Clinical trial NCT02604433: 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
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
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE3
Conditions: Erythrocyte Transfusion
Beta-Thalassemia
Keywords: ACE-536
Safety
Efficacy
Placebo
Red Blood Cell Transfusions
Beta -Thalassemia
Lead sponsor: Celgene
Sponsor class: INDUSTRY
Collaborators: name: Acceleron Pharma, Inc., a wholly-owned subsidiary of Merck & Co., Inc., Rahway, NJ USA
First posted: 2015-11-13
Enrollment: 336
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

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


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.

Primary outcomes:
measure: Percentage of Participants Who Achieved Erythroid Response - Week 13 to Week 24
timeFrame: Baseline: Day -83 to Day 1; Treatment: Weeks 13 to Week 24
Secondary outcomes:
measure: Percentage Of Participants Who Achieved ≥ 33% Reduction From Baseline in Transfusion Burden - Week 37 to Week 48
timeFrame: Baseline: Day -83 to Day 1; Treatment: Weeks 37 to Week 48
measure: Percentage Of Participants Who Achieve ≥ 50% Reduction From Baseline in Transfusion Burden - Week 13 to Week 24
timeFrame: Baseline: Day -83 to Day 1; Treatment: Weeks 13 to Week 24
measure: Percentage Of Participants Who Achieve ≥ 50% Reduction From Baseline in Transfusion Burden - Week 37 to Week 48
timeFrame: Baseline: Day -83 to Day 1; Treatment: Week 37 to Week 48
measure: Mean Change From Baseline in Transfusion Burden - Week 13 to Week 24
timeFrame: Baseline: Day -83 to Day 1; Treatment: Weeks 13 to Week 24
measure: Mean Change From Baseline In Liver Iron Concentration (LIC) At Week 48
timeFrame: Baseline: Week -12 to Day -1; Treatment: Week 48
measure: Mean Change From Baseline In Mean Daily Dose Of Iron Chelation Therapies (ICT) At Week 48
timeFrame: Baseline: Day -83 to Day 1; Treatment: Week 37 to Week 48
measure: Mean Change From Baseline In Mean Serum Ferritin At Week 48
timeFrame: Baseline: Day -83 to Day 1; Treatment: Week 37 to Week 48
measure: Mean Change From Baseline In Total Hip And Lumbar Spine Bone Mineral Density (BMD) At Week 48
timeFrame: Baseline: Day 1; Treatment: Week 48
measure: Mean Change From Baseline In Myocardial Iron At Week 48
timeFrame: Baseline: Day 1; Treatment: Week 48
measure: Mean Change From Baseline in the Transfusion-dependent Quality of Life (TranQol) Questionnaire At Week 24
timeFrame: Baseline: 4 weeks prior to Day 1; Treatment: Week 24
measure: Mean Change From Baseline in the 36-item Short Form Health Survey (SF-36) Questionnaire At Weeks 24
timeFrame: Baseline: 4 weeks prior to Day 1; Treatment: Weeks 24
measure: Number of Participants Who Utilized Healthcare Resources During Study
timeFrame: From informed consent signing (up to 12 weeks before start of treatment) to end of treatment (up to approximately 227 weeks)
measure: Number of Days Spent in Higher Care Hospital Units
timeFrame: From informed consent signing (up to 12 weeks before start of treatment) to end of treatment (up to approximately 227 weeks)
measure: Percentage Of Participants Who Were Transfusion Independent For ≥ 8 Weeks During Treatment
timeFrame: From first dose through 3 weeks post last dose (up to approximately 218 weeks)
measure: Duration of Reduction in Transfusion Burden
timeFrame: From first dose to end of study treatment (up to approximately 215 weeks)
measure: Longest Duration of Transfusion Independence
timeFrame: From first dose through 3 weeks post last dose (up to approximately 218 weeks)
measure: Time to Erythroid Response
timeFrame: From first dose to 48 weeks following first dose
measure: Post-Baseline Transfusion Event Frequency
timeFrame: From first dose through 3 weeks post last dose (up to approximately 218 weeks)
measure: Pharmacokinetic (PK) Parameters: Bayesian Estimate of Apparent Clearance (CL/F)
timeFrame: Blood serum samples taken pre-dose and on Days 1, 22, 64, 85, 106, 127, 169, 211, 253, 295, 337
measure: Pharmacokinetic (PK) Parameters: Bayesian Estimate of Apparent Volume of Distribution of the Central Compartment (V1/F)
