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Trial details
Trial details
A Study Evaluating the Efficacy and Safety of Mitapivat in Participants With Transfusion-Dependent Alpha- or Beta-Thalassemia (α- or β-TDT) (ENERGIZE-T).
Current status:
Approved
|
Date registered:
07/03/2022
Trial version(s)
Current: 15/07/2021
Click here to view the tips and fields' descriptions
Main Information
Primary registry identifying number
LBCTR2022014845
Protocol number
AG348-C-018
MOH registration number
Trial already registered with the MoPH
Study registered at the country of origin
Type of registration
Prospective
Date of registration in national regulatory agency
Primary sponsor
Agios Pharmaceuticals, Inc.
Primary sponsor: Country of origin
USA
Public title
A Study Evaluating the Efficacy and Safety of Mitapivat in Participants With Transfusion-Dependent Alpha- or Beta-Thalassemia (α- or β-TDT) (ENERGIZE-T).
Acronym
Scientific title
A Phase 3, Double-blind, Randomized, Placebo-Controlled, Multicenter Study Evaluating the Efficacy and Safety of Mitapivat in Subjects With Transfusion-Dependent Alpha- or Beta-Thalassemia (ENERGIZE-T)
Acronym
Brief summary of the study: English
Study AG348-C-018 is a Phase 3, double-blind, randomized, placebo-controlled, multicenter study evaluating the efficacy and safety of mitapivat versus placebo in adult subjects with α- or β-TDT followed by an Open-label Extension Period. The primary objective of the study is to compare the effect of mitapivat versus placebo on transfusion burden. Other secondary objectives include the evaluation of markers of iron overload, pharmacokinetic and pharmacodynamic parameters, and safety. Safety will be evaluated by the incidence, severity, and type of AEs, and by evaluation of vital signs, physical examination findings, clinical laboratory results, and bone mineral density scans.
Brief summary of the study: Arabic
هذه الدراسة في المرحلة 3 مزدوجة التعمية والعشوائية ، بالمقارنة مع دواء وهمي، و دراسة متعددة المراكز.إن الهدف من هذه الدراسة هوتقييم ما إذا كان دواء ميتابيفات mitapivat يساعدعلى تحسين مستويات الهيموغلوبين لدى مرضى الثلاسيميا من نوع ألفا أو بيتا الذين يحتاجون لنقل الدم بانتظام، وما إذا كان هذا الدواء آمنا. الأهداف الثانوية هي تقييم الحرائك الدوائية والديناميكا الدوائية .
Health conditions/problem studied: Specify
α- or β-Transfusion Dependent Thalassemia. Transfusion dependent is defined as 6 to 20 RBC units transfused and a ≤6-week transfusion-free period during the 24-week period before randomization.
Interventions: Specify
Study AG348-C-018 is a Phase 3, double-blind, randomized, placebo-controlled,nmulticenter study evaluating the efficacy and safety of mitapivat versus placebo in adult subjects with α- or β-TDT followed by an Open-label Extension Period. Subject eligibility will be determined during the (up to 8 weeks) Screening Period.
Key inclusion and exclusion criteria: Inclusion criteria
1. ≥18 years of age at the time of providing informed consent. 2. Documented diagnosis of thalassemia (β-thalassemia with or without α-globin gene mutations, HbE/β-thalassemia, or α-thalassemia/HbH disease) based on DNA analysis from the subject’s medical record. If this information is not available from the subject’s medical record, DNA analysis can be performed by a local laboratory during the Screening Period. If a local laboratory is unable to perform the test, results from the comprehensive α- and β-globin genotyping performed by the study central laboratory can be used. 3. Transfusion dependent, defined as 6 to 20 RBC units transfused and a ≤6-week transfusion-free period during the 24-week period before randomization. 4. If taking hydroxyurea, the hydroxyurea dose must be stable for ≥16 weeks before randomization. 5. Women of childbearing potential (WOCBP) and men with partners who are WOCBP must be abstinent of sexual activities that may induce pregnancy as part of their usual lifestyle or agree to use 2 forms of contraception, 1 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. 6. Written informed consent before any study-related procedures are conducted and willingto comply with all study procedures for the duration of the study.
