A Study Evaluating the Efficacy and Safety of Mitapivat in Participants With Transfusion-Dependent Alpha- or Beta-Thalassemia (α- or β-TDT)

Recruitment Status
ACTIVE, NOT RECRUITING - HAS RESULTS
(See Contacts and Locations)Verified March 2026 by Agios Pharmaceuticals, Inc.
Sponsor
Agios Pharmaceuticals, Inc.
Information Provided by (Responsible Party)
Agios Pharmaceuticals, Inc.
Clinicaltrials.gov Identifier
NCT04770779
Other Study ID Numbers:
AG348-C-018
First Submitted
February 17, 2021
First Posted
February 24, 2021
Results First Posted
April 10, 2025
Last Update Posted
April 23, 2026
Last Verified
March 2026

ClinicalTrials.gov processed this data on April 2026. Link to the current ClinicalTrials.gov record .

History of Changes

Study Details

Study Description

The mitapivat group included 171 participants. The placebo group included 87 participants.

Condition or DiseaseIntervention/Treatment
Transfusion-dependent Alpha-ThalassemiaTransfusion-dependent Beta-Thalassemia
Drug: MitapivatDrug: Placebo Matching Mitapivat

Study Design

Study TypeInterventional
Actual Enrollment258 participants
Design AllocationRandomized
Interventional ModelParallel Assignment
MaskingQuadruple
Primary PurposeTreatment
Official TitleA Phase 3, Double-Blind, Randomized, Placebo-Controlled, Multicenter Study Evaluating the Efficacy and Safety of Mitapivat in Subjects With Transfusion-Dependent Alpha- or Beta-Thalassemia (ENERGIZE-T)
Study Start DateNovember 29, 2021
Actual Primary Completion DateApril 10, 2024
Actual Study Completion Date3yrs 1w from now

Groups and Cohorts

Group/CohortIntervention/Treatment
Mitapivat
Participants randomized to receive mitapivat 100 milligrams (mg), orally, twice daily (BID) for 48 weeks in the double-blind (DB) period and for up to 5 years in the open label extension (OLE) period.
Drug: Mitapivat
Tablets
Placebo
Participants randomized to receive placebo matching mitapivat, orally, BID for 48 weeks in the DB period followed by mitapivat 100 mg, orally, BID for up to 5 years in the OLE period.
Drug: Placebo Matching Mitapivat
Tablets

