E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
sickle cell disease (SCD) |
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E.1.1.1 | Medical condition in easily understood language |
sickle cell disease (SCD) |
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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 |
• To assess the efficacy of Etavopivat in adolescents and adults with SCD as compared to placebo as measured by improvement in hemoglobin (Hb)
• To assess the efficacy of Etavopivat as compared to placebo on the annualized vaso-occlusive crisis (VOC) rate |
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E.2.2 | Secondary objectives of the trial |
• To measure the effects of Etavopivat on clinical measures and sequelae of hemolysis
• To assess changes in fatigue of adult sickle cell patients taking etavopivat
• To evaluate the effects of Etavopivat on the sequelae of VOC
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E.2.3 | Trial contains a sub-study | No |
E.3 | Principal inclusion criteria |
1) Provision of consent
2) Patient has a confirmed diagnosis of sickle cell disease
3) 2-15 episodes of documented vaso-occlusive crises in the past 12 months
4) Hemoglobin ≥ 5.5 and ≤ 10.5 g/dL (≥ 55 and ≤ 105 g/L) during screening
5) Patients taking hydroxyurea, must demonstrate a stable dose for at least 90 days prior to start of study treatment
6) Female patients of childbearing potential must use acceptable methods of contraception, male patients are willing to use acceptable methods of contraception
7)Patients on crizanlizumab or L-glutamine oral powder (Endari®) treatment at the time of consent may be eligible if they:
• Have been on a stable dose for ≥ 12 months at the time of consent (i.e., no changes to the dose except for changes to weight or for safety reasons)
• Have been ≥ 80% compliant with the planned regimen during the 12 months prior to the time of consent
• Meet the VOC eligibility requirement in Inclusion Criterion 4
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E.4 | Principal exclusion criteria |
Medical Conditions
1) More than 15 vaso-occlusive crises within the past 12 months prior to screening
2) Female who is breast feeding or pregnant
3) Hepatic dysfunction characterized by:
- Alanine aminotransferase (ALT) > 4.0 × upper limit of normal (ULN)
OR
- Direct bilirubin > 3.0 × ULN
4) Known HIV positive
5) Active hepatitis B or hepatitis C infection
6) Severe renal dysfunction or on chronic dialysis
7) History of unstable or deteriorating cardiac or pulmonary disease within 6 months prior to consent including but not limited to the following:
- Unstable angina pectoris or myocardial infarction or elective coronary intervention
- Congestive heart failure requiring hospitalization
- Uncontrolled clinically significant arrhythmias
- Symptomatic pulmonary hypertension
8) History of overt clinical stroke within previous 2 years or any history of an intracranial hemorrhage
9) History of deep venous thrombosis requiring systemic anti-coagulation therapy for ≥ 6 weeks, occurring within 6 months prior to Day 1 of study treatment.
Note: patients on ≥ 6 months of chronic or prophylactic anti-coagulation therapy are allowed on study.
Prior/Concomitant Therapy
1) Patients receiving regularly scheduled blood (RBC) transfusion therapy (also termed chronic, prophylactic, or preventive transfusion)
2) Receiving or use of concomitant medications that are strong inducers of CYP3A4/5 within 2 weeks of starting study treatment or anticipated need for such agents during the study
3) Use of voxelotor within 28 days prior to starting study treatment or anticipated need for this agent during the study
4) Use of an experimental selectin antagonist (e.g., monoclonal antibody or small molecule) within 28 days of starting study treatment or anticipated need for such agents during the study
5) Use of erythropoietin or other hematopoietic growth factor treatment within 28 days of starting study treatment or anticipated need for such agents during the study
6) Receipt of prior cellular-based therapy (e.g., hematopoietic cell transplant, gene modification therapy)
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E.5 End points |
E.5.1 | Primary end point(s) |
• Hb response rate at Week 24 (increase of > 1 g/dL [> 10 g/L] from baseline) during the blinded treatment period
• Annualized VOC rate during the 52-week blinded treatment period based on adjudicated VOC review |
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E.5.1.1 | Timepoint(s) of evaluation of this end point |
1. Hemoglobin response rate at Week 24 (increase of > 1 g/dL [> 10 g/L] from baseline) during the blinded treatment period [ Time Frame: 24 Weeks ]
2. Annualized vaso-occlusive crisis rate during the 52-week blinded treatment period based on adjudicated vaso-occlusive crisis review [ Time Frame: 52 Weeks ] |
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E.5.2 | Secondary end point(s) |
1. Change from baseline in Hb at Week 52 during the blinded treatment period
2. Change in SCD-related clinical laboratory measurements from baseline at Week 24 during the blinded treatment period in:
o Absolute reticulocyte count,
o Indirect bilirubin, and
o Lactate dehydrogenase (LDH)
3. Change from baseline in Patient-Reported Outcome Measurement Information System (PROMIS) Fatigue Scale in adult patients at Week 52 during the blinded treatment period
4. Time to first VOC during the blinded treatment period |
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E.5.2.1 | Timepoint(s) of evaluation of this end point |
1. Change from baseline in Hb during the blinded treatment period : at 52 weeks
2. Change in SCD-related clinical laboratory measurements from baseline during the blinded treatment period : at 24 weeks
3. Change from baseline in PROMIS Fatigue Scale during the blinded treatment period : at 52 weeks
4. Time to first VOC during the blinded treatment period |
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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 | No |
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 | 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 | 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 | 4 |
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 | 7 |
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 |
Ghana |
Nigeria |
Oman |
Canada |
India |
Kenya |
Lebanon |
Saudi Arabia |
United Kingdom |
United States |
France |
Germany |
Greece |
Italy |
Spain |
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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E.8.9 Initial estimate of the duration of the trial |
E.8.9.1 | In the Member State concerned years | 2 |
E.8.9.1 | In the Member State concerned months | 2 |
E.8.9.1 | In the Member State concerned days | |
E.8.9.2 | In all countries concerned by the trial years | 2 |
E.8.9.2 | In all countries concerned by the trial months | 2 |