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

A 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)

The primary objective of this study was to compare the effect of mitapivat versus placebo on transfusion burden in participants with α- or β-transfusion-dependent thalassemia.

Study Overview

• Status: Active, not recruiting
• Conditions: Transfusion-dependent Alpha-Thalassemia; Transfusion-dependent Beta-Thalassemia
• Intervention / Treatment: Drug: Mitapivat; Drug: Placebo Matching Mitapivat

Detailed Description

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

• Study Type: Interventional
• Enrollment (Actual): 258
• Phase: Phase 3

Contacts and Locations

Study Locations

• Brazil
  • Ribeirão Preto, Brazil, 14051-260
    • Hospital Das Clinicas da Faculdade de Medicina de Ribeirão Preto - USP
  • São Paulo, Brazil, 04006-002
    • GSH Banco de Sangue de São Paulo
• Bulgaria
  • Kyustendil, Bulgaria, 2500
    • MHAT "Dr. Nikola Vasiliev" AD
  • Pleven, Bulgaria, 5800
    • UMHAT "Dr. Georgi Stranski" Pleven
  • Plovdiv, Bulgaria, 4002
    • UMHAT "Sveti Georgi" EAD
  • Sofia, Bulgaria, 1756
    • SHATHD Sofia
  • Stara Zagora, Bulgaria, 6000
    • UMHAT "Prof. Dr. Stoyan Kirkovich"
• Canada
  • Alberta
    • Calgary, Alberta, Canada, T2N 2T9
      • Foothills Medical Centre
  • Ontario
    • Toronto, Ontario, Canada, M5G 2C4
      • Toronto General Hospital, University Health Network
• Denmark
  • Hovedstaden, Denmark, 2100
    • Rigshospitalet
• France
  • Créteil, France, 94010
    • CHU Hôpital Henri Mondor
  • Lyon, France, 69003
    • Hopital Edouard Herriot, CHU de Lyon
  • Marseille, France, 13385
    • CHU Hôpital de la Timone
  • Paris, France, 75015
    • Hôpital Necker Enfants Malades
• Germany
  • Berlin, Germany, 13353
    • Charité - UB - CVK - Medizinische Klinik
  • Essen, Germany, 45122
    • Universitatsklinikum Essen
  • Leipzig, Germany, 04103
    • Universitatsklinikum Leipzig
• Greece
  • Achaia, Greece, 26504
    • University General Hospital of Patras
  • Athens, Greece, 11527
    • Children's Hospital Agia Sophia, National and Kapodistrian University of Athens Medical School
  • Athens, Greece, 115 26
    • Laiko General Hospital
  • Ioannina, Greece, 455 00
    • University Hospital of Ioannina
  • Thessaloniki, Greece, 546 42
    • Ippokrateio General Hospital
• Italy
  • Brindisi, Italy, 72100
    • Ospedale "A. Perrino" - Brindisi
  • Cagliari, Italy, 09121
    • Ospedale Pediatrico Microcitemico
  • Ferrara, Italy, 44124
    • Ospedale Sant'Anna
  • Genova, Italy, 16128
    • Ente Ospedaliero Ospedali Galliera
  • Milan, Italy, 20122
    • Fondazione IRCCS Cà Granda Ospedale Maggiore Policlinico
  • Modena, Italy, 41124
    • A.O.U Di Modena
  • Naples, Italy, 80138
    • AOU L. Vanvitelli Universita degli Studi della Campania Luigi Vanvitelli
  • Orbassano, Italy, 10043
    • A.O.U. San Luigi Gonzaga
• Lebanon
  • Beirut, Lebanon, 9999
    • Chronic Care Center
• Malaysia
  • Alor Star, Malaysia, 05460
    • Hospital Sultanah Bahiyah
  • Johor Bahru, Malaysia, 80100
    • Hospital Sultanah Aminah Johor Bahru
  • Kota Kinabalu, Malaysia, 88586
    • Hospital Queen Elizabeth, Kota Kinabalu
  • Kuala Lumpur, Malaysia, 50300
    • Hospital Tunku Azizah
  • Kuantan, Malaysia, 25100
    • Hospital Tengku Ampuan Afzan
  • Kuching, Malaysia, 93586
