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

NCT ID: NCT04770779

Last Updated: 2026-01-29

Basic Information

• Recruitment Status: ACTIVE_NOT_RECRUITING
• Clinical Phase: PHASE3
• Total Enrollment: 258 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2021-11-30
• Study Completion Date: 2029-06-30

Brief Summary

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.

Detailed Description

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

Conditions

Transfusion-dependent Alpha-Thalassemia; Transfusion-dependent Beta-Thalassemia

Study Design

• Allocation Method: RANDOMIZED
• Intervention Model: PARALLEL
• Primary Study Purpose: TREATMENT
• Blinding Strategy: QUADRUPLE

Study Groups

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.

Group Type: EXPERIMENTAL

Mitapivat

Intervention Type: DRUG

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.

Group Type: PLACEBO_COMPARATOR

Placebo Matching Mitapivat

Intervention Type: DRUG

Tablets

Mitapivat

Intervention Type: DRUG

Tablets

Interventions

Placebo Matching Mitapivat

Tablets

Intervention Type: DRUG

Mitapivat

Tablets

Intervention Type: DRUG

Other Intervention Names

AG-348; AG-348 sulfate hydrate; Mitapivat sulfate

Eligibility Criteria

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).

• Minimum Eligible Age: 18 Years
• Eligible Sex: ALL
• Accepts Healthy Volunteers: No

Sponsors

Agios Pharmaceuticals, Inc.

INDUSTRY

Sponsor Role: lead

Responsible Party

Responsibility Role: SPONSOR

Principal Investigators

Medical Affairs

Role: STUDY_CHAIR

Agios Pharmaceuticals, Inc.

Locations

Phoenix Children's Hospital

Phoenix, Arizona, United States

San Diego Hospital, UC San Diego Health

La Jolla, California, United States

Children's Hospital Oakland

Oakland, California, United States

Stanford Medicine

Palo Alto, California, United States

Boston Children's Hospital

Boston, Massachusetts, United States

Children's Hospital of Michigan

Detroit, Michigan, United States

Weill Cornell Medical Center

New York, New York, United States

Duke University Medical Center

Durham, North Carolina, United States

Penn Medicine - University of Pennsylvania Health System

Philadelphia, Pennsylvania, 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

GSH Banco de Sangue de São Paulo

São Paulo, , Brazil

MHAT "Dr. Nikola Vasiliev" AD

Kyustendil, , Bulgaria

UMHAT "Dr. Georgi Stranski" Pleven

Pleven, , Bulgaria

UMHAT "Sveti Georgi" EAD

Plovdiv, , Bulgaria

SHATHD Sofia

Sofia, , Bulgaria

UMHAT "Prof. Dr. Stoyan Kirkovich"

Stara Zagora, , Bulgaria

Foothills Medical Centre

Calgary, Alberta, Canada

Toronto General Hospital, University Health Network

Toronto, Ontario, Canada

Rigshospitalet

Hovedstaden, , Denmark

CHU Hôpital Henri Mondor

Créteil, , France

Hôpital Edouard Herriot, CHU de Lyon

Lyon, , France

CHU Hôpital de la Timone

Marseille, , France

Hôpital Necker Enfants Malades

Paris, , France

Charité - UB - CVK - Medizinische Klinik

Berlin, , Germany

Universitätsklinikum Essen

Essen, , Germany

Universitätsklinikum Leipzig

Leipzig, , Germany

University General Hospital of Patras

Achaia, , Greece

Laiko General Hospital

Athens, , Greece

Children's Hospital Agia Sophia, National and Kapodistrian University of Athens Medical School

Athens, , Greece

University Hospital of Ioannina

Ioannina, , Greece

Ippokrateio General Hospital

Thessaloniki, , Greece

Ospedale "A. Perrino" - Brindisi

Brindisi, , Italy

Ospedale Pediatrico Microcitemico

Cagliari, , Italy

Ospedale Sant'Anna

Ferrara, , Italy

Ente Ospedaliero Ospedali Galliera

Genova, , Italy

Fondazione IRCCS Cà Granda Ospedale Maggiore Policlinico

Milan, , Italy

A.O.U Di Modena

Modena, , Italy

AOU L. Vanvitelli Universita degli Studi della Campania Luigi Vanvitelli

Napoli, , Italy

A.O.U. San Luigi Gonzaga

Orbassano, , Italy

Chronic Care Center

Beirut, , Lebanon

Hospital Sultanah Bahiyah

Alor Star, , Malaysia

Hospital Sultanah Aminah Johor Bahru

Johor Bahru, , Malaysia

Hospital Queen Elizabeth, Kota Kinabalu

Kota Kinabalu, , Malaysia

Hospital Tunku Azizah

Kuala Lumpur, , Malaysia

Hospital Tengku Ampuan Afzan

Kuantan, , Malaysia

Hospital Umum Sarawak

Kuching, , Malaysia

Hospital Ampang

Pandan Indah, , Malaysia

Hospital Pulau Pinang

Pulau Pinang, , Malaysia

Amsterdam Universitair Medisch Centrum, Locatie AMC

Amsterdam, , Netherlands

Universitair Medisch Centrum Utrecht

Utrecht, , Netherlands

Erasmus MC

Westzeedijk 353, , Netherlands

King Abdullah International Medical Research Center

Riyadh, , Saudi Arabia

King Khalid University Hospital

Riyadh, , 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

Seville, , Spain

National Taiwan University Hospital

Taipei, , Taiwan

Phramongkutklao Hospital

Bangkok, , Thailand

Ramathibodi Hospital

Bangkok, , Thailand

Faculty of Medicine Siriraj Hospital

Bangkok, , Thailand

Maharaj Nakorn Chiang Mai Hospital

Chiang Mai, , Thailand

Srinagarind Hospital, Khon Kaen University

Khon Kaen, , Thailand

Naresuan University Hospital

Mueang Phitsanulok, , Thailand

King Chulalongkorn Memorial Hospital

Pathum Wan, , Thailand

Acibadem Adana Hospital

Adana, , Turkey (Türkiye)

Akdeniz University Faculty of Medicine

Antalya, , Turkey (Türkiye)

Çukurova University

Balcalı, , Turkey (Türkiye)

Ege University Faculty of Medicine

Bornova, , Turkey (Türkiye)

Istanbul University Faculty of Medicine

Fatih, , Turkey (Türkiye)

Hacettepe University

Mersin, , Turkey (Türkiye)

Burjeel Medical City

Abu Dhabi, , United Arab Emirates

Imperial College Healthcare NHS Trust - Hammersmith Hospital

London, , United Kingdom

University College London

London, , United Kingdom

Countries

United States; Brazil; Bulgaria; Canada; Denmark; France; Germany; Greece; Italy; Lebanon; Malaysia; Netherlands; Saudi Arabia; Spain; Taiwan; Thailand; Turkey (Türkiye); United Arab Emirates; United Kingdom

Provided Documents

Document Type: Study Protocol

View Document

Document Type: Statistical Analysis Plan

View Document

Other Identifiers

2021-000212-34

Identifier Type: EUDRACT_NUMBER

Identifier Source: secondary_id

2024-512747-23-00

Identifier Type: CTIS

Identifier Source: secondary_id

AG348-C-018

Identifier Type: -

Identifier Source: org_study_id