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

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
NCT04770753
Other Study ID Numbers:
AG348-C-017
First Submitted
February 17, 2021
First Posted
February 24, 2021
Results First Posted
October 22, 2024
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 130 participants whereas the placebo group had 64 participants.

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

Study Design

Study TypeInterventional
Actual Enrollment194 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 Non-Transfusion-Dependent Alpha- or Beta-Thalassemia (ENERGIZE)
Study Start DateDecember 19, 2021
Actual Primary Completion DateNovember 12, 2023
Actual Study Completion Date2yrs 6mos from now

Groups and Cohorts

Group/CohortIntervention/Treatment
Mitapivat
Mitapivat 100 milligrams (mg), orally, twice daily (BID) for 24 weeks in double blind (DB) period and for up to 5 years in open label extension (OLE) period.
Drug: Mitapivat
Tablets
Placebo
Placebo matching mitapivat, orally, BID for 24 weeks in double blind period followed by Mitapivat 100 mg, orally, BID for up to 5 years in open label extension period.
Drug: Placebo Matching Mitapivat
Tablets

Outcome Measures

Primary Outcome Measures
  1. Double-Blind Period: Percentage of Participants Who Achieved Hemoglobin (Hb) Response From Week 12 Through Week 24 Compared With Baseline
    Hb response is defined as ≥10 grams/ liter (g/L) (1.0 gram per deciliter) (g/dL) increase in average Hb concentration from Week 12 through Week 24 compared with baseline. Hb response was tested using the Mantel-Haenszel stratum weighted method adjusting for randomization stratification factors. Baseline is defined as the average of all assessments within 42 days before randomization for subjects randomized and not dosed or within 42 days before the start of study treatment for subjects randomized and dosed.
Secondary Outcome Measures
  1. Double-Blind Period: Change From Baseline in Average Functional Assessment of Chronic Illness Therapy (FACIT) -Fatigue Subscale Score From Week 12 Through Week 24
    The FACIT-Fatigue subscale includes a 13-item self-reported fatigue subscale, which assesses the severity and impact of fatigue (including the impact on daily activities and functioning).The FACIT-Fatigue subscale is scored on a 5-point Likert scale: 0 (not at all) to 4 (very much). The total FACIT-Fatigue subscale score ranges from 0 to 52, with a higher score indicating better health-related quality of life (HRQOL). Baseline is defined as the last assessment before randomization for subjects randomized and not dosed or the last assessment before start of study treatment for subjects randomized and dosed.
  2. Double-Blind Period: Change From Baseline in Average Hb Concentration From Week 12 Through Week 24
    Baseline is defined as the average of all assessments within 42 days before randomization for subjects randomized and not dosed or within 42 days before the start of study treatment for subjects randomized and dosed.
  3. Double-Blind Period: Percentage of Participants Who Achieved Hb 1.5+ Response From Week 12 Through Week 24 Compared With Baseline
    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. Hb 1.5+ response will be summarized using the Mantel-Haenszel stratum weighted method adjusting for randomization stratification factors. Baseline is defined as the average of all assessments within 42 days before randomization for subjects randomized and not dosed or within 42 days before the start of study treatment for subjects randomized and dosed.
  4. Double-Blind Period: Change From Baseline in Indirect Bilirubin at Week 24
    Baseline is defined as the average of all assessments within 42 days before randomization for subjects randomized and not dosed or within 42 days before the start of study treatment for subjects randomized and dosed.
  5. Double-Blind Period: Change From Baseline in Lactate Dehydrogenase (LDH) at Week 24
    Baseline is defined as the average of all assessments within 42 days before randomization for subjects randomized and not dosed or within 42 days before the start of study treatment for subjects randomized and dosed.
