NCT02604433 · CITED IN SOURCE DOCUMENTS

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

An NCI or FDA source cites this study. A citation does not establish that it applies to an individual diagnosis.

Phase: PHASE3
Status at capture: COMPLETED
Registry last update: 2023-04-18

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 following periods: * Historical Period, * Screening/Run-in Period, * Double-blind Treatment Period (48 weeks), * Double-blind Long-term Treatment Period, (at the investigator's discretion an additional 48 weeks), * Open-Label Phase post unblinding and upon Data Monitoring Committee positive recommendation * Post-treatment Follow-up Period

Open the original ClinicalTrials.gov record → · Download preserved record

What did the study report?

Outcomes, safety and baseline populations are separate source sections. Quality-of-life measures appear under their original outcome titles.

flow

Participant flow

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baseline

Baseline characteristics

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outcome · POSTED

Percentage of Participants Who Achieved Erythroid Response - Week 13 to Week 24

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outcome · POSTED

Percentage Of Participants Who Achieved ≥ 33% Reduction From Baseline in Transfusion Burden - Week 37 to Week 48

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outcome · POSTED

Percentage Of Participants Who Achieve ≥ 50% Reduction From Baseline in Transfusion Burden - Week 13 to Week 24

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outcome · POSTED

Percentage Of Participants Who Achieve ≥ 50% Reduction From Baseline in Transfusion Burden - Week 37 to Week 48

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outcome · POSTED

Mean Change From Baseline in Transfusion Burden - Week 13 to Week 24

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outcome · POSTED

Mean Change From Baseline In Liver Iron Concentration (LIC) At Week 48

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outcome · POSTED

Mean Change From Baseline In Mean Daily Dose Of Iron Chelation Therapies (ICT) At Week 48

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outcome · POSTED

Mean Change From Baseline In Mean Serum Ferritin At Week 48

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outcome · POSTED

Mean Change From Baseline In Total Hip And Lumbar Spine Bone Mineral Density (BMD) At Week 48

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outcome · POSTED

Mean Change From Baseline In Myocardial Iron At Week 48

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outcome · POSTED

Mean Change From Baseline in the Transfusion-dependent Quality of Life (TranQol) Questionnaire At Week 24

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outcome · POSTED

Mean Change From Baseline in the 36-item Short Form Health Survey (SF-36) Questionnaire At Weeks 24

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outcome · POSTED

Number of Participants Who Utilized Healthcare Resources During Study

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outcome · POSTED

Number of Days Spent in Higher Care Hospital Units

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outcome · POSTED

Percentage Of Participants Who Were Transfusion Independent For ≥ 8 Weeks During Treatment

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outcome · POSTED

Duration of Reduction in Transfusion Burden

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outcome · POSTED

Longest Duration of Transfusion Independence

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outcome · POSTED

Time to Erythroid Response

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outcome · POSTED

Post-Baseline Transfusion Event Frequency

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outcome · POSTED

Pharmacokinetic (PK) Parameters: Bayesian Estimate of Apparent Clearance (CL/F)

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outcome · POSTED

Pharmacokinetic (PK) Parameters: Bayesian Estimate of Apparent Volume of Distribution of the Central Compartment (V1/F)

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outcome · POSTED

Pharmacokinetic (PK) Parameters: Bayesian Estimate of Elimination Half-life (t1/2)

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outcome · POSTED

Pharmacokinetic (PK) Parameters: Bayesian Estimate of Time to Reach Maximum Concentration (Tmax)

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outcome · POSTED

Pharmacokinetic (PK) Parameters: Bayesian Estimate of Maximum Concentration for the Starting Dose (Cmax)

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outcome · POSTED

Pharmacokinetic (PK) Parameters: Bayesian Estimate of Maximum Concentration at Steady State for the Starting Dose (Cmax,ss)

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outcome · POSTED

Pharmacokinetic (PK) Parameters: Bayesian Estimate of Area Under the Concentration-Time Curve at Steady State for the Starting Dose (AUCss)

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outcome · POSTED

Participants With Treatment-Emergent Adverse Events (TEAE)

