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ACE-536 Extension Study - Beta Thalassemia

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ClinicalTrials.gov Identifier: NCT02268409
Recruitment Status : Completed
First Posted : October 20, 2014
Last Update Posted : July 14, 2020
Sponsor:
Information provided by (Responsible Party):
Acceleron Pharma Inc.

Tracking Information
First Submitted Date  ICMJE October 6, 2014
First Posted Date  ICMJE October 20, 2014
Last Update Posted Date July 14, 2020
Study Start Date  ICMJE November 2014
Actual Primary Completion Date June 18, 2020   (Final data collection date for primary outcome measure)
Current Primary Outcome Measures  ICMJE
 (submitted: October 19, 2015)
Long-term safety and tolerability of ACE-536 in patients with β thalassemia who were previously enrolled in study A536-04 [ Time Frame: From first dose (Study Day 1) to end of treatment (Study Day 730) ]
safety and tolerability will be assessed by recording and classification of all adverse events (clinical and laboratory) reported by study investigators in all subjects who received at least one dose of study drug
Original Primary Outcome Measures  ICMJE
 (submitted: October 16, 2014)
  • Long-term safety - number of patients with adverse events [ Time Frame: From first dose (Study Day 1) to end of treatment (Study Day 365) ]
  • Long-term safety - change from baseline clinical laboratory values and vital signs. [ Time Frame: From first dose (Study Day 1) to end of treatment (Study Day 365) ]
Change History
Current Secondary Outcome Measures  ICMJE
 (submitted: January 8, 2018)
  • Erythroid response (8-week) in non-transfusion dependent (NTD) patients [ Time Frame: From first dose (Study Day 1) to end of treatment (Study Day 730) ]
    Proportion of patients with a mean hemoglobin increase ≥ 1.5 g/dL over continuous 8-week interval compared to baseline, not influenced by red blood cell (RBC) transfusion
  • Erythroid response (12-week) in non-transfusion dependent (NTD) patients [ Time Frame: From first dose (Study Day 1) to end of treatment (Study Day 730) ]
    Proportion of patients with a mean hemoglobin increase ≥ 1.5 g/dL over continuous 12-week interval compared to baseline, not influenced by red blood cell (RBC) transfusion
  • Erythroid response (8-week) in transfusion dependent (TD) patients [ Time Frame: From first dose (Study Day 1) to end of treatment (Study Day 730) ]
    Proportion of patients with a reduction in RBC transfusion burden by ≥ 20% over a continuous 8-week interval compared to the 8 weeks prior to the start of treatment
  • Erythroid response (12-week) in transfusion dependent (TD) patients [ Time Frame: From first dose (Study Day 1) to end of treatment (Study Day 730) ]
    Proportion of patients with a reduction in RBC transfusion burden by ≥ 50% over a continuous 12-week interval compared to the 12 weeks prior to the start of treatment
  • Time to, and duration of, erythroid response [ Time Frame: From first dose (Study Day 1) to end of treatment (Study Day 730) ]
    Length of time required to achieve erythroid response, and total duration of that response
  • Mean change from baseline in hemoglobin levels in NTD patients [ Time Frame: From first dose (Study Day 1) to end of treatment (Study Day 730 ]
    Mean change in hemoglobin, not influenced by RBC transfusion
  • Mean % change from baseline in transfusion burden in TD patients [ Time Frame: From first dose (Study Day 1) to end of treatment (Study Day 730) ]
    Mean change in transfusion burden from baseline burden
  • Mean change in pre-transfusion hemoglobin levels in TD patients [ Time Frame: From first dose (Study Day 1) to end of treatment (Study Day 730) ]
    Mean change in pre-transfusion hemoglobin
  • Changes in markers of erythropoiesis [ Time Frame: From first dose (Study Day 1) to end of treatment (Study Day 730) ]
    Assessment of erythropoietin levels, reticulocyte count, nucleated RBC count and solubel transferrin receptor
  • Changes in markers of iron metabolism [ Time Frame: From first dose (Study Day 1) to end of treatment (Study Day 730) ]
    Assessment of serum iron, TIBC, serum ferritin, transferrin saturation, hepcidin and NTBI
  • ACE-536 pharmacokinetic profileversus time curve (AUC) [ Time Frame: From first dose (Study Day 1) to end of treatment (Study Day 730) ]
    Assessment of Cmax, Tmax and area under the plasma concentration
  • Quality of Life assessments (exploratory) [ Time Frame: From first dose (Study Day 1) to end of treatment (Study Day 730) ]
    FACT-An and SF-36 health surveys
Original Secondary Outcome Measures  ICMJE
 (submitted: October 16, 2014)
  • Erythroid response in non-transfusion dependent (NTD) patients [ Time Frame: From first dose (Study Day 1) to end of treatment (Study Day 365) ]
    Proportion of patients with a mean hemoglobin increase ≥ 1.5 g/dL over continuous 8-week interval compared to baseline, not influenced by red blood cell (RBC) transfusion
  • Erythroid response in non-transfusion dependent (NTD) patients [ Time Frame: From first dose (Study Day 1) to end of treatment (Study Day 365) ]
    Proportion of patients with a mean hemoglobin increase ≥ 1.5 g/dL over continuous 12-week interval compared to baseline, not influenced by red blood cell (RBC) transfusion
  • Erythroid response in transfusion dependent (TD) patients [ Time Frame: From first dose (Study Day 1) to end of treatment (Study Day 365) ]
    Proportion of patients with a reduction in RBC transfusion burden by ≥ 20% over a continuous 8-week interval compared to the 8 weeks prior to the start of treatment
  • Erythroid response in transfusion dependent (TD) patients [ Time Frame: From first dose (Study Day 1) to end of treatment (Study Day 365) ]
    Proportion of patients with a reduction in RBC transfusion burden by ≥ 50% over a continuous 12-week interval compared to the 12 weeks prior to the start of treatment
  • Time to, and duration of, erythroid response [ Time Frame: From first dose (Study Day 1) to end of treatment (Study Day 365) ]
  • Mean change from baseline in hemoglobin levels in NTD patients not influenced by RBC transfusion [ Time Frame: From first dose (Study Day 1) to end of treatment (Study Day 365) ]
  • Mean % change from baseline in transfusion burden in TD patients [ Time Frame: From first dose (Study Day 1) to end of treatment (Study Day 365) ]
  • Mean change in pre-transfusion hemoglobin levels in TD patients [ Time Frame: From first dose (Study Day 1) to end of treatment (Study Day 365) ]
  • Changes in markers of erythropoiesis [ Time Frame: From first dose (Study Day 1) to end of treatment (Study Day 365) ]
  • Changes in markers of iron metabolism [ Time Frame: From first dose (Study Day 1) to end of treatment (Study Day 365) ]
  • ACE-536 pharmacokinetic profile - Cmax, Tmax and area under the plasma concentration versus time curve (AUC) [ Time Frame: From first dose (Study Day 1) to end of treatment (Study Day 365) ]
  • Quality of Life assessments (exploratory) [ Time Frame: From first dose (Study Day 1) to end of treatment (Study Day 365) ]
Current Other Pre-specified Outcome Measures Not Provided
Original Other Pre-specified Outcome Measures Not Provided
 
