| CTRI Number |
CTRI/2024/11/076871 [Registered on: 18/11/2024] Trial Registered Prospectively |
| Last Modified On: |
15/11/2024 |
| Post Graduate Thesis |
No |
| Type of Trial |
Interventional |
|
Type of Study
|
Drug |
| Study Design |
Randomized, Parallel Group, Multiple Arm Trial |
|
Public Title of Study
|
Research study investigating how well Etavopivat works in people with sickle cell disease |
|
Scientific Title of Study
|
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 |
| Trial Acronym |
NIL |
|
Secondary IDs if Any
|
| Secondary ID |
Identifier |
| 4202-HEM-204, Version 3.0 dated 18 March 2024 |
Protocol Number |
|
|
Details of Principal Investigator or overall Trial Coordinator (multi-center study)
|
| Name |
|
| Designation |
|
| Affiliation |
|
| Address |
|
| Phone |
|
| Fax |
|
| Email |
|
|
Details of Contact Person
Scientific Query
|
| Name |
Dr Maya Sharma |
| Designation |
Vice President - Clinical, Medical, Regulatory and Pharmacovigilance |
| Affiliation |
Novo Nordisk India Private Limited |
| Address |
Nxt Tower - 2 Floor 1 & 2,
Embassy Manyata Business Park,
Nagavara Village, Kasaba Hobli
Bangalore
KARNATAKA
560045
India |
| Phone |
9911497869 |
| Fax |
|
| Email |
yrms@novonordisk.com |
|
Details of Contact Person
Public Query
|
| Name |
Dr Maya Sharma |
| Designation |
Vice President - Clinical, Medical, Regulatory and Pharmacovigilance |
| Affiliation |
Novo Nordisk India Private Limited |
| Address |
Nxt Tower - 2 Floor 1 & 2,
Embassy Manyata Business Park,
Nagavara Village, Kasaba Hobli
Bangalore
KARNATAKA
560045
India |
| Phone |
9911497869 |
| Fax |
|
| Email |
yrms@novonordisk.com |
|
|
Source of Monetary or Material Support
|
| Forma Therapeutics, Inc.
300 North Beacon Street, Suite 501 |
|
|
Primary Sponsor
|
| Name |
Forma Therapeutics Inc |
| Address |
Forma Therapeutics, Inc.
300 North Beacon Street, Suite 501
Watertown, MA 02472 |
| Type of Sponsor |
Pharmaceutical industry-Global |
|
|
Details of Secondary Sponsor
|
| Name |
Address |
| Novo Nordisk India Private Limited |
Nxt Tower-2, Floor 1 & 2, Embassy Manyata Business Park, Nagavara Village, Kasaba Hobli, Bangalore-560045, India |
|
|
Countries of Recruitment
|
India
Nigeria
Oman |
|
Sites of Study
|
| No of Sites = 5 |
| Name of Principal
Investigator |
Name of Site |
Site Address |
Phone/Fax/Email |
| Dr Anil Goel |
All India Institute of Medical Sciences |
Tatibandh, GE Road, Raipur – 492099, Chhattisgarh, India
Raipur
CHHATTISGARH |
9810144784
akgoel@aiimsraipur.edu.in |
| Dr Tulika Seth |
All India Institute of Medical Sciences |
Ansari Nagar, New Delhi-110029, India
East
DELHI |
9868397236
drtulikaseth@gmail.com |
| Dr Apte Mohini Uday |
Indira Gandhi Govt. Medical College and Hospital |
C.A. Road, Nagpur - 440018, Maharashtra, India.
Nagpur
MAHARASHTRA |
9822709220
mohiniapte@yahoo.co.in |
| Dr Nirmalkumar Ganeshmal Choraria |
Nirmal Hospital Pvt.Ltd. |
Ring Road, Surat-395002, Gujarat, India
Surat
GUJARAT |
9825142549
drnirmalchoraria@gmail.com |
| Dr Ali Mustafa Fakhruddin |
Suretech Hospital and Research Centre Ltd |
13- A, Banerjee Marg, Dhantoli, Nagpur- 440012
Nagpur
MAHARASHTRA |
9881293805
ali@gmail.com |
|
|
Details of Ethics Committee
|
| No of Ethics Committees= 5 |
| Name of Committee |
Approval Status |
| Institute Ethics Committee, AIIMS Raipur |
Submittted/Under Review |
| Institutional Ethics Committee, AIIMS, New Delhi |
Approved |
| Institutional Ethics Committee, I.G.G.M.C.H, Nagpur |
Submittted/Under Review |
| Institutional Ethics Committee, Suretech Hospital |
Approved |
| Nirmal Hospital Pvt Ltd Ethics Committee |
Approved |
|
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Regulatory Clearance Status from DCGI
|
|
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Health Condition / Problems Studied
|
| Health Type |
Condition |
| Patients |
(1) ICD-10 Condition: D573||Sickle-cell trait, |
|
|
Intervention / Comparator Agent
|
| Type |
Name |
Details |
| Intervention |
Etavopivat |
Cohort A: Single-agent etavopivat in patients with cTCD, or patients with aTCD (11 maximum patients with cTCD). Patients will be enrolled into a 52-week primary treatment period and a 48-week optional extension treatment period. The optional extension treatment period will allow continued assessment of safety of etavopivat in paediatric patients. Patients will receive a dose of 400 mg (two 200 mg oral tablets) etavopivat QD (once daily).
