A Study Evaluating the Efficacy and Safety of Mitapivat in Participants With Transfusion-Dependent Alpha- or Beta-Thalassemia (α- or β-TDT)
- Conditions
- Transfusion-dependent Alpha-ThalassemiaTransfusion-dependent Beta-Thalassemia
- Interventions
- Registration Number
- NCT04770779
- Lead Sponsor
- Agios Pharmaceuticals, Inc.
- Brief Summary
The primary purpose of this study is to compare the effect of mitapivat versus placebo on transfusion burden in participants with transfusion-dependent alpha- or beta-thalassemia (TDT).
- Detailed Description
The mitapivat group will include approximately 160 participants. The placebo group will include approximately 80 participants.
Recruitment & Eligibility
- Status
- ACTIVE_NOT_RECRUITING
- Sex
- All
- Target Recruitment
- 258
- Documented diagnosis of thalassemia (β-thalassemia with or without α-globin gene mutations, hemoglobin E (HbE)/β-thalassemia, or α-thalassemia/hemoglobin H (HbH) disease) based on deoxyribonucleic acid (DNA) analysis;
- Considered transfusion-dependent, defined as 6 to 20 RBC units transfused and ≤6-week transfusion-free period during the 24-week period before randomization;
- If taking hydroxyurea, the hydroxyurea dose must be stable for ≥16 weeks before randomization;
- Women of childbearing potential (WOCBP) must be abstinent of sexual activities that may induce pregnancy as part of their usual lifestyle or agree to use two forms of contraception, one of which must be considered highly effective, from the time of providing informed consent, throughout the study, and for 28 days after the last dose of study drug. The second form of contraception can be an acceptable barrier method;
- Written informed consent before any study-related procedures are conducted and willing to comply with all study procedures for the duration of the study.
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Pregnant, breastfeeding, or parturient;
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Documented history of homozygous or heterozygous sickle hemoglobin (Hb S) or hemoglobin C (Hb C);
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Prior exposure to gene therapy or prior bone marrow or stem cell transplantation;
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Currently receiving treatment with luspatercept; the last dose must have been administered ≥36 weeks before randomization;
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Currently receiving treatment with hematopoietic stimulating agents; the last dose must have been administered ≥36 weeks before randomization;
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History of malignancy (active or treated) ≤5 years before providing informed consent, except for nonmelanomatous skin cancer in situ, cervical carcinoma in situ, or breast carcinoma in situ;
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History of active and/or uncontrolled cardiac or pulmonary disease ≤6 months before providing informed consent;
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Hepatobiliary disorders;
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Estimated glomerular filtration rate <45 milliliters per minute (mL/min)/1.73 meter (m)^2 by Chronic Kidney Disease Epidemiology Collaboration creatinine equation;
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Nonfasting triglycerides >440 milligrams per deciliter (mg/dL) (5 millimoles per liter [mmol/L]);
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Active infection requiring systemic antimicrobial therapy at the time of providing informed consent;
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Positive test for hepatitis C virus antibody (HCVAb) with evidence of active HCV infection, or positive test for hepatitis B surface antigen (HBsAg);
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Positive test for human immunodeficiency virus (HIV)-1 antibody (Ab) or HIV-2 Ab;
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History of major surgery (including splenectomy) ≤6 months before providing informed consent and/or a major surgical procedure planned during the study;
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Current enrollment or past participation (≤12 weeks before administration of the first dose of study drug or a timeframe equivalent to 5 half-lives of the investigational study drug, whichever is longer) in any other clinical study involving an investigational treatment or device;
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Receiving strong CYP3A4/5 inhibitors that have not been stopped for ≥5 days or a timeframe equivalent to 5 half-lives (whichever is longer); or strong CYP3A4 inducers that have not been stopped for ≥4 weeks or a timeframe equivalent to 5 half-lives (whichever is longer), before randomization;
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Receiving anabolic steroids that have not been stopped for at least 4 weeks before randomization. Testosterone replacement therapy to treat hypogonadism is allowed. The testosterone dose and preparation must be stable for ≥12 weeks before randomization;
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Known allergy, or other contraindication, to mitapivat or its excipients (microcrystalline cellulose, croscarmellose sodium, sodium stearyl fumarate, mannitol, and magnesium stearate, Opadry® II Blue [hypromellose, titanium dioxide, lactose monohydrate, triacetin, and FD&C Blue #2]);
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Any medical, hematological, psychological, or behavioral condition(s) or prior or current therapy that, in the opinion of the Investigator, may confer an unacceptable risk to participating in the study and/or could confound the interpretation of the study data. Also excluded are:
- Participants who are institutionalized by regulatory or court order
- Participants with any condition(s) that could create undue influence (including but not limited to incarceration, involuntary psychiatric confinement, and financial or familial affiliation with the Investigator or Sponsor).
