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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 ongoing, but not recruiting participants.
Sponsor:
ClinicalTrials.gov Identifier:
NCT02604433
First Posted: November 13, 2015
Last Update Posted: November 14, 2017
The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Read our disclaimer for details.
Collaborator:
Acceleron Pharma, Inc.
Information provided by (Responsible Party):
Celgene
  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: Quadruple (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 (β)-Thalassemia

Resource links provided by NLM:


Further study details as provided by Celgene:

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 maximum 9 years ]
    Number of participants with adverse events


Enrollment: 335
Actual Study Start Date: May 2, 2016
Estimated Study Completion Date: June 7, 2025
Estimated Primary Completion Date: November 24, 2017 (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

Information from the National Library of Medicine

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, Learn About Clinical Studies.


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. (β-thalassemia with mutation and/or multiplication of alpha globin is allowed).
  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.

    * Sites who prescribe transfusions and have the transfusion records only in volumes should use for conversion of volume to units the below criteria, in order to obtain number of units within the last 24 weeks to assess the eligibility: 1 unit in this protocol refers to a quantity of packed RBCs approximately 200-350 mL. (i) sites who use transfusion bags within this range, or ≥ 350 mL, the conversion in units should be done by dividing the volume transfused to the patient by 350 mL, (ii) sites who use transfusion bags < 200 mL, the conversion in units should be done by dividing the volume transfused to the patient by 200 mL.

  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:

    1. 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.
    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 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.

      • True abstinence is acceptable when this is in line with the preferred and usual lifestyle of the subject. [Periodic abstinence (eg, calendar, ovulation, symptothermal, post-ovulation methods) and withdrawal are not acceptable methods of contraception.] *** Agreement to use highly effective methods of contraception that alone or in combination result in a failure rate of a Pearl index of less than 1% per year when used consistently and correctly throughout the course of the study.

    Such methods include: Combined (estrogen and progesterone/progestin containing) hormonal contraception: Oral; Intravaginal; Transdermal; Progestogen/progestin only hormonal contraception associated with inhibition of ovulation: Oral; Injectable hormonal contraception; Implantable hormonal contraception; Placement of an intrauterine device (IUD); Placement of an intrauterine hormone-releasing system (IUS); Bilateral tubal occlusion; Vasectomized partner; Sexual Abstinence.

  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);
  5. Evidence of 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 HBsAg and/or HBVDNA-positive,, or known positive human immunodeficiency virus (HIV).

    Note: Subjects receiving antiviral therapies should have 2 negative HCVRNA tests 3 months apart.(ie, one test at the end of the antiviral therapy and a second test 3 months following the first test).

  6. Deep Vein Thrombosis (DVT) or stroke requiring medical intervention ≤ 24 weeks prior to randomization.
  7. Use of chronic anticoagulant therapy is excluded, unless the treatment stopped at least 28 days prior to randomization. Anticoagulant therapies used for prophylaxis for surgery or high risk procedures as well as low Molecular Weight (LMW) heparin for superficial venous thrombosis and chronic aspirin are allowed.
  8. Platelet count > 1000 x 109/L
  9. Poorly controlled diabetes mellitus within 24 weeks prior to randomization as defined by short term (eg, hyperosmolar or ketoacidotic crisis) and/or history of diabetic cardiovascular complications (eg, stroke or myocardial infarction).
  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:

    1. Liver disease with alanine aminotransferase (ALT) > 3 x the upper limit of normal (ULN) or history of evidence of cirrhosis;
    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 within 6 months of randomization.
    3. Lung disease, including pulmonary fibrosis or pulmonary hypertension which are clinically significant ie, ≥ Grade 3 NCI CTCAE version 4.0 (current active minor version).
    4. Creatinine clearance < 60 mL/min (per Cockroft-Gault formula).
  18. Proteinuria ≥ Grade 3 according to NCI CTCAE version 4.0 (current active minor version).
  19. Chronic systemic glucocorticoids ≤ 12 weeks prior to randomization (physiologic replacement therapy for adrenal insufficiency is allowed). Single day glucocorticoid treatment (eg, for prevention or treatment of transfusion reactions, is allowed).
  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 (ie, antithymocite globulin (ATG) or cyclosporine)
  23. History of malignancy with the exception of:

    1. Curatively resected nonmelanoma skin cancer.
    2. Curatively treated cervical carcinoma in situ.
    3. Other solid tumor with no known active disease in the opinion of the investigator.
  Contacts and Locations
Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT02604433


