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Trial details
A Study Evaluating the Efficacy and Safety of Mitapivat in Subjects With Sickle Cell Disease (SCD)
Current status:
Approved
|
Date registered:
20/04/2022
Trial version(s)
Current: 08/11/2021
Click here to view the tips and fields' descriptions
Main Information
Primary registry identifying number
LBCTR2022034916
Protocol number
AG348-C-020
MOH registration number
Trial already registered with the MoPH
Study registered at the country of origin
USA
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 Subjects With Sickle Cell Disease (SCD)
Acronym
Scientific title
A Phase 2/3, Double-Blind, Randomized, Placebo-Controlled, Multicenter Study to Evaluate the Efficacy and Safety of Mitapivat in Subjects With Sickle Cell Disease
Acronym
Brief summary of the study: English
This clinical trial is a Phase 2/3 study that will determine the recommended dose of mitapivat and evaluate the efficacy and safety of mitapivat in sickle cell disease by testing how well mitapivat works compared to placebo to increase the amount of hemoglobin in the blood and to reduce or prevent the occurrence of sickle cell pain crises. In addition, the long-term effect of mitapivat on efficacy and safety will be explored in an open-label extension portion.
Brief summary of the study: Arabic
هذه التجربة السريرية هي دراسة المرحلة 2/3 التي ستحدد الجرعة الموصى بها من mitapivat وتقييم فعالية وسلامة mitapivat في مرض الخلايا المنجلية عن طريق اختبار مدى عمل mitapivat مقارنة مع الدواء الوهمي لزيادة كمية الهيموغلوبين في الدم والحد من أو منع حدوث أزمات ألم الخلايا المنجلية. وبالإضافة إلى ذلك، سيتم استكشاف تأثير الميتابيفات على المدى الطويل على الفعالية والسلامة في جزء تمديد التسمية المفتوحة.
Health conditions/problem studied: Specify
Sickle Cell Disease (SCD) / Patients with SCD endure chronic hemolytic anemia and acute and recurrent clinical events that vary in frequency and severity, the most common being VOCs (vaso-occlusions). The use of curative options for SCD is currently limited to a small subgroup of patients who are deemed fit for bone marrow transplantation and have available donors. The current treatment options are not universally effective or globally available, tend to address only a single component of the disease, or are limited by their safety profile. Therefore, a significant unmet medical need exists for safe and effective therapies for the treatment of SCD that result in both an improvement in anemia and reduction in sickle cell–related crises.
Interventions: Specify
Study AG348-C-020 is a Phase 2/3, Double-Blind, Randomized, Placebo-Controlled, Multicenter Study to Evaluate the Efficacy and Safety of Mitapivat in Subjects With Sickle Cell Disease. In the phase 2 portion of the study, eligible subjects will be randomized in a 1:1:1 ratio to receive 50 mg mitapivat, 100 mg mitapivat, or matched placebo for BID oral administration. Subjects who did not participate in the Phase 2 portion of the study and who meet the eligibility criteria will be randomized in a 2:1 ratio to receive the selected Phase 3 dose of mitapivat or matched placebo for BID oral administration. Subjects who have completed the 12-week (Phase 2) or 52-week (Phase 3) Double-blind Period and do not have ongoing Grade ≥3 treatment-related AEs, unless approved by the Medical Monitor, will be eligible to receive mitapivat for up to 216 weeks (not including time to taper dose) in the Open-label Extension Period.