Descriptive Information
Brief Title  ICMJE ACE-536 Extension Study - Beta Thalassemia
Official Title  ICMJE An Open-Label Extension Study to Evaluate the Long-Term Effects of ACE-536 in Patients With β-Thalassemia Previously Enrolled in Study A536-04
Brief Summary Study A536-06 is an open-label extension study for patients previously enrolled in study A536-04 (ClinicalTrials.gov Identifier NCT01749540), to evaluate the long-term safety and tolerability of ACE-536 in adult patients with beta-thalassemia.
Detailed Description Study A536-06 is an open-label extension study for patients previously enrolled in study A536-04 (ClinicalTrials.gov Identifier NCT01749540), to evaluate the safety,tolerability and pharmacodynamic effects of up to 24 months of ACE-536 treatment in adult patients with beta-thalassemia previously treated with ACE-536 for up to 3 months in study A536-04. The starting dose level in A536-06 will be 0.8 mg/kg by subcutaneous (SC) injection once every 3 weeks. Dose titration/modification rules will be followed for individual patients and will be based upon safety and efficacy data collected during the course of treatment.
Study Type  ICMJE Interventional
Study Phase  ICMJE Phase 2
Study Design  ICMJE Allocation: N/A
Intervention Model: Single Group Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Condition  ICMJE Beta-Thalassemia
Intervention  ICMJE Drug: ACE-536
ACE-536 0.8 mg/kg once every 3 weeks by SC injection
Other Name: luspatercept
Study Arms  ICMJE Experimental: ACE-536 0.8 mg/kg once every 3 weeks SC
ACE-536 0.8 mg/kg once every 3 weeks by SC injection
Intervention: Drug: ACE-536
Publications * Piga A, Perrotta S, Gamberini MR, Voskaridou E, Melpignano A, Filosa A, Caruso V, Pietrangelo A, Longo F, Tartaglione I, Borgna-Pignatti C, Zhang X, Laadem A, Sherman ML, Attie KM. Luspatercept improves hemoglobin levels and blood transfusion requirements in a study of patients with β-thalassemia. Blood. 2019 Mar 21;133(12):1279-1289. doi: 10.1182/blood-2018-10-879247. Epub 2019 Jan 7.

