Transfusion-dependent Alpha-ThalassemiaPhase 3ENERGIZE-TNCT04770779
A Study Evaluating the Efficacy and Safety of Mitapivat in Participants With Transfusion-Dependent Alpha- or Beta-Thalassemia (α- or β-TDT)
A Phase 3 study testing Mitapivat in people with Transfusion-dependent Alpha-Thalassemia and Transfusion-dependent Beta-Thalassemia, run by Agios Pharmaceuticals, Inc. at 75 sites in 19 countries.
Trial 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. Read more about this study
- Who is it for?
- Ages 18 years and older
- Conditions the study is for
- Transfusion-dependent Alpha-Thalassemia, Transfusion-dependent Beta-Thalassemia
- What is being tested?
- Mitapivat
- Type of treatment
- Pill or oral medicine
- Could I receive a placebo?
- Yes, some participants may receive a placebo
- How many people
- 258 participants
- Where
- 75 sitesin 19 countries
- Study dates
- 30 Nov 2021to Jun 2029
- Phase
- Phase 3
- Are there results?
- Yes, posted in the registrySummary in the doctors' view
Key requirements
Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.
- Ages 18 years and older
- All sexes
- No healthy volunteers
- Adult, Older adult
Who may be able to join
- 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.
Who cannot join
- 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;
Show all 21Show fewer
- 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).
Trial locations and contacts
75 sites in 19 countries.
75 sites in 19 countries
United States10 sites
Boston Children's Hospital
Boston, Massachusetts, 02115
Children's Hospital of Michigan
Detroit, Michigan, 48201-2196
Duke University Medical Center
Durham, North Carolina, 27710-3038
San Diego Hospital, UC San Diego Health
La Jolla, California, 92093
Weill Cornell Medical Center
New York, New York, 10065-4870
Children's Hospital Oakland
Oakland, California, 94609-1809
Stanford Medicine
Palo Alto, California, 94304-1601
Penn Medicine - University of Pennsylvania Health System
Philadelphia, Pennsylvania, 19104
Phoenix Children's Hospital
Phoenix, Arizona, 85016-7710
Seattle Cancer Care Alliance, University of Washington
Seattle, Washington, 98101
Italy8 sites
Ospedale "A. Perrino" - Brindisi
Brindisi, 72100
Ospedale Pediatrico Microcitemico
Cagliari, 09121
Ospedale Sant'Anna
Ferrara, 44124
Ente Ospedaliero Ospedali Galliera
Genova, 16128
Fondazione IRCCS Cà Granda Ospedale Maggiore Policlinico
Milan, 20122
A.O.U Di Modena
Modena, 41124
AOU L. Vanvitelli Universita degli Studi della Campania Luigi Vanvitelli
Naples, 80138
A.O.U. San Luigi Gonzaga
Orbassano, 10043
Malaysia8 sites
Hospital Sultanah Bahiyah
Alor Star, 05460
Hospital Sultanah Aminah Johor Bahru
Johor Bahru, 80100
Hospital Queen Elizabeth, Kota Kinabalu
Kota Kinabalu, 88586
Hospital Tunku Azizah
Kuala Lumpur, 50300
Hospital Tengku Ampuan Afzan
Kuantan, 25100
Hospital Umum Sarawak
Kuching, 93586
Hospital Ampang
Pandan Indah, 68000
Hospital Pulau Pinang
Pulau Pinang, 10990
Thailand7 sites
Phramongkutklao Hospital
Bangkok, 10400
Ramathibodi Hospital
Bangkok, 10400
Faculty of Medicine Siriraj Hospital
Bangkok, 10700
Maharaj Nakorn Chiang Mai Hospital
Chiang Mai, 50200
Srinagarind Hospital, Khon Kaen University
Khon Kaen, 40000
Naresuan University Hospital
Mueang Phitsanulok, 65000
King Chulalongkorn Memorial Hospital
Pathum Wan
Turkey (Türkiye)6 sites
Acibadem Adana Hospital
Adana, 1130
Akdeniz University Faculty of Medicine
Antalya, 07059
Çukurova University
Balcalı, 01330
Ege University Faculty of Medicine
Bornova, 35040
Istanbul University Faculty of Medicine
Fatih, 34093
Hacettepe University
Mersin
Bulgaria5 sites
MHAT "Dr. Nikola Vasiliev" AD
Kyustendil, 2500
UMHAT "Dr. Georgi Stranski" Pleven
Pleven, 5800
UMHAT "Sveti Georgi" EAD
Plovdiv, 4002
SHATHD Sofia
Sofia, 1756
UMHAT "Prof. Dr. Stoyan Kirkovich"
Stara Zagora, 6000
Greece5 sites
University General Hospital of Patras
Achaia, 26504
Laiko General Hospital
Athens, 115 26
Children's Hospital Agia Sophia, National and Kapodistrian University of Athens Medical School
Athens, 11527
University Hospital of Ioannina
Ioannina, 455 00
Ippokrateio General Hospital
Thessaloniki, 546 42
France4 sites
CHU Hôpital Henri Mondor
Créteil, 94010
Hôpital Edouard Herriot, CHU de Lyon
Lyon, 69003
CHU Hôpital de la Timone
Marseille, 13385
Hôpital Necker Enfants Malades
Paris, 75015
Spain4 sites
