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

Sickle Cell Disease Clinical Trial

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)

Clinical Trial Details — Status: Recruiting

Administrative data

• NCT number: NCT04624659
• Other study ID #: 4202-HEM-301
• Status: Recruiting
• Phase: Phase 2/Phase 3
• Start date: March 26, 2021
• Est. completion date: December 2026

Study information

• Verified date: April 2024
• Source: Novo Nordisk A/S
• Contact: Novo Nordisk
• Phone: (+1) 866-867-7178
• Email: clinicaltrials[@]novonordisk.com
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial 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).

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.

Recruitment information / eligibility

• Status: Recruiting
• Enrollment: 344
• Est. completion date: December 2026
• Est. primary completion date: December 2025
• Accepts healthy volunteers: No
• Gender: All
• Age group: 12 Years to 65 Years

Eligibility

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)

Related Conditions & MeSH terms

• Anemia, Sickle Cell
• Sickle Cell Disease

Intervention

Drug:
• Etavopivat Tablets Low dose
200 mg once daily
• Etavopivat Tablets High dose
400 mg once daily
• Placebo Tablets
Placebo once daily
• Etavopivat Tablets
Selected dose once daily

Locations

Country	Name	City	State
Canada	Universite de Montreal - Centre Hospitalier Universitaire (CHU) Sainte-Justine	Montréal
Canada	The Hospital for Sick Children	Toronto
Canada	Providence Hematology	Vancouver
France	Hôpital Henri Mondor	Créteil
France	Hôpital Edouard HERRIOT	Lyon
France	CHU Montpellier, Hôpital Saint-Eloi	Montpellier	Montpellier Cedex 5
France	Hôpital Emile Muller	Mulhouse
France	CHU Paris - Hôpital Robert Debré	Paris
Germany	Universitätsklinikum Freiburg	Freiburg
Germany	University Hospital of Heidelberg	Heidelberg
Greece	Hippocratio General Hospital	Athens
Greece	General University Hospital of Larissa	Larissa
Greece	General University Hospital of Patras	Rio	Patras
Greece	General Hospital of Thessaloniki "Hippokration"	Thessaloniki
Italy	Azienda Ospedaliero Universitaria Policlinico "G. Rodolico - San Marco"	Catania
Italy	Azienda Ospedaliera Universitaria San Luigi Gonzaga	Orbassano
Italy	Azienda Ospedale Università Padova	Padova
Italy	Fondazione IRCCS Policlinico San Matteo	Pavia
Lebanon	American University of Beirut Medical Center	Beirut
Lebanon	Nini Hospital	Tripoli
Oman	Sultan Qaboos University Hospital	Muscat
Oman	Sultan Qaboos University Hospital	Muscat
Spain	Hospital De Cruces	Barakaldo
Spain	Hospital Universitari Vall d'Hebron de Barcelona	Barcelona
Spain	Hospital Clínico San Carlos	Madrid
Spain	Universidad Autonoma de Madrid (UAM) - Hospital Universitario La Paz	Madrid
Spain	Hospital Universitario Virgen del Rocio	Sevilla
United Kingdom	Leicester Royal Infirmary	Leicester
United Kingdom	Guy's and St Thomas' NHS Foundation Trust	London
United Kingdom	Hammersmith Hospital - Imperial College Healthcare NHS Trust	London
United Kingdom	Imperial College Healthcare NHS Trust - St Mary's Hospital	London
United Kingdom	King's College Hospital	London
United Kingdom	Oxford University Hospitals NHS Trust - Churchill Hospital - Cancer and Haematology Centre	Oxford
United Kingdom	The Royal Hallamshire Hospital, Sheffield Teaching Hospital NHS Foundation Trust	Sheffield
United States	Cornerstone Research Institute	Altamonte Springs	Florida
United States	Children's Healthcare of Atlanta - Pediatric Research Center	Atlanta	Georgia
United States	Emory University School of Medicine	Atlanta	Georgia
United States	Sonar Clinical Research	Atlanta	Georgia
United States	Augusta University Center for Blood Disorders.	Augusta	Georgia
United States	University of Maryland School of Medicine	Baltimore	Maryland
United States	University of Alabama at Birmingham (UAB)	Birmingham	Alabama
United States	Boston Medical Center	Boston	Massachusetts
United States	Children's Hospital at Montefiore	Bronx	New York
United States	Jacobi Medical Center	Bronx	New York
United States	Kings County Hospital	Brooklyn	New York
United States	UNC School of Medicine	Chapel Hill	North Carolina
United States	Medical University of South Carolina (MUSC)	Charleston	South Carolina
United States	Levine Cancer Institute	Charlotte	North Carolina
United States	University of Illinois at Chicago Sickle Cell Center	Chicago	Illinois
United States	Cincinnati Childrens Hospital Medical Center	Cincinnati	Ohio
United States	University of Cincinnati Cancer Center	Cincinnati	Ohio
United States	iResearch Atlanta, LLC	Decatur	Georgia
United States	Barbara Ann Karmanos Cancer Institute	Detroit	Michigan
United States	Duke University - Sickle Cell Center	Durham	North Carolina
United States	University of Connecticut (UCONN) Health	Farmington	Connecticut
United States	East Carolina University (ECU) Physicians	Greenville	North Carolina
United States	Prisma Health	Greenville	South Carolina
United States	Office of Gershwin T. Blyden, MD	Hollywood	Florida
United States	Baylor College of Medicine	Houston	Texas
United States	The University of Texas Health Science Center at Houston	Houston	Texas
United States	University of California, Irvine	Irvine	California
United States	Queens Hospital Center	Jamaica	New York
United States	Woodland International Research Group	Little Rock	Arkansas
United States	Collaborative Neuroscience Research, LLC.	Long Beach	California
United States	St. Jude Children's Research Hospital (SJCRH)	Memphis	Tennessee
United States	Advanced Pharma CR LLC.	Miami	Florida
United States	University of Miami - Miller School of Medicine	Miami	Florida
United States	Blood Center of Wisconsin (BCW)	Milwaukee	Wisconsin
United States	Methodist University Hospital	Nashville	Tennessee
United States	Yale University	New Haven	Connecticut
United States	Long Island Jewish Medical Center	New Hyde Park	New York
United States	Children's Hospital New Orleans	New Orleans	Louisiana
United States	Columbia University Medical Center	New York	New York
United States	Neuro-Behavioral Clinical Research	North Canton	Ohio
United States	Pacific Research Partners, LLC	Oakland	California
United States	UCSF Benioff Children's Hospital Oakland	Oakland	California
United States	University of Nebraska Medical Center	Omaha	Nebraska
United States	Arnold Palmer Hospital for Children - Haley Center for Children's Cancer and Blood Disorders	Orlando	Florida
United States	Thomas Jefferson University Hospital	Philadelphia	Pennsylvania
United States	Phoenix Children's Hospital	Phoenix	Arizona
United States	UC Davis Medical Center - UC Davis Comprehensive Cancer Center - Hemotology/Oncology Clinic	Sacramento	California
United States	Washington University School of Medicine Barnes - Jewish Hospital	Saint Louis	Missouri
United States	Mary Bridge Children's Health Center	Tacoma	Washington
United States	Lynn Institute of Tulsa	Tulsa	Oklahoma
United States	Children's National Health Center	Washington	District of Columbia
United States	Howard University	Washington	District of Columbia
United States	Wake Forest Baptist Medical Center	Winston-Salem	North Carolina

