E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
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E.1.1.1 | Medical condition in easily understood language |
Sickle cell disease is an inherited blood disorder where the red blood cells, which carry oxygen around the body, develop abnormally and become rigid and shaped like a crescent (sickle shape). |
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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 | 21.0 |
E.1.2 | Level | PT |
E.1.2 | Classification code | 10040644 |
E.1.2 | Term | Sickle cell disease |
E.1.2 | System Organ Class | 10010331 - Congenital, familial and genetic disorders |
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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 |
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) • Safety
Phase 3) To determine the effect of mitapivat versus placebo on: • Anemia in subjects with sickle cell disease (SCD) • Sickle cell pain crises (SCPCs) in subjects with SCD |
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E.2.2 | Secondary objectives of the trial |
Phase 2) To evaluate the effect of 2 doses of mitapivat versus placebo on: - Anemia - Markers of hemolysis and erythropoiesis - Patient-reported fatigue - Sickle cell pain crises (SCPCs). To evaluate the pharmacokinetic and pharmacodynamic effects of mitapivat.
Phase 3) To evaluate the effect of mitapivat versus placebo on: • Anemia in subjects with SCD • Markers of hemolysis • Markers of erythropoiesis • Patient-reported fatigue • Additional clinical efficacy measures related to SCPC |
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E.2.3 | Trial contains a sub-study | No |
E.3 | Principal inclusion criteria |
• Age ≥16 years; subjects age 16 or 17 years must physically have completed puberty. • Documented diagnosis of SCD (HbSS, HbSC, HbS/β0-thalassemia, HbS/β+ thalassemia, or other sickle cell syndrome variants). • At least 2 sickle cell pain crises (SCPCs) and no more than 10 SCPCs in the past 12 months. • Hemoglobin ≥5.5 and ≤10.5 g/dL. • If taking hydroxyurea, the hydroxyurea dose must be stable for at least 90 days before starting study drug. Discontinuation of hydroxyurea requires a 90-day washout prior to informed assent/consent. • Women capable of becoming pregnant and men with partners who are women that are capable of becoming pregnant must agree to use 2 forms of contraception. • Other protocol-defined inclusion criteria may apply. |
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E.4 | Principal exclusion criteria |
• Pregnant or breastfeeding. • Receiving regularly scheduled transfusions. • Hospitalized for an SCPC and/or other vaso-occlusive event within 14 days prior to providing informed assent/consent or during the Screening Period. A hospitalization is defined as an in-patient admission to a hospital that may or may not be preceded by an emergency room or out patient clinic visit. A visit to an emergency room that does not result in an in-patient admission does not meet the definition of hospitalization. • Currently receiving treatment for SCD (eg, voxelotor, crizanlizumab, L glutamine), with the exception of hydroxyurea. The last dose of voxelotor, crizanlizumab, and L-glutamine must have been administered at least 90 days before starting study drug. • Currently receiving treatment with hematopoietic stimulating agents; the last dose must have been administered at least 90 days before starting study drug. • Received treatment on another investigational trial within 90 days prior to start of study drug or plans to participate in another investigational drug trial. • Taking medications that are strong inhibitors of CYP3A4/5 or strong inducers of CYP3A4 that cannot be stopped in an acceptable timeframe before starting study drug (timeframe will be discussed with your doctor). • Other protocol defined exclusion criteria may apply. |
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E.5 End points |
E.5.1 | Primary end point(s) |
Phase 2 Primary Endpoints: • Percentage of participants with hemoglobin (Hb) response • Percentage of participants with treatment emergent adverse events (AEs) and treatment emergent serious adverse events (SAEs)
Phase 3 Primary Endpoints • Percentage of participants with hemoglobin (Hb) response • Annualized rate of Sickle Cell Pain Crises (SCPCs) |
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E.5.1.1 | Timepoint(s) of evaluation of this end point |
Phase 2 primary endpoint of percentage of participants with Hb response: Week 12
Phase 2 primary endpoint of percentage of participants with treatment emergent AEs and treatment emergent SAEs: Up to Week 12
Phase 3 primary endpoint of percentage of participants with Hb response: Week 52
Phase 3 primary endpoint of annualized rate of sickle cell pain crises: Up to Week 52 |
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E.5.2 | Secondary end point(s) |