timeFrame: Blood serum samples taken pre-dose and on Days 1, 22, 64, 85, 106, 127, 169, 211, 253, 295, 337
measure: Pharmacokinetic (PK) Parameters: Bayesian Estimate of Elimination Half-life (t1/2)
timeFrame: Blood serum samples taken pre-dose and on Days 1, 22, 64, 85, 106, 127, 169, 211, 253, 295, 337
measure: Pharmacokinetic (PK) Parameters: Bayesian Estimate of Time to Reach Maximum Concentration (Tmax)
timeFrame: Blood serum samples taken pre-dose and on Days 1, 22, 64, 85, 106, 127, 169, 211, 253, 295, 337
measure: Pharmacokinetic (PK) Parameters: Bayesian Estimate of Maximum Concentration for the Starting Dose (Cmax)
timeFrame: Blood serum samples taken pre-dose and on Days 1, 22, 64, 85, 106, 127, 169, 211, 253, 295, 337
measure: Pharmacokinetic (PK) Parameters: Bayesian Estimate of Maximum Concentration at Steady State for the Starting Dose (Cmax,ss)
timeFrame: Blood serum samples taken pre-dose and on Days 1, 22, 64, 85, 106, 127, 169, 211, 253, 295, 337
measure: Pharmacokinetic (PK) Parameters: Bayesian Estimate of Area Under the Concentration-Time Curve at Steady State for the Starting Dose (AUCss)
timeFrame: Blood serum samples taken pre-dose and on Days 1, 22, 64, 85, 106, 127, 169, 211, 253, 295, 337
measure: Participants With Treatment-Emergent Adverse Events (TEAE)
timeFrame: From first dose to 90 days following last dose (up to approximately 52 months)
measure: Participants With Pre-Existing and/or Treatment-Emergent Antidrug Antibodies (ADA)
timeFrame: Timeframe: pre-dose, Day 1, Days 22, 64, 106, 148, 232, 316
Other outcomes:
Locations:
city: Los Angeles
country: United States
facility: Children's Hospital of Los Angeles
state: California
city: Oakland
country: United States
facility: Children's Hospital and Research Center at Oakland
state: California
city: Chicago
country: United States
facility: Ann and Robert H Lurie Childrens Hospital of Chicago
state: Illinois
city: Boston
country: United States
facility: Boston Children's Hospital
state: Massachusetts
city: New York
country: United States
facility: Weill Cornell Medical College
state: New York
city: Philadelphia
country: United States
facility: Hospital of the University of Pennsylvania
state: Pennsylvania
city: Randwick
country: Australia
facility: Prince of Wales Hospital
state: New South Wales
city: South Brisbane
country: Australia
facility: Mater Hospital Brisbane
state: Queensland
city: Adelaide
country: Australia
facility: Royal Adelaide Hospital Institute of Medical and Veterinary Science
state: South Australia
city: Clayton
country: Australia
facility: Monash Medical Centre
state: Victoria
city: Nedlands
country: Australia
facility: Sir Charles Gairdner Hospital
state: Western Australia
city: Camperdown
country: Australia
facility: Royal Prince Alfred Hospital
city: Plovdiv
country: Bulgaria
facility: University Mulitiprofile Hospital for Active Treatment Sveti Georgi EAD
city: Sofia
country: Bulgaria
facility: Specialized Hospital for Active Treatment of Haematological Diseases - Sofia
city: Varna
country: Bulgaria
facility: Multiprofile Hospital for Active Treatment Sveta Marina EAD
city: Toronto
country: Canada
facility: University Health Network
state: Ontario
city: Creteil
country: France
facility: Hopital Henri Mondor
city: Lille
country: France
facility: GH de Institut Catholique St. VincentHématologie
city: Marseille Cedex 9
country: France
facility: Hopitaux de La Timone
city: Paris
country: France
facility: Hospital of Necker
city: Ampelokipi - Athens
country: Greece
facility: Laiko General Hospital of Athens
city: Ampelokipi - Athens
country: Greece
facility: Local Institution - 405
city: Athens
country: Greece
facility: General Children's Hospital "Agia Sophia"
city: Athens
country: Greece
facility: General Hospital Georgios Gennimatas of Athens
city: Rio Patras
country: Greece
facility: University General Hospital of Patras
city: Thessaloniki
country: Greece
facility: Hippokration Hospital
city: Thessaloniki
country: Greece
facility: Local Institution - 404
city: Beer Sheva
country: Israel
facility: Soroka University Medical Centre
city: Haifa
country: Israel
facility: Rambam Health Corporation