Study & Design
- Study Type
- INTERVENTIONAL
- Study Design
- PARALLEL
- Arm && Interventions
Group Intervention Description Placebo Placebo Matching Mitapivat Double-Blind Period: Participants will receive placebo matching mitapivat orally, BID for 48 weeks. Open-label Extension Period: Participants who do not discontinue study drug may choose to receive mitapivat for up to an additional 5 years after the Double-blind Period. Mitapivat Mitapivat Double-Blind Period: Participants will receive mitapivat 100 milligrams (mg) orally, twice daily (BID) for 48 weeks. Open-label Extension Period: Participants who do not discontinue study drug may choose to continue to receive mitapivat for up to an additional 5 years after the Double-blind Period. Placebo Mitapivat Double-Blind Period: Participants will receive placebo matching mitapivat orally, BID for 48 weeks. Open-label Extension Period: Participants who do not discontinue study drug may choose to receive mitapivat for up to an additional 5 years after the Double-blind Period.
- Primary Outcome Measures
Name Time Method Percentage of Participants With Transfusion Reduction Response (TRR) Baseline up to Week 48 TRR is defined as ≥50% reduction in transfused red blood cells (RBC) units with a reduction of ≥2 units of transfused RBCs in any consecutive 12-week period through Week 48 compared with baseline.
- Secondary Outcome Measures
Name Time Method Percentage of Participants With ≥50% Reduction in Transfused RBC Units in Any Consecutive 24-week Period Through Week 48 Compared With Baseline Baseline up to Week 48 Percentage of Participants With ≥50% Reduction in Transfused RBC Units From Week 13 Through Week 48 Compared With Baseline Baseline, Week 13 up to Week 48 Change From Baseline in Total Iron Binding Capacity Through Week 48 Baseline, Week 48 Percentage of Participants With Adverse Events (AEs) and Serious Adverse Events (SAEs) Up to Week 317 Percentage of Participants with Adverse Events (AEs) Considered by the Investigator to be Related to Study Drug Up to Week 317 Percentage of Participants With ≥33% Reduction in Transfused RBC Units From Week 13 Through Week 48 Compared With Baseline Baseline, Week 13 up to Week 48 Change From Baseline in Transfused RBC Units From Week 13 Through Week 48 Baseline, Week 13 up to Week 48 Percentage of Participants With Transfusion-Independence Up to Week 48 Transfusion-independence is defined as transfusion-free for ≥8 consecutive weeks through Week 48.