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Recruitment Information
Recruitment Status  ICMJE Completed
Actual Enrollment  ICMJE
 (submitted: July 13, 2020)
51
Original Estimated Enrollment  ICMJE
 (submitted: October 16, 2014)
72
Actual Study Completion Date  ICMJE June 18, 2020
Actual Primary Completion Date June 18, 2020   (Final data collection date for primary outcome measure)
Eligibility Criteria  ICMJE

Inclusion Criteria:

  1. Completion of the treatment period in the base study A536-04.
  2. 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 ACE-536. 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 ACE-536, even if he has undergone a successful vasectomy. Patients must be counseled concerning measures to be used to prevent pregnancy and potential toxicities prior to the first dose of ACE-536.
  3. Patient is able to adhere to the study visit schedule, understand and comply with all protocol requirements.
  4. Patient understands and is able to provide written informed consent

    Patients with treatment interruption (defined as patients who complete the EOS visit for study A536-04 and are ≥ 28 days post EOS visit) must also meet the following criteria

  5. Mean hemoglobin concentration < 10.0 g/dL of 2 measurements (not influenced by RBC transfusion) (one performed within one day prior to Cycle 1 Day 1 and the other performed during the screening period [Day -28 to Day -1]) in NTD patients.
  6. Adequate folate levels or on folate therapy.
  7. Platelet count ≥ 100 x 10(9) /L and ≤ 1,000 x 10(9) /L.
  8. Aspartate aminotransferase (AST) or alanine aminotransferase (ALT) < 3 x upper limit of normal (ULN).
  9. Serum creatinine ≤ 1.5 x ULN.
  10. Ejection fraction ≥ 50% by Echocardiogram (ECHO) or Multi gated acquisition scan (MUGA).

Exclusion Criteria:

  1. Discontinuation/withdrawal from study A536-04 due to patient request, patient unwillingness or inability to comply with the protocol, pregnancy, use of prohibited medication (e.g., hydroxyurea), medical reason or AE, hypersensitivity reaction to the study drug, at the discretion of the sponsor, or loss to follow-up prior to completion of the treatment period.
  2. 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 Cycle 1 Day 1.
  3. Symptomatic splenomegaly.
  4. Splenectomy within 56 days prior to Cycle 1 Day 1.
  5. Major surgery (except splenectomy) within 28 days prior to Cycle 1 Day 1. Patients must have completely recovered from any previous surgery prior to Cycle 1 Day 1.
  6. Patients receiving or planning to receive hydroxyurea treatment. Patients must not have had hydroxyurea within 90 days of Cycle 1 Day 1.
  7. For patients with treatment interruption: Iron chelation therapy if initiated within 56 days prior to Cycle 1 Day 1.
  8. Cytotoxic agents, systemic corticosteroids, immunosuppressants, or anticoagulant therapy such as warfarin or heparin within 28 days prior to Cycle 1 Day 1 (prophylactic aspirin up to 100 mg/day and low molecular weight (LMW) heparin for superficial vein thrombosis (SVT) is permitted).
  9. Treatment with another investigational drug (including sotatercept [ACE-011]) or device, or approved therapy for investigational use ≤ 28 days prior to Cycle 1 Day 1, or if the half-life of the previous investigational product is known, within 5 times the half-life prior to Cycle 1 Day 1, whichever is longer at any time between the end of treatment of the base study A536-04 and Cycle 1 Day 1.
  10. Known positive for human immunodeficiency virus (HIV), active infectious hepatitis B (HBV) or active infectious hepatitis C (HCV).
  11. Uncontrolled hypertension defined as systolic blood pressure (SBP) ≥ 150 mm Hg or diastolic blood pressure (DBP) ≥ 100 mm Hg.
  12. Known history of thromboembolic events ≥ grade 3 according to the National Cancer Institute-Common Terminology Criteria for Adverse Events (NCI-CTCAE) v.4.0 (current active minor version).
  13. Pregnant or lactating females.
  14. History of severe allergic or anaphylactic reactions or hypersensitivity to recombinant proteins or excipients in the investigational drug.
  15. Any other condition not specifically noted above which, in the judgment of the investigator, would preclude the patient from participating in the study.
Sex/Gender  ICMJE
Sexes Eligible for Study: All
Ages  ICMJE 18 Years and older   (Adult, Older Adult)
Accepts Healthy Volunteers  ICMJE No
Contacts  ICMJE Contact information is only displayed when the study is recruiting subjects
Listed Location Countries  ICMJE Greece,   Italy
Removed Location Countries  
 
Administrative Information
NCT Number  ICMJE NCT02268409
Other Study ID Numbers  ICMJE A536-06
Has Data Monitoring Committee No
U.S. FDA-regulated Product Not Provided
IPD Sharing Statement  ICMJE Not Provided
Responsible Party Acceleron Pharma Inc.
Study Sponsor  ICMJE Acceleron Pharma Inc.
Collaborators  ICMJE Not Provided
Investigators  ICMJE Not Provided
PRS Account Acceleron Pharma Inc.
Verification Date July 2020

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP