Phase 3 Randomized Double-Blind Placebo-Controlled Trial of Etavopivat in Adolescents and Adults with Sickle Cell Disease

Trial ID: 2023-509175-16-00
Protocol: NN7535-7807
Sponsor: Novo Nordisk A/S

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Diseases & Conditions

Sickle cell disease

Objectives

The primary objective of this study is to demonstrate the **superiority** of treatment with etavopivat versus placebo in adolescents and adults with **sickle cell disease**. This is clinically relevant as it aims to establish etavopivat as a more effective treatment option, potentially improving patient outcomes in this population.

Secondary objectives include:

Evaluating clinical efficacy measures of etavopivat treatment versus placebo in adolescents and adults with sickle cell disease.
Assessing clinically meaningful improvement in fatigue, functional exercise capacity, and Quality of Life measures in adolescents and adults with sickle cell disease taking etavopivat treatment compared to placebo.

Participants

The clinical trial involves a total of **333 participants** diagnosed with **sickle cell disease**. The study population includes both male and female subjects aged **12 years and above**. Participants were selected based on specific criteria, including a confirmed diagnosis of sickle cell disease and a history of 2 to 15 documented vaso-occlusive crises within the 12 months prior to screening. The trial population is characterized by a hemoglobin level between 5.0 and 10.0 g/dL at screening. The selection process ensures a diverse representation of adolescents and adults, with no specific lifestyle considerations such as diet or physical activity being highlighted. The trial does not specify any additional lifestyle factors or habits that may influence participation. The study aims to evaluate the efficacy of etavopivat compared to placebo in this population.

Plans and Procedures

The clinical trial is a **randomized**, **double-blind**, and **placebo-controlled** study designed to evaluate the efficacy and safety of **etavopivat** in adolescents and adults with **sickle cell disease**. The trial aims to demonstrate the superiority of treatment with etavopivat compared to a placebo. Participants will be randomly assigned to receive either etavopivat or a placebo, administered orally in tablet form. The trial is expected to last until September 2028, with recruitment starting in December 2024. The maximum treatment period for participants is 104 weeks.

Study visits are structured to ensure comprehensive data collection and participant safety. The initial inclusion visit, or screening, will confirm eligibility based on criteria such as age, confirmed diagnosis of sickle cell disease, and documented episodes of vaso-occlusive crises. Following randomization, participants will attend regular follow-up visits to monitor treatment effects and safety. These visits will assess primary endpoints, including the number of adjudicated vaso-occlusive crisis events with medical contact, and secondary endpoints such as changes in hemoglobin levels, fatigue scores, and walking test performance. The end-of-study visit will conclude the participant's involvement, ensuring all necessary data is collected and any post-treatment care is arranged.

Participant involvement is expected to last up to 104 weeks, depending on individual response and adherence to the study protocol. Conditions that may lead to early termination from the study include adverse reactions, withdrawal of consent, or non-compliance with study procedures. The trial is conducted under strict ethical guidelines to ensure participant safety and data integrity throughout the study duration.

Treatment

The clinical trial involves the administration of **Etavopivat**, a synthetic chemical compound, as the experimental medication. **Etavopivat** is provided in the form of a **tablet** with a dosage strength of 200 mg. The route of administration is **oral**, and the medication is intended for use in adolescents and adults diagnosed with sickle cell disease. The maximum treatment period for **Etavopivat** is 104 weeks. The trial aims to evaluate the efficacy and safety of this medication, with the primary objective being to demonstrate its superiority over a placebo. The pharmaceutical form of the tablet is designed for standard adult use and is not a pediatric formulation. The medication is manufactured by Novo Nordisk A/S and is identified by the product code PRD10987265.

The study also includes a **placebo** as a comparator treatment. The placebo is used to maintain the double-blind nature of the trial, ensuring that neither the participants nor the investigators are aware of the treatment assignments. The placebo does not contain any active pharmaceutical ingredients and serves as a control to assess the true efficacy of **Etavopivat**. The placebo is administered in a manner consistent with the experimental medication to ensure uniformity in the trial protocol.