Change From Baseline in Serum Ferritin Through Week 48 Baseline, Week 48 Change From Baseline in Transferrin Saturation Through Week 48 Baseline, Week 48 Time of Maximum Plasma Concentration (Tmax) of Mitapivat Pre-dose, 0.5, 1, 3, 5, 7 hours post-dose Week 36 Blood Concentration of 2,3 - diphosphoglycerate (2,3-DPG) Pre-dose Day 1; pre-dose Week 12; pre-dose Week 24; pre-dose, 0.5, 1, 3, 5, 7 hours post-dose Week 36 Change From Baseline in Iron Through Week 48 Baseline, Week 48 Percentage of Participants with Serious Adverse Events (SAEs) Considered by the Investigator to be Related to Study Drug Up to Week 317 Plasma or Blood Concentrations Over Time for Mitapivat Pre-dose Week 12; pre-dose Week 24; pre-dose, 0.5, 1, 3, 5, 7 hours post-dose Week 36 Area Under the Concentration-time Curve From Time Zero to the Last Measurable Concentration (AUClast) of Mitapivat Pre-dose, 0.5, 1, 3, 5, 7 hours post-dose Week 36 Maximum Plasma Concentration (Cmax) of Mitapivat Pre-dose, 0.5, 1, 3, 5, 7 hours post-dose Week 36 Percentage of Participants with Adverse Events (AEs) and Serious Adverse Events (SAEs), Graded by Severity Up to Week 317 AEs will be graded according to the National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE; Version 4.03) from Grades 1 to 4 where Grade 1 is mild and Grade 4 is life-threatening.
Blood Concentration of Adenosine Triphosphate (ATP) Pre-dose Day 1; pre-dose Week 12; pre-dose Week 24; pre-dose, 0.5, 1, 3, 5, 7 hours post-dose Week 36
Trial Locations
- Locations (78)
Penn Medicine - University of Pennsylvania Health System
🇺🇸Philadelphia, Pennsylvania, United States
Phoenix Children's Hospital
🇺🇸Phoenix, Arizona, United States
Ospedale Pediatrico Microcitemico
🇮🇹Cagliari, Italy
Boston Children's Hospital
🇺🇸Boston, Massachusetts, United States
Children's Hospital Oakland
🇺🇸Oakland, California, United States
Stanford Medicine
🇺🇸Palo Alto, California, United States
Children's Hospital of Michigan
🇺🇸Detroit, Michigan, United States
Dana Faber Cancer Institute
🇺🇸Boston, Massachusetts, United States
Seattle Cancer Care Alliance, University of Washington
🇺🇸Seattle, Washington, United States
Hospital Das Clínicas da Faculdade de Medicina de Ribeirão Preto - USP
🇧🇷Ribeirão Preto, Brazil
MHAT "Dr. Nikola Vasiliev" AD
🇧🇬Kyustendil, Bulgaria
GSH Banco de Sangue de São Paulo
🇧🇷São Paulo, Brazil
SHATHD Sofia
🇧🇬Sofia, Bulgaria
Hôpital Necker Enfants Malades
🇫🇷Paris, France
Hôpital Edouard Herriot, CHU de Lyon
🇫🇷Lyon, France
Toronto General Hospital, University Health Network
🇨🇦Toronto, Ontario, Canada
Rigshospitalet
🇩🇰Hovedstaden, Denmark
CHU Hôpital de la Timone
🇫🇷Marseille, France
CHU Hôpital Henri Mondor
🇫🇷Créteil, France
Universitätsklinikum Essen
🇩🇪Essen, Germany
Charité - UB - CVK - Medizinische Klinik
🇩🇪Berlin, Germany
Universitätsklinikum Leipzig
🇩🇪Leipzig, Germany
University General Hospital of Patras
🇬🇷Achaia, Greece
Laiko General Hospital
🇬🇷Athina, Greece
Ospedale "A. Perrino" - Brindisi
