A Study Evaluating the Efficacy and Safety of Mitapivat in Participants With Non-Transfusion-Dependent Alpha- or Beta-Thalassemia (α- or β-NTDT)
- Conditions
- Non-Transfusion-dependent Alpha-ThalassemiaNon-Transfusion-dependent Beta-Thalassemia
- Interventions
- Registration Number
- NCT04770753
- Lead Sponsor
- Agios Pharmaceuticals, Inc.
- Brief Summary
The primary purpose of this study is to compare the effect of mitapivat versus placebo on anemia in participants with alpha- or beta-non-transfusion dependent thalassemia (NTDT).
- Detailed Description
The mitapivat group will include approximately 114 participants. The placebo group will include approximately 57 participants.
Recruitment & Eligibility
- Status
- ACTIVE_NOT_RECRUITING
- Sex
- All
- Target Recruitment
- 194
- 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 Hb electrophoresis, Hb high-performance liquid chromatography (HPLC)), and/or deoxyribonucleic acid (DNA) analysis;
- Hb concentration ≤10.0 grams per deciliter (g/dL) (100.0 grams per liter [g/L]), based on an average of at least 2 Hb concentration measurements (separated by ≥7 days) collected during the Screening Period;
- Non-transfusion-dependent, defined as ≤5 red blood cell (RBC) units during the 24-week period before randomization; and no RBC transfusions ≤8 weeks before providing informed consent and no RBC transfusions during the Screening Period;
- If taking hydroxyurea, the hydroxyurea dose must be stable for ≥16 weeks before randomization;
- Women of child-bearing potential (WOCBP) must be abstinent of sexual activities that may result in pregnancy as part of their usual lifestyle or agree to use 2 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 (HbS) or hemoglobin C (HbC);
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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 ≥18 weeks before randomization;
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Currently receiving treatment with hematopoietic stimulating agents; the last dose must have been administered ≥18 weeks before randomization;
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History of malignancy, (active or treated) ≤5 years before providing informed consent;
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History of active and/or uncontrolled cardiac or pulmonary disease ≤6 months before providing informed consent, except for nonmelanomatous skin cancer in situ, cervical carcinoma in situ, or breast carcinoma in situ;
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Hepatobiliary disorders;
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Estimated glomerular filtration rate <45 milliliters per minute (mL/min)/1.73 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) ≤16 weeks 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 ≥10 weeks before randomization;
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Known allergy 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 Mitapivat Mitapivat Double-blind Period: Participants will receive mitapivat 100 milligrams (mg), orally, twice daily (BID) for 24 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 Placebo Matching Mitapivat Double-blind Period: Participants will receive placebo matching mitapivat, orally, BID for 24 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. Placebo Mitapivat Double-blind Period: Participants will receive placebo matching mitapivat, orally, BID for 24 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 Hemoglobin (Hb) Response Baseline, Week 12 up to Week 24 Hb response is defined as a ≥1.0 gram per deciliter (g/dL) increase in average Hb concentration from Week 12 through Week 24 compared with baseline.
- Secondary Outcome Measures
Name Time Method Maximum Plasma Concentration (Cmax) of Mitapivat Pre-dose, 0.5, 1, 3, 5, 7 hours post-dose Week 20 Change From Baseline in Average Functional Assessment of Chronic Illness Therapy (FACIT) -Fatigue Subscale Score from Week 12 through Week 24 Baseline, Week 12 up to Week 24 The 13-item FACIT-Fatigue subscale assesses severity and impact of fatigue. The subscale has a 7-day recall period, and total score ranges from 0 to 52, with a higher score indicating less fatigue.
Change From Baseline in Average Hb Concentration From Week 12 through Week 24 Baseline, Week 12 up to Week 24 Percentage of Participants With Hb 1.5+ Response Baseline, Week 12 up to Week 24 Hb 1.5+ response is defined as a ≥1.5 g/dL increase in average Hb concentration from Week 12 through Week 24 compared with baseline.