Cohort B: Etavopivat in combination with HU – a) patients with aTCD on stable dose of HU, b) patients with cTCD on stable dose of HU (11 maximum patients). Patients will be enrolled into a 52-week primary treatment period and a 48-week optional extension treatment period. The optional extension treatment period will allow continued assessment of safety of etavopivat in paediatric patients. Patients will receive a dose of 400 mg (two 200 mg oral tablets) etavopivat QD (once daily).
A separate study is planned to offer study patients prolonged etavopivat treatment until available for prescription in their country or until development of etavopivat is otherwise discontinued. If/when such a study becomes available, patients may transfer to the new study after completion of the 52-week primary treatment period. Patients need to perform the assessments scheduled for End of Primary Treatment (EOPT) and will not complete the End of Study (EOS) visit before transfer to a separate study. This will potentially lead to closure of study 4202-HEM-204 before all patients have completed the extension treatment period. |
| Comparator Agent |
NA |
NA |
|
|
Inclusion Criteria
|
| Age From |
12.00 Year(s) |
| Age To |
16.00 Year(s) |
| Gender |
Both |
| Details |
Inclusion criteria:
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
a. Documentation of any SCD genotype (e.g. 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 Greater than or equal to 170 cm per s in the ICA and or MCA during the Screening Period and confirmed on 2 occasions (TCD No. 1 and No. 2; see Table 1 and Section 8.3.1) 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 per s) or aTCD (Greater than or equal to 200 cm per s).
Note: Patients with aTCD must have refused transfusion therapy.
5. Hb Greater than or equal to 6g per dL and Lesser than or equal to 9 g per dL at Screening.
6. For participants with aTCD and cTCD and already taking HU, the dose of HU (mg per kg) must be stable (no more than a 20-percentage 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. |
|
| ExclusionCriteria |
| Details |
Exclusion criteria:
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. Concern for significant CNS injury, defined as one or more of the following:
a. Prior overt stroke (a focal neurological deficit of acute onset) by history or
significant concerns for history of overt stroke based on Screening MRI,
b. History of transient ischemic attack,
c. Focal neurological deficit on standardized neurological examination,
d. Concern for moderate or severe neurological deficit (which could be due to
stroke) based on a positive “10 questions†screening (see Section 8.1.2).
e. Patients with significant or suggestive severe CNS vasculopathy (ie, moya moya, significant stenosis) of Grade 4 or higher based on MRA read locally.
4. Significant cytopenias (absolute neutrophil count [ANC] Lesser than 1.0 × 103 per µL, platelets Lesser than 100,000 per µL, hemoglobin Lesser than 8g per dL with reticulocytes Lesser than 80,000 per µL)
5. Severe renal dysfunction (estimated glomerular filtration rate at the Screening visit; calculated by the local laboratory Lesser than 30 mL per min per 1.73 m2) or on chronic dialysis
6. Hepatic dysfunction characterized by alanine aminotransferase (ALT) Greater than 4 × upper limit of normal (ULN) and or direct bilirubin Greater than 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:
a. Patients with acute bacterial, fungal, parasitic, or viral infection requiring systemic therapy should delay screening or enrollment until active therapy has been completed.
b. Patients with acute viral infections (e.g., coronavirus disease 2019 [COVID-19]) should delay screening/enrollment until the acute infection has resolved.
c. 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 [HepBcAb] positive)
10. Positive Hepatitis C antibody
11. Untreated iron deficiency or other significant malnutrition detected or diagnosed by the Investigator
12. Significant malnutrition based on height, weight, BMI parameters or as deemed by the Investigator
13. Any condition affecting drug absorption, such as major surgery involving the stomach or small intestine (prior cholecystectomy is acceptable).
14. Hospitalized for sickle cell crisis or other VOC event within 14 days of time of consent or assent.
Prior or Concomitant Therapy
15. Current use within 28 days of starting study treatment or planned treatment with additional disease modifying therapies (i.e, voxelotor, L-glutamine, and crizanlizumab), including plans for initiating HU after enrollment. For cohort A, patients must be off HU for at least 28 days prior to starting treatment.