Efficacy

The efficacy of the investigational product, **etavopivat**, will be assessed in a global phase 3, randomized, double-blind, placebo-controlled study involving adolescents and adults with sickle cell disease. The primary endpoint for evaluating efficacy is the number of adjudicated vaso-occlusive crisis (VOC) events with a medical contact. Secondary endpoints include several parameters: change in hemoglobin (Hb) levels greater than 1 g/dL, time to onset of the first adjudicated VOC, change in distance traveled during the 6-minute walking test (6MWT), change in standardized T-score on the PROMIS Fatigue 7a Scale, and changes in various biomarkers such as lactate dehydrogenase (LDH), absolute reticulocyte count, and indirect bilirubin. Additionally, the study will assess the proportion of participants achieving clinically meaningful changes in the PROMIS Fatigue 7a Scale and the 6MWT.

These efficacy parameters will be measured and collected at specified timepoints throughout the trial. The use of validated scales and laboratory tests will ensure the accuracy and reliability of the data collected. The analysis of these endpoints will provide insights into the efficacy of etavopivat compared to placebo in the target population. The trial is designed to demonstrate the superiority of etavopivat over placebo in improving clinical outcomes for individuals with sickle cell disease.

Inclusion and Exclusion Criteria

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Inclusion Criteria

Male or female
Age 12 years or above at the time of signing the informed consent
Confirmed diagnosis of sickle cell disease (SCD): Documentation of SCD genotype (HbSS, HbSβ0-thalassemia or other sickle cell syndrome variants) based on prior history of laboratory testing or screening test results from central laboratory.
Have 2−15 episodes of documented vaso-occlusive crises (VOCs) within the 12 months prior to screening. Documentation must exist in the participant’s medical record prior to randomisation. Events based solely on participant recall without supporting documentation should not be counted towards eligibility.
Hb ≥5.0 and ≤10.0 g/dL (≥50 and ≤100 g/L) at screening.

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Exclusion Criteria

Use of voxelotor or similar agent within 28 days prior to starting study treatment or anticipated need for this agent during the study
Use of a selectin antagonist (e.g., crizanlizumab, monoclonal antibody or small molecule) within 28 days or 5 half-lives (whichever is longer) prior to starting study treatment or anticipated need for such agents during the study.
Receiving regularly scheduled blood (RBC) transfusion therapy (also termed chronic, prophylactic, or preventive transfusion) or ≥6 transfusion events in the previous 12 months (i.e., an average of 1 transfusion event every 60 days).
Participants who have received an RBC transfusion for any reason within 60 days of the screening period or 60 days of the randomisation day are only eligible if HbA (adult Hb) <10% by Hb electrophoresis is documented prior to starting study treatment.
Receiving or use of concomitant medications that are strong inducers of CYP3A4 within 2 weeks of starting study treatment or anticipated need for such agents during the study.
Use of erythropoietin or other haematopoietic 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 (e.g., haematopoietic cell transplant, gene modification therapy).
Hepatic dysfunction characterized by: Alanine aminotransferase (ALT) >4.0 × upper limit of normal (ULN) or Direct bilirubin >3.0 × ULN.
Participants who are not taking or are unable to take antimalarial prophylaxis at the time of consent and during the study if they live in areas of endemic malaria where prophylaxis is recommended.
Severe renal dysfunction (estimated glomerular filtration rate [eGFR] at screening, calculated by the central laboratory <30 mL/min/1.73 m2) or on chronic dialysis.
Travelled distance on standardized 6-minute walking test below 100m at screening.

Trial Status by Country

Country	Status	Start of Recruitment	Planned Patients
Belgium	Recruiting	16 Dec 2024	10
France	Recruiting	16 Dec 2024	12
Greece	Recruiting	16 Dec 2024	15
Italy	Recruiting	16 Dec 2024	20
The Netherlands	Recruiting	16 Dec 2024	—
Spain	Recruiting	16 Dec 2024	8
Netherlands	—	—	10