Hospital Universitario Vall d'Hebron
Barcelona, 08035
Hospital Universitario La Paz
Madrid, 28046
Hospital Universitario Virgen Arrixaca
Murcia, 30120
Hospital Universitario Virgen del Rocío
Seville, 41013
Germany3 sites
Charité - UB - CVK - Medizinische Klinik
Berlin, 13353
Universitätsklinikum Essen
Essen, 45122
Universitätsklinikum Leipzig
Leipzig, 04103
Netherlands3 sites
Amsterdam Universitair Medisch Centrum, Locatie AMC
Amsterdam, 1105 AZ
Universitair Medisch Centrum Utrecht
Utrecht, 3584 CX
Erasmus MC
Westzeedijk 353, 3015 AA
Brazil2 sites
Hospital Das Clínicas da Faculdade de Medicina de Ribeirão Preto - USP
Ribeirão Preto, 14051-260
GSH Banco de Sangue de São Paulo
São Paulo, 04006-002
Canada2 sites
Foothills Medical Centre
Calgary, Alberta, T2N 2T9
Toronto General Hospital, University Health Network
Toronto, Ontario, M5G 2C4
Saudi Arabia2 sites
King Abdullah International Medical Research Center
Riyadh, 14611
King Khalid University Hospital
Riyadh, 90210
United Kingdom2 sites
Imperial College Healthcare NHS Trust - Hammersmith Hospital
London, W12 0HS
University College London
London, WC1E 6BT
About this study
Official title: 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.
Read the detailed description
The mitapivat group included 171 participants. The placebo group included 87 participants.
- Being tested
- Placebo Matching Mitapivat, Mitapivat
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
Placebo Matching MitapivatDrug
Tablets
MitapivatDrug
Also called AG-348, AG-348 sulfate hydrate, Mitapivat sulfate
Tablets
| Study group | Role | What they receive |
|---|---|---|
| Mitapivat | Experimental | 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. Receives: Drug: Mitapivat |
| Placebo | Placebo comparator | 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. Receives: Drug: Placebo Matching Mitapivat; Drug: Mitapivat |
What is being measured
The primary outcome is the main question the study is designed to answer.
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.
Measured: Double-blind Period: Baseline through Week 48
Secondary outcomes (19)
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.
Measured: 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.
Measured: 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.
Measured: 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.
Measured: 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.
Measured: Double-blind Period: Baseline through Week 48
Double-blind Period: Change From Baseline in Iron Levels
Iron metabolism was assessed based on Iron levels.
Measured: 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.
Measured: 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.
Measured: 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.
Measured: 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.
Measured: 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.
Measured: Open-Label Extension Period: From Week 48 up to end of study (approximately 5 years)
Double-blind Period: Plasma Concentrations of Mitapivat
Measured: 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.
Measured: 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
Measured: 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
Measured: 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
Measured: 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.
Measured: 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)
Measured: 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)
Measured: 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
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted25 Feb 2021
- Study start30 Nov 2021
- Primary completion11 Apr 2024
- Study completionJun 2029 (estimated)
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Posted resultsParticipant flow, outcome measures and adverse events reported by the sponsor.
- Publications (1)Papers the sponsor has linked to this study.
- Other trials for Transfusion-dependent Alpha-ThalassemiaStudies of the same condition, open and under way.
- More trials run by Agios Pharmaceuticals, Inc.The sponsor's other registered studies.
- What the trial phases meanHow a treatment moves from first tests in people to approval.
More details
For doctors and researchers: how the study is designed, who runs it, and its registry IDs.
