Clinical trial NCT04987489: A Study of Etavopivat in Patients With Thalassemia or Sickle Cell Disease
Official title: A Phase 2 Open-Label Study to Evaluate Safety and Clinical Activity of Etavopivat in Patients With Thalassemia or Sickle Cell Disease
Study type: INTERVENTIONAL
Overall status: ACTIVE_NOT_RECRUITING
Phase: PHASE2
Conditions: Sickle Cell Disease
Thalassemia
Keywords: SCD
sickle cell disease
sickle cell
anemia
sickle cell anemia
hemolytic
hemoglobin
vaso-occlusive crisis
VOC
vaso-occlusive events
sickle cell crisis
pain crisis
pain episode
congenital anemia
hemolytic anemia
hematologic disease
hemoglobinopathy
hemoglobinopathies
genetic disease
inborn disease
sickle cell trait
pyruvate kinase
PKR
thalassemia
beta-thalassemia
alpha-thalassemia
transfusions
hemoglobin H
transfusion
transfusion-dependent
non-transfusion dependent
hemoglobin E
Lead sponsor: Novo Nordisk A/S
Sponsor class: INDUSTRY
First posted: 2021-08-03
Enrollment: 60
Sex: ALL
Minimum age (years): 12
Maximum age (years): 65
Standard ages: CHILD
ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NON_RANDOMIZED
Intervention model: SINGLE_GROUP
Primary purpose: TREATMENT

Brief summary: This clinical trial is a Phase 2 study that will evaluate the safety and clinical activity of etavopivat in patients with thalassemia or sickle cell disease and test how well etavopivat works to lower the number of red blood cell transfusions required and increase hemoglobin.

Detailed description: Etavopivat is a potent, selective, orally bioavailable, small-molecule activator of pyruvate kinase red blood cell (PKR) being developed by Forma Therapeutics, Inc and is intended for use as a treatment for patients with sickle cell disease (SCD) or other inherited hemoglobinopathies or refractory anemias. This study is a multicenter, Phase 2, open-label, multiple-cohort study examining the safety and efficacy of etavopivat for the treatment of patients, age 12 to 65 years, with SCD or thalassemia. Three treatment cohorts based on the patients hemoglobinopathy (SCD or thalassemia) and transfusion requirements will be evaluated.

Eligibility criteria: Inclusion Criteria:

* Provision of consent
* Female patients of childbearing potential must use acceptable methods of contraception, male patients are willing to use barrier methods of contraception

Cohort A (Sickle Cell Disease Transfusion Cohort)

* Confirmed diagnosis of sickle cell disease
* Chronically red blood cell transfused (sample or exchange \[manual or via electrophoresis\]) for primary stroke prevention or due to previous stroke. Chronic red blood cell transfusion is defined as: ≥ 6 red blood cell units in the previous 24 weeks before the first dose of study treatment and no transfusion-free period for \> 35 days during that period
* At least 24 months of chronic monthly red blood cell transfusions for secondary stroke prevention/treatment of primary stroke (initial completed overt clinical stroke with documented infarction on brain computed tomography \[CT\] or magnetic resonance imaging \[MRI\])
* Prior to screening OR at least 12 months of chronic RBC transfusions for primary stroke prevention (abnormal TCD) prior to screening
* Documented adequate monthly transfusions with average HbS ≤ 45% (the upper limit of the established academic community standard) for the previous 12 weeks of red blood cell transfusions before the first dose of study treatment

Cohort B (Thalassemia Transfusion Cohort)

* Documented diagnosis of β-thalassemia, Hemoglobin E/ β-thalassemia or Hemoglobin H (α-thalassemia), or other thalassemia variant
* Chronically transfused, defined as: ≥ 6 red blood cell units in the previous 24 weeks before the first dose of study treatment and no transfusion-free period for \> 35 days during that period

Cohort C (Thalassemia Non-transfused Cohort)

* Documented diagnosis of β-thalassemia, Hemoglobin E/ β-thalassemia or Hemoglobin H (α-thalassemia), or other thalassemia variant
* Hemoglobin ≤ 10 g/dL

Exclusion Criteria:

* Female who is breast feeding or pregnant
* Hepatic dysfunction characterized by:

  * Alanine aminotransferase (ALT) \> 4.0 × upper limit of normal (ULN)
  * Direct bilirubin \> 3.0 × ULN
  * History of cirrhosis
* Known human immunodeficiency virus (HIV) positivity
* Active hepatitis B or hepatitis C infection
* Severe renal dysfunction or on chronic dialysis
* 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 (eg, non- melanoma skin cancer, cancer of the cervix in-situ, ductal carcinoma in situ \[Stage 1\], Grade 1 endometrial cancer)
* 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

