Non-Transfusion-dependent Alpha-ThalassemiaPhase 3NCT04770753
A Study Evaluating the Efficacy and Safety of Mitapivat in Participants With Non-Transfusion-Dependent Alpha- or Beta-Thalassemia (α- or β-NTDT)
A Phase 3 study testing Mitapivat in people with Non-Transfusion-dependent Alpha-Thalassemia and Non-Transfusion-dependent Beta-Thalassemia, run by Agios Pharmaceuticals, Inc. at 68 sites in 18 countries.
Trial summary
The primary purpose of this study was to compare the effect of mitapivat versus placebo on hemolytic anemia in participants with alpha- or beta-non-transfusion dependent thalassemia (NTDT). Read more about this study
- Who is it for?
- Ages 18 years and older
- Conditions the study is for
- Non-Transfusion-dependent Alpha-Thalassemia, Non-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
- 194 participants
- Where
- 68 sitesin 18 countries
- Study dates
- 20 Dec 2021to Dec 2028
- 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
- 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.
Who cannot join
- 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;
Show all 21Show fewer
- 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)
Trial locations and contacts
68 sites in 18 countries.
68 sites in 18 countries
Italy9 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 Ca' Granda Ospedale Maggiore Policlinico
Milan, 20122
A.O.U Di Modena
Modena, 41124
A.O.R.N. "A. Cardarelli"
Naples, 80131
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 Ampang
Ampang, 68000
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 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, 40002
Naresuan University Hospital
Mueang Phitsanulok, 65000
King Chulalongkorn Memorial Hospital
Pathum Wan, 10330
United States6 sites
Massachusetts General Hospital
Boston, Massachusetts, 02114-2696
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
Stanford Medicine
Palo Alto, California, 94304-1601
Penn Medicine - University of Pennsylvania Health System
Philadelphia, Pennsylvania, 19104
Brazil6 sites
Universidade de Caxias do Sul
Caxias do Sul, 95070-560
Hospital das Clínicas da Faculdade de Medicina de Ribeirão Preto - USP
Ribeirão Preto, 14051-260
HEMORIO Instituto Nacional de Hematologia
Rio de Janeiro, 20211-030
Praxis Pesquisa Medica
Santo André, 09090-790
GSH Banco de Sangue de São Paulo
São Paulo, 04006-002
Instituto do Cancer do Estado de São Paulo, Hospital das Clínicas da Faculdade de Medicina da Universidad de São Paulo
São Paulo, 05403-000
Turkey (Türkiye)6 sites
Acibadem Adana Hospital
Adana, 01130
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, 06230
Greece4 sites
Laiko General Hospital
Athens, 115 26
Children's Hospital Agia Sophia, National and Kapodistrian University of Athens Medical School
Athens, 115 27
University General Hospital of Patras
Rio, 26504
Ippokrateio General Hospital
Thessaloniki, 546 42
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
United Kingdom4 sites
Cambridge University Hospitals NHS Foundation Trust - Addenbrookes Hospital
Cambridge, CAM, CB2 0QQ
University College London
London, NW1 2PG
Imperial College Healthcare NHS Trust - Hammersmith Hospital
London, W12 OHS
Manchester Royal Infirmary, Manchester University NHS Foundation Trust
Manchester, LAN, M13 9WL
Bulgaria2 sites
MHAT "Dr. Nikola Vasiliev" AD
Kyustendil, 2500
SHATHD Sofia
Sofia, 1756
France2 sites
CHU Hôpital Henri Mondor
Créteil, 94010
Hopital Edouard Herriot, CHU de Lyon
Lyon, 69003
Netherlands2 sites
Erasmus MC
Rotterdam, 3015 GD
Universitair Medisch Centrum Utrecht
Utrecht, 3584 CX
Saudi Arabia2 sites
King Abdulaziz Hospital - Al Ahsa
Al Mubarraz, 36428
King Abdullah International Medical Research Center
Riyadh, 14611
United Arab Emirates2 sites
Burjeel Medical City
Abu Dhabi
Thalassemia Centre Dubai
Dubai, 4545
Canada1 site
Toronto General Hospital, University Health Network
Toronto, M5G 2C4
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 Non-Transfusion-Dependent Alpha- or Beta-Thalassemia (ENERGIZE)
The primary purpose of this study was to compare the effect of mitapivat versus placebo on hemolytic anemia in participants with alpha- or beta-non-transfusion dependent thalassemia (NTDT).
Read the detailed description
The mitapivat group included 130 participants whereas the placebo group had 64 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 | 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. Receives: Drug: Mitapivat |
| Placebo | Placebo comparator | 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. 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 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.
Measured: Double-Blind Period: Baseline up to Week 12 through Week 24
Secondary outcomes (23)
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.
Measured: Double-Blind Period: Baseline, Week 12 through Week 24
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.
Measured: Double-Blind Period: Baseline, Week 12 through Week 24
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.
