E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
Non–Transfusion-Dependent Alpha- or Beta-Thalassemia |
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E.1.1.1 | Medical condition in easily understood language |
Thalassemia-genetic blood disorder where not enough hemoglobin is produced.2Types-α &β Non-transfusion-dependent thalassemias-Patients who do not require regular transfusions
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E.1.1.2 | Therapeutic area | Diseases [C] - Blood and lymphatic diseases [C15] |
MedDRA Classification |
E.1.2 Medical condition or disease under investigation |
E.1.2 | Version | 20.0 |
E.1.2 | Level | LLT |
E.1.2 | Classification code | 10074356 |
E.1.2 | Term | Non-transfusion dependent thalassemia |
E.1.2 | System Organ Class | 100000004850 |
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E.1.3 | Condition being studied is a rare disease | Yes |
E.2 Objective of the trial |
E.2.1 | Main objective of the trial |
• To compare the effect of mitapivat versus placebo on anemia in subjects with α- or β- non–transfusion-dependent thalassemia (NTDT) |
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E.2.2 | Secondary objectives of the trial |
Key Secondary Objectives • To compare the effect of mitapivat versus placebo on fatigue • To compare the effect of mitapivat versus placebo on additional measures of anemia
Secondary Objectives • To evaluate the effect of mitapivat versus placebo on anemia and markers of hemolysis and erythropoiesis • To evaluate the effect of mitapivat versus placebo on additional measures of fatigue • To evaluate the effect of mitapivat versus placebo on physical activity • To evaluate the effect of mitapivat versus placebo on iron metabolism • To evaluate the safety of mitapivat • To evaluate the pharmacokinetic and pharmacodynamic effects of mitapivat |
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E.2.3 | Trial contains a sub-study | No |
E.3 | Principal inclusion criteria |
Subjects are eligible to be included in the study only if all the following criteria apply: 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 Hb electrophoresis, Hb high-performance liquid chromatography, and/or DNA analysis from the subject’s medical record. If this information is not available from the subject’s medical record, the test(s) can be performed by a local laboratory during the Screening Period. If a local laboratory is unable to perform the test(s), results from the comprehensive α- and β-globin genotyping performed by the study central laboratory can be used. 3. Hb concentration ≤10.0 g/dL (100.0 g/L), based on an average of at least 2 Hb concentration measurements (separated by ≥7 days) collected during the Screening Period. 4. Non–transfusion dependent, defined as ≤5 RBC units during the 24-week period before randomization, and no RBC transfusions ≤8 weeks before providing informed consent and no RBC transfusions or during the Screening Period. 5. If taking hydroxyurea, the hydroxyurea dose must be stable for ≥16 weeks before randomization. 6. Women of childbearing 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, 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. The second form of contraception can be an acceptable barrier method. 7. Written informed consent before any study-related procedures are conducted and willing to comply with all study procedures for the duration of the study. |
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E.4 | Principal exclusion criteria |
Subjects are excluded from the study if any of the following criteria apply: 1. Pregnant, breastfeeding or parturient. 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 ≥12 weeks before randomisation. 5. Currently receiving treatment with hematopoietic stimulating agents; the last dose must have been administered ≥12 weeks before randomisation. 6. History of any malignancy (active or treated) =5 years before providing informed consent,, except for nonmelanomatous skin cancer in situ, cervical carcinoma in situ, or breast carcinoma in situ. 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 (males) or ≥470 milliseconds (females), 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 (AST) >2.5 × upper limit of normal (ULN); unless due to hemolysis and hepatic iron deposition) and alanine aminotransferase (ALT) >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 (HBsAg). 13. Positive test for HIV-1 Ab or HIV-2 Ab. 14. History of major surgery (including splenectomy) ≤16 weeks 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 study drug, whichever is longer) in any other clinical study involving an investigational treatment or device. 16. Receiving strong CYP3A4/5 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 randomisation. 17. Receiving anabolic steroids, including testosterone preparations, that have not been stopped for at least 4 weeks before randomisation. Testosterone replacement therapy to treat hypogonadism is allowed; the testosterone dose and preparation must be stable for ≥10 weeks before randomisation. 18. Known allergy, or other contraindication, 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]). 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. Also excluded are: • Subjects who are institutionalized by regulatory or court order • Subjects 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) |