Phase 2 Secondary Endpoints 1. Change from baseline in Hb concentration 2. Change from baseline in indirect bilirubin 3. Change from baseline in lactate dehydrogenase (LDH) 4. Change from baseline in absolute reticulocyte count 5. Change from baseline in percent reticulocytes 6. Change from baseline in erythropoietin 7. Change from baseline in Patient-Reported Outcomes Measurement Information System® (PROMIS®) Fatigue 13a Short Form (SF) Score 8. Annualized Rate of SCPCs 9. Pharmacokinetic/Pharmacodynamic Relationship: Evaluate the Exposure of Mitapivat to the Change in Adenosine Triphosphate (ATP) and 2,3-Diphosphoglycerate (2,3-DPG) 10. Mitapivat Concentration Over Time 11. Mitapivat Area Under the Concentration-time curve 12. Mitapivat Maximum (Peak) Concentration
Phase 3 Secondary Endpoints 1. Change From Baseline in Hb Concentration 2. Change From Baseline in Indirect Bilirubin 3. Change From Baseline in Percent Reticulocytes 4. Change From Baseline in PROMIS® Fatigue 13a SF Scores 5. Annualized Frequency of Hospitalizations for SCPC 6. Change From Baseline in LDH Concentration 7. Change From Baseline in Absolute Reticulocytes 8. Change From Baseline in Erythropoietin 9. Percentage of Participants With Improvement in the Patient Global Impression of Severity (PGIS) -Fatigue 10. Percentage of Participants With Improvement in the Patient Global Impression of Change (PGIC) -Fatigue 11. Time to First SCPC 12. Time to Second SCPC 13. Annualized Rate of Hospitalization Days for SCPC 14. Annualized Rate of Emergency Room Visits for SCPC 15. Change From Baseline in 6-Minute Walk Test (6MWT) 16. Change From Baseline in PROMIS Pain Intensity 17. Change From Baseline in Adult Sickle Cell Quality of Life Measurement Information System (ASCQ-Me) Pain Impact 18. PGIC of Pain 19. Change From Baseline in PGIS of Pain 20. Percentage of Participants With Treatment-Emergent Adverse Events (AEs) and Treatment-Emergent Serious AEs (SAEs) 21. Pharmacokinetic/Pharmacodynamic Relationship: Evaluate the Exposure of Mitapivat to the Change in ATP and 2,3-DPG Levels 22: Mitapivat Concentration Over Time 23: Mitapivat Area Under the Concentration Curve 24: Mitapivat Maximum (Peak) Concentration |
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E.5.2.1 | Timepoint(s) of evaluation of this end point |
Phase 2 Endpoints #1,2,3,4,5,6,7: Baseline, Week 10 up to Week 12 Endpoint #8: Up to Week 12 Endpoints #9,10,11,12: Day 1 up to Week 8
Phase 3 Endpoints #1,2,3,4,6,7,8: Baseline, Week 24 up to Week 52 Endpoint #5,11,12,13,14: Up to Week 52 Endpoints #9,10: Baseline, Weeks 24, 28, 40, and 52 Endpoints #15,18,19: Baseline, Week 52 Endpoints #16,17: Baseline, Week 24 and 52 Endpoint #20: Up to 56 weeks Endpoints #21,22,23,24: Day 1 up to Week 40 |
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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 | Yes |
E.6.10 | Pharmacogenetic | No |
E.6.11 | Pharmacogenomic | No |
E.6.12 | Pharmacoeconomic | No |
E.6.13 | Others | No |
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) | Yes |
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 | Yes |
E.8.1.6 | Cross over | No |
E.8.1.7 | Other | Yes |
E.8.1.7.1 | Other trial design description |
There is an open label extension period following completion of the double blind period. |
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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 | 3 |
E.8.3 |
The trial involves single site in the Member State concerned
| No |
E.8.4 | The trial involves multiple sites in the Member State concerned | Yes |
E.8.4.1 | Number of sites anticipated in Member State concerned | 5 |
E.8.5 | The trial involves multiple Member States | Yes |
E.8.5.1 | Number of sites anticipated in the EEA | 24 |
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 |
Nigeria |
Oman |
Brazil |
Canada |
Israel |
Kenya |
Lebanon |
Saudi Arabia |
United Kingdom |
United States |
Belgium |
France |
Germany |
Italy |
Netherlands |
Türkiye |
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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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The end of the study is defined as the time at which all subjects complete all study visits, are lost to follow-up, have withdrawn consent for further participation in the study, or when the Sponsor terminates the study. Study completion is the date of the last visit of the last subject in the study. |
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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 | 9 |
E.8.9.1 | In the Member State concerned months | 10 |
E.8.9.1 | In the Member State concerned days | 0 |
E.8.9.2 | In all countries concerned by the trial years | 9 |
E.8.9.2 | In all countries concerned by the trial months | 10 |
E.8.9.2 | In all countries concerned by the trial days | 0 |