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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

Primary Purpose

Sickle Cell Disease

Status
Recruiting
Phase
Phase 2
Locations
International
Study Type
Interventional
Intervention
Etavopivat
Hydroxyurea
Sponsored by
Novo Nordisk A/S
About
Eligibility
Locations
Arms
Outcomes
Full info

About this trial

This is an interventional treatment trial for Sickle Cell Disease

Eligibility Criteria

12 Years - 16 Years (Child)All SexesDoes not accept healthy volunteers

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.

Sites / Locations

  • All India Institute of Medical Sciences
  • All India Institute of Medical Sciences
  • Indira Gandhi Government Medical College & Hospital
  • Suretech Hospital and Research Centre Ltd.
  • The University of Ibadan University College Hospital
  • Aminu Kanu Teaching Hospital
  • Lagos University Teaching Hospital
  • Sultan Qaboos University HospitalRecruiting

Arms of the Study

Arm 1

Arm 2

Arm Type

Experimental

Experimental

Arm Label

Etavopivat

Etavopivat with HU

Arm Description

Participants will receive Etavopivat 400 mg once daily (QD) orally.

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.

Outcomes

Primary Outcome Measures

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

Secondary Outcome Measures

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

Full Information

First Posted
July 11, 2023
Last Updated
October 16, 2023
Sponsor
Novo Nordisk A/S
Collaborators
Forma Therapeutics, Inc. (a Novo Nordisk company)
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1. Study Identification

Unique Protocol Identification Number
NCT05953584
Brief Title
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
Official Title
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 Type
Interventional

2. Study Status

Record Verification Date
October 2023
Overall Recruitment Status
Recruiting
Study Start Date
June 20, 2023 (Actual)
Primary Completion Date
October 20, 2024 (Anticipated)
Study Completion Date
August 18, 2025 (Anticipated)

3. Sponsor/Collaborators

Responsible Party, by Official Title
Sponsor
Name of the Sponsor
Novo Nordisk A/S
Collaborators
Forma Therapeutics, Inc. (a Novo Nordisk company)

4. Oversight

Studies a U.S. FDA-regulated Drug Product
Yes
Studies a U.S. FDA-regulated Device Product
No
Product Manufactured in and Exported from the U.S.
Yes
Data Monitoring Committee
No

5. Study Description

Brief Summary
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.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Sickle Cell Disease

7. Study Design

Primary Purpose
Treatment
Study Phase
Phase 2
Interventional Study Model
Parallel Assignment
Masking
None (Open Label)
Allocation
Non-Randomized
Enrollment
46 (Anticipated)

8. Arms, Groups, and Interventions

Arm Title
Etavopivat
Arm Type
Experimental
Arm Description
Participants will receive Etavopivat 400 mg once daily (QD) orally.
Arm Title
Etavopivat with HU
Arm Type
Experimental
Arm Description
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.
Intervention Type
Drug
Intervention Name(s)
Etavopivat
Intervention Description
Participants will receive a dose of 400 mg (two 200 mg oral tablets) etavopivat once daily.
Intervention Type
Drug
Intervention Name(s)
Hydroxyurea
Intervention Description
Participants will receive a stable dose of HU.
Primary Outcome Measure Information:
Title
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
Time Frame
Baseline and Week 12
Secondary Outcome Measure Information:
Title
Change in TAMMV at Weeks 2, 4, 24, and 52 versus baseline, as measured by TCD
Time Frame
Baseline, Weeks 2,4, 24 and 52
Title
Incidence of conversion to normal (< 170 cm/s), conditionally abnormal (170-199 cm/s), and abnormal (≥ 200 cm/s) TCD velocities
Time Frame
Weeks 2, 4, 12, 24, and 52

10. Eligibility

Sex
All
Minimum Age & Unit of Time
12 Years
Maximum Age & Unit of Time
16 Years
Accepts Healthy Volunteers
No
Eligibility Criteria
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.
Central Contact Person:
First Name & Middle Initial & Last Name or Official Title & Degree
Marcus Carden
Phone
+18572092374
Email
TCDmedical_monitor@novonordisk.com
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
Marcus Carden
Organizational Affiliation
Novo Nordisk A/S
Official's Role
Study Director
Facility Information:
Facility Name
All India Institute of Medical Sciences
City
New Delhi
State/Province
Delhi
ZIP/Postal Code
110029
Country
India
Individual Site Status
Not yet recruiting
Facility Name
All India Institute of Medical Sciences
City
Raipur
State/Province
Delhi
ZIP/Postal Code
110029
Country
India
Individual Site Status
Not yet recruiting
Facility Contact:
First Name & Middle Initial & Last Name & Degree
All IIOM Sciences
Facility Name
Indira Gandhi Government Medical College & Hospital
City
Nagpur
State/Province
Maharashtra
ZIP/Postal Code
440012
Country
India
Individual Site Status
Not yet recruiting
Facility Contact:
First Name & Middle Initial & Last Name & Degree
Suretech HARC Ltd.
Facility Name
Suretech Hospital and Research Centre Ltd.
City
Nagpur
State/Province
Maharashtra
ZIP/Postal Code
440012
Country
India
Individual Site Status
Not yet recruiting
Facility Name
The University of Ibadan University College Hospital
City
Ibadan
Country
Nigeria
Individual Site Status
Not yet recruiting
Facility Name
Aminu Kanu Teaching Hospital
City
Kano
Country
Nigeria
Individual Site Status
Not yet recruiting
Facility Name
Lagos University Teaching Hospital
City
Lagos
Country
Nigeria
Individual Site Status
Not yet recruiting
Facility Name
Sultan Qaboos University Hospital
City
Al-khoudh PC 123, Muscat
State/Province
Muscat
Country
Oman
Individual Site Status
Recruiting
Facility Contact:
First Name & Middle Initial & Last Name & Degree
Sultan QU Hospital

12. IPD Sharing Statement

Plan to Share IPD
Yes
IPD Sharing Plan Description
All IPD will be stripped off identifiers and may be available upon request

Learn more about this trial

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

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