Key inclusion and exclusion criteria: Inclusion criteria
1. Age ≥16 years; subjects age 16 or 17 years must be documented Tanner Stage 5. 2. Documented diagnosis of SCD (HbSS, HbSC, HbS/β0-thalassemia, HbS/β+-thalassemia, or other sickle cell syndrome variants). 3. At least 2 SCPCs and no more than 10 SCPCs in the 12 months prior to providing informed assent/consent. 4. Hemoglobin ≥5.5 and ≤10.5 g/dL. 5. If taking hydroxyurea, the hydroxyurea dose must be stable for at least 90 days prior to randomization. 6. 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, one of which must be considered highly effective, from the time of providing informed assent/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 include an acceptable barrier method. 7. Written informed assent/consent (for subjects under 18 years of age, parental permission and child assent will be obtained) must be obtained before any study-related procedures are conducted and subjects must be willing to 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
16
Key inclusion and exclusion criteria: Age maximum
99
Key inclusion and exclusion criteria: Exclusion criteria
1. Pregnant or breastfeeding. 2. Receiving regularly scheduled RBC transfusion therapy (also termed chronic, prophylactic, or preventative transfusion); episodic transfusion in response to worsened anemia or VOC is permitted. Additionally, subjects may not have received a transfusion within 60 days before providing informed assent/consent or during the Screening Period. 3. Hospitalized for an SCPC or other vaso-occlusive event within 14 days prior to providing informed assent/consent or during the Screening Period. 4. Currently receiving treatment with a disease-modifying therapy for SCD (eg, voxelotor, crizanlizumab, L-glutamine), with the exception of hydroxyurea. The last dose of such therapies must have been administered at least 90 days before randomization. 5. 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 assent/consent. 6. History of active and/or uncontrolled cardiac or pulmonary disease within 6 months before providing informed assent/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 of ≥470 milliseconds forfemale subjects and ≥450 milliseconds for male subjects, 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 heart failure, and oxygen indicated. 7. Hepatobiliary disorders including but not limited to: a. Liver disease with histopathological evidence of cirrhosis or severe fibrosis. b. Clinically symptomatic cholelithiasis or cholecystitis (subjects with prior cholecystectomy are eligible). c. History of drug-induced cholestatic hepatitis. d. Aspartate aminotransferase >2.5× the upper limit of normal (ULN) (unless due to hemolysis and/or hepatic iron deposition) and alanine aminotransferase >2.5× the ULN (unless due to hepatic iron deposition). 8. Renal dysfunction as defined by an estimated glomerular filtration rate <30 mL/min/1.73 m2 by the Chronic Kidney Disease Epidemiology Collaboration creatinine equation. 9. Nonfasting triglycerides >440 mg/dL (5 mmol/L). 10. Active uncontrolled infection requiring systemic antimicrobial therapy. 11. Positive test for hepatitis C virus antibody with evidence of active hepatitis C virus infection, or positive test for hepatitis B surface antigen. 12. Positive test for HIV-1 antibody or HIV-2 antibody. 13. History of major surgery (including splenectomy) ≤16 weeks before providing informed assent/consent and/or planning on undergoing a major surgical procedure during the study. 14. Current enrollment or past participation (within 90 days before randomization or a time frame equivalent to 5 half-lives of the investigational study drug, whichever is longer) in any other clinical study involving an investigational study drug or device. 15. Prior exposure to gene therapy or prior bone marrow or stem cell transplantation. 16. Currently receiving treatment with hematopoietic stimulating agents; the last dose must have been administered at least 90 days before randomization. 17. Receiving products that are strong inhibitors of CYP3A4/5 that have not been stopped for ≥5 days or a time frame equivalent to 5 half-lives (whichever is longer), or strong inducers of CYP3A4 that have not been stopped for ≥28 days or a time frame equivalent to 5 half-lives (whichever is longer), prior to randomization. 18. Receiving anabolic steroids, including testosterone preparations, that have not been stopped for at least 28 days before randomization. 19. Known allergy to mitapivat or tablet excipients (microcrystalline cellulose, croscarmellose sodium, sodium stearyl fumarate, mannitol, and magnesium stearate). 20. 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. 21. Phase 3 only: Participated in the Phase 2 portion of Study AG348-C-020.
Type of Study
Type
Interventional
Type of intervention
Pharmaceutical
Trial scope
Therapy
Trial scope: Specify scope
Study design: Allocation
Randomized controlled trial
Study design: Masking
Blinded (masking used)
Study design: Control
Placebo
Study phase
2 to 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
Chemical Agent: Mitapivat is a heteroaromatic sulfonamide that also possesses benzamide and aliphatic tertiary amine functionalities.
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
Sickle Cell Disease (SCD).
