A Phase 2 Open-label Study to Evaluate the Activity of Etavopivat on Transcranial Doppler Velocities in Pediatric Patients With Sickle Cell Disease Who Are at Increased Risk for Primary Stroke

Study Overview
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Brief Summary
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The study will test a new medicine, etavopivat, for sickle cell disease and see if it is safe and helpful for participants with sickle cell disease who are at an increased risk of stroke. Participants will be divided into two cohorts depending on their transcranial doppler (TCD) ultrasound results and whether or not they receive hydroxyurea (medication that they may already be taking). In one cohort, participants with conditional transcranial doppler (TCD) or participants with abnormal TCD who are not able to receive hydroxyurea will be included. The study doctor will determine if the TCD result is conditional or abnormal. In another cohort, participants with conditional TCD or participants with abnormal TCD who are receiving a stable dose of hydroxyurea will be included. The study doctor will determine if the TCD result is conditional or abnormal. The participant will start a 52-week (1 year) treatment period. The participant will take 400 milligrams (mg) of etavopivat once a day for the 52 weeks. The dose of 400 mg will be taken as 2 tablets by mouth, each containing 200 mg of etavopivat. Etavopivat may be taken with or without food. Each dose should be taken with a glass of water. As part of the study, the participants will be asked to visit the clinic frequently. At the end of the study, if deemed appropriate by you, your child, and the study doctor, your child may be offered the opportunity to participate in a separate study to continue receiving etavopivat.

Official Title
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A Phase 2 Open-label Study to Evaluate the Activity of Etavopivat on Transcranial Doppler Velocities in Pediatric Patients With Sickle Cell Disease Who Are at Increased Risk for Primary Stroke

Conditions
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Sickle Cell Disease

Intervention / Treatment
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* Drug: Etavopivat
* Drug: Hydroxyurea


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Patient's parent, legal guardian, or legal representative has provided documented informed consent and patients have provided age-appropriate assent Age: 12 to 16 years of age (inclusive) at time of screening Type of Participant and Disease Characteristics: Confirmed diagnosis of SCD • Documentation of SCD genotype (HbSS, HbSβ0 -thalassemia) based on prior history of laboratory testing. Molecular genotyping is not required. SCD genotype may be determined from the results of Hb electrophoresis, high-performance liquid chromatography, or similar testing. TAMMV greater than or equal to (≥) 170 cm/s in the ICA and/or MCA during the Screening Period and confirmed on 2 occasions and without history of primary ischemic or hemorrhagic stroke, transient ischemic attack, or severe central nervous system (CNS) vasculopathy on magnetic resonance angiography (MRA). This includes patients with cTCD (170-199 centimeter per second [cm/s]) or aTCD (≥ 200 cm/s). Patients in the aTCD cohort must refuse transfusion therapy. Hb ≥ 6 grams per deciliter (g/dL) and lesser than or equal to (≤) 9 g/dL at screening For participants with aTCD and cTCD and already taking HU, the dose of HU milligram per kilogram (mg/kg) must be stable (no more than a 20% change in dosing except for weight-based changes) for at least 90 days prior to start of study treatment with no anticipated need for dose adjustments except for weight-based changes during the study, in the opinion of the Investigator. Sex and Contraceptive Requirements Patients, who if female and of childbearing potential, are using acceptable methods of contraception and agree not to donate ova from study start to 90 days after the last dose of study drug, and who if male, are willing to use acceptable methods of contraception and agree not to donate sperm, from study start to 90 days after the last dose of study drug. Exclusion Criteria: Medical Conditions Female who is breast feeding or pregnant History of seizure disorder Prior overt stroke (a focal neurological deficit of acute onset) by history or evidence on Screening MRI, history of transient ischemic attack, focal neurological deficit on standardized neurological examination, or concern for moderate or severe neurological deficit (which could be due to stroke) based on a positive 10 questions screening. Patients with significant or suggestive severe CNS vasculopathy (ie, moya moya) of Grade 4 or higher based on MRA read locally. Significant cytopenias (absolute neutrophil count [ANC] < 1.5 × 10^3/microliter (µL), platelets < 150,000/µL, reticulocytes < 80,000/µL) Severe renal dysfunction (estimated glomerular filtration rate at the Screening visit; calculated by the local laboratory < 30 mL/min/1.73 m^2) or on chronic dialysis Hepatic dysfunction characterized by alanine aminotransferase (ALT) > 4 × upper limit of normal (ULN) and/or direct bilirubin > 3 × ULN Patients with clinically significant bacterial, fungal, parasitic, or viral infection requiring systemic therapy or history of such infections leading to significant neurological impairment: Patients with acute bacterial, fungal, parasitic, or viral infection requiring systemic therapy should delay screening/enrollment until active therapy has been completed. Patients with acute viral infections (eg, coronavirus disease 2019 [COVID-19]) should delay screening/enrollment until the acute infection has resolved. Patients enrolled in areas where malaria is prevalent must be on malaria prophylaxis based on regional guidance and resistance results. Note: Infection prophylaxis is allowed (see concomitant medication restrictions). Known human immunodeficiency virus (HIV) positivity Known infection with hepatitis B virus (hepatitis B surface antigen [HepBsAg] and hepatitis B core antibody [HepBcAb] positive.

Ages Eligible for Study
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Minimum Age: 12 Years
Maximum Age: 16 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: Non-Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Etavopivat<br>Participants will receive Etavopivat 400 mg once daily (QD) orally. | Drug: Etavopivat<br>* Participants will receive a dose of 400 mg (two 200 mg oral tablets) etavopivat once daily.<br>Drug: Hydroxyurea<br>* Participants will receive a stable dose of HU.<br>|
| Experimental: Etavopivat with HU<br>Participants will receive Etavopivat 400 mg QD orally in combination with HU. The dose of HU (mg/kg) will be stable (no more than a 20% change in dosing except for weight-based changes) during the study, in the opinion of the Investigator. | Drug: Hydroxyurea<br>* Participants will receive a stable dose of HU.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change in the timed-average-mean-maximum-velocity (TAMMV) arterial cerebral blood flow of index artery (L/R internal carotid artery [ICA], L/R middle cerebral artery [MCA]) at Week 12 versus baseline, as measured by TCD |  | Baseline and Week 12 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change in TAMMV at Weeks 2, 4, 24, and 52 versus baseline, as measured by TCD |  | Baseline, Weeks 2,4, 24 and 52 | 
| Incidence of conversion to normal (< 170 cm/s), conditionally abnormal (170-199 cm/s), and abnormal (≥ 200 cm/s) TCD velocities |  | Weeks 2, 4, 12, 24, and 52 |