  6. Double-Blind Period: Change From Baseline in Haptoglobin at Week 24
    Baseline is defined as the average of all assessments within 42 days before randomization for subjects randomized and not dosed or within 42 days before the start of study treatment for subjects randomized and dosed.
  7. Double-Blind Period: Change From Baseline in Reticulocytes at Week 24
    Baseline is defined as the average of all assessments within 42 days before randomization for subjects randomized and not dosed or within 42 days before the start of study treatment for subjects randomized and dosed.
  8. Double-Blind Period: Change From Baseline in Erythropoietin at Week 24
    Baseline is defined as the average of all assessments within 42 days before randomization for subjects randomized and not dosed or within 42 days before the start of study treatment for subjects randomized and dosed.
  9. Double-Blind Period: Percentage of Participants Who Achieved Patient Global Impression of Severity (PGIS)- Fatigue Response at Weeks 12, 16, 20, and 24
    PGIS-Fatigue measured participants' perception of their fatigue severity (7-day recall) on a 4-point scale ranging from '1=none' to '4=severe'. A participant was considered to have achieved the PGIS-Fatigue response at Weeks 12, 16, 20, or 24, if their baseline to postbaseline score met one of the following conditions: 'none' at baseline to 'none' postbaseline; 'mild' to 'mild' or 'none'; 'moderate' to 'mild' or 'none'; or 'severe' to 'moderate', 'mild', or 'none'.
  10. Double-Blind Period: Percentage of Participants Who Achieved the Patient Global Impression of Change (PGIC)- Fatigue Response at Weeks 12, 16, 20, and 24
    The PGIC-Fatigue assesses change over time compared with baseline on a 5-point scale ranging from 0 to 4 where 0 indicates Much better and 4 as Much worse. A participant was considered to have achieved the PGIC-Fatigue response at Weeks 12, 16, 20, or 24 if their baseline PGIS and corresponding PGIC met one of the following conditions: if the PGIS at baseline was 'none' or 'mild' and PGIC at the visit was 'no change', 'a little better', or 'much better'; or if the PGIS at baseline was 'moderate' or 'severe' and PGIC at the visit was 'a little better' or 'much better'.
  11. Double-Blind Period: Change From Baseline in the 6-minute Walk Test (6MWT) Distance at Week 24
    The 6MWT is a well-established performance outcome (PerfO) measure that is widely used to evaluate physical activity in terms of distance walked in patients with a variety of conditions. The test measures the distance an individual can walk on a hard, flat surface in 6 minutes.
  12. Double-Blind Period: Change From Baseline in Serum Ferritin at Week 24
    Iron metabolism was assessed based on serum ferritin levels.
  13. Double-Blind Period: Change From Baseline in Transferrin Saturation (TSAT) at Week 24
    Iron metabolism was assessed based on TSAT levels. Transferrin saturation is reported by dividing value of serum iron by total iron binding capacity.
  14. 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
    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.
  15. Double-Blind Period: Plasma Concentration of Mitapivat
  16. 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.
  17. Double-Blind Period: Time of Last Quantifiable Concentration (Tlast) of Mitapivat
  18. Double-Blind Period: Maximum Observed Plasma Concentration (Cmax) of Mitapivat
  19. Double-Blind Period: Time to Reach Maximum Observed Plasma Concentration (Tmax) of Mitapivat
  20. Double-Blind Period: Last Quantifiable Plasma Concentration (Clast) of Mitapivat
  21. Double-Blind Period: Blood Concentration of Adenosine Triphosphate (ATP)
  22. Double-Blind Period: Blood Concentration of 2,3 - Diphosphoglycerate (2,3-DPG)
  23. Open-Label Extension Period: Number of Participants With Treatment-Emergent Adverse Events (TEAEs), Serious TEAEs, Related TEAEs and TEAEs With Severity of Greater Than or Equal to Grade 3
    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.