Therapeutic benefit
Mitapivat is a therapeutic candidate for the treatment of adult patients with SCD with the potential to provide clinical benefit by both improvement of anemia and reduction in sickle cell pain crises (SCPCs). In addition, based on the cumulative nonclinical and clinical data generated with mitapivat in SCD and other hemolytic anemias, the potential benefits outweigh the potential risks in patients with SCD, the intended population for this study.
Biospecimen retention
Samples without DNA
Biospecimen description
Blood samples may also be collected for exploratory analyses of the following biomarkers: blood smears, C-reactive protein, free Hb, haptoglobin, hepcidin, N-terminal-prohormone brain natriuretic peptide, selectin, soluble erythroferrone, soluble transferrin receptor, and vascular cell adhesion molecule. Blood samples will be analyzed by a central laboratory. Samples may be retained for a maximum of 5 years (or according to local regulations) after the end of the study at a facility selected by the Sponsor for further exploratory analysis of biomarker responses to mitapivat for those subjects who consent to this optional research in the ICF.
Target sample size
267
Actual enrollment target size
Date of first enrollment: Type
Anticipated
Date of first enrollment: Date
11/02/2022
Date of study closure: Type
Anticipated
Date of study closure: Date
30/11/2030
Recruitment status
Pending
Date of completion
IPD sharing statement plan
No
IPD sharing statement description
NA
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
+961 71 008 269
aziz.zoghbi@mct-cro.com
Director of Country Oversight and Manageme nt MENA, Gulf and Africa
Scientific
Ali
Taher
American University Of Beirut Medical Center, Cairo Street, Beirut, Lebanon
Lebanon
+9613 755 669
ataher@aub.edu. lb
PI
Scientific
Adlette
Inati
Nini hospital, Al Maarad Street, Tripoli, Lebanon
Lebanon
+9613 228 033
adlette.inati@lau.edu.lb
PI
Scientific
Wissam
Houhou
Hammoud Hospital University Medical Center, Dr. Ghassan Hammoud Street, Saida , Lebanon
Lebanon
+9617 723 111
dr.wissam.h@hotmail.com
PI
Centers/Hospitals Involved in the Study
Center/Hospital name
Name of principles investigator
Principles investigator speciality
Ethical approval
American University Of Beirut Medical Center
Dr. Ali Taher
Professor of Medicine, Hematology & Oncology
Approved
Nini hospital
Dr. Adlette Inati
Pediatric Hematology/Oncology
Approved
Hammoud Hospital University Medical Center
Dr. Wissam Houhou
Hematologist/Oncologist
Approved
Ethics Review
Ethics approval obtained
Approval date
Contact name
Contact email
Contact phone
Nini Hospital
08/02/2022
Dr Nabil Kabbara
nabil.kabbara@hopitalnini.com
06 431 400, Ext 3165
Hammoud Hospital University Medical Center
11/02/2022
Ghada Aoun
medical@hammoudhospital.org
00961 3 408 947
Countries of Recruitment
Name
United States of America
Health Conditions or Problems Studied
Condition
Code
Keyword
Sickle Cell Disease
Sickle-cell disorders (D57)
Anemia, Sickle Cell Anemia, Hemolytic, Congenital Anemia, Hemolytic Anemia, Hematologic Diseases Hemoglobinopathies Genetic Diseases, Inborn
Interventions
Intervention
Description
Keyword
Mitapivat
In the Phase 2 portion of the study, eligible subjects will be randomized 1:1:1 to receive 50 mg BID mitapivat, 100 mg BID mitapivat, or matched placebo. In the Phase 3 portion of the study, eligible subjects will be randomized 2:1 to receive mitapivat or matched placebo. Subjects who have completed the Phase 2 portion of the study and had been receiving active treatment will be eligible to continue receiving the same dose in the Open-label Extension Period. Subjects who had been receiving placebo will be randomized 1:1 to receive either 50 mg BID mitapivat or 100 mg BID mitapivat in the Open-label Extension Period. Subjects who have completed the Phase 3 portion of the study will be eligible to continue to receive, if previously receiving active treatment, or begin to receive, if previously receiving placebo, the selected dose of mitapivat for the Phase 3 portion of the study.
