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

Phase 3

Active, not recruiting

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

Interventions: Drug: Mitapivat
Drug: Placebo Matching Mitapivat

Registration Number: NCT04770779

Lead Sponsor: Agios Pharmaceuticals, Inc.

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

Detailed Description: The mitapivat group included 171 participants. The placebo group included 87 participants.

Recruitment & Eligibility

Status: ACTIVE_NOT_RECRUITING

Sex: All

Target Recruitment: 258

Inclusion Criteria

Greater than or equal to (≥)18 years of age at the time of providing informed consent;
Documented diagnosis of thalassemia (β-thalassemia with or without α-globin gene mutations, hemoglobin E (HbE)/β-thalassemia, or α-thalassemia/hemoglobin H (HbH) disease) based on deoxyribonucleic acid (DNA) analysis;
Considered transfusion-dependent, defined as 6 to 20 red blood cells (RBC) units transfused and ≤6-week transfusion-free period during the 24-week period before randomization;
If taking hydroxyurea, the hydroxyurea dose must be stable for ≥16 weeks before randomization;
Women of childbearing potential (WOCBP) must be abstinent of sexual activities that may induce pregnancy as part of their usual lifestyle or agree to use two forms of contraception, one of which must be considered highly effective, from the time of providing informed consent, throughout the study, and for 28 days after the last dose of study drug. The second form of contraception can be an acceptable barrier method;
Written informed consent before any study-related procedures are conducted and willing to comply with all study procedures for the duration of the study.

Exclusion Criteria

Pregnant, breastfeeding, or parturient;
Documented history of homozygous or heterozygous sickle hemoglobin (Hb S) or hemoglobin C (Hb C);
Prior exposure to gene therapy or prior bone marrow or stem cell transplantation;
Currently receiving treatment with luspatercept; the last dose must have been administered ≥36 weeks before randomization;
Currently receiving treatment with hematopoietic stimulating agents; the last dose must have been administered ≥36 weeks before randomization;
History of malignancy (active or treated) ≤5 years before providing informed consent, except for nonmelanomatous skin cancer in situ, cervical carcinoma in situ, or breast carcinoma in situ;
History of active and/or uncontrolled cardiac or pulmonary disease ≤6 months before providing informed consent;
Hepatobiliary disorders;
Estimated glomerular filtration rate <45 milliliters per minute (mL/min)/1.73 meter (m)^2 by Chronic Kidney Disease Epidemiology Collaboration creatinine equation;
Nonfasting triglycerides >440 milligrams per deciliter (mg/dL) (5 millimoles per liter [mmol/L]);
Active infection requiring systemic antimicrobial therapy at the time of providing informed consent;
Positive test for hepatitis C virus antibody (HCVAb) with evidence of active HCV infection, or positive test for hepatitis B surface antigen (HBsAg);
Positive test for human immunodeficiency virus (HIV)-1 antibody (Ab) or HIV-2 Ab;
History of major surgery (including splenectomy) ≤6 months before providing informed consent and/or a major surgical procedure planned during the study;
Current enrollment or past participation (≤12 weeks before administration of the first dose of study drug or a timeframe equivalent to 5 half-lives of the investigational study drug, whichever is longer) in any other clinical study involving an investigational treatment or device;
Receiving strong CYP3A4/5 inhibitors that have not been stopped for ≥5 days or a timeframe equivalent to 5 half-lives (whichever is longer); or strong CYP3A4 inducers that have not been stopped for ≥4 weeks or a timeframe equivalent to 5 half-lives (whichever is longer), before randomization;
Receiving anabolic steroids that have not been stopped for at least 4 weeks before randomization. Testosterone replacement therapy to treat hypogonadism is allowed. The testosterone dose and preparation must be stable for ≥12 weeks before randomization;
Known allergy, or other contraindication, to mitapivat or its excipients (microcrystalline cellulose, croscarmellose sodium, sodium stearyl fumarate, mannitol, and magnesium stearate, Opadry® II Blue [hypromellose, titanium dioxide, lactose monohydrate, triacetin, and Federal Food, Drug, and Cosmetic (FD&C) Blue #2]);
Any medical, hematological, psychological, or behavioral condition(s) or prior or current therapy that, in the opinion of the Investigator, may confer an unacceptable risk to participating in the study and/or could confound the interpretation of the study data. Also excluded are:
- Participants who are institutionalized by regulatory or court order
- Participants with any condition(s) that could create undue influence (including but not limited to incarceration, involuntary psychiatric confinement, and financial or familial affiliation with the Investigator or Sponsor).

Study & Design

Study Type: INTERVENTIONAL

Study Design: PARALLEL

Arm && Interventions

Group	Intervention	Description
Mitapivat	Mitapivat	Participants randomized to receive mitapivat 100 milligrams (mg), orally, twice daily (BID) for 48 weeks in the double-blind (DB) period and for up to 5 years in the open label extension (OLE) period.
Placebo	Placebo Matching Mitapivat	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.
Placebo	Mitapivat	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.

Primary Outcome Measures

Name	Time	Method
Double-blind Period: Percentage of Participants Who Achieved Transfusion Reduction Response (TRR)	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.

