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Trial record 2 of 1333 for:    BELIEVE

An Efficacy and Safety Study of Luspatercept (ACE-536) Versus Placebo in Adults Who Require Regular Red Blood Cell Transfusions Due to Beta (β) Thalassemia (BELIEVE)

This study is currently recruiting participants. (see Contacts and Locations)
Verified December 2016 by Celgene Corporation
Sponsor:
Collaborator:
Acceleron Pharma, Inc.
Information provided by (Responsible Party):
Celgene Corporation
ClinicalTrials.gov Identifier:
NCT02604433
First received: October 21, 2015
Last updated: December 28, 2016
Last verified: December 2016
  Purpose

This is a Phase 3, double-blind, randomized, placebo-controlled, multicenter study to determine the efficacy and safety of luspatercept (ACE-536) plus Best supportive care (BSC) versus placebo plus BSC in adults who require regular red blood cell transfusion due to (β)-thalassemia.

The study is divided into the Screening/Run-in Period, double-blind Treatment Period, double-blind Long-term Treatment Period, and Post-treatment Follow-up Period.


Condition Intervention Phase
Erythrocyte Transfusion
Beta-Thalassemia
Drug: Luspatercept
Other: Placebo
Phase 3

Study Type: Interventional
Study Design: Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Double Blind (Participant, Care Provider, Investigator, Outcomes Assessor)
Primary Purpose: Treatment
Official Title: A Phase 3, Double-Blind, Placebo Controlled Multicenter Study to Determine the Efficacy and Safety of Luspatercept (ACE-536) in Adults With Transfusion Dependent Beta (B)-Thalassemia

Resource links provided by NLM:


Further study details as provided by Celgene Corporation:

Primary Outcome Measures:
  • Proportion of subjects with hematological improvement from Week 13 to Week 24 compared to 12-week prior to randomization [ Time Frame: Up to approximately week 24 ]
    Hematological improvement(HI) is defined as ≥ 33% reduction from baseline in red blood cell count (RBC) transfusion burden with a reduction of at least 2 units from Week 13 to Week 24 compared to the 12-week. Reported as the Number of RBC units transfused from Week 13 to Week 24, and in the 12 weeks prior to randomization


Secondary Outcome Measures:
  • Proportion of subjects with hematological improvement from Week 37 to Week 48 compared to the 12-week interval prior to randomization [ Time Frame: Up to approximately 48 weeks ]
    Hematological improvement(HI) is defined as ≥ 33% reduction from baseline in red blood cell count (RBC) transfusion burden with a reduction of at least 2 units from Week 37 to Week 48 compared to the 12-week. Reported as the number of RBC units transfused from Week 37 to Week 48, and in the 12 weeks prior to randomization

  • Proportion of subjects with a ≥50% reduction in red blood cell (RBC) transfusion burden from week 37 to Week 48 [ Time Frame: Up to approximately 48 weeks ]
    A reduction of ≥50% in transfusion burden is defined as a reduction of at least 2 units from week 37 to week 48 compared to the 12 week interval prior to randomization for luspatercept plus (best supportive care) BSC Versus placebo plus BSC. Reported as the number of RBC units transfused from Week 37 to Week 48, and in the 12 weeks prior to randomization

  • Proportion of subjects with a ≥50% reduction in red blood cell (RBC) transfusion burden from week 13 to Week 24 [ Time Frame: Up to approximately 24 weeks ]
    A reduction of ≥50% in transfusion burden is defined as a reduction of at least 2 units from week 13 to week 24 compared to the 12 week interval prior to randomization for luspatercept plus (best supportive care) BSC Versus placebo plus BSC. Reported as the number of RBC units transfused from Week 37 to Week 48, and in the 12 weeks prior to randomization

  • Mean change from baseline in transfusion burden (RBC units) from Week 13 to Week 24 [ Time Frame: Up to approximately 24 weeks ]
    Change from baseline as continuous variable

  • Mean change from baseline in liver iron concentration (LIC, mg/g dw) by magnetic resonance imaging (MRI) [ Time Frame: Up to approximately 48 weeks ]
    Liver iron concentration (LIC) by Magnetic resonance imaging (MRI)

  • Mean change from baseline in mean daily dose of iron chelation therapy (ICT) [ Time Frame: Up to approximately 48 weeks ]
    Daily dose of iron chelation therapy (ICT)

  • Mean change from baseline in serum ferritin [ Time Frame: Up to approximately 48 weeks ]
    Mean Change in Serum ferritin