Outcome Measures

Primary Outcome Measures
  1. Double-blind Period: Percentage of Participants Who Achieved Transfusion Reduction Response (TRR)
    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 transfusion burden standardized to 12 weeks. Baseline transfusion burden standardized to 12 weeks= (12/24) × total number of RBC units transfused during 24-week period before the randomization date for participants randomized and not dosed or the start of study treatment for participants randomized and dosed. Participants withdrawn from the study before Week 12 (Day 85) were considered nonresponders.
Secondary Outcome Measures
  1. Double-blind Period: Percentage of Participants Who Achieved TRR2
    TRR2, defined as a ≥50% reduction in transfused RBC units in any consecutive 24-week period through Week 48 compared with the 24-week baseline transfusion burden, is reported. Baseline transfusion burden standardized to 24 weeks is the total number of RBC units transfused during the 24-week period before the randomization date for participants randomized and not dosed or the start of study treatment for participants randomized and dosed. Participants withdrawn from the study before Week 24 (Day 169) were considered nonresponders.
  2. Double-blind Period: Percentage of Participants Who Achieved TRR3
    TRR3, defined as a ≥33% reduction in transfused RBC units from Week 13 through Week 48 compared with the baseline transfusion burden standardized to 36 weeks, is reported. Baseline transfusion burden standardized to 36 weeks= (36/24) × total number of RBC units transfused during the 24-week period before the randomization date for participants randomized and not dosed or the start of study treatment for participants randomized and dosed. Participants withdrawn from the study before Week 48 were considered nonresponders.
  3. Double-blind Period: Percentage of Participants Who Achieved TRR4
    TRR4, defined as a ≥50% reduction in transfused RBC units from Week 13 through Week 48 compared with the baseline transfusion burden standardized to 36 weeks, is reported. Baseline transfusion burden standardized to 36 weeks = (36/24) × total number of RBC units transfused during the 24-week period before the randomization date for participants randomized and not dosed or the start of study treatment for participants randomized and dosed. Participants withdrawn from the study before Week 48 were considered nonresponders.
  4. Double-blind Period: Percent Change From Baseline in Transfused RBC Units
    Transfusion burden from Week 13 through Week 48 standardized to 36 weeks is defined as number of transfused RBC units from Day 85 through Week 48 in the Double-blind Period ×36/(Number of days from Day 85 through Week 48 in the Double-blind Period/7). Baseline transfusion burden standardized to 36 weeks= (36/24)× is the total number of RBC units transfused during the 24-week period before the randomization date for participants randomized and not dosed or within 168 days before the start of study treatment for participants randomized and dosed.
  5. Double-blind Period: Percentage of Participants Who Achieved Transfusion-Independence
    Transfusion-independence is defined as transfusion-free for ≥8 consecutive weeks through Week 48 in the double-blind period.
  6. Double-blind Period: Change From Baseline in Iron Levels
    Iron metabolism was assessed based on Iron levels.
  7. Double-blind Period: Change From Baseline in Serum Ferritin Levels
    Iron metabolism was assessed based on serum ferritin levels.
  8. Double-blind Period: Change From Baseline in Total Iron Binding Capacity
    Iron metabolism was assessed based on total iron binding capacity.
  9. Double-blind Period: Change From Baseline in Transferrin Saturation (TSAT) Levels
    Iron metabolism was assessed based on TSAT levels. Transferrin saturation is reported by dividing value of serum iron by total iron binding capacity.
  10. Double-blind Period: Number of Participants With Treatment-Emergent Adverse Events (TEAEs), Serious TEAEs, Related TEAEs and TEAEs With Severity Greater Than or Equal to Grade 3
    An AE is any untoward medical occurrence in a participant administered a pharmaceutical product and which does not necessarily have a causal relationship with the study drug. A serious adverse event (SAE) is any untoward medical occurrence that resulted in any of the following outcomes: death; life threatening; persistent/significant disability/incapacity; initial or prolonged inpatient hospitalization; congenital anomaly/birth defect or was otherwise considered medically important. TEAEs are AEs with an initial onset date during the on-treatment period or worsening from baseline and includes both serious \& non-serious TEAEs. Severity of AEs was evaluated using the National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE; Version 4.03): grade 1: mild; grade 2: moderate; grade 3: severe or medically significant but not immediately life-threatening; grade 4: life threatening or disabling; grade 5: death related to AE.
  11. Open-label Extension Period: Number of Participants With TEAEs, Serious TEAEs, Related TEAEs, Related TEAEs and TEAEs With Severity of Greater Than or Equal to 3
    An AE is any untoward medical occurrence in a participant administered a pharmaceutical product and which does not necessarily have a causal relationship with the study drug. A serious adverse event (SAE) is any untoward medical occurrence that resulted in any of the following outcomes: death; life threatening; persistent/significant disability/incapacity; initial or prolonged inpatient hospitalization; congenital anomaly/birth defect or was otherwise considered medically important. TEAEs are AEs with an initial onset date during the on-treatment period or worsening from baseline and includes both serious \& non-serious TEAEs. Severity of abnormalities was evaluated using the National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE; Version 4.03): grade 1: mild; grade 2: moderate; grade 3: severe or medically significant but not immediately life-threatening; grade 4: life threatening or disabling; grade 5: death related to AE.
  12. Double-blind Period: Plasma Concentrations of Mitapivat
  13. Double-blind Period: Area Under the Plasma Concentration-time Curve From Time Zero to the Last Measurable Concentration (AUC0-last) of Mitapivat
    Area under the concentration-time curve from time zero to Tlast on dosing day, calculated using the linear-log trapezoidal rule.
  14. Double-blind Period: Maximum Observed Plasma Concentration (Cmax) of Mitapivat
  15. Double-blind Period: Time to Reach of Maximum Observed Plasma Concentration (Tmax) of Mitapivat
  16. Double-blind Period: Time of Last Quantifiable Concentration (Tlast) of Mitapivat
  17. Double-blind Period: Last Quantifiable Plasma Concentration (Clast) of Mitapivat
    Clast is the last quantifiable concentration after a single dose or within the dosing interval (tau) for multiple doses.
  18. Double-blind Period: Blood Concentration of Adenosine Triphosphate (ATP)
  19. Double-blind Period: Blood Concentration of 2,3 - Diphosphoglycerate (2,3-DPG)

