Pan African Clinical Trials Registry
South African Medical Research Council, South African Cochrane Centre
PO Box 19070, Tygerberg, 7505, South Africa
Telephone: +27 21 938 0506 / +27 21 938 0834 Fax: +27 21 938 0836
Email: pactradmin@mrc.ac.za Website: pactr.samrc.ac.za
Trial no.: PACTR202301655446404 Date of Approval: 09/01/2023
Trial Status: Registered in accordance with WHO and ICMJE standards
TRIAL DESCRIPTION
Public 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 scientific 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
Brief summary describing the background and objectives of the trial Etavopivat (FT-4202) is a potent, selective, orally bioavailable, small-molecule activator of erythrocyte pyruvate kinase (PKR) under investigation as a treatment for patients with sickle cell disease (SCD) and other hemoglobinopathies. In Phase 1 trial results, which enrolled over 40 patients with SCD, markers of anemia and hemolysis improved within 2 weeks in patients with SCD. Among pediatric patients with SCD, the risk of stroke and other cerebrovascular events correlates with the degree of anemia and is associated with significant morbidity (ie, neurocognitive deficits and reduction of executive or physical functioning) and increased mortality. Transcranial doppler (TCD) velocities, typically reported as the timed-average-mean-maximum-velocity (TAMMV), are a well validated surrogate marker and non-invasive means of assessing pediatric stroke risk. Previous research suggests children with abnormal TCD (aTCD) or conditional TCD (cTCD) velocities are at an increased risk for primary stroke when compared to those with normal TCD. Regular blood transfusions are one validated approach to decreasing aTCD velocities and reducing primary stroke risk, but there are times and places where regular blood transfusions may not always be feasible or desired. As such, innovative measures, including disease-modifying therapies, are desperately needed to reduce the risk of stroke in these situations. Furthermore, as there is no standard of care for patients with cTCD, prospective trials are also needed to determine additional effective therapies that can be used to reduce velocities and prevent conversion to aTCD in those with cTCD. We are proposing a Phase 2 study evaluating the change in timed-average-mean-maximum-velocity (TAMMV) with etavopivat for meaningful TCD velocity reduction – a surrogate marker for primary stroke risk Primary Objective: To evaluate the impact of etavopivat on TCD velocities in patients with aTCD or cTCD velocities Secondary objective:To evaluat
Type of trial CCT
Acronym (If the trial has an acronym then please provide)
Disease(s) or condition(s) being studied Haematological Disorders
Sub-Disease(s) or condition(s) being studied
Purpose of the trial Treatment: Drugs
Anticipated trial start date 04/09/2023
Actual trial start date 09/04/2024
Anticipated date of last follow up 30/05/2025
Actual Last follow-up date
Anticipated target sample size (number of participants) 46
Actual target sample size (number of participants)
Recruitment status Recruiting
Publication URL
Secondary Ids Issuing authority/Trial register
STUDY DESIGN
Intervention assignment Allocation to intervention If randomised, describe how the allocation sequence was generated Describe how the allocation sequence/code was concealed from the person allocating the participants to the intervention arms Masking If masking / blinding was used
Parallel: different groups receive different interventions at same time during study Non-randomised Open-label(Masking Not Used)
INTERVENTIONS
Intervention type Intervention name Dose Duration Intervention description Group size Nature of control
Experimental Group etavopivat 400mg Daily 52 weeks Single-agent etavopivat in patients with cTCD, or patients with aTCD who are not candidates for hydroxyurea (HU), as determined by investigator 23
Experimental Group Etavopivat in combination with HU 400mg Daily 52 weeks Etavopivat in combination with HU – a) patients with aTCD on stable dose of HU, b) patients with cTCD on stable dose of HU 23
Control Group NA NA NA This trial has no control group. 0 Dose Comparison
ELIGIBILITY CRITERIA
List inclusion criteria List exclusion criteria Age Category Minimum age Maximum age Gender