Key inclusion and exclusion criteria: Gender
Both
Key inclusion and exclusion criteria: Age minimum
18
Key inclusion and exclusion criteria: Age maximum
99
Key inclusion and exclusion criteria: Exclusion criteria
1. Pregnant or breastfeeding. 2. Documented history of homozygous or heterozygous HbS or HbC. 3. Prior exposure to gene therapy or prior bone marrow or stem cell transplantation. 4. Currently receiving treatment with luspatercept; the last dose must have been administered ≥36 weeks before administration of the first dose of study drug. 5. Currently receiving treatment with hematopoietic stimulating agents; the last dose must have been administered ≥36 weeks before administration of the first dose of study drug. 6. History of any malignancy, except for nonmelanomatous skin cancer in situ, cervical carcinoma in situ, or breast carcinoma in situ. Subjects must not have active disease or received anticancer treatment ≤5 years before providing informed consent. 7. History of active and/or uncontrolled cardiac or pulmonary disease ≤6 months before providing informed consent, including but not limited to: a. New York Heart Association Class III or IV heart failure or clinically significant dysrhythmia b. Myocardial infarction or unstable angina pectoris; hemorrhagic, embolic, or thrombotic stroke; deep venous thrombosis; or pulmonary or arterial embolism c. Heart rate–corrected QT interval using Fridericia’s method ≥450 milliseconds, except for right or left bundle branch block d. Severe pulmonary fibrosis as defined by severe hypoxia, evidence of right-sided heart failure, and radiographic pulmonary fibrosis >50% e. Severe pulmonary hypertension as defined by severe symptoms associated with hypoxia, right-sided heart failure, and oxygen indicated 8. Hepatobiliary disorders, including but not limited to: a. Liver disease with histopathological evidence of cirrhosis or severe fibrosis b. Clinically symptomatic cholelithiasis or cholecystitis (prior cholecystectomy is not exclusionary) c. History of drug-induced cholestatic hepatitis d. Aspartate aminotransferase >2.5 × upper limit of normal (ULN); unless due to hemolysis and hepatic iron deposition) and alanine aminotransferase >2.5 × ULN (unless due to hepatic iron deposition) 9. Estimated glomerular filtration rate <45 mL/min/1.73 m2 by Chronic Kidney Disease Epidemiology Collaboration creatinine equation. 10. Nonfasting triglycerides >440 mg/dL (5 mmol/L). 11. Active infection requiring systemic antimicrobial therapy at the time of providing informed consent. If antimicrobial therapy is required during the Screening Period, screening procedures should not be performed while antimicrobial therapy is being administered, and the last dose of antimicrobial therapy must be administered ≥7 days before randomization. 12. Positive test for hepatitis C virus (HCV) antibody (Ab) with evidence of active HCV infection, or positive test for hepatitis B surface antigen. 13. Positive test for HIV-1 Ab or HIV-2 Ab. 14. History of major surgery (including splenectomy) ≤6 months before providing informed consent and/or a major surgical procedure planned during the study. 15. Current enrollment or past participation (≤12 weeks before administration of the first dose of study drug or a time frame equivalent to 5 half-lives of the investigational treatment, whichever is longer) in any other clinical study involving an investigational treatment or device. 16. Receiving strong cytochrome P450 (CYP)3A4/5 inhibitors that have not been stopped for ≥5 days or a time frame equivalent to 5 half-lives (whichever is longer), or strong CYP3A4 inducers that have not been stopped for ≥4 weeks or a time frame equivalent to 5 half-lives (whichever is longer), before administration of the first dose of study drug. 17. Receiving anabolic steroids, including testosterone preparations, that have not been stopped for ≤4 weeks before administration of the first dose of study drug. 18. Known allergy to mitapivat or its excipients (microcrystalline cellulose, croscarmellose sodium, sodium stearyl fumarate, mannitol, and magnesium stearate). 19. 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.
Type of Study
Type
Interventional
Type of intervention
Pharmaceutical
Trial scope
Other
Trial scope: Specify scope
Efficacy and safety
Study design: Allocation
Randomized controlled trial
Study design: Masking
Blinded (masking used)
Study design: Control
Placebo
Study phase
3
Study design: Purpose
Treatment
Study design: Assignment
Parallel
IMP has market authorization
No
Name of IMP
Mitapivat
Type of IMP
Others
Type of IMP: Specify
orally bioavailable, allosteric pyruvate kinase activator
Pharmaceutical class
The investigational drug mitapivat (also known as mitapivat sulfate and AG-348) is a first-in-class, orally bioavailable, potent, allosteric activator of wild-type RBC-specific form of pyruvate kinase (PKR) and a range of PKR-mutant enzymes (Kung et al, 2017). The RBC-specific form of pyruvate kinase is 1 of 4 pyruvate kinase isoenzymes expressed in human tissues from 2 separate genes, liver-specific form of pyruvate kinase (PKL) and pyruvate kinase muscle isozyme (PKM). Both PKR and PKL are splice isoforms of the PKLR gene, while PKM1 and PKM2 are both expressed from the PKM gene. Mitapivat is an allosteric activator of the PKR, PKL, and PKM2 isoenzymes, with similar potency against each.
