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

Phase 3

Active, not recruiting

Conditions: Non-Transfusion-dependent Alpha-Thalassemia
Non-Transfusion-dependent Beta-Thalassemia

Interventions: Drug: Mitapivat
Drug: Placebo Matching Mitapivat

Registration Number: NCT04770753

Lead Sponsor: Agios Pharmaceuticals, Inc.

Brief 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).

Detailed Description: The mitapivat group included 130 participants whereas the placebo group had 64 participants.

Recruitment & Eligibility

Status: ACTIVE_NOT_RECRUITING

Sex: All

Target Recruitment: 194

Inclusion Criteria

Documented diagnosis of thalassemia (β-thalassemia with or without α-globin gene mutations, hemoglobin E (HbE)/β-thalassemia, or α-thalassemia/hemoglobin H [HbH] disease) based on Hb electrophoresis, Hb high-performance liquid chromatography (HPLC)), and/or deoxyribonucleic acid (DNA) analysis;
Hb concentration ≤10.0 grams per deciliter (g/dL) (100.0 grams per liter [g/L]), based on an average of at least 2 Hb concentration measurements (separated by ≥7 days) collected during the Screening Period;
Non-transfusion-dependent, defined as ≤5 red blood cell (RBC) units during the 24-week period before randomization; and no RBC transfusions ≤8 weeks before providing informed consent and no RBC transfusions during the Screening Period;
If taking hydroxyurea, the hydroxyurea dose must be stable for ≥16 weeks before randomization;
Women of child-bearing potential (WOCBP) must be abstinent of sexual activities that may result in pregnancy as part of their usual lifestyle or agree to use 2 forms of contraception, one of which must be considered highly effective, from the time of providing informed consent, throughout the study, and for 28 days after the last dose of study drug. The second form of contraception can be an acceptable barrier method;
Written informed consent before any study-related procedures are conducted and willing to comply with all study procedures for the duration of the study.

Exclusion Criteria

Pregnant, breastfeeding, or parturient
Documented history of homozygous or heterozygous sickle hemoglobin (HbS) or hemoglobin C (HbC);
Prior exposure to gene therapy or prior bone marrow or stem cell transplantation;
Currently receiving treatment with luspatercept; the last dose must have been administered ≥18 weeks before randomization;
Currently receiving treatment with hematopoietic stimulating agents; the last dose must have been administered ≥18 weeks before randomization;
History of malignancy, (active or treated) ≤5 years before providing informed consent;
History of active and/or uncontrolled cardiac or pulmonary disease ≤6 months before providing informed consent, except for nonmelanomatous skin cancer in situ, cervical carcinoma in situ, or breast carcinoma in situ;
Hepatobiliary disorders;
Estimated glomerular filtration rate <45 milliliters per minute (mL/min)/1.73 m^2 by Chronic Kidney Disease Epidemiology Collaboration creatinine equation;
Nonfasting triglycerides >440 milligrams per deciliter (mg/dL) (5 millimoles per liter [mmol/L]);
Active infection requiring systemic antimicrobial therapy at the time of providing informed consent;
Positive test for hepatitis C virus antibody (HCVAb) with evidence of active HCV infection, or positive test for hepatitis B surface antigen (HBsAg);
Positive test for human immunodeficiency virus (HIV)-1 antibody (Ab) or HIV-2 Ab;
History of major surgery (including splenectomy) ≤16 weeks before providing informed consent and/or a major surgical procedure planned during the study;
Current enrollment or past participation (≤12 weeks before administration of the first dose of study drug or a timeframe equivalent to 5 half-lives of the investigational study drug, whichever is longer) in any other clinical study involving an investigational treatment or device;
Receiving strong CYP3A4/5 inhibitors that have not been stopped for ≥5 days or a timeframe equivalent to 5 half-lives (whichever is longer); or strong CYP3A4 inducers that have not been stopped for ≥4 weeks or a timeframe equivalent to 5 half-lives (whichever is longer), before randomization;
Receiving anabolic steroids that have not been stopped for at least 4 weeks before randomization. Testosterone replacement therapy to treat hypogonadism is allowed. The testosterone dose and preparation must be stable for ≥10 weeks before randomization;
Known allergy to mitapivat or its excipients (microcrystalline cellulose, croscarmellose sodium, sodium stearyl fumarate, mannitol, and magnesium stearate, Opadry® II Blue [hypromellose, titanium dioxide, lactose monohydrate, triacetin, and FD&C Blue #2]);
Any medical, hematological, psychological, or behavioral condition(s) or prior or current therapy that, in the opinion of the Investigator, may confer an unacceptable risk to participating in the study and/or could confound the interpretation of the study data Also excluded are:
- Participants who are institutionalized by regulatory or court order
- Participants with any condition(s) that could create undue influence (including but not limited to incarceration, involuntary psychiatric confinement, and financial or familial affiliation with the Investigator or Sponsor)