Measured: Double-Blind Period: Baseline up to Week 12 through Week 24
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.
Measured: Double-Blind Period: Baseline, Week 24
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.
Measured: Double-Blind Period: Baseline, Week 24
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.
Measured: Double-Blind Period: Baseline, Week 24
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.
Measured: Double-Blind Period: Baseline, Week 24
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.
Measured: Double-Blind Period: Baseline, Week 24
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'.
Measured: Double-Blind Period: At Weeks 12, 16, 20, and 24
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'.
Measured: Double-Blind Period: At Weeks 12, 16, 20, and 24
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.
Measured: Double-Blind Period: Baseline, Week 24
Double-Blind Period: Change From Baseline in Serum Ferritin at Week 24
Iron metabolism was assessed based on serum ferritin levels.
Measured: Double-Blind Period: Baseline, Week 24
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.
Measured: Double-Blind Period: Baseline, Week 24
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.
Measured: Double-Blind Period: From the time of signing informed consent to Week 24
Double-Blind Period: Plasma Concentration of Mitapivat
Measured: Double-Blind Period: Pre-dose at Week 12; pre-dose, 0.5, 1, 3, 5, 7 hours post-dose at Week 20
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 20
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 at Week 20
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 at Week 20
Double-Blind Period: Time to Reach Maximum Observed Plasma Concentration (Tmax) of Mitapivat
Measured: Double-Blind Period: Pre-dose, 0.5, 1, 3, 5, 7 hours post-dose at Week 20
Double-Blind Period: Last Quantifiable Plasma Concentration (Clast) of Mitapivat
Measured: Double-Blind Period: Pre-dose, 0.5, 1, 3, 5, 7 hours post-dose at Week 20
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, 0.5, 1, 3, 5, 7 hours post-dose at Week 20
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, 0.5, 1, 3, 5, 7 hours post-dose at Week 20
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.
Measured: Open-Label Extension Period: From week 24 up to end of study (approximately 5 years)
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 start20 Dec 2021
- Primary completion13 Nov 2023
- Study completionDec 2028 (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 Non-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
- 194 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
- NCT04770753
- Sponsor's protocol ID
- AG348-C-017
- Other IDs
- 2021-000211-23
- Status last verified
- Oct 2026
- First submitted
- 18 Feb 2021
- Last updated
- 30 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
Taher AT, Al-Samkari H, Aydinok Y, Besser M, Boscoe AN, Dahlin JL, De Luna G, Estepp JH, Gheuens S, Gilroy KS, Glenthoj A, Sim Goh A, Iyer V, Kattamis A, Loggetto SR, Morris S, Musallam KM, Osman K, Ricchi P, Salido-Fierrez E, Sheth S, Tai F, Tevich H, Uhlig K, Urbstonaitis R, Viprakasit V, Cappellini MD, Kuo KHM; ENERGIZE investigators. Mitapivat in adults with non-transfusion-dependent alpha-thalassaemia or beta-thalassaemia (ENERGIZE): a phase 3, international, randomised, double-blind, placebo-controlled trial. Lancet. 2025 Jul 5;406(10498):33-42. doi: 10.1016/S0140-6736(25)00635-X. Epub 2025 Jun 19.
PubMed 40544857
Study at a glance
From the registry record, last updated by the sponsor on 30 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 Non-Transfusion-Dependent Alpha- or Beta-Thalassemia (ENERGIZE)
- ClinicalTrials.gov ID
- NCT04770753
- Acronym / sponsor ID
- AG348-C-017
- Phase
- Phase 3
- Study type
- Interventional
- Recruitment status
- Active, not recruiting
- Enrolment
- 194 participants (actual)
- Lead sponsor
- Agios Pharmaceuticals, Inc.Industry (pharma, biotech, devices)
- Study start
- 20 Dec 2021 (actual)
- Primary completion
- 13 Nov 2023 (actual)
- Study completion
- Dec 2028 (estimated)
- First posted
- 25 Feb 2021 (actual)
- Results
- Posted 24 Jan 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 purpose of this study was to compare the effect of mitapivat versus placebo on hemolytic anemia in participants with alpha- or beta-non-transfusion dependent thalassemia (NTDT).
Detailed description
The mitapivat group included 130 participants whereas the placebo group had 64 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: MitapivatMitapivat 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. |
| Placebo | Placebo comparator | Drug: Placebo Matching Mitapivat, Drug: MitapivatPlacebo 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. |
Who may qualify
- Ages
- 18 years and older
- Sex
- All
- Healthy volunteers
- Not accepted
- Age groups
- Adult, Older adult
Key inclusion criteria (6 listed)
- 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;
Key exclusion criteria (21 listed)
- 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;
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 Hemoglobin (Hb) Response From Week 12 Through Week 24 Compared With Baseline
Time frame: Double-Blind Period: Baseline up to Week 12 through Week 24
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.