Eligibility Criteria

Ages Eligible for Study(Adult, Older Adult)
Sexes Eligible for StudyAll
Accepts Healthy VolunteersNo
Inclusion Criteria
Greater than or equal to (≥)18 years of age at the time of providing informed consent;
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 red blood cells (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.
Exclusion Criteria
Pregnant, breastfeeding, or parturient;
Documented history of homozygous or heterozygous sickle hemoglobin (Hb S) or hemoglobin C (Hb C);
Prior exposure to gene therapy or prior bone marrow or stem cell transplantation;
Currently receiving treatment with luspatercept; the last dose must have been administered ≥36 weeks before randomization;
Currently receiving treatment with hematopoietic stimulating agents; the last dose must have been administered ≥36 weeks before randomization;
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;
History of active and/or uncontrolled cardiac or pulmonary disease ≤6 months before providing informed consent;
Hepatobiliary disorders;
Estimated glomerular filtration rate \<45 milliliters per minute (mL/min)/1.73 meter (m)\^2 by Chronic Kidney Disease Epidemiology Collaboration creatinine equation;
Nonfasting triglycerides \>440 milligrams per deciliter (mg/dL) (5 millimoles per liter \[mmol/L\]);
Active infection requiring systemic antimicrobial therapy at the time of providing informed consent;
Positive test for hepatitis C virus antibody (HCVAb) with evidence of active HCV infection, or positive test for hepatitis B surface antigen (HBsAg);
Positive test for human immunodeficiency virus (HIV)-1 antibody (Ab) or HIV-2 Ab;
History of major surgery (including splenectomy) ≤6 months before providing informed consent and/or a major surgical procedure planned during the study;
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;
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;
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;
Known allergy, or other contraindication, to mitapivat or its excipients (microcrystalline cellulose, croscarmellose sodium, sodium stearyl fumarate, mannitol, and magnesium stearate, Opadry® II Blue \[hypromellose, titanium dioxide, lactose monohydrate, triacetin, and Federal Food, Drug, and Cosmetic (FD\&C) Blue #2\]);
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).

