Trial Review

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Trial details imported from ClinicalTrials.gov

For full trial details, please see the original record at https://clinicaltrials.gov/study/NCT02604433




Registration number
NCT02604433
Ethics application status
Date submitted
21/10/2015
Date registered
13/11/2015
Date last updated
18/04/2023

Titles & IDs
Public title
An Efficacy and Safety Study of Luspatercept (ACE-536) Versus Placebo in Adults Who Require Regular Red Blood Cell Transfusions Due to Beta (ß) Thalassemia
Scientific 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
Secondary ID [1] 0 0
ACE-536-B-THAL-001
Universal Trial Number (UTN)
Trial acronym
BELIEVE
Linked study record

Health condition
Health condition(s) or problem(s) studied:
Erythrocyte Transfusion 0 0
Beta-Thalassemia 0 0
Condition category
Condition code
Blood 0 0 0 0
Haematological diseases
Blood 0 0 0 0
Other blood disorders
Human Genetics and Inherited Disorders 0 0 0 0
Other human genetics and inherited disorders

Intervention/exposure
Study type
Interventional
Description of intervention(s) / exposure
Treatment: Drugs - Luspatercept
Other interventions - Placebo

Experimental: Luspatercept (ACE-536) plus Best Supportive Care (BSC) - Luspatercept, subcutaneous(ly) (SC) once every 21 days

Placebo comparator: Placebo plus Best Supportive Care (BSC) - normal saline solution subcutaneous(ly) (SC) once every 21 days


Treatment: Drugs: Luspatercept
Subjects will start with luspatercept at 1 mg/kg dose level.

Other interventions: Placebo
Placebo, Subcutaneous, every 21 days.
Intervention code [1] 0 0
Treatment: Drugs
Intervention code [2] 0 0
Other interventions
Comparator / control treatment
Control group