city: Haïfa (Afula)
country: Israel
facility: HaEmek Medical Center
city: Jerusalem
country: Israel
facility: Shaare Zedek Medical Center
city: Jerusalem
country: Israel
facility: Hadassah Medical Center
city: Nahariya
country: Israel
facility: Galilee Medical Center
city: Petah Tikva
country: Israel
facility: Rabin Medical Center
city: Brindisi
country: Italy
facility: Presidio Ospedaliero Antonio Perrino
city: Cagliari
country: Italy
facility: Universita degli Studi di Cagliari - ASL8
city: Ferrara
country: Italy
facility: Azienda Ospedaliero-Universitaria di Ferrara - Arcispedale Sant'Anna
city: Genoa
country: Italy
facility: Ente Ospedaliero Ospedali Galliera - Centro della Microcitemia e delle Anemie Congenite
city: Milan
country: Italy
facility: Fondazione Ca Granda IRCCS Ospedale Maggiore
city: Naples
country: Italy
facility: Seconda Universita Degli Studi Di Napoli
city: Napoli
country: Italy
facility: AORN A Cardarelli
city: Orbassano
country: Italy
facility: Azienda Ospedaliero Universitaria S. Luigi Gonzaga
city: Palermo
country: Italy
facility: Azienda Ospedaliera Ospedali Riuniti Villa Sofia-Cervello
city: Verona
country: Italy
facility: Azienda Ospedaliera Universitaria Integrata Di Verona
city: Beirut
country: Lebanon
facility: Chronic Care Center
city: Johor Bahru
country: Malaysia
facility: Hospital Sultanah Aminah
state: Johor
city: Alor Setar
country: Malaysia
facility: Hospital Sultanah Bahiyah
state: Kedah
city: Ipoh
country: Malaysia
facility: Hospital Raja Permaisuri Bainun
state: Perak
city: Kota Kinabalu
country: Malaysia
facility: Queen Elizabeth Hospital
state: Sabah
city: Kuching
country: Malaysia
facility: Hospital Umum Sarawak
state: Sarawak
city: Kuala Lumpur
country: Malaysia
facility: University Malaya Medical Centre
state: Wilayah Persekutuan Kuala Lumpur
city: Georgetown
country: Malaysia
facility: Hospital Pulau Pinang c/o Penang Medical College
city: Changhua City
country: Taiwan
facility: Changhua Christian Hospital
city: Kaohsiung
country: Taiwan
facility: Kaohsiung Medical University Hospital
city: Taichung
country: Taiwan
facility: China Medical University Hospital
city: Taipei, Zhongzheng Dist.
country: Taiwan
facility: National Taiwan University Hospital
city: Bangkok
country: Thailand
facility: Chulalongkorn University Faculty of Medicine - King Chulalongkorn Memorial Hospital
city: Bangkok
country: Thailand
facility: Siriraj Hospital Mahidol University
city: Chiang Mai
country: Thailand
facility: Chiang Mai University - Maharaj Nakorn Chiang Mai Hospital
city: Sousse
country: Tunisia
facility: University Hospital Farhat Hached
city: Tunis
country: Tunisia
facility: Bone Marrow Transplant Center
city: Tunis
country: Tunisia
facility: Aziza Othmana Hospital
city: Tunis
country: Tunisia
facility: Military Hospital of Tunis
city: Adana
country: Turkey
facility: Acibadem Adana Hospital
city: Adana
country: Turkey
facility: Cukurova University Medical Faculty Balcali Hospital
city: Adana
country: Turkey
facility: Local Institution - 524
city: Ankara
country: Turkey
facility: Hacettepe Universitesi
city: Antalya
country: Turkey
facility: Antalya Egitim Arastirma
city: Istanbul
country: Turkey
facility: Istanbul Universitesi Istanbul Tip Fakultesi Hastanesi
city: Izmir
country: Turkey
facility: Ege Universitesi Tip Fakultesi Hastanesi
city: Mersin
country: Turkey
facility: Mersin University Medical Faculty
city: Leeds
country: United Kingdom
facility: St James University Hospital
city: London Bloomsbury
country: United Kingdom
facility: University College Hospital Trust
city: London
country: United Kingdom
facility: Barts Health NHS Trust - The Royal London Hospital
city: London
country: United Kingdom
facility: Whittington Hospital
city: Manchester
country: United Kingdom
facility: Manchester Royal Infirmary
Study officials:
affiliation: Bristol-Myers Squibb
name: Bristol-Myers Squibb
role: STUDY_DIRECTOR
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.
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.
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.
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.