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E.5 End points |
E.5.1 | Primary end point(s) |
• Hemoglobin (Hb) response, defined as a ≥1.0 g/dL increase in average Hb concentration from Week 12 through Week 24 compared with baseline |
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E.5.1.1 | Timepoint(s) of evaluation of this end point |
Please refer to the schedule of assessment |
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E.5.2 | Secondary end point(s) |
Key Secondary Endpoints • Change from baseline in average Functional Assessment of Chronic Illness Therapy-Fatigue (FACIT-Fatigue) subscale score from Week 12 through Week 24 • Change from baseline in average Hb concentration from Week 12 through Week 24
Secondary Endpoints • Hb 1.5+ response, defined as a ≥1.5 g/dL increase in average Hb concentration from Week 12 through Week 24 compared with baseline • Change from baseline in indirect bilirubin, lactate dehydrogenase, and haptoglobin at Week 24 • Change from baseline in reticulocytes and erythropoietin at Week 24 • 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 • 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 • Change from baseline in the 6-minute walk test (6MWT) distance at Week 24 • Change from baseline in markers of iron metabolism, including serum ferritin and transferrin saturation, at Week 24 • Type, severity, and relationship of adverse events (AEs) and serious adverse events • Plasma or blood concentrations and pharmacokinetic parameters of mitapivat and pharmacodynamic parameters, including adenosine triphosphate (ATP) and 2,3-diphosphoglycerate (2,3-DPG) |
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E.5.2.1 | Timepoint(s) of evaluation of this end point |
Please refer to the schedule of assessment |
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E.6 and E.7 Scope of the trial |
E.6 | Scope of the trial |
E.6.1 | Diagnosis | No |
E.6.2 | Prophylaxis | No |
E.6.3 | Therapy | No |
E.6.4 | Safety | Yes |
E.6.5 | Efficacy | Yes |
E.6.6 | Pharmacokinetic | Yes |
E.6.7 | Pharmacodynamic | Yes |
E.6.8 | Bioequivalence | No |
E.6.9 | Dose response | No |
E.6.10 | Pharmacogenetic | No |
E.6.11 | Pharmacogenomic | No |
E.6.12 | Pharmacoeconomic | No |
E.6.13 | Others | Yes |
E.6.13.1 | Other scope of the trial description |
Targeted genotyping, exploratory analysis of biomarkers |
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E.7 | Trial type and phase |
E.7.1 | Human pharmacology (Phase I) | No |
E.7.1.1 | First administration to humans | No |
E.7.1.2 | Bioequivalence study | No |
E.7.1.3 | Other | No |
E.7.1.3.1 | Other trial type description | |
E.7.2 | Therapeutic exploratory (Phase II) | No |
E.7.3 | Therapeutic confirmatory (Phase III) | Yes |
E.7.4 | Therapeutic use (Phase IV) | No |
E.8 Design of the trial |
E.8.1 | Controlled | Yes |
E.8.1.1 | Randomised | Yes |
E.8.1.2 | Open | No |
E.8.1.3 | Single blind | No |
E.8.1.4 | Double blind | Yes |
E.8.1.5 | Parallel group | No |
E.8.1.6 | Cross over | Yes |
E.8.1.7 | Other | No |
E.8.2 | Comparator of controlled trial |
E.8.2.1 | Other medicinal product(s) | No |
E.8.2.2 | Placebo | Yes |
E.8.2.3 | Other | No |
E.8.2.4 | Number of treatment arms in the trial | 2 |
E.8.3 |
The trial involves single site in the Member State concerned
| Yes |
E.8.4 | The trial involves multiple sites in the Member State concerned | No |
E.8.5 | The trial involves multiple Member States | Yes |
E.8.5.1 | Number of sites anticipated in the EEA | 31 |
E.8.6 Trial involving sites outside the EEA |
E.8.6.1 | Trial being conducted both within and outside the EEA | Yes |
E.8.6.2 | Trial being conducted completely outside of the EEA | No |
E.8.6.3 | If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned |
Egypt |
Malaysia |
United Arab Emirates |
Taiwan |
Brazil |
Canada |
Lebanon |
Saudi Arabia |
Thailand |
Turkey |
United Kingdom |
United States |
Bulgaria |
Denmark |
France |
Germany |
Greece |
Italy |
Netherlands |
Spain |
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E.8.7 | Trial has a data monitoring committee | Yes |
E.8.8 |
Definition of the end of the trial and justification where it is not the last
visit of the last subject undergoing the trial
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E.8.9 Initial estimate of the duration of the trial |
E.8.9.1 | In the Member State concerned years | 7 |
E.8.9.1 | In the Member State concerned months | |
E.8.9.1 | In the Member State concerned days | 4 |
E.8.9.2 | In all countries concerned by the trial years | 7 |
E.8.9.2 | In all countries concerned by the trial months | 1 |