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).
Brief Title
A Study of Etavopivat in Adults and Adolescents With Sickle Cell Disease (HIBISCUS)
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 is one 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 conclusion of the double-blind treatment period. Following completion of 52 weeks of double-blind treatment, patients may enter a 112-week etavopivat open-label extension period.
Categories
Central Contacts
Central Contact Role
Contact
Central Contact Phone
(+1) 866-867-7178
Central Contact Email
clinicaltrials@novonordisk.com
Completion Date
Completion Date Type
Estimated
Conditions
Sickle Cell Disease
Eligibility Criteria
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 15 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)
* 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 15 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)
Inclusion Criteria
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
* 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
Gender
All
Gender Based
false
Keywords
Sickle Cell Disease
Sickle Cell
Anemia
Sickle Cell Anemia
Hemolytic
Hemoglobin
Vaso-occlusive Crisis
Sickle Cell Crisis
Congenital Anemia
Hemolytic Anemia
Hematologic Disease
Hemoglobinopathies
Genetic Disease
Inborn Disease
Sickle Cell Trait
Pyruvate Kinase
Healthy Volunteers
No
Last Update Post Date
Last Update Post Date Type
Actual
Last Update Submit Date
Maximum Age
65 Years
Minimum Age
12 Years
NCT Id
NCT04624659
Org Class
Industry
Org Full Name
Novo Nordisk A/S
Org Study Id
4202-HEM-301
Overall Status
Active, not recruiting
Phases
Phase 3
Primary Completion Date
Primary Completion Date Type
Estimated
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)
Primary Outcomes
Outcome Description
Hemoglobin response rate at Week 24 (increase of \> 1 g/dL \[\> 10 g/L\] from baseline) during the blinded treatment period
Outcome Measure
Hemoglobin response rate
Outcome Time Frame
24 Weeks
Outcome Description
Annualized vaso-occlusive crisis rate during the 52-week blinded treatment period based on adjudicated vaso-occlusive crisis review
Outcome Measure
Annualized vaso-occlusive crisis
Outcome Time Frame
52 Weeks
Secondary Outcomes
Outcome Description
Change from baseline in hemoglobin at Week 52 during the blinded treatment period
Outcome Time Frame
52 Weeks
Outcome Measure
Hemoglobin
Outcome Description
Change in absolute reticulocyte count from baseline at Week 24 during the blinded treatment period
Outcome Time Frame
24 Weeks
Outcome Measure
Absolute reticulocyte count
Outcome Description
Change in unconjugated bilirubin from baseline at Week 24 during the blinded treatment period
Outcome Time Frame
24 Weeks
Outcome Measure
Indirect bilirubin
Outcome Description
Change in lactate dehydrogenase from baseline at Week 24 during the blinded treatment period
Outcome Time Frame
24 Weeks
Outcome Measure
Lactate dehydrogenase
Outcome Description
Time to first vaso-occlusive crisis during the blinded treatment period
Outcome Time Frame
52 Weeks
Outcome Measure
Vaso-occlusive crisis
Outcome Description
Change in Patient-Reported Outcome Measurement Information System (PROMIS) Fatigue Scale from baseline in adult patients at Week 52 during the blinded treatment period
Outcome Time Frame
52 Weeks
Outcome Measure
Fatigue
Start Date
Start Date Type
Actual
Status Verified Date
First Post Date
First Post Date Type
Actual
First Submit Date
First Submit QC Date
Std Ages
Child
Adult
Older Adult
Locked Fields
Render the field
Maximum Age Number (converted to Years and rounded down)
65
Minimum Age Number (converted to Years and rounded down)
12
Investigators
Investigator Type
Principal Investigator
Investigator Name
Kaitlin Strumph
Investigator Email
kstrumph@montefiore.org