PCS) and mental component summary (MCS) scores of the Medical Outcomes Study 36-Item Short Form (SF-36) at Week 24 and Week 48 11. Proportion of subjects with improvement of iron overload at Week 24 and Week 48, as measured by: o For subjects with baseline liver iron concentration (LIC) (by magnetic resonance imaging [MRI]) =3 mg/g dw: =20% reduction in LIC, OR = 33% decrease in iron chelation therapy (ICT) daily dose o For subjec | — |
Countries
Greece, Lebanon, Thailand, United Kingdom, United States
Contacts
Public ContactPPD Project Manager
PPD
Outcome results
None listed