Outcomes
Primary outcome [1] 0 0
Percentage of Participants Who Achieved Erythroid Response - Week 13 to Week 24
Timepoint [1] 0 0
Baseline: Day -83 to Day 1; Treatment: Weeks 13 to Week 24
Secondary outcome [1] 0 0
Percentage Of Participants Who Achieved = 33% Reduction From Baseline in Transfusion Burden - Week 37 to Week 48
Timepoint [1] 0 0
Baseline: Day -83 to Day 1; Treatment: Weeks 37 to Week 48
Secondary outcome [2] 0 0
Percentage Of Participants Who Achieve = 50% Reduction From Baseline in Transfusion Burden - Week 13 to Week 24
Timepoint [2] 0 0
Baseline: Day -83 to Day 1; Treatment: Weeks 13 to Week 24
Secondary outcome [3] 0 0
Percentage Of Participants Who Achieve = 50% Reduction From Baseline in Transfusion Burden - Week 37 to Week 48
Timepoint [3] 0 0
Baseline: Day -83 to Day 1; Treatment: Week 37 to Week 48
Secondary outcome [4] 0 0
Mean Change From Baseline in Transfusion Burden - Week 13 to Week 24
Timepoint [4] 0 0
Baseline: Day -83 to Day 1; Treatment: Weeks 13 to Week 24
Secondary outcome [5] 0 0
Mean Change From Baseline In Liver Iron Concentration (LIC) At Week 48
Timepoint [5] 0 0
Baseline: Week -12 to Day -1; Treatment: Week 48
Secondary outcome [6] 0 0
Mean Change From Baseline In Mean Daily Dose Of Iron Chelation Therapies (ICT) At Week 48
Timepoint [6] 0 0
Baseline: Day -83 to Day 1; Treatment: Week 37 to Week 48
Secondary outcome [7] 0 0
Mean Change From Baseline In Mean Serum Ferritin At Week 48
Timepoint [7] 0 0
Baseline: Day -83 to Day 1; Treatment: Week 37 to Week 48
Secondary outcome [8] 0 0
Mean Change From Baseline In Total Hip And Lumbar Spine Bone Mineral Density (BMD) At Week 48
Timepoint [8] 0 0
Baseline: Day 1; Treatment: Week 48
Secondary outcome [9] 0 0
Mean Change From Baseline In Myocardial Iron At Week 48
Timepoint [9] 0 0
Baseline: Day 1; Treatment: Week 48
Secondary outcome [10] 0 0
Mean Change From Baseline in the Transfusion-dependent Quality of Life (TranQol) Questionnaire At Week 24
Timepoint [10] 0 0
Baseline: 4 weeks prior to Day 1; Treatment: Week 24
Secondary outcome [11] 0 0
Mean Change From Baseline in the 36-item Short Form Health Survey (SF-36) Questionnaire At Weeks 24
Timepoint [11] 0 0
Baseline: 4 weeks prior to Day 1; Treatment: Weeks 24
Secondary outcome [12] 0 0
Number of Participants Who Utilized Healthcare Resources During Study
Timepoint [12] 0 0
From informed consent signing (up to 12 weeks before start of treatment) to end of treatment (up to approximately 227 weeks)
Secondary outcome [13] 0 0
Number of Days Spent in Higher Care Hospital Units
Timepoint [13] 0 0
From informed consent signing (up to 12 weeks before start of treatment) to end of treatment (up to approximately 227 weeks)
Secondary outcome [14] 0 0
Percentage Of Participants Who Were Transfusion Independent For = 8 Weeks During Treatment
Timepoint [14] 0 0
From first dose through 3 weeks post last dose (up to approximately 218 weeks)
Secondary outcome [15] 0 0
Duration of Reduction in Transfusion Burden
Timepoint [15] 0 0
From first dose to end of study treatment (up to approximately 215 weeks)
Secondary outcome [16] 0 0
Longest Duration of Transfusion Independence
Timepoint [16] 0 0
From first dose through 3 weeks post last dose (up to approximately 218 weeks)
Secondary outcome [17] 0 0
Time to Erythroid Response
Timepoint [17] 0 0
From first dose to 48 weeks following first dose
Secondary outcome [18] 0 0
Post-Baseline Transfusion Event Frequency
Timepoint [18] 0 0
From first dose through 3 weeks post last dose (up to approximately 218 weeks)
Secondary outcome [19] 0 0
Pharmacokinetic (PK) Parameters: Bayesian Estimate of Apparent Clearance (CL/F)
Timepoint [19] 0 0
Blood serum samples taken pre-dose and on Days 1, 22, 64, 85, 106, 127, 169, 211, 253, 295, 337
Secondary outcome [20] 0 0
Pharmacokinetic (PK) Parameters: Bayesian Estimate of Apparent Volume of Distribution of the Central Compartment (V1/F)
Timepoint [20] 0 0
Blood serum samples taken pre-dose and on Days 1, 22, 64, 85, 106, 127, 169, 211, 253, 295, 337
Secondary outcome [21] 0 0
Pharmacokinetic (PK) Parameters: Bayesian Estimate of Elimination Half-life (t1/2)
Timepoint [21] 0 0
Blood serum samples taken pre-dose and on Days 1, 22, 64, 85, 106, 127, 169, 211, 253, 295, 337
Secondary outcome [22] 0 0
Pharmacokinetic (PK) Parameters: Bayesian Estimate of Time to Reach Maximum Concentration (Tmax)
Timepoint [22] 0 0
Blood serum samples taken pre-dose and on Days 1, 22, 64, 85, 106, 127, 169, 211, 253, 295, 337
Secondary outcome [23] 0 0
Pharmacokinetic (PK) Parameters: Bayesian Estimate of Maximum Concentration for the Starting Dose (Cmax)
Timepoint [23] 0 0
Blood serum samples taken pre-dose and on Days 1, 22, 64, 85, 106, 127, 169, 211, 253, 295, 337
Secondary outcome [24] 0 0
Pharmacokinetic (PK) Parameters: Bayesian Estimate of Maximum Concentration at Steady State for the Starting Dose (Cmax,ss)
Timepoint [24] 0 0
Blood serum samples taken pre-dose and on Days 1, 22, 64, 85, 106, 127, 169, 211, 253, 295, 337
Secondary outcome [25] 0 0
Pharmacokinetic (PK) Parameters: Bayesian Estimate of Area Under the Concentration-Time Curve at Steady State for the Starting Dose (AUCss)
Timepoint [25] 0 0
Blood serum samples taken pre-dose and on Days 1, 22, 64, 85, 106, 127, 169, 211, 253, 295, 337
Secondary outcome [26] 0 0
Participants With Treatment-Emergent Adverse Events (TEAE)
Timepoint [26] 0 0
From first dose to 90 days following last dose (up to approximately 52 months)
Secondary outcome [27] 0 0
Participants With Pre-Existing and/or Treatment-Emergent Antidrug Antibodies (ADA)
Timepoint [27] 0 0
Timeframe: pre-dose, Day 1, Days 22, 64, 106, 148, 232, 316