Sponsors (2)

Lead Sponsor	Collaborator
Forma Therapeutics, Inc.	Novo Nordisk A/S

Countries where clinical trial is conducted

United States,  Canada,  France,  Germany,  Greece,  Italy,  Lebanon,  Oman,  Spain,  United Kingdom, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Hemoglobin response rate	Hemoglobin response rate at Week 24 (increase of > 1 g/dL [> 10 g/L] from baseline) during the blinded treatment period	24 Weeks
Primary	Annualized vaso-occlusive crisis	Annualized vaso-occlusive crisis rate during the 52-week blinded treatment period based on adjudicated vaso-occlusive crisis review	52 Weeks
Secondary	Hemoglobin	Change from baseline in hemoglobin at Week 24 during the blinded treatment period	24 Weeks
Secondary	Hemoglobin	Change from baseline in hemoglobin at Week 52 during the blinded treatment period	52 Weeks
Secondary	Absolute reticulocyte count	Change in absolute reticulocyte count from baseline at Week 24 during the blinded treatment period	24 Weeks
Secondary	Unconjugated bilirubin	Change in unconjugated bilirubin from baseline at Week 24 during the blinded treatment period	24 Weeks
Secondary	Lactate dehydrogenase	Change in lactate dehydrogenase from baseline at Week 24 during the blinded treatment period	24 Weeks
Secondary	Vaso-occlusive crisis	Time to first vaso-occlusive crisis during the blinded treatment period	52 Weeks
Secondary	Patient-Reported Outcome Measurement Information System (PROMIS)	Change in PROMIS Fatigue Scale from baseline in adult patients at Week 24 during the blinded treatment period	24 Weeks
Secondary	Patient-Reported Outcome Measurement Information System (PROMIS) Fatigue Scale	Change in PROMIS Fatigue Scale from baseline in adult patients at Week 52 during the blinded treatment period	52 Weeks