Eligibility Criteria

Ages Eligible for Study(Adult, Older Adult)
Sexes Eligible for StudyAll
Accepts Healthy VolunteersNo
Inclusion Criteria
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.
Exclusion Criteria
Pregnant, breastfeeding, or parturient
Documented history of homozygous or heterozygous sickle hemoglobin (HbS) or hemoglobin C (HbC);
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 ≥18 weeks before randomization;
Currently receiving treatment with hematopoietic stimulating agents; the last dose must have been administered ≥18 weeks before randomization;
History of malignancy, (active or treated) ≤5 years before providing informed consent;
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;
Hepatobiliary disorders;
Estimated glomerular filtration rate \<45 milliliters per minute (mL/min)/1.73 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) ≤16 weeks 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 ≥10 weeks before randomization;
Known allergy to mitapivat or its excipients (microcrystalline cellulose, croscarmellose sodium, sodium stearyl fumarate, mannitol, and magnesium stearate, Opadry® II Blue \[hypromellose, titanium dioxide, lactose monohydrate, triacetin, and FD\&C Blue #2\]);
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
San Diego Hospital, UC San Diego Health | La Jolla California, United States, 92093Stanford Medicine | Palo Alto California, United States, 94304-1601Massachusetts General Hospital | Boston Massachusetts, United States, 02114-2696Weill 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, 19104Universidade de Caxias do Sul | Caxias do Sul , Brazil, 95070-560Hospital das Clínicas da Faculdade de Medicina de Ribeirão Preto - USP | Ribeirão Preto , Brazil, 14051-260HEMORIO Instituto Nacional de Hematologia | Rio de Janeiro , Brazil, 20211-030Praxis Pesquisa Medica | Santo André , Brazil, 09090-790GSH Banco de Sangue de São Paulo | São Paulo , Brazil, 04006-002Instituto do Cancer do Estado de São Paulo, Hospital das Clínicas da Faculdade de Medicina da Universidad de São Paulo | São Paulo , Brazil, 05403-000MHAT "Dr. Nikola Vasiliev" AD | Kyustendil , Bulgaria, 2500SHATHD Sofia | Sofia , Bulgaria, 1756Toronto General Hospital, University Health Network | Toronto , Canada, M5G 2C4Rigshospitalet | Copenhagen , Denmark, 2100CHU Hôpital Henri Mondor | Créteil , France, 94010Hopital Edouard Herriot, CHU de Lyon | Lyon , France, 69003Laiko General Hospital | Athens , Greece, 115 26Children's Hospital Agia Sophia, National and Kapodistrian University of Athens Medical School | Athens , Greece, 115 27University General Hospital of Patras | Rio , Greece, 26504Ippokrateio 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 Ca' Granda Ospedale Maggiore Policlinico | Milan , Italy, 20122A.O.U Di Modena | Modena , Italy, 41124A.O.R.N. "A. Cardarelli" | Naples , Italy, 80131AOU 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 Ampang | Ampang , Malaysia, 68000Hospital 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 Pulau Pinang | Pulau Pinang , Malaysia, 10990Erasmus MC | Rotterdam , Netherlands, 3015 GDUniversitair Medisch Centrum Utrecht | Utrecht , Netherlands, 3584 CXKing Abdulaziz Hospital - Al Ahsa | Al Mubarraz , Saudi Arabia, 36428King Abdullah International Medical Research Center | Riyadh , Saudi Arabia, 14611Hospital 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, 41013China Medical University, Taiwan | Taichung , Taiwan, 40447Phramongkutklao 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, 40002Naresuan University Hospital | Mueang Phitsanulok , Thailand, 65000King Chulalongkorn Memorial Hospital | Pathum Wan , Thailand, 10330Acibadem Adana Hospital | Adana , Turkey (Türkiye), 01130Akdeniz 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), 06230Burjeel Medical City | Abu Dhabi , United Arab Emirates, Thalassemia Centre Dubai | Dubai , United Arab Emirates, 4545Cambridge University Hospitals NHS Foundation Trust - Addenbrookes Hospital | Cambridge CAM, United Kingdom, CB2 0QQManchester Royal Infirmary, Manchester University NHS Foundation Trust | Manchester LAN, United Kingdom, M13 9WLUniversity College London | London , United Kingdom, NW1 2PGImperial College Healthcare NHS Trust - Hammersmith Hospital | London , United Kingdom, W12 OHS
Investigators
Study Chair: Medical Affairs, Agios Pharmaceuticals, Inc.
Study Documents (Full Text)
Documents provided by Agios Pharmaceuticals, Inc.: Study Protocol  August 4, 2024Documents provided by Agios Pharmaceuticals, Inc.: Statistical Analysis Plan  November 13, 2022