    • Hospital Umum Sarawak
  • Pandan Indah, Malaysia, 68000
    • Hospital Ampang
  • Pulau Pinang, Malaysia, 10990
    • Hospital Pulau Pinang
• Netherlands
  • Amsterdam, Netherlands, 1105 AZ
    • Amsterdam Universitair Medisch Centrum, Locatie AMC
  • Utrecht, Netherlands, 3584 CX
    • Universitair Medisch Centrum Utrecht
  • Westzeedijk 353, Netherlands, 3015 AA
    • Erasmus MC
• Saudi Arabia
  • Riyadh, Saudi Arabia, 14611
    • King Abdullah International Medical Research Center
  • Riyadh, Saudi Arabia, 90210
    • King Khalid University Hospital
• Spain
  • Barcelona, Spain, 08035
    • Hospital Universitario Vall d'Hebron
  • Madrid, Spain, 28046
    • Hospital Universitario La Paz
  • Murcia, Spain, 30120
    • Hospital Universitario Virgen Arrixaca
  • Seville, Spain, 41013
    • Hospital Universitario Virgen del Rocio
• Taiwan
  • Taipei, Taiwan, 100
    • National Taiwan University Hospital
• Thailand
  • Bangkok, Thailand, 10400
    • Phramongkutklao Hospital
  • Bangkok, Thailand, 10400
    • Ramathibodi Hospital
  • Bangkok, Thailand, 10700
    • Faculty of Medicine Siriraj Hospital
  • Chiang Mai, Thailand, 50200
    • Maharaj Nakorn Chiang Mai Hospital
  • Khon Kaen, Thailand, 40000
    • Srinagarind Hospital, Khon Kaen University
  • Mueang Phitsanulok, Thailand, 65000
    • Naresuan University Hospital
  • Pathum Wan, Thailand
    • King Chulalongkorn Memorial Hospital
• Turkey (Türkiye)
  • Adana, Turkey (Türkiye), 1130
    • Acibadem Adana Hospital
  • Antalya, Turkey (Türkiye), 07059
    • Akdeniz University Faculty of Medicine
  • Balcalı, Turkey (Türkiye), 01330
    • Cukurova University
  • Bornova, Turkey (Türkiye), 35040
    • Ege University Faculty of Medicine
  • Fatih, Turkey (Türkiye), 34093
    • Istanbul University Faculty of Medicine
  • Mersin, Turkey (Türkiye)
    • Hacettepe University
• United Arab Emirates
  • Abu Dhabi, United Arab Emirates
    • Burjeel Medical City
• United Kingdom
  • London, United Kingdom, WC1E 6BT
    • University College London
  • London, United Kingdom, W12 0HS
    • Imperial College Healthcare NHS Trust - Hammersmith Hospital
• United States
  • Arizona
    • Phoenix, Arizona, United States, 85016-7710
      • Phoenix Children's Hospital
  • California
    • La Jolla, California, United States, 92093
      • San Diego Hospital, UC San Diego Health
    • Oakland, California, United States, 94609-1809
      • Children's Hospital Oakland
    • Palo Alto, California, United States, 94304-1601
      • Stanford Medicine
  • Massachusetts
    • Boston, Massachusetts, United States, 02115
      • Boston Children's Hospital
  • Michigan
    • Detroit, Michigan, United States, 48201-2196
      • Children's Hospital of Michigan
  • New York
    • New York, New York, United States, 10065-4870
      • Weill Cornell Medical Center
  • North Carolina
    • Durham, North Carolina, United States, 27710-3038
      • Duke University Medical Center
  • Pennsylvania
    • Philadelphia, Pennsylvania, United States, 19104
      • Penn Medicine - University of Pennsylvania Health System
  • Washington
    • Seattle, Washington, United States, 98101
      • Seattle Cancer Care Alliance, University of Washington

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Description

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).