Secondary Outcome Measures

Name	Time	Method
Double-blind Period: Time to Reach of Maximum Observed Plasma Concentration (Tmax) of Mitapivat	Double-blind Period: Pre-dose, 0.5, 1, 3, 5, 7 hours post-dose Week 36
Double-blind Period: Time of Last Quantifiable Concentration (Tlast) of Mitapivat	Double-blind Period: Pre-dose, 0.5, 1, 3, 5, 7 hours post-dose Week 36
Double-blind Period: Change From Baseline in Total Iron Binding Capacity	Double-blind Period: Baseline through Week 48	Iron metabolism was assessed based on 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 first dose of study drug up to week 48	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.
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	Open-Label Extension Period: From Week 48 up to end of study (approximately 5 years)	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.
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 36	Area under the concentration-time curve from time zero to Tlast on dosing day, calculated using the linear-log trapezoidal rule.
Double-blind Period: Maximum Observed Plasma Concentration (Cmax) of Mitapivat	Double-blind Period: Pre-dose, 0.5, 1, 3, 5, 7 hours post-dose Week 36
Double-blind Period: Percentage of Participants Who Achieved TRR2	Double-blind period: Baseline through Week 48	TRR2, defined as a ≥50% reduction in transfused RBC units in any consecutive 24-week period through Week 48 compared with the 24-week baseline transfusion burden, is reported. Baseline transfusion burden standardized to 24 weeks is the total number of RBC units transfused during the 24-week period before the randomization date for participants randomized and not dosed or the start of study treatment for participants randomized and dosed. Participants withdrawn from the study before Week 24 (Day 169) were considered nonresponders.
Double-blind Period: Percentage of Participants Who Achieved TRR3	Double-blind period: Baseline up to Week 13 through Week 48	TRR3, defined as a ≥33% reduction in transfused RBC units from Week 13 through Week 48 compared with the baseline transfusion burden standardized to 36 weeks, is reported. Baseline transfusion burden standardized to 36 weeks= (36/24) × total number of RBC units transfused during the 24-week period before the randomization date for participants randomized and not dosed or the start of study treatment for participants randomized and dosed. Participants withdrawn from the study before Week 48 were considered nonresponders.
Double-blind Period: Percentage of Participants Who Achieved TRR4	Double-blind period: Baseline up to Week 13 through Week 48	TRR4, defined as a ≥50% reduction in transfused RBC units from Week 13 through Week 48 compared with the baseline transfusion burden standardized to 36 weeks, is reported. Baseline transfusion burden standardized to 36 weeks = (36/24) × total number of RBC units transfused during the 24-week period before the randomization date for participants randomized and not dosed or the start of study treatment for participants randomized and dosed. Participants withdrawn from the study before Week 48 were considered nonresponders.
Double-blind Period: Percent Change From Baseline in Transfused RBC Units	Double-blind Period: Baseline, Week 13 through Week 48	Transfusion burden from Week 13 through Week 48 standardized to 36 weeks is defined as number of transfused RBC units from Day 85 through Week 48 in the Double-blind Period ×36/(Number of days from Day 85 through Week 48 in the Double-blind Period/7). Baseline transfusion burden standardized to 36 weeks= (36/24)× is the total number of RBC units transfused during the 24-week period before the randomization date for participants randomized and not dosed or within 168 days before the start of study treatment for participants randomized and dosed.
Double-blind Period: Percentage of Participants Who Achieved Transfusion-Independence	Double-blind Period: Baseline through Week 48	Transfusion-independence is defined as transfusion-free for ≥8 consecutive weeks through Week 48 in the double-blind period.
Double-blind Period: Change From Baseline in Iron Levels	Double-blind Period: Baseline through Week 48	Iron metabolism was assessed based on Iron levels.
Double-blind Period: Last Quantifiable Plasma Concentration (Clast) of Mitapivat	Double-blind Period: Pre-dose, 0.5, 1, 3, 5, 7 hours post-dose Week 36	Clast is the last quantifiable concentration after a single dose or within the dosing interval (tau) for multiple doses.
Double-blind Period: Blood Concentration of Adenosine Triphosphate (ATP)	Double-blind Period: Pre-dose at Day 1; pre-dose at Week 12; pre-dose at Week 24; pre-dose, 0.5, 1, 3, 5, 7 hours post-dose at Week 36
Double-blind Period: Blood Concentration of 2,3 - Diphosphoglycerate (2,3-DPG)	Double-blind Period: Pre-dose at Day 1; pre-dose at Week 12; pre-dose at Week 24; pre-dose, 0.5, 1, 3, 5, 7 hours post-dose at Week 36
Double-blind Period: Change From Baseline in Serum Ferritin Levels	Double-blind Period: Baseline through Week 48	Iron metabolism was assessed based on serum ferritin levels.
Double-blind Period: Change From Baseline in Transferrin Saturation (TSAT) Levels	Double-blind Period: Baseline through Week 48	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: Plasma Concentrations of Mitapivat	Double-blind Period: Pre-dose at Week 12; pre-dose at Week 24; pre-dose, 0.5, 1, 3, 5, 7 hours post-dose at Week 36

Trial Locations

Locations (75): Phoenix Children's Hospital
🇺🇸
Phoenix, Arizona, United States
San Diego Hospital, UC San Diego Health
🇺🇸
La Jolla, California, United States
Children's Hospital Oakland
🇺🇸
Oakland, California, United States
Stanford Medicine
🇺🇸
Palo Alto, California, United States
Boston Children's Hospital
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Boston, Massachusetts, United States
Children's Hospital of Michigan
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Detroit, Michigan, United States
Weill Cornell Medical Center
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New York, New York, United States
Duke University Medical Center
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Durham, North Carolina, United States
Penn Medicine - University of Pennsylvania Health System
🇺🇸
Philadelphia, Pennsylvania, United States
Seattle Cancer Care Alliance, University of Washington
🇺🇸
Seattle, Washington, United States
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Phoenix Children's Hospital
🇺🇸Phoenix, Arizona, United States