Change From Baseline in Indirect Bilirubin at Week 24 Baseline, Week 24 Change From Baseline in Lactate Dehydrogenase (LDH) at Week 24 Baseline, Week 24 Change From Baseline in Haptoglobin at Week 24 Baseline, Week 24 Change From Baseline in Reticulocytes at Week 24 Baseline, Week 24 Change From Baseline in Erythropoietin at Week 24 Baseline, Week 24 Percentage of Participants With Improvement in the Patient Global Impression of Severity (PGIS) -Fatigue by at Least 1 Category at Weeks 12, 16, 20, and 24 Compared With Baseline, or "No Change" if No or Mild Fatigue at Baseline Baseline, Weeks 12, 16, 20, and 24 The PGIS-Fatigue assesses severity of fatigue (on a 4-point scale ranging from "None" to "Severe") over a 7-day recall period. Improvement in the PGIS-Fatigue by at least one category or no change if "None" or "Mild" PGIS-Fatigue response at baseline will be assessed separately at Weeks 12, 16, 20, and 24 compared to baseline.
Percentage of Participants With Improvement in the Patient Global Impression of Change (PGIC) -Fatigue at Weeks 12, 16, 20, and 24, or "No Change" if No or Mild Fatigue at Baseline Weeks 12, 16, 20, and 24 The PGIC-Fatigue assesses change in fatigue compared with baseline (on a 5-point scale ranging from "Much better" to "Much worse"). Participants reporting improvement in the PGIC-Fatigue or reporting "No change" if "None" or "Mild" PGIS-Fatigue response at baseline will be assessed separately at Weeks 12, 16, 20, and 24.
Change From Baseline in the 6-minute Walk Test (6MWT) Distance at Week 24 Baseline, Week 24 Change From Baseline in Serum Ferritin at Week 24 Baseline, Week 24 Change From Baseline in Transferrin Saturation (TSAT) at Week 24 Baseline, Week 24 Percentage of Participants With Adverse Events (AEs) and Serious Adverse Events (SAEs) Up to Week 293 Percentage of Participants With Adverse Events (AEs) and Serious Adverse Events (SAEs), Graded by Severity Up to Week 293 AEs and SAEs 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.
Percentage of Participants With Adverse Events (AEs) Considered by the Investigator to be Related to Study Drug Up to Week 293 Percentage of Participants With Serious Adverse Events (SAEs) Considered by the Investigator to be Related to Study Drug Up to Week 293 Plasma or Blood Concentrations Over Time for Mitapivat Pre-dose Week 12; pre-dose, 0.5, 1, 3, 5, 7 hours post-dose Week 20 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 20 Time of Maximum Plasma Concentration (Tmax) of Mitapivat Pre-dose, 0.5, 1, 3, 5, 7 hours post-dose Week 20 Blood Concentration of Adenosine Triphosphate (ATP) Pre-dose Day 1; pre-dose Week 12; pre-dose, 0.5, 1, 3, 5, 7 hours post-dose Week 20 Blood Concentration of 2,3 - diphosphoglycerate (2,3-DPG) Pre-dose Day 1; pre-dose Week 12; pre-dose, 0.5, 1, 3, 5, 7 hours post-dose Week 20
Trial Locations
- Locations (71)
UMHAT "Sveti Georgi" EAD
🇧🇬Plovdiv, Bulgaria
SHATHD Sofia
🇧🇬Sofia, Bulgaria
Children's Hospital Agia Sophia, National and Kapodistrian University of Athens Medical School
🇬🇷Athens, Greece
Laiko General Hospital
🇬🇷Athina, Greece
Ippokrateio General Hospital
🇬🇷Thessaloniki, Greece
Hospital Sultanah Bahiyah
🇲🇾Alor Setar, Malaysia
King Abdulaziz Hospital - Al Ahsa
🇸🇦Al-Ahsa, Saudi Arabia
King Khalid University Hospital
🇸🇦Riyadh, Saudi Arabia
King Abdullah International Medical Research Center
🇸🇦Riyadh, Saudi Arabia
Phramongkutklao Hospital
🇹🇭Bangkok, Thailand
Burjeel Medical City
🇦🇪Abu Dhabi, United Arab Emirates
