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

Study Overview
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Brief Summary
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The primary purpose of this study is to compare the effect of mitapivat versus placebo on anemia in participants with alpha- or beta-non-transfusion dependent thalassemia (NTDT).

Detailed Description
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The mitapivat group will include approximately 114 participants. The placebo group will include approximately 57 participants.

Official Title
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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)

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

Intervention / Treatment
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* Drug: Placebo Matching Mitapivat
* Drug: Mitapivat


Participation Criteria
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Eligibility Criteria
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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)

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Mitapivat<br>Double-blind Period: Participants will receive mitapivat 100 milligrams (mg), orally, twice daily (BID) for 24 weeks. Open-label Extension Period: Participants who do not discontinue study drug may choose to continue to receive mitapivat for up to an additional 5 years after the Double-blind Period. | Drug: Mitapivat<br>* Tablets<br>* Other names: Mitapivat sulfate;|
| Placebo Comparator: Placebo<br>Double-blind Period: Participants will receive placebo matching mitapivat, orally, BID for 24 weeks. Open-label Extension Period: Participants who do not discontinue study drug may choose to receive mitapivat for up to an additional 5 years after the Double-blind Period. | Drug: Placebo Matching Mitapivat<br>* Tablets<br>Drug: Mitapivat<br>* Tablets<br>* Other names: Mitapivat sulfate;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Percentage of Participants With Hemoglobin (Hb) Response | Hb response is defined as a ≥1.0 gram per deciliter (g/dL) increase in average Hb concentration from Week 12 through Week 24 compared with baseline. | Baseline, Week 12 up to Week 24 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change From Baseline in Average Functional Assessment of Chronic Illness Therapy (FACIT) -Fatigue Subscale Score from Week 12 through Week 24 | The 13-item FACIT-Fatigue subscale assesses severity and impact of fatigue. The subscale has a 7-day recall period, and total score ranges from 0 to 52, with a higher score indicating less fatigue. | Baseline, Week 12 up to Week 24 | 
| Change From Baseline in Average Hb Concentration From Week 12 through Week 24 |  | Baseline, Week 12 up to Week 24 | 
| Percentage of Participants With Hb 1.5+ Response | 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. | Baseline, Week 12 up to Week 24 | 
| Change From Baseline in Indirect Bilirubin at Week 24 |  | Baseline, Week 24 | 
| Change From Baseline in Lactate Dehydrogenase (LDH) at Week 24 |  | Baseline, Week 24 | 
| Change From Baseline in Haptoglobin at Week 24 |  | Baseline, Week 24 | 
| Change From Baseline in Reticulocytes at Week 24 |  | Baseline, Week 24 | 
| Change From Baseline in Erythropoietin at Week 24 |  | Baseline, Week 24 | 
| Percentage of Participants With Improvement in the Patient Global Impression of Severity (PGIS) -Fatigue by at Least 1 Category at Weeks 12, 16, 20, and 24 Compared With Baseline, or No Change if No or Mild Fatigue at Baseline | The PGIS-Fatigue assesses severity of fatigue (on a 4-point scale ranging from None to Severe) over a 7-day recall period. Improvement in the PGIS-Fatigue by at least one category or no change if None or Mild PGIS-Fatigue response at baseline will be assessed separately at Weeks 12, 16, 20, and 24 compared to baseline. | Baseline, Weeks 12, 16, 20, and 24 | 
| Percentage of Participants With Improvement in the Patient Global Impression of Change (PGIC) -Fatigue at Weeks 12, 16, 20, and 24, or No Change if No or Mild Fatigue at Baseline | The PGIC-Fatigue assesses change in fatigue compared with baseline (on a 5-point scale ranging from Much better to Much worse). Participants reporting improvement in the PGIC-Fatigue or reporting No change if None or Mild PGIS-Fatigue response at baseline will be assessed separately at Weeks 12, 16, 20, and 24. | Weeks 12, 16, 20, and 24 | 
| Change From Baseline in the 6-minute Walk Test (6MWT) Distance at Week 24 |  | Baseline, Week 24 | 
| Change From Baseline in Serum Ferritin at Week 24 |  | Baseline, Week 24 | 
| Change From Baseline in Transferrin Saturation (TSAT) at Week 24 |  | Baseline, Week 24 | 
| Percentage of Participants With Adverse Events (AEs) and Serious Adverse Events (SAEs) |  | Up to Week 293 | 
| Percentage of Participants With Adverse Events (AEs) and Serious Adverse Events (SAEs), Graded by Severity | AEs and SAEs will be graded according to the National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE; Version 4.03) from Grades 1 to 4 where Grade 1 is mild and Grade 4 is life-threatening. | Up to Week 293 | 
| Percentage of Participants With Adverse Events (AEs) Considered by the Investigator to be Related to Study Drug |  | Up to Week 293 | 
| Percentage of Participants With Serious Adverse Events (SAEs) Considered by the Investigator to be Related to Study Drug |  | Up to Week 293 | 
| Plasma or Blood Concentrations Over Time for Mitapivat |  | Pre-dose Week 12; pre-dose, 0.5, 1, 3, 5, 7 hours post-dose Week 20 | 
| Area Under the Concentration-time Curve From Time Zero to the Last Measurable Concentration (AUClast) of Mitapivat |  | Pre-dose, 0.5, 1, 3, 5, 7 hours post-dose Week 20 | 
| Maximum Plasma Concentration (Cmax) of Mitapivat |  | Pre-dose, 0.5, 1, 3, 5, 7 hours post-dose Week 20 | 
| Time of Maximum Plasma Concentration (Tmax) of Mitapivat |  | Pre-dose, 0.5, 1, 3, 5, 7 hours post-dose Week 20 | 
| Blood Concentration of Adenosine Triphosphate (ATP) |  | Pre-dose Day 1; pre-dose Week 12; pre-dose, 0.5, 1, 3, 5, 7 hours post-dose Week 20 | 
| Blood Concentration of 2,3 - diphosphoglycerate (2,3-DPG) |  | Pre-dose Day 1; pre-dose Week 12; pre-dose, 0.5, 1, 3, 5, 7 hours post-dose Week 20 |