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outcome · POSTED

Participants With Pre-Existing and/or Treatment-Emergent Antidrug Antibodies (ADA)

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adverse events

Adverse events

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more info

Limitations, agreements, and source contact

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Who could take part

eligibility 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.
healthy Volunteers: false
minimum Age: 18 Years
sex: ALL
std Ages: ADULT
OLDER_ADULT

Treatment arms and interventions

arm Groups

description
Luspatercept, subcutaneous(ly) (SC) once every 21 days
intervention Names
Drug: Luspatercept
label
Luspatercept (ACE-536) plus Best Supportive Care (BSC)
type
EXPERIMENTAL
description
normal saline solution subcutaneous(ly) (SC) once every 21 days
intervention Names
Other: Placebo
label
Placebo plus Best Supportive Care (BSC)
type
PLACEBO_COMPARATOR

interventions

arm Group Labels
Luspatercept (ACE-536) plus Best Supportive Care (BSC)
description
Subjects will start with luspatercept at 1 mg/kg dose level.
name
Luspatercept
other Names
ACE-536
type
DRUG
arm Group Labels
Placebo plus Best Supportive Care (BSC)
description
Placebo, Subcutaneous, every 21 days.
name
Placebo
type
OTHER

Study design

allocation

RANDOMIZED

intervention Model

PARALLEL

masking Info

masking: QUADRUPLE
who Masked: PARTICIPANT
CARE_PROVIDER
INVESTIGATOR
OUTCOMES_ASSESSOR

primary Purpose

TREATMENT

Enrollment

count: 336
type: ACTUAL

Registered outcome plans (not posted results)

primary Outcomes

description
Erythroid Response was defined as red blood cell (RBC) transfusion burden reduction from baseline ≥ 33% with a reduction of at least 2 units during Week 13 - 24 compared to the 12-week interval on or prior to Dose 1 Day 1.
measure
Percentage of Participants Who Achieved Erythroid Response - Week 13 to Week 24
time Frame
Baseline: Day -83 to Day 1; Treatment: Weeks 13 to Week 24