University General Hospital of Patras
🇬🇷Achaia, Greece
HEMORIO Instituto Nacional de Hematologia
🇧🇷Rio De Janeiro, Brazil
CHU Hôpital Henri Mondor
🇫🇷Créteil, France
A.O.R.N. "A. Cardarelli"
🇮🇹Napoli, Italy
Chronic Care Center
🇱🇧Beyrouth, Lebanon
Massachusetts General Hospital
🇺🇸Boston, Massachusetts, United States
Imperial College Healthcare NHS Trust - Hammersmith Hospital
🇬🇧London, United Kingdom
Erasmus MC
🇳🇱Westzeedijk 353, Netherlands
Ospedale Sant'Anna
🇮🇹Ferrara, Italy
Hacettepe University
🇹🇷Mersin, Turkey
Manchester Royal Infirmary, Manchester University NHS Foundation Trust
🇬🇧Manchester, LAN, United Kingdom
Universidade de Caxias do Sul
🇧🇷Caxias Do Sul, Brazil
GSH Banco de Sangue de São Paulo
🇧🇷São Paulo, Brazil
Hospital Universitario La Paz
🇪🇸Madrid, Spain
Penn Medicine - University of Pennsylvania Health System
🇺🇸Philadelphia, Pennsylvania, United States
Hopital Edouard Herriot, CHU de Lyon
🇫🇷Lyon, France
Praxis Pesquisa Medica
🇧🇷Santo André, Brazil
Hospital Ampang
🇲🇾Ampang, Malaysia
Hospital Umum Sarawak
🇲🇾Kuching, Malaysia
Hospital Universitario Virgen Arrixaca
🇪🇸Murcia, Spain
A.O.U Di Modena
🇮🇹Modena, Italy
Toronto General Hospital, University Health Network
🇨🇦Toronto, Canada
Hospital Tengku Ampuan Afzan
🇲🇾Kuantan, Malaysia
Srinagarind Hospital, Khon Kaen University
🇹🇭Mueang Khon Kaen, Thailand
Ospedale Pediatrico Microcitemico
🇮🇹Cagliari, Italy
Cambridge University Hospitals NHS Foundation Trust - Addenbrookes Hospital
🇬🇧Cambridge, CAM, United Kingdom
Ente Ospedaliero Ospedali Galliera
🇮🇹Genova, Italy
Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico
🇮🇹Milano, Italy
Hospital Universitario Vall d'Hebron
🇪🇸Barcelona, Spain
Hospital Universitario Virgen del Rocío
🇪🇸Sevilla, Spain
China Medical University, Taiwan
🇨🇳Taichung, Taiwan
Thalassemia Centre Dubai
🇦🇪Dubai, United Arab Emirates
Rigshospitalet
🇩🇰Hovedstaden, Denmark
A.O.U. San Luigi Gonzaga
🇮🇹Orbassano, Italy
University College London
🇬🇧London, United Kingdom
Instituto do Cancer do Estado de São Paulo, Hospital das Clínicas da Faculdade de Medicina da Universidad de São Paulo
🇧🇷Sao Paulo, Brazil
Stanford Medicine
🇺🇸Palo Alto, California, United States
San Diego Hospital, UC San Diego Health
🇺🇸La Jolla, California, United States
Weill Cornell Medical Center
🇺🇸New York, New York, United States
Duke University Medical Center
🇺🇸Durham, North Carolina, United States
Hospital das Clínicas da Faculdade de Medicina de Ribeirão Preto - USP
🇧🇷Ribeirão Preto, Brazil
MHAT "Dr. Nikola Vasiliev" AD
🇧🇬Kyustendil, Bulgaria
Ospedale "A. Perrino" - Brindisi
🇮🇹Brindisi, Italy
AOU L. Vanvitelli Universita degli Studi della Campania Luigi Vanvitelli
🇮🇹Napoli, Italy
Hospital Queen Elizabeth, Kota Kinabalu
🇲🇾Kota Kinabalu, Malaysia
Hospital Sultanah Aminah Johor Bahru
🇲🇾Johor Bahru, Malaysia
Hospital Tunku Azizah
🇲🇾Kuala Lumpur, Malaysia
Hospital Pulau Pinang
🇲🇾Pulau Pinang, Malaysia
Universitair Medisch Centrum Utrecht
🇳🇱Utrecht, Netherlands
National Taiwan University Hospital
🇨🇳Taipei, Taiwan
Ramathibodi Hospital
🇹🇭Bangkok, Thailand
Faculty of Medicine Siriraj Hospital
🇹🇭Bangkok, Thailand
Maharaj Nakorn Chiang Mai Hospital
🇹🇭Chiang Mai, Thailand
King Chulalongkorn Memorial Hospital
🇹🇭Pathum Wan, Thailand
Naresuan University Hospital
🇹🇭Mueang Phitsanulok, Thailand
Acibadem Adana Hospital
🇹🇷Adana, Turkey
Akdeniz University Faculty of Medicine
🇹🇷Antalya, Turkey
Çukurova University
🇹🇷Balcali, Turkey
Istanbul University Faculty of Medicine
🇹🇷Fatih, Turkey
Ege University Faculty of Medicine
🇹🇷Bornova, Turkey