Eligibility
Key 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 ß-thalassemia or Hemoglobin E/ß-thalassemia. (ß-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.
Minimum age
18 Years
Maximum age
No limit
Sex
Both males and females
Can healthy volunteers participate?
No
Key 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/ß-thalassemia or alpha (a)-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.

Study design
Purpose of the study
Treatment
Allocation to intervention
Randomised controlled trial
Procedure for enrolling a subject and allocating the treatment (allocation concealment procedures)
Methods used to generate the sequence in which subjects will be randomised (sequence generation)
Masking / blinding
Blinded (masking used)
Who is / are masked / blinded?
The people receiving the treatment/s
The people administering the treatment/s
The people assessing the outcomes
The people analysing the results/data
Intervention assignment
Parallel
Other design features
Phase
Phase 3
Type of endpoint/s
Statistical methods / analysis

Recruitment
Recruitment status
Completed
Data analysis
Reason for early stopping/withdrawal
Other reasons
Date of first participant enrolment
Anticipated
Actual
2/05/2016
Date of last participant enrolment
Anticipated
Actual
Date of last data collection
Anticipated
Actual
5/01/2021
Sample size
Target
Accrual to date
Final
336
Recruitment in Australia
Recruitment state(s)
NSW,QLD,SA,VIC,WA
Recruitment hospital [1] 0 0
Prince of Wales Hospital - Randwick
Recruitment hospital [2] 0 0
Mater Hospital Brisbane - South Brisbane
Recruitment hospital [3] 0 0
Royal Adelaide Hospital Institute of Medical and Veterinary Science - Adelaide
Recruitment hospital [4] 0 0
Monash Medical Centre - Clayton
Recruitment hospital [5] 0 0
Sir Charles Gairdner Hospital - Nedlands
Recruitment hospital [6] 0 0
Royal Prince Alfred Hospital - Camperdown
Recruitment postcode(s) [1] 0 0
2031 - Randwick
Recruitment postcode(s) [2] 0 0
4101 - South Brisbane
Recruitment postcode(s) [3] 0 0
5000 - Adelaide
Recruitment postcode(s) [4] 0 0
3168 - Clayton
Recruitment postcode(s) [5] 0 0
6009 - Nedlands
Recruitment postcode(s) [6] 0 0
2050 - Camperdown
Recruitment outside Australia
Country [1] 0 0
United States of America
State/province [1] 0 0
California
Country [2] 0 0
United States of America
State/province [2] 0 0
Illinois
Country [3] 0 0
United States of America
State/province [3] 0 0
Massachusetts
Country [4] 0 0
United States of America
State/province [4] 0 0
New York
Country [5] 0 0
United States of America
State/province [5] 0 0
Pennsylvania
Country [6] 0 0
Bulgaria
State/province [6] 0 0
Plovdiv
Country [7] 0 0
Bulgaria
State/province [7] 0 0
Sofia
Country [8] 0 0
Bulgaria
State/province [8] 0 0
Varna
Country [9] 0 0
Canada
State/province [9] 0 0
Ontario
Country [10] 0 0
France
State/province [10] 0 0
Creteil
Country [11] 0 0
France
State/province [11] 0 0
Lille
Country [12] 0 0
France
State/province [12] 0 0
Marseille Cedex 9
Country [13] 0 0
France
State/province [13] 0 0
Paris
Country [14] 0 0
Greece
State/province [14] 0 0
Ampelokipi - Athens
Country [15] 0 0
Greece
State/province [15] 0 0
Athens
Country [16] 0 0
Greece
State/province [16] 0 0
Rio Patras
Country [17] 0 0
Greece
State/province [17] 0 0
Thessaloniki
Country [18] 0 0
Israel
State/province [18] 0 0