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Quadruple

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: 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; Other Names: AG-348; AG-348 sulfate hydrate; Mitapivat sulfate
Placebo Comparator: 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: Mitapivat; Tablets; Other Names: AG-348; AG-348 sulfate hydrate; Mitapivat sulfate; Drug: Placebo Matching Mitapivat; Tablets

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
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.	Double-blind Period: Baseline through Week 48

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
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.	Double-blind period: Baseline through Week 48
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.	Double-blind period: Baseline up to Week 13 through Week 48
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.	Double-blind period: Baseline up to Week 13 through Week 48
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.	Double-blind Period: Baseline, Week 13 through Week 48
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.	Double-blind Period: Baseline through Week 48
Double-blind Period: Change From Baseline in Iron Levels	Iron metabolism was assessed based on Iron levels.	Double-blind Period: Baseline through Week 48
Double-blind Period: Change From Baseline in Serum Ferritin Levels	Iron metabolism was assessed based on serum ferritin levels.	Double-blind Period: Baseline through Week 48
Double-blind Period: Change From Baseline in Total Iron Binding Capacity	Iron metabolism was assessed based on total iron binding capacity.	Double-blind Period: Baseline through Week 48
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.	Double-blind Period: Baseline through Week 48
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.	Double-blind Period: From first dose of study drug up to week 48
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.	Open-Label Extension Period: From Week 48 up to end of study (approximately 5 years)
Double-blind Period: Plasma Concentrations of Mitapivat		Double-blind Period: Pre-dose at Week 12; pre-dose at Week 24; pre-dose, 0.5, 1, 3, 5, 7 hours post-dose at Week 36
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.	Double-blind Period: Pre-dose, 0.5, 1, 3, 5, 7 hours post-dose at Week 36
Double-blind Period: Maximum Observed Plasma Concentration (Cmax) of Mitapivat		Double-blind Period: Pre-dose, 0.5, 1, 3, 5, 7 hours post-dose Week 36
Double-blind Period: Time to Reach of Maximum Observed Plasma Concentration (Tmax) of Mitapivat		Double-blind Period: Pre-dose, 0.5, 1, 3, 5, 7 hours post-dose Week 36
Double-blind Period: Time of Last Quantifiable Concentration (Tlast) of Mitapivat		Double-blind Period: Pre-dose, 0.5, 1, 3, 5, 7 hours post-dose Week 36
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.	Double-blind Period: Pre-dose, 0.5, 1, 3, 5, 7 hours post-dose Week 36
Double-blind Period: Blood Concentration of Adenosine Triphosphate (ATP)		Double-blind Period: Pre-dose at Day 1; pre-dose at Week 12; pre-dose at Week 24; pre-dose, 0.5, 1, 3, 5, 7 hours post-dose at Week 36
Double-blind Period: Blood Concentration of 2,3 - Diphosphoglycerate (2,3-DPG)		Double-blind Period: Pre-dose at Day 1; pre-dose at Week 12; pre-dose at Week 24; pre-dose, 0.5, 1, 3, 5, 7 hours post-dose at Week 36

Collaborators and Investigators

• Sponsor: Agios Pharmaceuticals, Inc.
• Investigators: Study Chair: Medical Affairs, Agios Pharmaceuticals, Inc.

Study record dates

Study Major Dates

• Study Start (Actual): November 30, 2021
• Primary Completion (Actual): April 11, 2024
• Study Completion (Estimated): June 1, 2029

Study Registration Dates

• First Submitted: February 18, 2021
• First Submitted That Met QC Criteria: February 22, 2021
• First Posted (Actual): February 25, 2021

Study Record Updates

• Last Update Posted (Actual): April 24, 2026
• Last Update Submitted That Met QC Criteria: April 22, 2026
• Last Verified: April 1, 2026

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Genetic Diseases, Inborn; Hematologic Diseases; Anemia, Hemolytic, Congenital; Anemia, Hemolytic; Anemia; Hemoglobinopathies; Thalassemia; beta-Thalassemia; alpha-Thalassemia; Molecular Mechanisms of Pharmacological Action; Enzyme Activators; mitapivat
• Other Study ID Numbers: AG348-C-018; 2021-000212-34 (EudraCT Number); 2024-512747-23-00 (Ctis)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: No