  • Mean change from baseline in total hip and lumbar spine bone mineral density (BMD)by Dual energy x-ray absorptiometry (DXA) [ Time Frame: Up to approximately 48 weeks ]
    Total hip and lumbar spine bone mineral density (BMD) by Dual energy x-ray absorptiometry (DXA)

  • Mean change from baseline in myocardial iron by magnetic resonance imaging (MRI) [ Time Frame: Up to approximately 48 weeks ]
    Myocardial iron by T2 magnetic resonance imaging (MRI)

  • TranQOL Quality of Life tool administered within 4 weeks prior to Dose 1 Day 1, and weeks 12, 24, 36 and 48, then every 12 weeks during long term period [ Time Frame: Up to approximately 3 years ]
    Summary statistics for scores from the pre-specified domains will be calculated at each administration time point. Summary statistics will also be calculated for change from baseline in each score at each administration time point.

  • SF-36 Quality of Life tool administered within 4 weeks prior to Dose 1 Day 1, and weeks 12, 24, 36 and 48, then every 12 weeks during long term treatment period [ Time Frame: Up to approximately 3 years ]
    Summary statistics for the Physical functioning, Role - Physical, General Health, Vitality, Social Functioning domain scores, and the Physical Component summary score, as well as change from baseline in these scores, will be assessed at Week 12, 24, 36 and 48 and then every 12 weeks during the Long-term Treatment Period.

  • The effect of luspatercept on healthcare resource utilization (hospitalizations) versus placebo [ Time Frame: Up to approximately 3 years ]
    hospitalizations in the treatment and placebo arms

  • The effect of luspatercept on healthcare resource utilization (prior concomitant therapies and surgeries) versus placebo [ Time Frame: Up to approximately 3 years ]
    prior concomitant therapies and surgeries in the treatment and placebo arms

  • The effect of luspatercept on healthcare resource utilization (RBC transfusion utilization) versus placebo [ Time Frame: Up to approximately 3 years ]
    RBC transfusion utilization in the treatment and placebo arms

  • Proportion of subjects who are transfusion independent for ≥8 weeks during treatment [ Time Frame: Up to approximately 48 weeks ]
    Myocardial iron by T2 MRI

  • Duration of reduction in transfusion burden [ Time Frame: Up to approximately 48 weeks ]
    The duration of the first response will be calculated for each subject who achieves a response

  • Duration of transfusion independence [ Time Frame: Up to approximately 48 weeks ]
    Transfusion independence is defined as absence of any transfusion during any consecutive rolling 8-week time interval within the treatment period, ie, Days 1 to 56, Days 2 to 57 and so on

  • Time to erythroid response [ Time Frame: Up to approximately 48 weeks ]
    Erythroid response is defined as ≥ 33% reduction from baseline in transfusion burden (units RBCs / time) with a reduction of at least 2 units. The analysis of time to response will be based on the data collected during the double-blind phase.

  • Post-baseline transfusion events frequency versus placebo [ Time Frame: Up to approximately 48 weeks ]
    Annualized mean change from baseline number of transfusion events will be summarized by treatment groups

  • Pharmacokinetic - AUC [ Time Frame: up to 9 weeks post last dose ]
    Area under the plasma concentration‐time curve

  • Pharmacokinetic - Cmax [ Time Frame: up to 9 weeks post last dose ]
    Maximum observed concentration in plasma

  • Adverse Events (AEs) [ Time Frame: Up to approximately 3.5 years ]
    Number of participants with adverse events


Estimated Enrollment: 300
Study Start Date: May 2016
Estimated Study Completion Date: April 2019
Estimated Primary Completion Date: September 2018 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Experimental: Luspatercept (ACE-536) plus Best Supportive Care (BSC)
Luspatercept, subcutaneous(ly) (SC) once every 21 days
Drug: Luspatercept
Subjects will start with luspatercept at 1 mg/kg dose level.
Other Name: ACE-536
Placebo Comparator: Placebo plus Best Supportive Care (BSC)
normal saline solution subcutaneous(ly) (SC) once every 21 days
Other: Placebo
Placebo, Subcutaneous, every 21 days.