Participants are eligible to be included in the study only if all the following criteria apply: Informed Consent 1. Patient’s parent, legal guardian, or legal representative has provided documented informed consent and patients have provided age-appropriate assent Age 2. 12 to 16 years of age (inclusive) at time of Screening Type of Participant and Disease Characteristics 3. 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. Note that Hb electrophoresis, and other forms of Hb subtype quantification, is performed by the local laboratory at Screening. 4. TAMMV ≥ 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 CNS vasculopathy on magnetic resonance angiography (MRA). This includes patients with cTCD (170-199 cm/s) or aTCD (≥ 200 cm/s). Patients in the aTCD cohort must refuse transfusion therapy. 5. Hb ≥ 6 g/dL and ≤ 9 g/dL at Screening 6. For participants with aTCD and cTCD and already taking HU, the dose of HU (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 7. 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 Patients are excluded from the study if they meet any of the following criteria: Medical Conditions 1. Female who is breast feeding or pregnant 2. History of seizure disorder 3. 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. 4. Significant cytopenias (absolute neutrophil count [ANC] < 1.5 × 103/µL, platelets < 150,000/µL, reticulocytes < 80,000/µL) 5. Severe renal dysfunction (estimated glomerular filtration rate at the Screening visit; calculated by the local laboratory < 30 mL/min/1.73 m2) or on chronic dialysis 6. Hepatic dysfunction characterized by alanine aminotransferase (ALT) > 4 × upper limit of normal (ULN) and/or direct bilirubin > 3 × ULN 7. 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). 8. Known human immunodeficiency virus (HIV) positivity 9. Known infection with hepatitis B virus (hepatitis B surface antigen [HepBsAg] and hepatitis B core antibody [HepB Adolescent: 13 Year-18 Year,Child: 6 Year-12 Year 12 Year(s) 16 Year(s) Both
ETHICS APPROVAL
Has the study received appropriate ethics committee approval Date the study will be submitted for approval Date of approval Name of the ethics committee
Yes 25/04/2023 NHREC
Ethics Committee Address
Street address City Postal code Country
11th Floor Federal Secretariat Complex Phase 3 Abuja N/A Nigeria
Has the study received appropriate ethics committee approval Date the study will be submitted for approval Date of approval Name of the ethics committee
Yes 09/05/2023 NAFDAC
Ethics Committee Address
Street address City Postal code Country
NAFDAC Corporate Headquarters Plot 2032 Olusegun Obasanjo Way Zone 7 Wuse Abuja Nigeria Abuja NA Nigeria
Has the study received appropriate ethics committee approval Date the study will be submitted for approval Date of approval Name of the ethics committee
Yes 24/05/2023 Lagos University Teaching Hospital Health Research Ethics Committee
Ethics Committee Address
Street address City Postal code Country
Room 107 1st Floor LUTH Administrative Block Lagos 12003 Nigeria
Has the study received appropriate ethics committee approval Date the study will be submitted for approval Date of approval Name of the ethics committee
Yes 17/08/2023 UIUCH Research Ethics committee
Ethics Committee Address
Street address City Postal code Country
Queen Elizabeth I I Road Ibadan 200285 Nigeria Ibadan 200285 Nigeria
Has the study received appropriate ethics committee approval Date the study will be submitted for approval Date of approval Name of the ethics committee
Yes 08/08/2023 Aminu Kano Research Ethics committee
Ethics Committee Address
Street address City Postal code Country
PMB 3452 Zaria Road Kano Nigeria Kano PMB Nigeria
Has the study received appropriate ethics committee approval Date the study will be submitted for approval Date of approval Name of the ethics committee
Yes 11/01/2024 NATIONAL AGENCY FOR FOOD AND DRUG ADMINISTRATION AND CONTROL
Ethics Committee Address
Street address City Postal code Country
Plot 1, Isolo Industrial Scheme, Oshodi-Apapa Expressway, Isolo, Lagos Lagos N/A Nigeria
Has the study received appropriate ethics committee approval Date the study will be submitted for approval Date of approval Name of the ethics committee
Yes 01/12/2023 National Health Research Ethics Committee of Nigeria NHREC
Ethics Committee Address
Street address City Postal code Country
11th Floor Federal Secretariat complex phase 3 Ahmadu Bello Way Abuja Abuja unknown Nigeria
Has the study received appropriate ethics committee approval Date the study will be submitted for approval Date of approval Name of the ethics committee