16. Transfusion history restrictions defined as one or more of the following:
a. Transfusion within 90 days of informed consent/assent,
b. History of recently being on a regular transfusion program within the last 1 year or plans to implement a regular transfusion program (also termed chronic, prophylactic, or preventative transfusion),
c. History of RBC autoantibody,
d. Significant iron overload (ferritin Greater than 1000 ng per mL), or
e. History of significant alloimmunization to RBCs
17. Receiving or use of concomitant medications that are moderate/strong inducers of cytochrome p40 (CYP) 3A4 within 14 days of starting study treatment
Prior or Concurrent Clinical Study Experience
18. Participated in another clinical trial of an investigational agent (or medical device) within 30 days or 5 half-lives of date of last dose prior to date of informed consent, whichever is
longer, participated in other etavopivat trials, or is currently participating in another trial of an investigational agent (or medical device)
Other Exclusions
19. Inadequate venous access as determined by the Investigator or site staff
20. Medical, psychological, or behavioral conditions, which, in the opinion of the Investigator, may preclude safe participation, confound study interpretation, interfere with
compliance, or preclude informed consent/assent
21. Receipt of erythropoietin or other hematopoietic growth factor treatment within 28 days of starting study treatment or anticipated need for such agents during the study
22. Receipt of prior cellular based therapy (e.g., hematopoietic cell transplant, gene modification therapy)
23. History of malignancy within the past 2 years prior to treatment Day 1 requiring systemic chemotherapy and or radiation. Patients with malignancy considered surgically cured are eligible (e.g., non-melanoma skin cancer, cancer of the cervix in situ, ductal carcinoma in situ [stage 1], Grade 1 endometrial cancer) |
|
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Method of Generating Random Sequence
|
Computer generated randomization |
|
Method of Concealment
|
Centralized |
|
Blinding/Masking
|
Open Label |
|
Primary Outcome
|
| Outcome |
TimePoints |
| To evaluate the impact of etavopivat on TCD velocities in patients with aTCD or cTCD velocities |
Baseline and Week 12 |
|
|
Secondary Outcome
|
| Outcome |
TimePoints |
| To evaluate the change in TCD velocity over time |
Baseline, Weeks 2, 4, 24 and 52 |
| To evaluate changes in category of TCD velocity over time |
Weeks 2, 4, 12, 24, and 52 |
|
|
Target Sample Size
|
Total Sample Size="46"
Sample Size from India="23"
Final Enrollment numbers achieved (Total)= "Applicable only for Completed/Terminated trials"
Final Enrollment numbers achieved (India)="Applicable only for Completed/Terminated trials" |
|
Phase of Trial
|
Phase 2 |
|
Date of First Enrollment (India)
|
14/02/2025 |
| Date of Study Completion (India) |
Applicable only for Completed/Terminated trials |
| Date of First Enrollment (Global) |
19/07/2023 |
| Date of Study Completion (Global) |
Applicable only for Completed/Terminated trials |
|
Estimated Duration of Trial
|
Years="2"
Months="1"
Days="7" |
|
Recruitment Status of Trial (Global)
|
Open to Recruitment |
| Recruitment Status of Trial (India) |
Not Yet Recruiting |
|
Publication Details
|
N/A |
|
Individual Participant Data (IPD) Sharing Statement
|
Will individual participant data (IPD) be shared publicly (including data dictionaries)?
Response - NO
|
|
Brief Summary
|
This is an open-label, Phase 2 study in adolescent patients 12 to 16 years old (inclusive) with increased risk of stroke based on elevated TAMMV in the MCA and/or ICA as measured by TCD, including both cTCD and aTCD. The study will enroll 23 patients (accounting for potential 20% drop-out) into each of 2 treatment cohorts:
Cohort A: Single-agent etavopivat in patients with cTCD, or patients with aTCD who are not candidates for hydroxyurea (HU), as determined by investigator (11 maximum patients with cTCD) Cohort B: Etavopivat in combination with HU – a)
patients with aTCD on stable dose of HU, b) patients with cTCD on stable dose
of HU (11 maximum patients)
Patients will be enrolled into a 52-week primary
treatment period and a 48-week optional extension treatment period. The
optional extension treatment period will allow continued assessment of safety
of etavopivat in paediatric patients. A separate study is planned to offer
study patients prolonged etavopivat treatment until available for prescription
in their country or until development of etavopivat is otherwise discontinued.
If/when such a study becomes available, patients may transfer to the new study
after completion of the 52-week primary treatment period. Patients need to
perform the assessments scheduled for End of Primary Treatment (EOPT) and will
not complete the End of Study (EOS) visit before transfer to a separate study.
This will potentially lead to closure of study 4202-HEM-204 before all patients
have completed the optional extension treatment period. Etavopivat will be
administered at 400 mg once daily (QD). The study objectives to assess impact
on TCD velocities will be met after all subjects complete 52 weeks of
treatment, discontinue, or withdraw |