  Hide Study Locations
Locations
United States, California
Children's Hospital of Los Angeles
Los Angeles, California, United States, 90027
Children's Hospital and Research Center at Oakland
Oakland, California, United States, 94609
United States, Illinois
Ann and Robert H Lurie Childrens Hospital of Chicago
Chicago, Illinois, United States, 60611
United States, Massachusetts
Boston Children's Hospital
Boston, Massachusetts, United States, 02115
United States, New York
Weill Cornell Medical College
New York, New York, United States, 10065
United States, Pennsylvania
Hospital of the University of Pennsylvania
Philadelphia, Pennsylvania, United States, 19104
Australia, New South Wales
Prince of Wales Hospital
Randwick, New South Wales, Australia, 2031
Australia, Queensland
Mater Adult Hospital
South Brisbane, Queensland, Australia, 4101
Australia, South Australia
Royal Adelaide Hospital Institute of Medical and Veterinary Science
Adelaide, South Australia, Australia, 5000
Australia, Victoria
Monash Medical Centre
Clayton, Victoria, Australia, 3168
Australia, Western Australia
Sir Charles Gairdner Hospital
Nedlands, Western Australia, Australia, 6009
Australia
Royal Prince Alfred Hospital
Camperdown, Australia, 2050
Bulgaria
University Mulitiprofile Hospital for Active Treatment Sveti Georgi EAD
Plovdiv, Bulgaria, 4002
Specialized Hospital for Active Treatment of Haematological Diseases - Sofia
Sofia, Bulgaria, 1756
Multiprofile Hospital for Active Treatment Sveta Marina EAD
Varna, Bulgaria, 9010
Canada, Ontario
University Health Network
Toronto, Ontario, Canada, M5G 2C4
France
Hopital Henri Mondor
Creteil, France, 94010
GH de Institut Catholique St. VincentHématologie
Lille, France, 59000
Hôpitaux de La Timone
Marseille Cedex 9, France, 13385
Hospital of Necker
Paris, France, 75015
Greece
Laiko General Hospital
Ampelokipi - Athens, Greece, 11526
Childrens' Hospital of Athens Aghoa Sofia
Athens, Greece, 115 27
General Hospital Georgios Gennimatas of Athens
Athens, Greece, 11527
University General Hospital of Patras
Rio Patras, Greece, 26500
Hippokration Hospital
Thessaloniki, Greece, 54642
Israel
Soroka University Medical Centre
Beer Sheva, Israel, 84101
Rambam Health Corporation
Haifa, Israel, 31096
HaEmek Medical Center
Haïfa (Afula), Israel, 18101
Shaare Zedek Medical Center
Jerusalem, Israel, 91031
Hadassah Medical Center
Jerusalem, Israel, 91120
Galilee Medical Center
Nahariya, Israel, 22100
Rabin Medical Center
Petah Tikva, Israel, 49100
Italy
Presidio Ospedaliero Antonio Perrino
Brindisi, Italy, 72100
Universita degli Studi di Cagliari - ASL8
Cagliari, Italy, 09121
Azienda Ospedaliera Universitaria Di Ferrara Arcispedale Sanna
Ferrara, Italy, 44124
Ospedale Galliera
Genoa, Italy, 16128
Fondazione Ca Granda IRCCS Ospedale Maggiore
Milan, Italy, 20122
Seconda Universita Degli Studi Di Napoli
Naples, Italy, 80131
AORN A Cardarelli
Napoli, Italy, 80131
Azienda Ospedaliero Universitaria S. Luigi Gonzaga
Orbassano, Italy, 10043
Azienda Ospedaliera Ospedali Riuniti Villa Sofia-Cervello
Palermo, Italy, 90146
Azienda Ospedaliera Universitaria Integrata Di Verona
Verona, Italy, 37134
Lebanon
Chronic Care Center
Beirut, Lebanon
Malaysia
Hospital Sultanah Aminah
Johor Bahru, Johor, Malaysia, 80100
Hospital Sultanah Bahiyah
Alor Setar, Kedah, Malaysia, 5460
Hospital Raja Permaisuri Bainun
Ipoh, Perak, Malaysia, 30990
Queen Elizabeth Hospital
Kota Kinabalu, Sabah, Malaysia, 88586
Hospital Umum Sarawak
Kuching, Sarawak, Malaysia, 93586
University Malaya Medical Centre
Kuala Lumpur, Wilayah Persekutuan Kuala Lumpur, Malaysia, 59100
Hospital Pulau Pinang c/o Penang Medical College
Georgetown, Malaysia, 10990
Taiwan
Changhua Christian Hospital
Changhua City, Taiwan, 500
Kaohsiung Medical University Hospital
Kaohsiung, Taiwan, 807
China Medical University Hospital
Taichung, Taiwan, 40447
National Taiwan University Hospital
Taipei, Zhongzheng Dist., Taiwan, 100
Thailand
Chulalongkorn University
Bangkok, Thailand, 10330
Siriraj Hospital Mahidol University
Bangkok, Thailand, 10700
Maharaj Nakorn Chiang Mai Chiang Mai University
Chiang Mai, Thailand, 50200
Tunisia
University Hospital Farhat Hached
Sousse, Tunisia, 4031
Bone Marrow Transplant Center
Tunis, Tunisia, 1006
Aziza Othmana Hospital
Tunis, Tunisia, 1008
Military Hospital of Tunis
Tunis, Tunisia, 1089
Turkey
Acibadem Adana Hospital
Adana, Turkey, 01130
Cukurova University Medical Faculty Balcali Hospital
Adana, Turkey, 01330
Hacettepe Universitesi
Ankara, Turkey, 01660
Antalya Egitim Arastirma
Antalya, Turkey, 07100
Istanbul Universitesi Istanbul Tip Fakultesi Hastanesi
Istanbul, Turkey, 34093
Ege Universitesi Tip Fakultesi Hastanesi
Izmir, Turkey, 35100
Mersin University Medical Faculty
Mersin, Turkey, 33343
United Kingdom
St James University Hospital
Leeds, United Kingdom, LS9 7TF
University College Hospital Trust
London Bloomsbury, United Kingdom, WC1E 6AU
Barts Health NHS Trust
London, United Kingdom, E1 1BB
Whittington Hospital
London, United Kingdom, N19 5NF
Manchester Royal Infirmary
Manchester, United Kingdom, M13 9WL
Sponsors and Collaborators
Celgene
Acceleron Pharma, Inc.
Investigators
Study Director: Abderrahmane Laadem, MD Celgene Corporation
  More Information

Responsible Party: Celgene
ClinicalTrials.gov Identifier: NCT02604433     History of Changes
Other Study ID Numbers: ACE-536-B-THAL-001
First Submitted: October 21, 2015
First Posted: November 13, 2015
Last Update Posted: November 14, 2017
Last Verified: November 2017

Keywords provided by Celgene:
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