secondary Outcomes

description
Percentage of participants who achieved a red blood cell (RBC) transfusion burden reduction from baseline ≥ 33% with a reduction of at least 2 units during Weeks 37 - 48 compared to the 12-week interval on or prior to Dose 1 Day 1.
measure
Percentage Of Participants Who Achieved ≥ 33% Reduction From Baseline in Transfusion Burden - Week 37 to Week 48
time Frame
Baseline: Day -83 to Day 1; Treatment: Weeks 37 to Week 48
description
Percentage of participants who achieved a red blood cell (RBC) transfusion burden reduction from baseline ≥ 50% with a reduction of at least 2 units during Weeks 13 - 24 compared to the 12-week interval on or prior to Dose 1 Day 1.
measure
Percentage Of Participants Who Achieve ≥ 50% Reduction From Baseline in Transfusion Burden - Week 13 to Week 24
time Frame
Baseline: Day -83 to Day 1; Treatment: Weeks 13 to Week 24
description
Percentage of participants who achieved a red blood cell (RBC) transfusion burden reduction from baseline ≥ 50% with a reduction of at least 2 units during Week 37 to Week 48 compared to the 12-week interval on or prior to Dose 1 Day 1.
measure
Percentage Of Participants Who Achieve ≥ 50% Reduction From Baseline in Transfusion Burden - Week 37 to Week 48
time Frame
Baseline: Day -83 to Day 1; Treatment: Week 37 to Week 48
description
Baseline was defined as the total number of Red Blood Cells (RBC) units transfused during the 12-week interval on or prior to Dose 1 Day 1. This is compared to the total number of RBC units transfused during the 12-week interval from treatment weeks 13-24.
measure
Mean Change From Baseline in Transfusion Burden - Week 13 to Week 24
time Frame
Baseline: Day -83 to Day 1; Treatment: Weeks 13 to Week 24
description
Baseline was defined as the last value on or before the first dose of study drug was administered; if multiple values were present for the same date, the average of these values was used. If a participant had 1 postbaseline assessment, it was used as the Week 48 value. If a participant had multiple postbaseline assessments, the last one was used as the Week 48 value. The value of LIC was collected by magnetic resonance imaging. Participants with a LIC value \> 43 mg/g were not included in the analysis.
measure
Mean Change From Baseline In Liver Iron Concentration (LIC) At Week 48
time Frame
Baseline: Week -12 to Day -1; Treatment: Week 48
description
Three different types of Iron Chelation Therapy (ICT) were analyzed: 1. Deferasirox 2. Deferiprone 3. Deferoxamine Mesilate/Deferoxamine The baseline mean daily dose was calculated using the ICT dosage during the 12 weeks prior to first study drug administration and the postbaseline mean daily dose was calculated during the last 12 weeks of the 48-week double-blind Treatment Period or the last 12 weeks of the study treatment for early discontinued participants.
measure
Mean Change From Baseline In Mean Daily Dose Of Iron Chelation Therapies (ICT) At Week 48
time Frame
Baseline: Day -83 to Day 1; Treatment: Week 37 to Week 48
description
For each participant, the baseline mean serum ferritin level was calculated during the 12 weeks prior to first study drug administration. The postbaseline mean serum ferritin level was calculated during the last 12 weeks of the 48-week double-blind Treatment Period or last 12 weeks of study treatment, if discontinued early. The change was calculated as the difference of post baseline mean serum ferritin level and baseline mean serum ferritin level.
measure
Mean Change From Baseline In Mean Serum Ferritin At Week 48
time Frame
Baseline: Day -83 to Day 1; Treatment: Week 37 to Week 48
description
For BMD, the lumbar spine and total hip were measured at baseline and 48 weeks by dual energy x-ray absorptiometry (DXA). Baseline was defined as the last value on or before the first dose of study drug is administered; if multiple values are present for the same date, the average of these values was used. If during the 48 week double-blinded treatment period, a participant has only one assessment, it is counted as 'Week 48' visit; if a participant has multiple assessments, the last one is used as 'Week 48' visit. The analysis was done on the population that had at least 2 measurements.
measure
Mean Change From Baseline In Total Hip And Lumbar Spine Bone Mineral Density (BMD) At Week 48
time Frame
Baseline: Day 1; Treatment: Week 48
description
Myocardial Iron levels were measured by Magnetic Resonance Imaging (MRI), using MRI parameter T2\* (Unit: ms). T2\* values correlates with heart failure (HF) risk (e.g. T2\*\<6ms: high HF risk).
measure
Mean Change From Baseline In Myocardial Iron At Week 48
time Frame
Baseline: Day 1; Treatment: Week 48
description
The TranQol is a self-administered quality of life tool developed for beta-thalassemia patients. The adult self-report version used in this study, includes 36 questions assessed on a 5-point response, that are grouped into 5 domains (Physical Health, Emotional Health, Sexual Health, Family Functioning, School/Career Functioning). Scores are calculated according to specific scoring algorithms developed by the authors. Both individual domains score and the total score range from 0 (worst) to 100 (best). Total Score and Physical Health domain score are reported. Positive change from baseline values indicate improvement.
measure
Mean Change From Baseline in the Transfusion-dependent Quality of Life (TranQol) Questionnaire At Week 24
time Frame
Baseline: 4 weeks prior to Day 1; Treatment: Week 24
description
The SF-36 (version 2) is a generic, self-administered instrument consisting of 8 multi-item scales that assess 8 health domains. The raw score for each health domain is transformed into a 0 (worst) to 100 (best) domain score. The 0-100 scale score for each health domain is further converted to normbased scores using a T-score transformation, with a mean of 50 and a standard deviation (SD) of 10. Higher norm-based T-scores indicate better heath/QoL. The domains/summaries reported are: 1. Physical Functioning (Range of possible T-scores is 19.26 - 57.54) 2. General Health (Range of possible T-scores is 18.95 - 66.50) 3. Physical Component summary (PCS) (Range of possible T-scores is 5.02 - 79.78). Positive change from baseline values indicate improvement.
measure
Mean Change From Baseline in the 36-item Short Form Health Survey (SF-36) Questionnaire At Weeks 24
time Frame
Baseline: 4 weeks prior to Day 1; Treatment: Weeks 24
description
Number of participants who had any of the following types of Healthcare Resource Utilization (HRU): - a doctor office visit (non-study scheduled) - an emergency department visit - a hospitalization
measure
Number of Participants Who Utilized Healthcare Resources During Study
time Frame
From informed consent signing (up to 12 weeks before start of treatment) to end of treatment (up to approximately 227 weeks)