Study & Design

Study Type: INTERVENTIONAL

Study Design: PARALLEL

Arm && Interventions

Group	Intervention	Description
Mitapivat	Mitapivat	Mitapivat 100 milligrams (mg), orally, twice daily (BID) for 24 weeks in double blind (DB) period and for up to 5 years in open label extension (OLE) period.
Placebo	Placebo Matching Mitapivat	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.
Placebo	Mitapivat	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.

Primary Outcome Measures

Name	Time	Method
Double-Blind Period: Percentage of Participants Who Achieved Hemoglobin (Hb) Response From Week 12 Through Week 24 Compared With Baseline	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.

Secondary Outcome Measures

Name	Time	Method
Double-Blind Period: Change From Baseline in Serum Ferritin at Week 24	Double-Blind Period: Baseline, Week 24	Iron metabolism was assessed based on serum ferritin levels.
Double-Blind Period: Change From Baseline in Average Functional Assessment of Chronic Illness Therapy (FACIT) -Fatigue Subscale Score From Week 12 Through Week 24	Double-Blind Period: Baseline, 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.
Double-Blind Period: Change From Baseline in Average Hb Concentration From Week 12 Through Week 24	Double-Blind Period: Baseline, 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.
Double-Blind Period: Percentage of Participants Who Achieved Hb 1.5+ Response From Week 12 Through Week 24 Compared With Baseline	Double-Blind Period: Baseline up to Week 12 through Week 24	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.
Double-Blind Period: Change From Baseline in Indirect Bilirubin at Week 24	Double-Blind Period: Baseline, 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.
Double-Blind Period: Change From Baseline in Lactate Dehydrogenase (LDH) at Week 24	Double-Blind Period: Baseline, 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.
Double-Blind Period: Change From Baseline in Haptoglobin at Week 24	Double-Blind Period: Baseline, 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.
Double-Blind Period: Change From Baseline in Reticulocytes at Week 24	Double-Blind Period: Baseline, 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.
Double-Blind Period: Change From Baseline in Erythropoietin at Week 24	Double-Blind Period: Baseline, 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.
Double-Blind Period: Percentage of Participants Who Achieved Patient Global Impression of Severity (PGIS)- Fatigue Response at Weeks 12, 16, 20, and 24	Double-Blind Period: 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'.
Double-Blind Period: Percentage of Participants Who Achieved the Patient Global Impression of Change (PGIC)- Fatigue Response at Weeks 12, 16, 20, and 24	Double-Blind Period: 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'.
Double-Blind Period: Change From Baseline in the 6-minute Walk Test (6MWT) Distance at Week 24	Double-Blind Period: Baseline, 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.
Double-Blind Period: Change From Baseline in Transferrin Saturation (TSAT) at Week 24	Double-Blind Period: Baseline, 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.
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	Double-Blind Period: From the time of signing informed consent to Week 24	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: Plasma Concentration of Mitapivat	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	Double-Blind Period: Pre-dose, 0.5, 1, 3, 5, 7 hours post-dose at Week 20	Area under the concentration-time curve from time zero to Tlast on dosing day, calculated using the linear-log trapezoidal rule.
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 at Week 20
Double-Blind Period: Maximum Observed Plasma Concentration (Cmax) of Mitapivat	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	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	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)	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)	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	Open-Label Extension Period: From week 24 up to end of study (approximately 5 years)	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.