Yes 26/04/2024 National Health Research Ethics Committee of Nigeria NHREC
Ethics Committee Address
Street address City Postal code Country
11th floor federal secretariat complex phase 3 Ahmadu bello way abuja Abuja unknown Nigeria
Has the study received appropriate ethics committee approval Date the study will be submitted for approval Date of approval Name of the ethics committee
Yes 08/09/2023 UI UCH Ethics committee
Ethics Committee Address
Street address City Postal code Country
Queen Elizabeth I I Road, Agodi Ibadan 200285 Nigeria
Has the study received appropriate ethics committee approval Date the study will be submitted for approval Date of approval Name of the ethics committee
Yes 30/08/2023 Lagos Univeristy Teaching Hospital health research ethics commitee
Ethics Committee Address
Street address City Postal code Country
Ishaga Rd Idi Araba Lagos unknown Nigeria
Has the study received appropriate ethics committee approval Date the study will be submitted for approval Date of approval Name of the ethics committee
Yes 28/09/2023 Aminu Kano Teaching Hospital Research ethics commitee
Ethics Committee Address
Street address City Postal code Country
Zaria Road Kano State Kano state P.M.B 345 Nigeria
Has the study received appropriate ethics committee approval Date the study will be submitted for approval Date of approval Name of the ethics committee
Yes 24/04/2024 NAFDAC
Ethics Committee Address
Street address City Postal code Country
1 st Floor NAFDAC Office Complex Isolo Industrial Estate Oshodi-Apapa Expressway Isolo Lagos unknown Nigeria
Has the study received appropriate ethics committee approval Date the study will be submitted for approval Date of approval Name of the ethics committee
Yes 30/04/2024 LUTH HREC
Ethics Committee Address
Street address City Postal code Country
Ishaga Rd Idi Araba Lagos unknown Nigeria
Has the study received appropriate ethics committee approval Date the study will be submitted for approval Date of approval Name of the ethics committee
Yes 07/06/2024 LUTH HREC
Ethics Committee Address
Street address City Postal code Country
Ishanga Road Lagos None Nigeria
OUTCOMES
Type of outcome Outcome Timepoint(s) at which outcome measured
Primary Outcome Change in the 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 Change in TAMMV at Weeks 2, 4, 24, and 52 versus baseline, as measured by TCD Week 2,4, 24 and 52
Secondary Outcome 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
RECRUITMENT CENTRES
Name of recruitment centre Street address City Postal code Country
Aminu Kanu Teaching Hospital 2 New Hospital Road, Tarauni Kanu Nigeria
Lagos University Teaching Hospital Ishaga Road, Idi-Araba Lagos Nigeria
The University of Ibadan University College Hospital Ibadan, 200285 Ibadan Nigeria
FUNDING SOURCES
Name of source Street address City Postal code Country
Forma Therapeutics Inc. 300 North Beacon Street, Suite 501 Watertown, MA 02472 Watertown United States of America
SPONSORS
Sponsor level Name Street address City Postal code Country Nature of sponsor
Primary Sponsor Forma Therapeutics Inc 300 North Beacon Street, Suite 501 Watertown, MA 02472 Watertown United States of America Commercial Sector/Industry
COLLABORATORS
Name Street address City Postal code Country
CONTACT PEOPLE
Role Name Email Phone Street address
Scientific Enquiries Marcus Carden TCDmedical_monitor@novonordisk.com +18572092374 300 North Beacon Street, Suite 501 Watertown, MA 02472
City Postal code Country Position/Affiliation
Watertown United States of America Sponsor affiliation
Role Name Email Phone Street address
Public Enquiries Michelle Botha michelle.botha@quintiles.com +27126712334 Pretoria
City Postal code Country Position/Affiliation
Pretoria South Africa Regulatory
Role Name Email Phone Street address
Principal Investigator Iheanyi Okpala iheanyi.okpala@unn.edu.ng +2348025453354 TUKU OZALLA PMB 01129
City Postal code Country Position/Affiliation
Enugu Nigeria National Coordinating Principal Investigator
REPORTING
Share IPD Description Additional Document Types Sharing Time Frame Key Access Criteria
Yes All IPD will be stripped off identifiers and may be available upon request Informed Consent Form,Study Protocol Approximately 18 months after trial completion N/A
URL Results Available Results Summary Result Posting Date First Journal Publication Date
No
Result Upload 1: Result Upload 2: Result Upload 3: Result Upload 4: Result Upload 5:
Result URL Hyperlinks Link To Protocol
Result URL Hyperlinks
Changes to trial information