Beer Sheva
Country [19] 0 0
Israel
State/province [19] 0 0
Haifa
Country [20] 0 0
Israel
State/province [20] 0 0
Haïfa (Afula)
Country [21] 0 0
Israel
State/province [21] 0 0
Jerusalem
Country [22] 0 0
Israel
State/province [22] 0 0
Nahariya
Country [23] 0 0
Israel
State/province [23] 0 0
Petah Tikva
Country [24] 0 0
Italy
State/province [24] 0 0
Brindisi
Country [25] 0 0
Italy
State/province [25] 0 0
Cagliari
Country [26] 0 0
Italy
State/province [26] 0 0
Ferrara
Country [27] 0 0
Italy
State/province [27] 0 0
Genoa
Country [28] 0 0
Italy
State/province [28] 0 0
Milan
Country [29] 0 0
Italy
State/province [29] 0 0
Naples
Country [30] 0 0
Italy
State/province [30] 0 0
Napoli
Country [31] 0 0
Italy
State/province [31] 0 0
Orbassano
Country [32] 0 0
Italy
State/province [32] 0 0
Palermo
Country [33] 0 0
Italy
State/province [33] 0 0
Verona
Country [34] 0 0
Lebanon
State/province [34] 0 0
Beirut
Country [35] 0 0
Malaysia
State/province [35] 0 0
Johor
Country [36] 0 0
Malaysia
State/province [36] 0 0
Kedah
Country [37] 0 0
Malaysia
State/province [37] 0 0
Perak
Country [38] 0 0
Malaysia
State/province [38] 0 0
Sabah
Country [39] 0 0
Malaysia
State/province [39] 0 0
Sarawak
Country [40] 0 0
Malaysia
State/province [40] 0 0
Wilayah Persekutuan Kuala Lumpur
Country [41] 0 0
Malaysia
State/province [41] 0 0
Georgetown
Country [42] 0 0
Taiwan
State/province [42] 0 0
Changhua City
Country [43] 0 0
Taiwan
State/province [43] 0 0
Kaohsiung
Country [44] 0 0
Taiwan
State/province [44] 0 0
Taichung
Country [45] 0 0
Taiwan
State/province [45] 0 0
Taipei, Zhongzheng Dist.
Country [46] 0 0
Thailand
State/province [46] 0 0
Bangkok
Country [47] 0 0
Thailand
State/province [47] 0 0
Chiang Mai
Country [48] 0 0
Tunisia
State/province [48] 0 0
Sousse
Country [49] 0 0
Tunisia
State/province [49] 0 0
Tunis
Country [50] 0 0
Turkey
State/province [50] 0 0
Adana
Country [51] 0 0
Turkey
State/province [51] 0 0
Ankara
Country [52] 0 0
Turkey
State/province [52] 0 0
Antalya
Country [53] 0 0
Turkey
State/province [53] 0 0
Istanbul
Country [54] 0 0
Turkey
State/province [54] 0 0
Izmir
Country [55] 0 0
Turkey
State/province [55] 0 0
Mersin
Country [56] 0 0
United Kingdom
State/province [56] 0 0
Leeds
Country [57] 0 0
United Kingdom
State/province [57] 0 0
London Bloomsbury
Country [58] 0 0
United Kingdom
State/province [58] 0 0
London
Country [59] 0 0
United Kingdom
State/province [59] 0 0
Manchester

Funding & Sponsors
Primary sponsor type
Commercial sector/industry
Name
Celgene
Address
Country
Other collaborator category [1] 0 0
Commercial sector/industry
Name [1] 0 0
Acceleron Pharma, Inc., a wholly-owned subsidiary of Merck & Co., Inc., Rahway, NJ USA
Address [1] 0 0
Country [1] 0 0

Ethics approval
Ethics application status

Summary
Brief summary
Trial website
Trial related presentations / publications
Public notes

Contacts
Principal investigator
Name 0 0
Bristol-Myers Squibb
Address 0 0
Bristol-Myers Squibb
Country 0 0
Phone 0 0
Fax 0 0
Email 0 0
Contact person for public queries
Name 0 0
Address 0 0
Country 0 0
Phone 0 0
Fax 0 0
Email 0 0
Contact person for scientific queries

No information has been provided regarding IPD availability


What supporting documents are/will be available?




Results publications and other study-related documents


Results are available at https://clinicaltrials.gov/study/NCT02604433