Trial Locations

Locations (68): King Abdulaziz Hospital - Al Ahsa
🇸🇦
Al-Mubarraz, Saudi Arabia
San Diego Hospital, UC San Diego Health
🇺🇸
La Jolla, California, United States
Stanford Medicine
🇺🇸
Palo Alto, California, United States
Massachusetts General Hospital
🇺🇸
Boston, Massachusetts, 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
Universidade de Caxias do Sul
🇧🇷
Caxias Do Sul, Brazil
Hospital das Clínicas da Faculdade de Medicina de Ribeirão Preto - USP
🇧🇷
Ribeirão Preto, Brazil
HEMORIO Instituto Nacional de Hematologia
🇧🇷
Rio De Janeiro, Brazil
Praxis Pesquisa Medica
🇧🇷
Santo André, Brazil
Instituto do Cancer do Estado de São Paulo, Hospital das Clínicas da Faculdade de Medicina da Universidad de São Paulo
🇧🇷
Sao Paulo, Brazil
GSH Banco de Sangue de São Paulo
🇧🇷
São Paulo, Brazil
MHAT "Dr. Nikola Vasiliev" AD
🇧🇬
Kyustendil, Bulgaria
SHATHD Sofia
🇧🇬
Sofia, Bulgaria
Toronto General Hospital, University Health Network
🇨🇦
Toronto, Canada
Rigshospitalet
🇩🇰
Copenhagen, Denmark
CHU Hôpital Henri Mondor
🇫🇷
Créteil, France
Hopital Edouard Herriot, CHU de Lyon
🇫🇷
Lyon, France
Laiko General Hospital
🇬🇷
Athens, Greece
Children's Hospital Agia Sophia, National and Kapodistrian University of Athens Medical School
🇬🇷
Athens, Greece
University General Hospital of Patras
🇬🇷
Rio, 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 Ca' Granda Ospedale Maggiore Policlinico
🇮🇹
Milano, Italy
A.O.U Di Modena
🇮🇹
Modena, Italy
A.O.R.N. "A. Cardarelli"
🇮🇹
Napoli, Italy
AOU L. Vanvitelli Universita degli Studi della Campania Luigi Vanvitelli
🇮🇹
Napoli, Italy
A.O.U. San Luigi Gonzaga
🇮🇹
Orbassano, Italy
Chronic Care Center
🇱🇧
Beyrouth, Lebanon
Hospital Sultanah Bahiyah
🇲🇾
Alor Setar, Malaysia
Hospital Ampang
🇲🇾
Ampang, 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 Pulau Pinang
🇲🇾
Pulau Pinang, Malaysia
Erasmus MC
🇳🇱
Rotterdam, Netherlands
Universitair Medisch Centrum Utrecht
🇳🇱
Utrecht, Netherlands
King Abdullah International Medical Research Center
🇸🇦
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
🇪🇸
Sevilla, Spain
China Medical University, Taiwan
🇨🇳
Taichung, 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
Akdeniz University Faculty of Medicine
🇹🇷
Antalya, Turkey
Çukurova University
🇹🇷
Balcali, Turkey
Ege University Faculty of Medicine
🇹🇷
Bornova, Turkey
Istanbul University Faculty of Medicine
🇹🇷
Fatih, Turkey
Hacettepe University
🇹🇷
Mersin, Turkey
Burjeel Medical City
🇦🇪
Abu Dhabi, United Arab Emirates
Thalassemia Centre Dubai
🇦🇪
Dubai, United Arab Emirates
Cambridge University Hospitals NHS Foundation Trust - Addenbrookes Hospital
🇬🇧
Cambridge, CAM, United Kingdom
Manchester Royal Infirmary, Manchester University NHS Foundation Trust
🇬🇧
Manchester, LAN, United Kingdom
University College London
🇬🇧
London, United Kingdom
Imperial College Healthcare NHS Trust - Hammersmith Hospital
🇬🇧
London, United Kingdom