| Protocol No: | ECCT/25/05/05 | Date of Protocol: | 30-09-2024 |
| Study Title: | A global phase 3, randomised, double-blind and placebo-controlled study evaluating the efficacy and safety of etavopivat in adolescents and adults with sickle cell disease. |
| Study Objectives: |
The objective of the present study is to confirm efficacy and safety of etavopivat (compared to
placebo) on annualised vaso-occlusive crises (VOC) rates, measures of end organ damage,
functional exercise capacity, as measured by the 6-minute walk test (6MWT), and quality of life
(QOL) measures (including fatigue) in adolescents and adults with sickle cell disease (SCD)
enrolled in the study. Additional Patient Reported Outcome (PRO) QOL measures, including pain,
emotional and functional impact, will also be used to confirm efficacy of etavopivat in adult and
adolescents with SCD. These results are intended to support additional clinical studies within the
etavopivat SCD program.
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| Laymans Summary: |
What is the problem/background?
Sickle cell disease (SCD) is a disease that can be passed on from both parents to a child. It affects the red blood cells that carry oxygen to the body. Normal red blood cells have a circular shape and are very flexible. For patients with SCD, their red blood cells can look like a sickle or crescent moon and become very stiff. These sickle-shaped red blood cells can get stuck in the blood vessels leading to early destruction of these abnormal red blood cells.
These blocked blood vessels and loss of red blood cells makes it hard for the blood to transport oxygen. The lack of oxygen can cause severe body pains, which is a key symptom of SCD.
These results in the manifestation of SCD including; recurrent pain referred to as a painful vaso-occlusive crisis (VOC), low blood level and organ damage.
Before 2017, the only known medication approved for preventing the painful episodes and other SCD problems was hydroxyurea. Hydroxyurea works by reducing the number of the sickle red blood cells.
Sickle cell disease is associated with significant burden in quality of life. The cure is not readily and locally available. The available medications include drugs for; pain relief, boosting low blood level, prevention of infection and vaccination to prevent infection that is common in Sickle Cell Disease. They are also provided with mental and social support. However, despite these treatments, people with Sickle Cell Disease continue to suffer due to problems of SCD resulting in early death because, none of them results in both significant improvement of blood level and a reduction in the rate of pain episodes and other SCD problems. More research and development of SCD treatments are necessary to improve the effects of the disease and quality of life of the Sickle cell patients.
What questions is the study trying to answer?
Etavopivat is a small molecule that can activate a specific protein found in the red blood cells. This protein helps the red blood cells to make energy and to bind oxygen, ultimately improving the health of the red blood cells. These effects may help in treating blood disorders such as sickle cell disease.
The objective of the present study is to confirm how well and how safe etavopivat is compared to placebo on annualised vaso-occlusive crises (VOC) rates, measures of end organ damage,functional exercise capacity, as measured by the 6-minute walk test, and quality of life measures (including fatigue) in adolescents and adults with sickle cell disease enrolled in the study.
A placebo is a medication with similar physical characteristics (shape, color, taste, packing) as the etavopivat but does not contain any active chemical ingredients that affect the body.
Where is the study taking place, how many people does it involve and how are they selected?
The study will be conducted in many centres across the world including at 4 sites in Kenya, in children aged 12 years and above and adult patients aged 18 years and older with 2-15 VOC. Globally, about 408 patients will be enrolled into the study. Kenya is expected to contribute a total of 67 participants to the study population. Of 408 participants, up to 100 participants will be children and teenagers between 12 and 17 years old, with approximately 25 expected to be enrolled across the 4 sites in Kenya.
What does the study involve for those who are in it?
The participants will be asked to come to 20 visits at the clinic. The participants will have physical examinations as well as other tests, including a walking exercise, heart checks and blood and urine tests. During specific clinic visits, participants will be asked to answer short questionnaires about their health and quality of life. In some countries, participants may also have additional blood samples collected for future research if they accept to do so. Every day during the study, participants will use the Study App to register when they took the study medicine and register if they had any sickle cell pain.
Participants will have a two times chance to receive the etavopivat or the placebo in the first 52 weeks of the study after which they will all receive etavopivat for another 52 weeks. Etavopivat or placebo will be taken once a day for the entire duration of the study.
What are the benefits and risks/costs of the study for those involved?
