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

Sponsor

Forma Therapeutics, Inc. (Industry)

Overall Status

Recruiting

CT.gov ID

NCT04624659

Collaborator

(none)

344

Enrollment

Locations

Arms

68.2

Anticipated Duration (Months)

Patients Per Site

0.1

Patients Per Site Per Month

Study Details

Study Description

Brief Summary

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).

Condition or Disease	Intervention/Treatment	Phase
Sickle Cell Disease	Drug: Etavopivat Tablets Drug: Etavopivat Tablets Drug: Placebo Tablets Drug: Etavopivat Tablets	Phase 2/Phase 3

Detailed Description

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.

Study Design

Study Type:

Interventional

Anticipated Enrollment :

344 participants

Allocation:

Randomized

Intervention Model:

Parallel Assignment

Masking:

Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)

Primary Purpose:

Treatment

Official Title:

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

Actual Study Start Date :

Mar 26, 2021

Anticipated Primary Completion Date :

Dec 1, 2025

Anticipated Study Completion Date :

Dec 1, 2026

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Double blind etavopivat Low Dose Double blind etavopivat Low Dose	Drug: Etavopivat Tablets 200 mg once daily
Experimental: Double blind etavopivat High Dose Double blind etavopivat High Dose	Drug: Etavopivat Tablets 400 mg once daily
Experimental: Double blind placebo Double blind placebo	Drug: Placebo Tablets Placebo once daily
Experimental: Open label etavopivat Open label etavopivat	Drug: Etavopivat Tablets Selected dose once daily

Outcome Measures

Primary Outcome Measures

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

Secondary Outcome Measures

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

Eligibility Criteria

Criteria

Ages Eligible for Study:

12 Years to 65 Years

Sexes Eligible for Study:

All

Accepts Healthy Volunteers:

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)

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	University of Alabama at Birmingham (UAB)	Birmingham	Alabama	United States	35249
2	Phoenix Children's Hospital	Phoenix	Arizona	United States	85016
3	Woodland International Research Group	Little Rock	Arkansas	United States	72211
4	Collaborative Neuroscience Research, LLC.	Long Beach	California	United States	90806
5	Pacific Research Partners, LLC	Oakland	California	United States	94607
6	UC Davis Medical Center - UC Davis Comprehensive Cancer Center - Hemotology/Oncology Clinic	Sacramento	California	United States	95817
7	University of Connecticut (UCONN) Health	Farmington	Connecticut	United States	06030
8	Children's National Health Center	Washington	District of Columbia	United States	20010
9	Howard University	Washington	District of Columbia	United States	20060
10	Cornerstone Research Institute	Altamonte Springs	Florida	United States	32701
11	Foundation for Sickle Cell Disease Research	Hollywood	Florida	United States	33021
12	Advanced Pharma CR LLC.	Miami	Florida	United States	33147
13	Emory University School of Medicine	Atlanta	Georgia	United States	30322
14	Sonar Clinical Research	Atlanta	Georgia	United States	30331
15	Children's Healthcare of Atlanta - Pediatric Research Center	Atlanta	Georgia	United States	30342
16	Augusta University Center for Blood Disorders.	Augusta	Georgia	United States	30912
17	University of Illinois at Chicago Sickle Cell Center	Chicago	Illinois	United States	60612
18	Children's Hospital New Orleans	New Orleans	Louisiana	United States	70118
19	University of Maryland School of Medicine	Baltimore	Maryland	United States	21201
20	Boston Medical Center	Boston	Massachusetts	United States	02118
21	Barbara Ann Karmanos Cancer Institute	Detroit	Michigan	United States	48201
22	Washington University School of Medicine Barnes - Jewish Hospital	Saint Louis	Missouri	United States	63110
23	University of Nebraska Medical Center	Omaha	Nebraska	United States	68198
24	Jacobi Medical Center	Bronx	New York	United States	10461
25	Children's Hospital at Montefiore	Bronx	New York	United States	10467
26	Kings County Hospital	Brooklyn	New York	United States	11203
27	Queens Hospital Center	Jamaica	New York	United States	11432
28	Colombia University Medical Center	New York	New York	United States	10032
29	UNC School of Medicine	Chapel Hill	North Carolina	United States	27514
30	Duke University - Sickle Cell Center	Durham	North Carolina	United States	27705
31	East Carolina University (ECU) Physicians	Greenville	North Carolina	United States	27834
32	University of Cincinnati Cancer Center	Cincinnati	Ohio	United States	45219
33	Cincinnati Childrens Hospital Medical Center	Cincinnati	Ohio	United States	45229
34	Neuro-Behavioral Clinical Research	North Canton	Ohio	United States	44720
35	Lynn Institute of Tulsa	Tulsa	Oklahoma	United States	74135
36	Thomas Jefferson University Hospital	Philadelphia	Pennsylvania	United States	19107
37	Medical University of South Carolina (MUSC)	Charleston	South Carolina	United States	29425
38	Prisma Health	Greenville	South Carolina	United States	29605
39	St. Jude Children's Research Hospital (SJCRH)	Memphis	Tennessee	United States	38105
40	Methodist University Hospital	Nashville	Tennessee	United States	38104
41	The University of Texas Health Science Center at Houston	Houston	Texas	United States	77030
42	Mary Bridge Children's Health Center	Tacoma	Washington	United States	98405
43	Universite de Montreal - Centre Hospitalier Universitaire (CHU) Sainte-Justine	Montréal		Canada	H3T 1C5
44	The Hospital for Sick Children	Toronto		Canada	M5G 1X8
45	CHU Montpellier, Hôpital Saint-Eloi	Montpellier	Montpellier Cedex 5	France	34295
46	Hôpital Edouard HERRIOT	Lyon		France	69437
47	Hôpital Emile Muller	Mulhouse		France	68100
48	CHU Paris - Hôpital Robert Debré	Paris		France
49	Universitätsklinikum Freiburg	Freiburg		Germany	79106
50	University Hospital of Heidelberg	Heidelberg		Germany	69120
51	Azienda Ospedaliera Universitaria San Luigi Gonzaga	Orbassano		Italy	10043
52	Azienda Ospedale Università Padova	Padova		Italy	35128
53	Hospital De Cruces	Barakaldo		Spain	48013
54	Hospital Universitari Vall d'Hebron de Barcelona	Barcelona		Spain	08035
55	Universidad Autonoma de Madrid (UAM) - Hospital Universitario La Paz	Madrid		Spain	28046
56	Hospital Universitario Virgen del Rocio	Sevilla		Spain	41013
57	Guy's and St Thomas' NHS Foundation Trust	London		United Kingdom	SE18 3RA