Evaluation of Etavopivat, a Pyruvate Kinase Activator, in a Randomized, Placebo-Controlled Study for Sickle Cell Disease in Patients Aged 12 to 65 Years

Trial ID: 2024-511535-97-00
Protocol: 4202-HEM-301
Sponsor: Novo Nordisk A/S

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Diseases & Conditions

Sickle cell disease

Objectives

The primary objective of this study is to assess the **efficacy** of Etavopivat in adolescents and adults with sickle cell disease (SCD) compared to placebo. This will be measured by improvement in hemoglobin (Hb) levels and the annualized rate of vaso-occlusive crises (VOC). Evaluating these parameters is clinically relevant as they directly impact the management and quality of life of patients with SCD, a condition characterized by chronic hemolytic anemia and recurrent painful episodes.

Secondary objectives include: • Measuring the effects of Etavopivat on clinical measures and sequelae of hemolysis. • Assessing changes in fatigue among adult sickle cell patients taking Etavopivat. • Evaluating the effects of Etavopivat on the sequelae of VOC. These objectives aim to provide a comprehensive understanding of the potential benefits of Etavopivat beyond primary efficacy endpoints, addressing additional clinical challenges faced by patients with SCD.

Participants

The clinical trial involves a total of **356 participants** diagnosed with **sickle cell disease (SCD)**. The study population includes both male and female subjects, encompassing adolescents and adults. Participants were selected based on specific criteria, including a confirmed diagnosis of SCD and a history of 2-15 documented vaso-occlusive crises in the past 12 months. The age range of the participants spans from adolescents to adults, ensuring a comprehensive assessment across different life stages. The trial includes individuals who are on stable doses of hydroxyurea, crizanlizumab, or L-glutamine oral powder, provided they meet the compliance and stability requirements. Participants are required to have a hemoglobin level between 5.5 and 10.5 g/dL during screening. Lifestyle considerations such as the use of contraception are mandated for female patients of childbearing potential and male patients. The trial population is carefully selected to include a vulnerable population, ensuring the study's findings are applicable to those most affected by SCD.

Plans and Procedures

The clinical trial is designed as an **adaptive, randomized, placebo-controlled, double-blind, multi-center study** to evaluate the efficacy of **Etavopivat**, a pyruvate kinase activator, in patients with **sickle cell disease (SCD)**. The trial is structured in two phases, Phase II and Phase III, and aims to assess the improvement in hemoglobin levels and the annualized rate of vaso-occlusive crises (VOC) in adolescents and adults with SCD. The study will involve the administration of Etavopivat in tablet form, with doses of 100 mg and 200 mg, compared to a placebo, all administered orally.

The trial is expected to span from January 29, 2021, to February 28, 2027. Participants will be involved in the study for a maximum treatment period of 164 weeks. The study includes several key visits: an initial screening visit to confirm eligibility based on criteria such as a confirmed diagnosis of SCD, a specific range of hemoglobin levels, and a history of VOC episodes. Following the screening, participants will undergo regular follow-up visits to monitor hemoglobin response and VOC rates, with primary endpoints assessed at Week 24 and secondary endpoints at Week 52. The end-of-study visit will conclude the participant's involvement, ensuring all data is collected and any necessary follow-up care is arranged.

Participants may be withdrawn from the study early if they experience significant adverse effects, fail to comply with the study protocol, or if the study is terminated for any reason. The trial's primary endpoints include the hemoglobin response rate at Week 24 and the annualized VOC rate during the 52-week blinded treatment period. Secondary endpoints focus on changes in hemoglobin and other SCD-related clinical laboratory measurements, as well as patient-reported outcomes related to fatigue. The study is not classified as low intervention, given its comprehensive design and the nature of the investigational product.