Full study description

brief Summary: 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 following periods: * Historical Period, * Screening/Run-in Period, * Double-blind Treatment Period (48 weeks), * Double-blind Long-term Treatment Period, (at the investigator's discretion an additional 48 weeks), * Open-Label Phase post unblinding and upon Data Monitoring Committee positive recommendation * Post-treatment Follow-up Period

Source references

references

citation
Porter J. Beyond transfusion therapy: new therapies in thalassemia including drugs, alternate donor transplant, and gene therapy. Hematology Am Soc Hematol Educ Program. 2018 Nov 30;2018(1):361-370. doi: 10.1182/asheducation-2018.1.361.
pmid
30504333
type
RESULT
citation
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 beta-thalassemia. Blood. 2019 Mar 21;133(12):1279-1289. doi: 10.1182/blood-2018-10-879247. Epub 2019 Jan 7.
pmid
30617198
type
RESULT
citation
Cappellini MD, Viprakasit V, Georgiev P, Coates TD, Origa R, Khelif A, Liew HK, Tantiworawit A, Chew LP, Khalil A, Ho PJ, Kuo KHM, Holot N, Perin M, Giuseppi AC, Kuo WL, Lai Y, Medlin LF, Bueno LM, Kattamis A, Taher AT. Long-term efficacy and safety of luspatercept for the treatment of anaemia in patients with transfusion-dependent beta-thalassaemia (BELIEVE): final results from a phase 3 randomised trial. Lancet Haematol. 2025 Mar;12(3):e180-e189. doi: 10.1016/S2352-3026(24)00376-4. Epub 2025 Feb 10.
pmid
39947215
type
DERIVED
citation
Garbowski MW, Ugidos M, Risueno A, Shetty JK, Schwickart M, Hermine O, Porter JB, Thakurta A, Vodala S. Luspatercept stimulates erythropoiesis, increases iron utilization, and redistributes body iron in transfusion-dependent thalassemia. Am J Hematol. 2024 Feb;99(2):182-192. doi: 10.1002/ajh.27102. Epub 2023 Oct 2.
pmid
37782758
type
DERIVED
citation
Denton CC, Vodala S, Veluswamy S, Hofstra TC, Coates TD, Wood JC. Splenic iron decreases without change in volume or liver parameters during luspatercept therapy. Blood. 2023 Nov 30;142(22):1932-1934. doi: 10.1182/blood.2023021839.
pmid
37704579
type
DERIVED
citation
Cappellini MD, Taher AT. The use of luspatercept for thalassemia in adults. Blood Adv. 2021 Jan 12;5(1):326-333. doi: 10.1182/bloodadvances.2020002725.
pmid
33570654
type
DERIVED
citation
Cappellini MD, Viprakasit V, Taher AT, Georgiev P, Kuo KHM, Coates T, Voskaridou E, Liew HK, Pazgal-Kobrowski I, Forni GL, Perrotta S, Khelif A, Lal A, Kattamis A, Vlachaki E, Origa R, Aydinok Y, Bejaoui M, Ho PJ, Chew LP, Bee PC, Lim SM, Lu MY, Tantiworawit A, Ganeva P, Gercheva L, Shah F, Neufeld EJ, Thompson A, Laadem A, Shetty JK, Zou J, Zhang J, Miteva D, Zinger T, Linde PG, Sherman ML, Hermine O, Porter J, Piga A; BELIEVE Investigators. A Phase 3 Trial of Luspatercept in Patients with Transfusion-Dependent beta-Thalassemia. N Engl J Med. 2020 Mar 26;382(13):1219-1231. doi: 10.1056/NEJMoa1910182.
pmid
32212518
type
DERIVED