Study design
- Study type
- Interventional
- Phase
- Phase 3
- Primary purpose
- Treatment
- Allocation
- Randomised
- Intervention model
- Parallel groups
- Masking
- Quadruple blind
- Who is masked
- Participant, Care provider, Investigator, Outcomes assessor
- Enrolment
- 258 participants (actual)
Sponsor and investigators
- Lead sponsor
- Agios Pharmaceuticals, Inc.
- Sponsor type
- Industry (pharma, biotech, devices)
- Responsible party
- Sponsor
- Investigators
- Medical Affairs, Study chair, Agios Pharmaceuticals, Inc.
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT04770779
- Sponsor's protocol ID
- AG348-C-018
- Other IDs
- 2021-000212-34, 2024-512747-23-00
- Acronym
- ENERGIZE-T
- Status last verified
- Oct 2026
- First submitted
- 18 Feb 2021
- Last updated
- 28 Oct 2026
- Results posted
- Yes, on ClinicalTrials.gov
- Data monitoring committee
- Yes
- FDA-regulated drug
- Yes
- FDA-regulated device
- No
- Individual data sharing
- No
Publications
Cappellini MD, Sheth S, Taher A, Al-Samkari H, Antmen AB, Beneitez D, Cannas G, Coates T, Czapla L, Dahlin JL, Estepp JH, Feenstra E, Georgiev P, Gheuens S, Price GM, Glenthoj A, Musallam KM, Osman K, Porter JB, Shao H, Uhlig K, van Beers EJ, Viprakasit V, Kuo KHM, Kattamis A; ENERGIZE-T Investigators. Efficacy and safety of mitapivat in adults with transfusion-dependent alpha-thalassaemia or beta-thalassaemia (ENERGIZE-T): a double-blind, randomised, multicentre, placebo-controlled, phase 3 trial. Lancet. 2026 Sep 12;408(10559):1010-1018. doi: 10.1016/S0140-6736(26)00874-3.
PubMed 42721980
Study at a glance
From the registry record, last updated by the sponsor on 28 Oct 2026. Recruitment status is as the sponsor reported it: confirm with the study team.
- Official title
- 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)
- ClinicalTrials.gov ID
- NCT04770779
- Acronym / sponsor ID
- ENERGIZE-T / AG348-C-018
- Phase
- Phase 3
- Study type
- Interventional
- Recruitment status
- Active, not recruiting
- Enrolment
- 258 participants (actual)
- Lead sponsor
- Agios Pharmaceuticals, Inc.Industry (pharma, biotech, devices)
- Study start
- 30 Nov 2021 (actual)
- Primary completion
- 11 Apr 2024 (actual)
- Study completion
- Jun 2029 (estimated)
- First posted
- 25 Feb 2021 (actual)
- Results
- Posted 25 May 2025
Clinical summary
The research question as the sponsor registered it. This describes what the study plans to test, not what it found.
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.
Study design
- Primary purpose
- Treatment
- Allocation
- Randomised
- Intervention model
- Parallel groups
- Masking
- Quadruple blind (participant, care provider, investigator, outcomes assessor)
- Number of arms
- 2
| Arm | Type | Receives |
|---|---|---|
| Mitapivat | Experimental | Drug: MitapivatParticipants 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. |
| Placebo | Placebo comparator | Drug: Placebo Matching Mitapivat, Drug: MitapivatParticipants 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. |
Who may qualify
- Ages
- 18 years and older
- Sex
- All
- Healthy volunteers
- Not accepted
- Age groups
- Adult, Older adult
Key inclusion criteria (6 listed)
- 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;
Key exclusion criteria (21 listed)
- 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;
Eligibility is decided by the study team after screening; this overview does not establish that a patient qualifies. Full inclusion and exclusion criteria.
Interventions
| Intervention | Type | Arms |
|---|---|---|
| Placebo Matching MitapivatTablets | Drug | Placebo |
| MitapivatAlso: AG-348, AG-348 sulfate hydrate, Mitapivat sulfateTablets | Drug | Mitapivat, Placebo |
Primary outcome
Double-blind Period: Percentage of Participants Who Achieved Transfusion Reduction Response (TRR)
Time frame: Double-blind Period: Baseline through Week 48
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.