Treatment
Primary Outcomes
Name
Time points
Measure
Phase 2: To determine the recommended Phase 3 dose of mitapivat by evaluating the effect of 2 dose levels of mitapivat versus placebo on Anemia in subjects with sickle cell disease (SCD)
Week 12
Hemoglobin (Hb) response, defined as a ≥1.0 g/dL increase in average Hb concentration from Week 10 through Week 12 compared with baseline
Phase 2: To determine the recommended Phase 3 dose of mitapivat by evaluating the effect of 2 dose levels of mitapivat versus placebo on Safety
Up to Week 12
Type, severity, and relationship to study drug of adverse events (AEs) and serious (SAEs)
Phase 3: To determine the effect of mitapivat versus placebo on Anemia in subjects with sickle cell disease (SCD)
Week 52
Hemoglobin (Hb) response, defined as a ≥1.0 g/dL increase in average Hb concentration from Week 24 through Week 52 compared with baseline
Phase 3: To determine the effect of mitapivat versus placebo on Sickle cell pain crises (SCPCs) in subjects with SCD
Up to Week 52
Annualized rate of SCPCs
Key Secondary Outcomes
Name
Time points
Measure
Phase 2: To evaluate the effect of 2 doses of mitapivat versus placebo on Anemia
Baseline, Week 10 up to Week 12
Average change from baseline in Hb concentration from Week 10 through Week 12
Phase 2: To evaluate the effect of 2 doses of mitapivat versus placebo on Markers of hemolysis and erythropoiesis
Baseline, Week 10 up to Week 12
Average change from baseline in markers of hemolysis, including indirect bilirubin and lactate dehydrogenase (LDH), from Week 10 through Week 12. Average change from baseline in markers of erythropoiesis, including absolute reticulocyte count, percent reticulocyte, and erythropoietin, from Week 10 through Week 12
Phase 2: To evaluate the effect of 2 doses of mitapivat versus placebo on Patient-reported fatigue
Baseline, Week 10 up to Week 12
Average change from baseline in Patient-Reported Outcomes Measurement Information System® (PROMIS) Fatigue 13a Short Form (SF) score from Week 10 through Week 12
Phase 2: To evaluate the effect of 2 doses of mitapivat versus placebo on Sickle cell pain crises (SCPCs)
Up to Week 12
Annualized rate of SCPCs
Phase 2: To evaluate the pharmacokinetic and pharmacodynamic effects of mitapivat
Day 1 up to Week 8
Pharmacokinetic/Pharmacodynamic Relationship: Evaluate the Exposure of Mitapivat to the Change in Adenosine Triphosphate (ATP) and 2,3-Diphosphoglycerate (2,3-DPG)
Phase 2: To evaluate the pharmacokinetic and pharmacodynamic effects of mitapivat
Day 1 up to Week 8
Mitapivat Concentration Over Time/Mitapivat Area Under the Concentration/Mitapivat Maximum (Peak) Concentration
Phase 3: To evaluate the effect of mitapivat versus placebo on Anemia in subjects with SCD
Baseline, Week 24 up to Week 52
Change from baseline in average Hb concentration from Week 24 through Week 52
Phase 3: To evaluate the effect of mitapivat versus placebo on Markers of hemolysis
Baseline, Week 24 up to Week 52
Change from baseline in average indirect bilirubin from Week 24 through Week 52
Phase 3: To evaluate the effect of mitapivat versus placebo on Markers of erythropoiesis
Baseline, Week 24 up to Week 52
Change from baseline in average percent reticulocyte from Week 24 through Week 52
Phase 3: To evaluate the effect of mitapivat versus placebo on Patient-reported fatigue
Baseline, Week 24 up to Week 52
Change from baseline in average Patient-Reported Outcomes Measurement Information System® (PROMIS) Fatigue 13a Short Form (SF) scores from Week 24 through Week 52
Phase 3: To evaluate the effect of mitapivat versus placebo on Additional clinical efficacy measures related to SCPC
Up to Week 52
Annualized frequency of hospitalizations for SCPC
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