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

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ClinicalTrials.gov Identifier: NCT04770753
Recruitment Status : Recruiting
First Posted : February 25, 2021
Last Update Posted : November 11, 2021
Sponsor:
Information provided by (Responsible Party):
Agios Pharmaceuticals, Inc.

Brief Summary:
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).

Condition or disease Intervention/treatment Phase
Non-Transfusion-dependent Alpha-Thalassemia Non-Transfusion-dependent Beta-Thalassemia Drug: Placebo Matching Mitapivat Drug: Mitapivat Phase 3

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

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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 171 participants
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Primary Purpose: Treatment
Official 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)
Estimated Study Start Date : November 2021
Estimated Primary Completion Date : December 2023
Estimated Study Completion Date : December 2023


Arm Intervention/treatment
Experimental: Mitapivat

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
Tablets
Other Names:
  • AG-348
  • AG-348 sulfate hydrate
  • Mitapivat sulfate

Placebo Comparator: Placebo

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
Tablets

Drug: Mitapivat
Tablets
Other Names:
  • AG-348
  • AG-348 sulfate hydrate
  • Mitapivat sulfate




Primary Outcome Measures :
  1. Percentage of Participants With Hemoglobin (Hb) Response [ Time Frame: Baseline, Week 12 up to Week 24 ]
    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.


Secondary Outcome Measures :
  1. Change From Baseline in Average Functional Assessment of Chronic Illness Therapy (FACIT) -Fatigue Subscale Score from Week 12 through Week 24 [ Time Frame: Baseline, Week 12 up to 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.

  2. Change From Baseline in Average Hb Concentration From Week 12 through Week 24 [ Time Frame: Baseline, Week 12 up to Week 24 ]
  3. Percentage of Participants With Hb 1.5+ Response [ Time Frame: Baseline, Week 12 up to 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.

  4. Change From Baseline in Indirect Bilirubin at Week 24 [ Time Frame: Baseline, Week 24 ]
  5. Change From Baseline in Lactate Dehydrogenase (LDH) at Week 24 [ Time Frame: Baseline, Week 24 ]
  6. Change From Baseline in Haptoglobin at Week 24 [ Time Frame: Baseline, Week 24 ]
  7. Change From Baseline in Reticulocytes at Week 24 [ Time Frame: Baseline, Week 24 ]
  8. Change From Baseline in Erythropoietin at Week 24 [ Time Frame: Baseline, Week 24 ]
  9. 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 [ Time Frame: Baseline, Weeks 12, 16, 20, and 24 ]
    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.

  10. 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 [ Time Frame: Weeks 12, 16, 20, and 24 ]
    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.

  11. Change From Baseline in the 6-minute Walk Test (6MWT) Distance at Week 24 [ Time Frame: Baseline, Week 24 ]
  12. Change From Baseline in Serum Ferritin at Week 24 [ Time Frame: Baseline, Week 24 ]
  13. Change From Baseline in Transferrin Saturation (TSAT) at Week 24 [ Time Frame: Baseline, Week 24 ]
  14. Percentage of Participants With Adverse Events (AEs) and Serious Adverse Events (SAEs) [ Time Frame: Up to Week 293 ]
  15. Percentage of Participants With Adverse Events (AEs) and Serious Adverse Events (SAEs), Graded by Severity [ Time Frame: Up to Week 293 ]
    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.

  16. Percentage of Participants With Adverse Events (AEs) Considered by the Investigator to be Related to Study Drug [ Time Frame: Up to Week 293 ]
  17. Percentage of Participants With Serious Adverse Events (SAEs) Considered by the Investigator to be Related to Study Drug [ Time Frame: Up to Week 293 ]
  18. Plasma or Blood Concentrations Over Time for Mitapivat [ Time Frame: Pre-dose Week 12; pre-dose, 0.5, 1, 3, 5, 7 hours post-dose Week 20 ]
  19. Area Under the Concentration-time Curve From Time Zero to the Last Measurable Concentration (AUClast) of Mitapivat [ Time Frame: Pre-dose, 0.5, 1, 3, 5, 7 hours post-dose Week 20 ]
  20. Maximum Plasma Concentration (Cmax) of Mitapivat [ Time Frame: Pre-dose, 0.5, 1, 3, 5, 7 hours post-dose Week 20 ]
  21. Time of Maximum Plasma Concentration (Tmax) of Mitapivat [ Time Frame: Pre-dose, 0.5, 1, 3, 5, 7 hours post-dose Week 20 ]
  22. Blood Concentration of Adenosine Triphosphate (ATP) [ Time Frame: Pre-dose Day 1; pre-dose Week 12; pre-dose, 0.5, 1, 3, 5, 7 hours post-dose Week 20 ]
  23. Blood Concentration of 2,3 - diphosphoglycerate (2,3-DPG) [ Time Frame: Pre-dose Day 1; pre-dose Week 12; pre-dose, 0.5, 1, 3, 5, 7 hours post-dose Week 20 ]


Information from the National Library of Medicine

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Ages Eligible for Study:   18 Years and older   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

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 or during the Screening Period;
  • If taking hydroxyurea, the hydroxyurea dose must be stable for ≥16 weeks before randomization;
  • Women of child-bearing potential (WOCBP) and men with partners who are 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 for women and 90 days after the last dose of study drug for men. 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 or breastfeeding;
  • 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 any malignancy, except for nonmelanomatous skin cancer in situ, cervical carcinoma in situ, or breast carcinoma in situ. Participants must not have active disease or received anticancer treatment ≤5 years before providing informed consent;
  • 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 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);
  • 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.

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT04770753


Contacts
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Contact: Medical Affairs 833-228-8474 medinfo@agios.com

Locations
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United States, Massachusetts
Massachusetts General Hospital Recruiting
Boston, Massachusetts, United States, 02114
Canada, Ontario
Toronto General Hospital Recruiting
Toronto, Ontario, Canada, M5G 2C4
Sponsors and Collaborators
Agios Pharmaceuticals, Inc.
Investigators
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Study Chair: Medical Affairs Agios Pharmaceuticals, Inc.
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Responsible Party: Agios Pharmaceuticals, Inc.
ClinicalTrials.gov Identifier: NCT04770753    
Other Study ID Numbers: AG348-C-017
2021-000211-23 ( EudraCT Number )
First Posted: February 25, 2021    Key Record Dates
Last Update Posted: November 11, 2021
Last Verified: November 2021
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: No

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Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No
Additional relevant MeSH terms:
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Thalassemia
beta-Thalassemia
alpha-Thalassemia
Anemia, Hemolytic, Congenital
Anemia, Hemolytic
Anemia
Hematologic Diseases
Hemoglobinopathies
Genetic Diseases, Inborn