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NCT Number: NCT04770753

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

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).

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This study is active but is not currently recruiting participants.

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Key information

Conditions

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

Age range

18 year and older

Sex eligibility

All sexes

Study type

Interventional

Phase

Phase 3

Primary location

Universidade de Caxias do Sul, Caxias do Sul, Brazil

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About this study

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

Who can participate

Healthy volunteers accepted: No

Only the study team can determine whether someone qualifies for participation.

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)

Treatment and study plan

Placebo Matching Mitapivat

Drug

Tablets

Mitapivat

Drug

Tablets

Other names: AG-348, AG-348 sulfate hydrate, Mitapivat sulfate

Primary outcomes

  1. 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.

Secondary outcomes

  1. 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

    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.

  2. 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

    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.

  3. 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

    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.

  4. Double-Blind Period: Change From Baseline in Indirect Bilirubin at Week 24

    Time frame: 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.

  5. Double-Blind Period: Change From Baseline in Lactate Dehydrogenase (LDH) at Week 24

    Time frame: 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.

  6. Double-Blind Period: Change From Baseline in Haptoglobin at Week 24

    Time frame: 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.

  7. Double-Blind Period: Change From Baseline in Reticulocytes at Week 24

    Time frame: 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.

  8. Double-Blind Period: Change From Baseline in Erythropoietin at Week 24

    Time frame: 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.

  9. 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

    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'.

  10. 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

    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'.

  11. 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

    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.

  12. Double-Blind Period: Change From Baseline in Serum Ferritin at Week 24

    Time frame: Double-Blind Period: Baseline, Week 24

    Iron metabolism was assessed based on serum ferritin levels.

  13. Double-Blind Period: Change From Baseline in Transferrin Saturation (TSAT) at Week 24

    Time frame: 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.

  14. 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

    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.

  15. 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

  16. 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

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

  17. 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

  18. 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

  19. 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

  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

  21. 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

  22. 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

  23. 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)

    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.

Sponsors and collaborators

Lead sponsor

Agios Pharmaceuticals, Inc.

Industry

Registry information

Official study 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)

Important dates

Study start
2021
Primary completion
2023
Study completion
2028
First posted
Feb 25, 2021
Registry last updated
Jul 31, 2026

OpenTrials presents study information sourced from ClinicalTrials.gov. The official registry record should be consulted for the latest information.

View the official ClinicalTrials.gov record (opens in a new tab)

This listing is for discovery and informational purposes only. It is not medical advice, does not guarantee that a study is recruiting, and does not determine eligibility. Contact the study team and a qualified healthcare professional when considering participation.

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