23 secondary outcomes
Double-Blind Period: Change From Baseline in Average Functional Assessment of Chronic Illness Therapy (FACIT) -Fatigue Subscale Score From Week 12 Through Week 24
Time frame: Double-Blind Period: Baseline, Week 12 through Week 24
Double-Blind Period: Change From Baseline in Average Hb Concentration From Week 12 Through Week 24
Time frame: Double-Blind Period: Baseline, Week 12 through Week 24
Double-Blind Period: Percentage of Participants Who Achieved Hb 1.5+ Response From Week 12 Through Week 24 Compared With Baseline
Time frame: Double-Blind Period: Baseline up to Week 12 through Week 24
Double-Blind Period: Change From Baseline in Indirect Bilirubin at Week 24
Time frame: Double-Blind Period: Baseline, Week 24
Double-Blind Period: Change From Baseline in Lactate Dehydrogenase (LDH) at Week 24
Time frame: Double-Blind Period: Baseline, Week 24
Double-Blind Period: Change From Baseline in Haptoglobin at Week 24
Time frame: Double-Blind Period: Baseline, Week 24
Double-Blind Period: Change From Baseline in Reticulocytes at Week 24
Time frame: Double-Blind Period: Baseline, Week 24
Double-Blind Period: Change From Baseline in Erythropoietin at Week 24
Time frame: Double-Blind Period: Baseline, Week 24
Double-Blind Period: Percentage of Participants Who Achieved Patient Global Impression of Severity (PGIS)- Fatigue Response at Weeks 12, 16, 20, and 24
Time frame: Double-Blind Period: At Weeks 12, 16, 20, and 24
Double-Blind Period: Percentage of Participants Who Achieved the Patient Global Impression of Change (PGIC)- Fatigue Response at Weeks 12, 16, 20, and 24
Time frame: Double-Blind Period: At Weeks 12, 16, 20, and 24
Double-Blind Period: Change From Baseline in the 6-minute Walk Test (6MWT) Distance at Week 24
Time frame: Double-Blind Period: Baseline, Week 24
Double-Blind Period: Change From Baseline in Serum Ferritin at Week 24
Time frame: Double-Blind Period: Baseline, Week 24
Double-Blind Period: Change From Baseline in Transferrin Saturation (TSAT) at Week 24
Time frame: Double-Blind Period: Baseline, Week 24
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 the time of signing informed consent to Week 24
Double-Blind Period: Plasma Concentration of Mitapivat
Time frame: Double-Blind Period: Pre-dose at Week 12; pre-dose, 0.5, 1, 3, 5, 7 hours post-dose at Week 20
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 20
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 at Week 20
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 at Week 20
Double-Blind Period: Time to Reach Maximum Observed Plasma Concentration (Tmax) of Mitapivat
Time frame: Double-Blind Period: Pre-dose, 0.5, 1, 3, 5, 7 hours post-dose at Week 20
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 at Week 20
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, 0.5, 1, 3, 5, 7 hours post-dose at Week 20
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, 0.5, 1, 3, 5, 7 hours post-dose at Week 20
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
Time frame: Open-Label Extension Period: From week 24 up to end of study (approximately 5 years)
Results and safety
Loading the posted results from ClinicalTrials.gov…
Research links
- Official record on ClinicalTrials.govLast updated by the sponsor 30 Oct 2026.
- Posted resultsParticipant flow, baseline, all outcome measures and adverse events.
- Derived from this study: PubMed 40544857Taher AT, Al-Samkari H, Aydinok Y, Besser M, Boscoe AN, Dahlin JL, De Luna G, Estepp JH, Gheuens S, Gilroy KS, Glenthoj A, Sim Goh A, Iyer V, Kattamis A, Loggetto SR, Morris S, Musallam KM, Osman K, Ricchi P, Salido-Fierrez E, Sheth S, Tai F, Tevich H, Uhlig K, Urbstonaitis R, Viprakasit V, Cappellini MD, Kuo KHM; ENERGIZE investigators. Mitapivat in adults with non-transfusion-dependent alpha-thalassaemia or beta-thalassaemia (ENERGIZE): a phase 3, international, randomised, double-blind, placebo-controlled trial. Lancet. 2025 Jul 5;406(10498):33-42. doi: 10.1016/S0140-6736(25)00635-X. Epub 2025 Jun 19.
- 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.
68 sites in 18 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 Non-Transfusion-dependent Alpha-Thalassemia and Non-Transfusion-dependent Beta-Thalassemia, run by Agios Pharmaceuticals, Inc. at 68 sites in 18 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 30 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 68 sites in Italy, Malaysia, Thailand, United States, Brazil and 13 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 24 Jan 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 Hemoglobin (Hb) Response From Week 12 Through Week 24 Compared With Baseline (time frame: Double-Blind Period: Baseline up to Week 12 through Week 24). 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 NCT04770753, 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 30 Oct 2026.