  Eligibility

Ages Eligible for Study:   18 Years and older   (Adult, Senior)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  • Subjects must satisfy the following criteria to be enrolled in the study:

    1. Male or female, ≥ 18 years of age at the time of signing the informed consent document (ICF).
    2. Subject must understand and voluntarily sign an Inform Consent Form prior to any study-related assessments/procedures being conducted.
    3. Subject is willing and able to adhere to the study visit schedule and other protocol requirements.
    4. Documented diagnosis of β-thalassemia or Hemoglobin E/β-thalassemia.
    5. Regularly transfused, defined as: 6-20 Red Blood Cell (RBC) units in the 24 weeks prior to randomization and no transfusion-free period for ≥ 35 days during that period.
    6. Performance status: Eastern Cooperative Oncology Group (ECOG) score of 0 or 1.
    7. 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). FCBP participating in the study must:
  • Have two 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.
  • Either commit to true abstinence from heterosexual contact (which must be reviewed on a monthly basis and source documented) or agree to use, and be able to comply with, effective contraception without interruption, 28 days prior to starting investigational product, during the study therapy (including dose interruptions), and for 12 weeks (approximately five times the mean terminal half-life of luspatercept based on multiple-dose Pharmacokinetic PK) data) after discontinuation of study therapy.

    8. Male subjects must:

  • Practice true abstinence 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 five times the mean terminal half-life of luspatercept based on multiple-dose PK data) following investigational product 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. A diagnosis of Hemoglobin S/β-thalassemia or alpha (α)-thalassemia (eg, Hemoglobin H); β-thalassemia combined with α-thalassemia is allowed.
  5. Evidence of active hepatitis C (HCV) infection, or active infectious hepatitis B, or known positive human immunodeficiency virus (HIV).
  6. Deep Vein Thrombosis (DVT) or stroke requiring medical intervention ≤ 24 weeks prior to randomization.
  7. Chronic anticoagulant therapy ≤ 28 days prior to randomization, Low Molecular Weight (LMW) heparin for Sinus venous Thrombosis (SVT) and chronic aspirin are allowed.
  8. Platelet count > 1000 x 109/L
  9. Insulin-dependent diabetes, ie, chronic treatment with insulin.
  10. Treatment with another investigational drug or device ≤ 28 days prior to randomization.
  11. Prior exposure to sotatercept (ACE-011) or luspatercept (ACE-536).
  12. Use of an erythropoiesis-stimulating agent (ESA) ≤ 24 weeks prior to randomization.
  13. Iron chelation therapy, if initiated ≤ 24 weeks prior to randomization (allowed if initiated > 24 weeks before or during treatment).
  14. Hydroxyurea treatment ≤ 24 weeks prior to randomization.
  15. Pregnant or lactating females.
  16. Uncontrolled hypertension. Controlled hypertension for this protocol is considered ≤ Grade 1 according to NCI Common Terminology Criteria for Adverse Events (CTCAE) version 4.0 (current active minor version).
  17. Major organ damage, including:

    • Liver disease with alanine aminotransferase (ALT) > 3 x the upper limit of normal (ULN) or histopathological evidence of liver cirrhosis/fibrosis on liver biopsy;
    • 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 within 6 months of randomization.
    • Lung disease, including pulmonary fibrosis or pulmonary hypertension which are clinically significant.
    • Creatinine clearance < 60 mL/min (per Cockroff-Gault method).
  18. Proteinuria ≥ Grade 3 according to NCI CTCAE version 4.0 (current active minor version).
  19. Adrenal insufficiency.
  20. Major surgery ≤ 12 weeks prior to randomization (subjects must have completely recovered from any previous surgery prior to randomization).
  21. History of severe allergic or anaphylactic reactions or hypersensitivity to recombinant proteins or excipients in the investigational product (see Investigator Brochure).
  22. Cytotoxic agents, immunosuppressants ≤ 28 days prior to randomization.
  Contacts and Locations
Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the Contacts provided below. For general information, see Learn About Clinical Studies.

Please refer to this study by its ClinicalTrials.gov identifier: NCT02604433

Contacts
Contact: Associate Director Clinical Trial Disclosure 1-888-260-1599 clinicaltrialdisclosure@celgene.com

  Show 88 Study Locations
Sponsors and Collaborators
Celgene Corporation
Acceleron Pharma, Inc.
Investigators
Study Director: Abderrahmane Laadem, MD Celgene Corporation
  More Information

Responsible Party: Celgene Corporation
ClinicalTrials.gov Identifier: NCT02604433     History of Changes
Other Study ID Numbers: ACE-536-B-THAL-001
Study First Received: October 21, 2015
Last Updated: December 28, 2016

Keywords provided by Celgene Corporation:
ACE-536
Safety
Efficacy
Placebo
Red Blood Cell Transfusions
Beta -Thalassemia

Additional relevant MeSH terms:
Thalassemia
beta-Thalassemia
Anemia, Hemolytic, Congenital
Anemia, Hemolytic
Anemia
Hematologic Diseases
Hemoglobinopathies
Genetic Diseases, Inborn

ClinicalTrials.gov processed this record on April 24, 2017