Contacts and Locations

Sponsors and CollaboratorsAgios Pharmaceuticals, Inc.
Locations
Phoenix Children's Hospital | Phoenix Arizona, United States, 85016-7710San Diego Hospital, UC San Diego Health | La Jolla California, United States, 92093Children's Hospital Oakland | Oakland California, United States, 94609-1809Stanford Medicine | Palo Alto California, United States, 94304-1601Boston Children's Hospital | Boston Massachusetts, United States, 02115Children's Hospital of Michigan | Detroit Michigan, United States, 48201-2196Weill Cornell Medical Center | New York New York, United States, 10065-4870Duke University Medical Center | Durham North Carolina, United States, 27710-3038Penn Medicine - University of Pennsylvania Health System | Philadelphia Pennsylvania, United States, 19104Seattle Cancer Care Alliance, University of Washington | Seattle Washington, United States, 98101Hospital Das Clínicas da Faculdade de Medicina de Ribeirão Preto - USP | Ribeirão Preto , Brazil, 14051-260GSH Banco de Sangue de São Paulo | São Paulo , Brazil, 04006-002MHAT "Dr. Nikola Vasiliev" AD | Kyustendil , Bulgaria, 2500UMHAT "Dr. Georgi Stranski" Pleven | Pleven , Bulgaria, 5800UMHAT "Sveti Georgi" EAD | Plovdiv , Bulgaria, 4002SHATHD Sofia | Sofia , Bulgaria, 1756UMHAT "Prof. Dr. Stoyan Kirkovich" | Stara Zagora , Bulgaria, 6000Foothills Medical Centre | Calgary Alberta, Canada, T2N 2T9Toronto General Hospital, University Health Network | Toronto Ontario, Canada, M5G 2C4Rigshospitalet | Hovedstaden , Denmark, 2100CHU Hôpital Henri Mondor | Créteil , France, 94010Hôpital Edouard Herriot, CHU de Lyon | Lyon , France, 69003CHU Hôpital de la Timone | Marseille , France, 13385Hôpital Necker Enfants Malades | Paris , France, 75015Charité - UB - CVK - Medizinische Klinik | Berlin , Germany, 13353Universitätsklinikum Essen | Essen , Germany, 45122Universitätsklinikum Leipzig | Leipzig , Germany, 04103University General Hospital of Patras | Achaia , Greece, 26504Laiko General Hospital | Athens , Greece, 115 26Children's Hospital Agia Sophia, National and Kapodistrian University of Athens Medical School | Athens , Greece, 11527University Hospital of Ioannina | Ioannina , Greece, 455 00Ippokrateio General Hospital | Thessaloniki , Greece, 546 42Ospedale "A. Perrino" - Brindisi | Brindisi , Italy, 72100Ospedale Pediatrico Microcitemico | Cagliari , Italy, 09121Ospedale Sant'Anna | Ferrara , Italy, 44124Ente Ospedaliero Ospedali Galliera | Genova , Italy, 16128Fondazione IRCCS Cà Granda Ospedale Maggiore Policlinico | Milan , Italy, 20122A.O.U Di Modena | Modena , Italy, 41124AOU L. Vanvitelli Universita degli Studi della Campania Luigi Vanvitelli | Naples , Italy, 80138A.O.U. San Luigi Gonzaga | Orbassano , Italy, 10043Chronic Care Center | Beirut , Lebanon, 9999Hospital Sultanah Bahiyah | Alor Star , Malaysia, 05460Hospital Sultanah Aminah Johor Bahru | Johor Bahru , Malaysia, 80100Hospital Queen Elizabeth, Kota Kinabalu | Kota Kinabalu , Malaysia, 88586Hospital Tunku Azizah | Kuala Lumpur , Malaysia, 50300Hospital Tengku Ampuan Afzan | Kuantan , Malaysia, 25100Hospital Umum Sarawak | Kuching , Malaysia, 93586Hospital Ampang | Pandan Indah , Malaysia, 68000Hospital Pulau Pinang | Pulau Pinang , Malaysia, 10990Amsterdam Universitair Medisch Centrum, Locatie AMC | Amsterdam , Netherlands, 1105 AZUniversitair Medisch Centrum Utrecht | Utrecht , Netherlands, 3584 CXErasmus MC | Westzeedijk 353 , Netherlands, 3015 AAKing Abdullah International Medical Research Center | Riyadh , Saudi Arabia, 14611King Khalid University Hospital | Riyadh , Saudi Arabia, 90210Hospital Universitario Vall d'Hebron | Barcelona , Spain, 08035Hospital Universitario La Paz | Madrid , Spain, 28046Hospital Universitario Virgen Arrixaca | Murcia , Spain, 30120Hospital Universitario Virgen del Rocío | Seville , Spain, 41013National Taiwan University Hospital | Taipei , Taiwan, 100Phramongkutklao Hospital | Bangkok , Thailand, 10400Ramathibodi Hospital | Bangkok , Thailand, 10400Faculty of Medicine Siriraj Hospital | Bangkok , Thailand, 10700Maharaj Nakorn Chiang Mai Hospital | Chiang Mai , Thailand, 50200Srinagarind Hospital, Khon Kaen University | Khon Kaen , Thailand, 40000Naresuan University Hospital | Mueang Phitsanulok , Thailand, 65000King Chulalongkorn Memorial Hospital | Pathum Wan , Thailand, Acibadem Adana Hospital | Adana , Turkey (Türkiye), 1130Akdeniz University Faculty of Medicine | Antalya , Turkey (Türkiye), 07059Çukurova University | Balcalı , Turkey (Türkiye), 01330Ege University Faculty of Medicine | Bornova , Turkey (Türkiye), 35040Istanbul University Faculty of Medicine | Fatih , Turkey (Türkiye), 34093Hacettepe University | Mersin , Turkey (Türkiye), Burjeel Medical City | Abu Dhabi , United Arab Emirates, Imperial College Healthcare NHS Trust - Hammersmith Hospital | London , United Kingdom, W12 0HSUniversity College London | London , United Kingdom, WC1E 6BT
Investigators
Study Chair: Medical Affairs, Agios Pharmaceuticals, Inc.
Study Documents (Full Text)
Documents provided by Agios Pharmaceuticals, Inc.: Study Protocol  September 27, 2022Documents provided by Agios Pharmaceuticals, Inc.: Statistical Analysis Plan  November 13, 2022