Necessary precautions have been put in the design and planned conduct of this study in order to minimise risks and inconveniences of participation. The etavopivat safety data, deriving from the nonclinical safety studies and data from Phase 1 studies and the Phase 2 part of study 4202-HEM-301, have not identified major safety issues. Together with the benefit data that has been gathered and presented, this supports further clinical development of etavopivat and suggests that participants with SCD enrolled in this study have the potential to benefit from treatment with etavopivat and that such benefits could be clinically meaningful. The research study will be done at no cost to the participants and they will be reimbursed for “out-of-pocket” expenses, such as travel costs as well as for time spent, meals and inconvenience.
How will the study benefit society?
By participating in the study, the participants will help contribute to the new information on the dosage and usefulness of etavopivat in the management of SCD. Upon public availability of the study results, the results will be disseminated to various community stakeholders.
When does the study start and finish?
The study will start as soon as ethical approval is received. Duration of study participation for an individual patient may last up to 112 weeks and includes the screening period (up to 4 weeks before study treatment), the double-blind treatment period of the study for up to 52 weeks, participation in the open-label extension treatment period for up to 52 weeks and an End of Study (EOS) visit at 4 weeks after the last dose of study drug.
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| Abstract of Study: |
SCD is caused by a specific point mutation (E6V) in the gene encoding hemoglobin (Hb) subunit beta that leads to the production of abnormal Hb (“sickle hemoglobin” or HbS). Sickled haemoglobin leads to several patho-physiological changes that culminates in the vascular obstruction and ischemia responsible for much of the observed morbidity in SCD. Prior to July 2017, the only drug specifically approved for the treatment of SCD was hydroxyurea (HU). HU reduces painful crises and the need for blood transfusions at least in part by increasing levels of fetal hemoglobin (HbF), which reduces RBC sickling and improves blood flow. Unfortunately, HU is often poorly tolerated, and its widespread use is limited by concerns about its potential impact on fertility and reproduction, challenges achieving and maintaining an efficacious dose due to its hematologic toxicities, and requirements for monthly monitoring.
In the US, recently approved treatment options include L-glutamine, voxelotor, and crizanlizumab-tmca. L-glutamine is indicated to reduce the acute complications of SCD, though its adoption remains somewhat limited by lingering questions regarding limitations of the clinical studies, cost concerns, potential for reduced adherence due to twice-daily administration. Voxelotor leads to increased Hb O2 affinity along with a reduction in clinical markers of hemolysis and an increase in Hb levels. Crizanlizumab-tmca administered via intravenous (IV) infusion, has been shown to reduce the incidence of VOCs in patients with SCD. While these new therapies provide promise, additional therapies with the potential to target the underlying pathophysiology of SCD are still needed to manage patients with this devastating disease.
Etavopivat is a potent and effective activator of pyruvate kinase red blood cell PKR in both human and mouse red blood cells (RBC). The potential clinical consequence of PKR activation was demonstrated in cellular assays with RBC from patients with SCD in which etavopivat increased haemoglobin-oxygen (Hb-O2) affinity and reduced sickling under severe hypoxic conditions. The study is made up of two parts:
• Double-blind treatment period: Research patients will take the study drug (etavopivat or placebo, depending on which treatment group they are in) for 52 weeks. This part of the study is “double-blind,” meaning neither the patient nor study doctor will know which specific treatment (etavopivat or placebo) the patient is receiving. For every 1 participant receiving a placebo, two will receive etavopivat.
• Open-label extension: Patients who complete the double-blind treatment period will be eligible to receive etavopivat in the 52-week open-label extension. In this part of the study, the participant will receive etavopivat even if he/she was assigned to receive placebo in the double-blind treatment period.
This is an interventional, multi-national, multi-centre, randomised (2:1), double-blind, placebo controlled, Phase 3 study in participants aged 12 and older with sickle cell disease (SCD), who had 2−15 vaso-occlusive crises (VOCs) in the year prior to screening and who have moderate to severe anaemia. This study will enroll up to approximately 408 adult and adolescent patients with SCD, including a maximum of 100 in the age group 12 to 17 years. Kenya is expected to contribute a total of 67 participants to the study population.
Participants will be seen at the study sites at week 2 and week 6 then approximately every 6 weeks until week 52 which is the End of Blinded Treatment in the study. Participants in the open-label extension will have visits at weeks 52,56,60,68,76,84,92 and 104. Week 104 is the end of study treatment and will be followed by an end of study visit after 4 weeks. Safety will be monitored throughout the study, and PD, QoL, and clinical outcome measures will be performed at specified visits.
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