🇮🇹Brindisi, Italy
Ospedale Sant'Anna
🇮🇹Ferrara, Italy
Ente Ospedaliero Ospedali Galliera
🇮🇹Genova, Italy
Fondazione IRCCS Cà Granda Ospedale Maggiore Policlinico
🇮🇹Milano, Italy
Chronic Care Center
🇱🇧Beyrouth, Lebanon
Hospital Sultanah Aminah Johor Bahru
🇲🇾Johor Bahru, Malaysia
Hospital Sultanah Bahiyah
🇲🇾Kota Setar, Malaysia
Hospital Umum Sarawak
🇲🇾Kuching, Malaysia
Hospital Tunku Azizah
🇲🇾Kuala Lumpur, Malaysia
King Abdulaziz Hospital - Al Ahsa
🇸🇦Al-Ahsa, Saudi Arabia
Hospital Universitario Vall d'Hebron
🇪🇸Barcelona, Spain
Hospital Universitario La Paz
🇪🇸Madrid, Spain
Hospital Universitario Virgen Arrixaca
🇪🇸Murcia, Spain
Hospital Universitario Virgen del Rocío
🇪🇸Sevilla, Spain
National Taiwan University Hospital
🇨🇳Taipei, Taiwan
Faculty of Medicine Siriraj Hospital
🇹🇭Bangkok, Thailand
Naresuan University Hospital
🇹🇭Mueang Phitsanulok, Thailand
Srinagarind Hospital, Khon Kaen University
🇹🇭Mueang Khon Kaen, Thailand
Akdeniz University Faculty of Medicine
🇹🇷Antalya, Turkey
Çukurova University
🇹🇷Balcali, Turkey
Ege University Faculty of Medicine
🇹🇷Bornova, Turkey
Hacettepe University
🇹🇷Mersin, Turkey
Istanbul University Faculty of Medicine
🇹🇷Fatih, Turkey
University College London
🇬🇧London, United Kingdom
Weill Cornell Medical Center
🇺🇸New York, New York, United States
San Diego Hospital, UC San Diego Health
🇺🇸La Jolla, California, United States
Duke University Medical Center
🇺🇸Durham, North Carolina, United States
Children's Hospital Agia Sophia, National and Kapodistrian University of Athens Medical School
🇬🇷Athens, Greece
Hospital Queen Elizabeth, Kota Kinabalu
🇲🇾Kota Kinabalu, Malaysia
A.O.U Di Modena
🇮🇹Modena, Italy
A.O.U. San Luigi Gonzaga
🇮🇹Orbassano, Italy
AOU L. Vanvitelli Universita degli Studi della Campania Luigi Vanvitelli
🇮🇹Napoli, Italy
Acibadem Adana Hospital
🇹🇷Adana, Turkey
Imperial College Healthcare NHS Trust - Hammersmith Hospital
🇬🇧London, United Kingdom
UMHAT "Sveti Georgi" EAD
🇧🇬Plovdiv, Bulgaria
Universitair Medisch Centrum Utrecht
🇳🇱Utrecht, Netherlands
UMHAT "Prof. Dr. Stoyan Kirkovich"
🇧🇬Stara Zagora, Bulgaria
Hospital Tengku Ampuan Afzan
🇲🇾Kuantan, Malaysia
Foothills Medical Centre
🇨🇦Calgary, Alberta, Canada
UMHAT "Dr. Georgi Stranski" Pleven
🇧🇬Pleven, Bulgaria
Erasmus MC
🇳🇱Westzeedijk 353, Netherlands
Maharaj Nakorn Chiang Mai Hospital
🇹🇭Chiang Mai, Thailand
Hospital Ampang
🇲🇾Pandan Indah, Malaysia
Amsterdam Universitair Medisch Centrum, Locatie AMC
🇳🇱Amsterdam, Netherlands
Burjeel Medical City
🇦🇪Abu Dhabi, United Arab Emirates
University Hospital of Ioannina
🇬🇷Ioannina, Greece
Ippokrateio General Hospital
🇬🇷Thessaloníki, Greece
Hospital Pulau Pinang
🇲🇾Pulau Pinang, Malaysia
King Abdullah International Medical Research Center
🇸🇦Riyadh, Saudi Arabia
King Khalid University Hospital
🇸🇦Riyadh, Saudi Arabia
Changhua Christian Hospital
🇨🇳Changhua, Taiwan
Phramongkutklao Hospital
🇹🇭Bangkok, Thailand
Ramathibodi Hospital
🇹🇭Bangkok, Thailand
King Chulalongkorn Memorial Hospital
🇹🇭Pathum Wan, Thailand