Therapeutic indication
α- or β-Transfusion Dependent Thalassemia (TDT)
Therapeutic benefit
Mitapivat, has the potential to improve the transfusion burden in patients with TDT with the added benefit of oral administration.
Biospecimen retention
Samples with DNA**
Biospecimen description
Blood samples collected for comprehensive α- and β-globin genotyping and for UGT1A1 and PKLR genotyping will be analyzed by Centogene. Samples will be maintained in a secure storage facility with adequate measures to protect subject confidentiality. Samples will be retained for a maximum of 10 years.
Target sample size
240
Actual enrollment target size
Date of first enrollment: Type
Anticipated
Date of first enrollment: Date
01/02/2022
Date of study closure: Type
Anticipated
Date of study closure: Date
Recruitment status
Pending
Date of completion
IPD sharing statement plan
No
IPD sharing statement description
No IPD sharing statement plan
Additional data URL
Summary Results
Secondary Identifying Numbers
Full name of issuing authority
Secondary identifying number
NA
NA
Sources of Monetary or Material Support
Name
Agios Pharmaceuticals, Inc.
Secondary Sponsors
Name
NA
Contact for Public/Scientific Queries
Contact type
First name
Last name
Address
Country
Telephone
Email
Affiliation
Public
Aziz
Zoghbi
MCT-CRO, Berytech Technology and Health, 5th Floor Damascus Road, Beirut, Lebanon
Lebanon
009617100 8269
aziz.zoghbi@mct -cro.com
Director of Country Oversight and Manageme nt MENA, Gulf and Africa
Scientific
Ali
Taher
Chronic Care Center (CCC), Hazmieh, Lebanon
Lebanon
+9613 755 669
ataher@aub.edu.lb
PI
Centers/Hospitals Involved in the Study
Center/Hospital name
Name of principles investigator
Principles investigator speciality
Ethical approval
Chronic Care Center
Dr.Ali Taher
Professor of Medicine, Hematology & Oncology
Pending
Ethics Review
Ethics approval obtained
Approval date
Contact name
Contact email
Contact phone
Chronic Care Center
18/11/2021
Michelle Abi Saad
cccmas@chroniccare.org.lb
05-455101
Countries of Recruitment
Name
Health Conditions or Problems Studied
Condition
Code
Keyword
Transfusion dependent thalassemia
Thalassaemia (D56)
Thalassemia beta-Thalassemia alpha- Thalassemia Anemia, Hemolytic, Congenital Anemia, Hemolytic Anemia Hematologic Diseases
Interventions
Intervention
Description
Keyword
Mitapivat
Subjects will receive 100 mg twice-daily mitapivat for oral administration. Subjects will be randomly assigned in a 2;1 ratio to receive study drug (mitapivat or placebo, respectively)
Treatment
Primary Outcomes
Name
Time points
Measure
Effect of mitapivat versus placebo on transfusion burden
any consecutive 12-week period through Week 48 compared with baseline
Transfusion reduction response (TRR), defined as a ≥50% reduction in transfused red blood cell (RBC) units with a reduction of ≥2 units of transfused RBCs
Key Secondary Outcomes
Name
Time points
Measure
To compare the durability of the effect of mitapivat versus placebo on transfusion burden
Week 13 through Week 48 compared with baseline
• ≥33% reduction in transfused RBC units from Week 13 through Week 48 compared with baseline (TRR3) • ≥50% reduction in transfused RBC units in any consecutive 24-week period through Week 48 compared with baseline (TRR2) • ≥50% reduction in transfused RBC units from Week 13 through Week 48 compared with baseline (TRR4)
Trial Results
Summary results in Lebanon
Study results globally
Date of posting of results summaries
Date of first journal publication of results
Results URL link
Baseline characteristics
Participant flow
Adverse events
Outcome measures
URL to protocol files
Link(s) to publications related to the study
Changes History
Change
Date
Download as PDF
Save a PDF copy of the summary of the trial