19 secondary outcomes
Double-blind Period: Percentage of Participants Who Achieved TRR2
Time frame: Double-blind period: Baseline through Week 48
Double-blind Period: Percentage of Participants Who Achieved TRR3
Time frame: Double-blind period: Baseline up to Week 13 through Week 48
Double-blind Period: Percentage of Participants Who Achieved TRR4
Time frame: Double-blind period: Baseline up to Week 13 through Week 48
Double-blind Period: Percent Change From Baseline in Transfused RBC Units
Time frame: Double-blind Period: Baseline, Week 13 through Week 48
Double-blind Period: Percentage of Participants Who Achieved Transfusion-Independence
Time frame: Double-blind Period: Baseline through Week 48
Double-blind Period: Change From Baseline in Iron Levels
Time frame: Double-blind Period: Baseline through Week 48
Double-blind Period: Change From Baseline in Serum Ferritin Levels
Time frame: Double-blind Period: Baseline through Week 48
Double-blind Period: Change From Baseline in Total Iron Binding Capacity
Time frame: Double-blind Period: Baseline through Week 48
Double-blind Period: Change From Baseline in Transferrin Saturation (TSAT) Levels
Time frame: 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
Time frame: 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
Time frame: Open-Label Extension Period: From Week 48 up to end of study (approximately 5 years)
Double-blind Period: Plasma Concentrations of Mitapivat
Time frame: 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
Time frame: 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
Time frame: 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
Time frame: 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
Time frame: 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
Time frame: 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)
Time frame: 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)
Time frame: 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
Results and safety
Loading the posted results from ClinicalTrials.gov…
Research links
- Official record on ClinicalTrials.govLast updated by the sponsor 28 Oct 2026.
- Posted resultsParticipant flow, baseline, all outcome measures and adverse events.
- Derived from this study: PubMed 42721980Cappellini MD, Sheth S, Taher A, Al-Samkari H, Antmen AB, Beneitez D, Cannas G, Coates T, Czapla L, Dahlin JL, Estepp JH, Feenstra E, Georgiev P, Gheuens S, Price GM, Glenthoj A, Musallam KM, Osman K, Porter JB, Shao H, Uhlig K, van Beers EJ, Viprakasit V, Kuo KHM, Kattamis A; ENERGIZE-T Investigators. Efficacy and safety of mitapivat in adults with transfusion-dependent alpha-thalassaemia or beta-thalassaemia (ENERGIZE-T): a double-blind, randomised, multicentre, placebo-controlled, phase 3 trial. Lancet. 2026 Sep 12;408(10559):1010-1018. doi: 10.1016/S0140-6736(26)00874-3.
- Individual participant dataSharing planned: No
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Referral and contact
AzTrials does not enrol participants or take referrals. Contact the study team or a site listed below; they decide who can take part. This study is not recruiting at the moment.
Medical Affairs study chair
Agios Pharmaceuticals, Inc.
75 sites in 19 countries: see every site and its status.
Questions about this trial
What is this clinical trial studying?
A Phase 3 study testing Mitapivat in people with Transfusion-dependent Alpha-Thalassemia and Transfusion-dependent Beta-Thalassemia, run by Agios Pharmaceuticals, Inc. at 75 sites in 19 countries.
The full registered description is in the About this study section and the official record.
Who may be eligible to take part?
The sponsor lists 6 inclusion and 21 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.
Is this clinical trial currently recruiting?
The record says: under way, not looking for participants, as of the sponsor's last update on 28 Oct 2026. Status can change between updates, so confirm with the study contact before making plans.
Where is the study taking place?
The record lists 75 sites in United States, Italy, Malaysia, Thailand, Turkey (Türkiye) and 14 more countries. Whether a site is taking part right now should be confirmed with that site. See every site.
What are the possible benefits and risks?
They depend on the study and the treatment, and no study can promise a benefit. Some participants in this study may receive a placebo. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.
What does this phase mean?
Phase 3 studies compare the treatment with the current standard treatment or a placebo in a large group, to confirm how well it works and watch for side effects.
Not every study follows the same path, and some studies (observational studies, device studies) have no phase.
Are results available for this study?
Yes. Results are posted in the registry (first posted 25 May 2025). A summary is in the For doctors view, and the full results are on ClinicalTrials.gov.
How can a doctor refer a patient or contact the research team?
The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.
What does the primary outcome measure?
Double-blind Period: Percentage of Participants Who Achieved Transfusion Reduction Response (TRR) (time frame: Double-blind Period: Baseline through Week 48). It is what the study was designed to measure, not a finding.
Where can I read the original study information?
On the ClinicalTrials.gov record for NCT04770779, which also lists 1 linked publication.
Does a listing mean the treatment is approved or proven to work?
No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.
How often is this information updated?
AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 28 Oct 2026.