A Study of Etavopivat in Adults and Adolescents With Sickle Cell Disease (HIBISCUS)

Study Overview
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Brief Summary
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This clinical trial is a Phase 2/3 study that will evaluate the efficacy and safety of etavopivat and test how well etavopivat works compared to placebo to improve the amount of hemoglobin in the blood and to reduce the number of vaso-occlusive crises (times when the blood vessels become blocked and cause pain).

Detailed Description
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Etavopivat is designed to activate PKR and thereby modulate RBC metabolism by impacting two critical pathways in RBCs. The etavopivat clinical development program will investigate whether decreasing 2,3-DPG may help oxygen bind to hemoglobin (i.e. increasing oxygen affinity), and thereby increase ATP and impact RBC function. This study is a randomized, placebo-controlled, double-blind, multicenter Phase 2/3 study of patients age 12 to 65 years (inclusive), with sickle cell disease. There are two planned interim analyses in this study design. Initially, patients will be randomized at 1:1:1 to one of two dose levels of etavopivat or placebo. At the first interim analysis, one of the two etavopivat dose levels will be selected for the Phase 3 portion of the study, in which patients will be randomized at 1:1 to the selected etavopivat dose or placebo. Efficacy on hemoglobin will be evaluated at the second interim analysis, and then will be tested along with evaluation of efficacy on vaso-occlusive crises at the final analysis. Following completion of 52 weeks of double-blind treatment, patients may enter a 52-week etavopivat open-label extension period.

Official Title
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An Adaptive, Randomized, Placebo-controlled, Double-blind, Multi-center Study of Oral Etavopivat, a Pyruvate Kinase Activator in Patients With Sickle Cell Disease (HIBISCUS)

Conditions
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Sickle Cell Disease

Intervention / Treatment
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* Drug: Etavopivat Tablets Low dose
* Drug: Etavopivat Tablets High dose
* Drug: Placebo Tablets
* Drug: Etavopivat Tablets


Participation Criteria
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Eligibility Criteria
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Key Inclusion Criteria: Provision of consent Patient has a confirmed diagnosis of sickle cell disease At least 2 episodes of vaso-occlusive crises in the past 12 months Hemoglobin ≥ 5.5 and ≤ 10.5 g/dL (≥ 55 and ≤ 105 g/L) during screening Patients taking hydroxyurea, must demonstrate a stable dose for at least 90 days prior to start of study treatment Patients on crizanlizumab or L-glutamine treatment at the time of consent must be on a stable dose for ≥ 12 months and must be ≥ 80% compliant with the planned regimen at the time of consent and meet the VOC eligibility criteria Female patients of childbearing potential must use highly effective methods of contraception, male patients are willing to use barrier methods of contraception Key Exclusion Criteria: More than 10 vaso-occlusive crises within the past 12 months Female who is breastfeeding or pregnant Hepatic dysfunction characterized by: Alanine aminotransferase (ALT) > 4.0 × upper limit of normal (ULN) Direct bilirubin > 3.0 × ULN Known HIV positivity Active hepatitis B or hepatitis C infection Severe renal dysfunction or on chronic dialysis 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 History of overt clinical stroke within previous 2 years or any history of an intracranial hemorrhage History of deep venous thrombosis requiring systemic anti-coagulation therapy for ≥ 6 weeks, occurring within 6 months prior to Day 1 of study treatment. Prior/Concomitant Therapy Patients receiving regularly scheduled blood (RBC) transfusion therapy (also termed chronic, prophylactic, or preventive transfusion) 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 Use of voxelotor within 28 days prior to starting study treatment or anticipated need for this agent during the study Use of an experimental selectin antagonist (eg, monoclonal antibody or small molecule) within 28 days of starting study treatment or anticipated need for such agents during the study 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 Receipt of prior cellular-based therapy (eg, hematopoietic cell transplant, gene modification therapy)

Ages Eligible for Study
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Minimum Age: 12 Years
Maximum Age: 65 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Double blind etavopivat Low Dose<br>Double blind etavopivat Low Dose | Drug: Etavopivat Tablets Low dose<br>* 200 mg once daily<br>* Other names: FT-4202;|
| Experimental: Double blind etavopivat High Dose<br>Double blind etavopivat High Dose | Drug: Etavopivat Tablets High dose<br>* 400 mg once daily<br>* Other names: FT-4202;|
| Experimental: Double blind placebo<br>Double blind placebo | Drug: Placebo Tablets<br>* Placebo once daily<br>* Other names: placebo;|
| Experimental: Open label etavopivat<br>Open label etavopivat | Drug: Etavopivat Tablets<br>* Selected dose once daily<br>* Other names: FT-4202;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Hemoglobin response rate | Hemoglobin response rate at Week 24 (increase of > 1 g/dL [> 10 g/L] from baseline) during the blinded treatment period | 24 Weeks | 
| Annualized vaso-occlusive crisis | Annualized vaso-occlusive crisis rate during the 52-week blinded treatment period based on adjudicated vaso-occlusive crisis review | 52 Weeks | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Hemoglobin | Change from baseline in hemoglobin at Week 24 during the blinded treatment period | 24 Weeks | 
| Hemoglobin | Change from baseline in hemoglobin at Week 52 during the blinded treatment period | 52 Weeks | 
| Absolute reticulocyte count | Change in absolute reticulocyte count from baseline at Week 24 during the blinded treatment period | 24 Weeks | 
| Unconjugated bilirubin | Change in unconjugated bilirubin from baseline at Week 24 during the blinded treatment period | 24 Weeks | 
| Lactate dehydrogenase | Change in lactate dehydrogenase from baseline at Week 24 during the blinded treatment period | 24 Weeks | 
| Vaso-occlusive crisis | Time to first vaso-occlusive crisis during the blinded treatment period | 52 Weeks | 
| Patient-Reported Outcome Measurement Information System (PROMIS) | Change in PROMIS Fatigue Scale from baseline in adult patients at Week 24 during the blinded treatment period | 24 Weeks | 
| Patient-Reported Outcome Measurement Information System (PROMIS) Fatigue Scale | Change in PROMIS Fatigue Scale from baseline in adult patients at Week 52 during the blinded treatment period | 52 Weeks | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Sickle Cell Disease, Sickle Cell, Anemia, Sickle Cell Anemia, Hemolytic, Hemoglobin, Vaso-occlusive Crisis, Sickle Cell Crisis, Congenital Anemia, Hemolytic Anemia, Hematologic Disease, Hemoglobinopathies, Genetic Disease, Inborn Disease, Sickle Cell Trait, Pyruvate Kinase