Treatment

The clinical trial involves the administration of **Etavopivat**, a pyruvate kinase activator, in patients with **Sickle Cell Disease**. The experimental medication, Etavopivat, is provided in two dosages: 200 mg and 100 mg. Both formulations are in the form of tablets and are intended for **oral use**. The active substance in these tablets is Etavopivat, also known by the synonym FT-4202. The maximum treatment period for the administration of Etavopivat is 164 days. The trial aims to assess the efficacy of Etavopivat in improving hemoglobin levels and reducing the annualized vaso-occlusive crisis rate in adolescents and adults with Sickle Cell Disease.

In addition to the experimental medication, a placebo is used as a comparator treatment in this study. The placebo is designed to match the Etavopivat tablets in appearance and is also administered orally. The use of a placebo allows for a double-blind study design, ensuring that neither the participants nor the investigators know which treatment is being administered, thereby reducing bias in the assessment of the treatment's efficacy.

Efficacy

The efficacy of Etavopivat in patients with **Sickle Cell Disease** (SCD) will be assessed through a series of primary and secondary endpoints. The primary endpoints include the hemoglobin (Hb) response rate at Week 24, defined as an increase of more than 1 g/dL from baseline during the blinded treatment period, and the annualized vaso-occlusive crisis (VOC) rate during the 52-week blinded treatment period based on adjudicated VOC review.

Secondary endpoints will evaluate additional parameters, including the change from baseline in Hb at Week 52, changes in SCD-related clinical laboratory measurements at Week 24, such as absolute reticulocyte count, indirect bilirubin, and lactate dehydrogenase (LDH). Furthermore, the change from baseline in the Patient-Reported Outcome Measurement Information System (PROMIS) Fatigue Scale in adult patients at Week 52 and the time to the first VOC during the blinded treatment period will also be assessed.

These efficacy parameters will be measured and collected at specified timepoints, including Week 24 and Week 52, using validated laboratory tests and patient-reported outcomes. The analysis will focus on comparing the efficacy of Etavopivat to placebo in improving these clinical outcomes in adolescents and adults with SCD.

Inclusion and Exclusion Criteria

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Inclusion Criteria

Provision of consent
Patient has a confirmed diagnosis of sickle cell disease
2-15 episodes of documented 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
Female patients of childbearing potential must use acceptable methods of contraception; male patients are willing to use acceptable methods of contraception
7)Patients on crizanlizumab or L-glutamine oral powder (Endari®) treatment at the time of consent may be eligible if they: • Have been on a stable dose for ≥ 12 months at the time of consent (i.e., no changes to the dose except for changes to weight or for safety reasons) • Have been ≥ 80% compliant with the planned regimen during the 12 months prior to the time of consent • Meet the VOC eligibility requirement in Inclusion Criterion 4.

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Exclusion Criteria

Medical Conditions 1) More than 15 vaso-occlusive crises within the past 12 months prior to screening
Female who is breast feeding or pregnant
Hepatic dysfunction characterized by: - Alanine aminotransferase (ALT) > 4.0 × upper limit of normal (ULN) OR - Direct bilirubin > 3.0 × ULN
Known HIV positive
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 anticoagulation therapy for ≥ 6 weeks, occurring within 6 months prior to Day 1 of study treatment. Note: patients on ≥ 6 months of chronic or prophylactic anti-coagulation therapy are allowed on study.
Prior/Concomitant Therapy 1) 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 (e.g., monoclonal antibody or small molecule) within 28 days of starting study treatment or anticipated need for such agents during the study
Uso de eritropoyetina u otro tratamiento con factor de crecimiento hematopoyético dentro de los 28 días posteriores al inicio del tratamiento del estudio o la necesidad anticipada de dichos agentes durante el estudio.
Receipt of prior cellular-based therapy (e.g., hematopoietic cell transplant, gene modification therapy)

Trial Status by Country

Country	Status	Start of Recruitment	Planned Patients
France	Not Recruiting	29 Jan 2021	19
Germany	Not Recruiting	29 Jan 2021	15
Greece	Not Recruiting	29 Jan 2021	30
Italy	Not Recruiting	29 Jan 2021	20
Spain	Not Recruiting	29 Jan 2021	10