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

Phase 3Active Not RecruitingNCT04770753

Agios Pharmaceuticals, Inc.194 enrolled

Overview

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).

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

Study Type

INTERVENTIONAL

Allocation

RANDOMIZED

Purpose

TREATMENT

Masking

QUADRUPLE

Enrollment

194

Conditions

Non-Transfusion-dependent Alpha-Thalassemia Non-Transfusion-dependent Beta-Thalassemia

Interventions

Placebo Matching MitapivatDRUG

Tablets

MitapivatDRUG

Tablets

Eligibility

Sex: ALLMin age: 18 Years

Medical Language ↔ Plain English

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)

Locations (68)

Outcomes

Primary Outcomes

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.

Time frame: Double-Blind Period: Baseline up to Week 12 through Week 24

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

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.

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

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.

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

Data from ClinicalTrials.gov

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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

...and 58 more locations

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.

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

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'.

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

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'.

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

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.

Time frame: 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.

Time frame: 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.

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

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.

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

Area under the concentration-time curve from time zero to Tlast on dosing day, calculated using the linear-log trapezoidal rule.

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

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.

Time frame: Open-Label Extension Period: From week 24 up to end of study (approximately 5 years)