Primary outcomes:
measure: Cohorts A: Proportion of patients with ≥ 20% reduction in red blood cell transfusions over a continuous 12-week treatment period versus baseline red blood cell transfusion history
timeFrame: 12 weeks
measure: Cohorts B: Proportion of patients with ≥ 20% reduction in red blood cell transfusions over a continuous 12-week treatment period versus baseline red blood cell transfusion history
timeFrame: 12 weeks
measure: Cohort C: Hemoglobin response rate at Week 12 (increase of ≥ 1.0 g/dL from baseline)
timeFrame: 12 weeks
Secondary outcomes:
measure: Cohort A: Proportion of patients with ≥ 33% reduction in red blood cell transfusion over a continuous 12-week treatment period versus baseline red blood cell transfusion history
timeFrame: 12 weeks
measure: Cohort B: Proportion of patients with ≥ 33% reduction in red blood cell transfusion over a continuous 12-week treatment period versus baseline red blood cell transfusion history
timeFrame: 12 weeks
measure: Cohort A: Reduction in red blood cell transfusions over 12 weeks
timeFrame: 12 weeks
measure: Cohort A: Reduction in red blood cell transfusions over 24 weeks
timeFrame: 24 weeks
measure: Cohort A: Reduction in red blood cell transfusions over 48 weeks
timeFrame: 48 weeks
measure: Cohort B: Reduction in red blood cell transfusions over 12 weeks
timeFrame: 12 weeks
measure: Cohort B: Reduction in red blood cell transfusions over 24 weeks
timeFrame: 24 weeks
measure: Cohort B: Reduction in red blood cell transfusions over 48 weeks
timeFrame: 48 weeks
measure: Cohort C: Hemoglobin response rate at Week 24 (increase of ≥ 1.0 g/dL from baseline).
timeFrame: 24 weeks
measure: Cohort C: Hemoglobin response rate at Week 48 (increase of ≥ 1.0 g/dL from baseline).
timeFrame: 48 weeks
measure: Change from baseline in hemoglobin over 12 weeks
timeFrame: 12 weeks
measure: Change from baseline in hemoglobin over 24 weeks
timeFrame: 24 weeks
measure: Change from baseline in hemoglobin over 48 weeks
timeFrame: 48 weeks
measure: Changes in serum ferritin levels at 12 weeks versus baseline
timeFrame: 12 weeks
measure: Changes in serum ferritin levels at 24 weeks versus baseline
timeFrame: 24 weeks
measure: Changes in serum ferritin levels at 48 weeks versus baseline
timeFrame: 48 weeks
measure: Changes in liver iron concentration at 48 weeks versus baseline
timeFrame: 48 weeks
Other outcomes:
Locations:
city: Los Angeles
country: United States
facility: [Legal] Children's Hospital Los Angeles
state: California
city: Oakland
country: United States
facility: UCSF Oakland Benioff ChildHosp
state: California
city: Orange
country: United States
facility: [Legal] Children's Hospital of Orange County on behalf of CHOC Children's Hospital of Orange County
state: California
city: New York
country: United States
facility: Weill Medical College of Cornell University
state: New York
city: Greenville
country: United States
facility: East Carolina University
state: North Carolina
city: Cincinnati
country: United States
facility: [Legal] Children's Hospital Medical Center dba Cincinnati Children's
state: Ohio
city: Toronto
country: Canada
facility: The Hospital for Sick Children
state: Ontario
city: Toronto
country: Canada
facility: University Health Network - Toronto General Hospital
state: Ontario
city: Montreal
country: Canada
facility: CHU Sainte-Justine Mother and Child University Hospital
state: Quebec
city: Cairo, Egypt
country: Egypt
facility: Abu El-Reesh El-Mounira Children University Hospital
city: Cairo
country: Egypt
facility: Cairo University
city: Baabda
country: Lebanon
facility: Chronic Care Center
city: Tripoli
country: Lebanon
facility: Hospital Nini
city: London
country: United Kingdom
facility: Barts Health NHS Trust - The Royal London Hospital
city: London
country: United Kingdom
facility: Imperial College Healthcare NHS Trust - Hammersmith Hospital
city: Manchester
country: United Kingdom
facility: Manchester University NHS Foundation Trust
Study officials:
affiliation: Novo Nordisk A/S
name: Clinical Transparency (dept. 2834)
role: STUDY_DIRECTOR
References: