| Protocol No: | ECCT/21/10/02 | Date of Protocol: | 22-09-2020 |
| Study Title: | A Phase 4, Multicenter, Randomized, Double-Blind, Placebo-Controlled Trial to Evaluate the Efficacy of Voxelotor for the Treatment of Leg Ulcers in Patients with Sickle Cell Disease |
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| A Phase 3, Multicenter, Randomized, Double-Blind, Placebo‑Controlled Trial to Evaluate the Efficacy of Voxelotor for the Treatment of Leg Ulcers in Patients with Sickle Cell Disease
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| Study Objectives: | Primary Objective The primary objective of this study is to assess the effect of voxelotor and SOC compared to placebo and SOC on leg ulcer healing in participants ≥ 12 years of age with SCD, as measured by the proportion of participants achieving resolution of target ulcer(s) in each treatment group by Week 12.
Secondary Objectives The secondary objectives of this study are to evaluate the effect of voxelotor and SOC compared to placebo and SOC on:
Exploratory Objectives The exploratory objectives will assess the effect of voxelotor and SOC compared to placebo and SOC (or open-label voxelotor and SOC, where applicable) on:
Safety Objective The safety objective is to assess the safety and tolerability of voxelotor compared to placebo based on AEs, clinical laboratory tests, physical examinations, vital signs, and other clinical measures (eg, discontinuations due to AEs, dose reductions). |
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| 2 | Explorative objectives: Patient-Reported Outcome Measurements Information System (PROMIS) Pediatric Profile-37_v2.0/PROMIS-43 v2.1. | ||
| Laymans Summary: |
Sickle cell disease is an inherited blood abnormality caused by a change in the makeup of the Red blood cell forming genes that result in the clumping of the red cells. These abnormal red cells tend to change shape and stick to each other and walls of blood vessels whenever they are exposed to low oxygen levels.
Persons with this gene abnormality experience several complications among them being leg ulcers because of damage of blood vessels. The prevalence of the leg ulcers varies with geographical location and is estimated to be about 30% in Sub Sahara Africa among people with Sickle cell disease (SCD). No data on the prevalence of leg ulcers in Kenya is available. There are no known effective treatments for leg ulcers in people with SCD. Current management is based on practice guidelines for treating other skin ulcers which include use of dressings and application of medications on the ulcers and or surgical trimming and cleaning of the wounds.
Voxelotor is medicine that prevents the change on the shape of the red cells that causes clumping of the red cells. In the HOPE trial, though this was not among the main study objectives, it was found that participants who had initially joined the study with leg ulcers experienced complete resolution of the ulcers and implies that voxelotor may be useful in management of leg ulcers.
In this study, the effect of voxelotor on leg ulcer healing and safety will be studied in participants 12 years of age and older with SCD and active leg ulcer(s). Eighty (80) participants will be recruited globally from the approximately 10 global sites. The primary objective of this study is to assess the effect of voxelotor and SOC compared to placebo and SOC on leg ulcer healing in participants ≥ 12 years of age with SCD. The secondary objectives of this study are to evaluate the effect of voxelotor and SOC compared to placebo and SOC on: • Time to healing of target ulcer(s) • Change in total surface area(s) of target ulcer(s), incidence of new ulcers. The primary outcome will be measured by the proportion of participants achieving healing of the target ulcer(s). Exploratory outcomes will be summarized by descriptive statistics. Safety Analysis will be performed on all participants receiving at least 1 dose of study drug.
Lay man Summary : Sickle cell disease (SCD) is a condition where red blood cells are shaped like a “sickle” (crescent moon) instead of being round. These sickle cells break down more quickly asnd can block blood flow. This makes it harder for the blood to carry oxygen around the body, leading to problems such as anemia (low levels of red blood cells). A complication of SCD includes open sores (“ulcers”) on the legs, likely due to poor blood flow and the breakdown of red blood cells. Leg ulcers are very painful, heal slowly, and even after they heal, often come back again. No therapies are available for treating or managing leg ulcers caused by SCD. The main purpose of this study was to find out whether voxelotor could help treat leg ulcers in participants with SCD compared to placebo. A placebo does not have any medicine in it, but it looks just like voxelotor Researchers wanted to know: • Can voxelotor help treat leg ulcers compared to placebo after 12 weeks of treatment? • What medical problems did participants have during the study? This study stopped early and was not completed as planned. How was the study done? During the Screening and Run-in Periods, researchers checked the participants’ health to make sure they could join the study. After the Screening Period, participants entered the 2-week Run-in Period, wherein researchers checked the participants’ leg ulcers. During this period, participants started wound care for their leg ulcers according to the study plan. Double-blind Period Researchers used a computer program to randomly divide the participants into 2 groups. • Voxelotor Group: Participants took voxelotor tablets once per day. • Placebo Group: Participants took placebo tablets once per day. Participants took voxelotor or placebo for 12 weeks while continuing wound care for their leg ulcers according to the study plan. During this period, the participants and researchers did not know to which treatment group the participants were assigned. This is known as the “Double-blind” Period. During this period, researchers looked at the participants’ leg ulcers to answer the main question of the study. Open-label Period After the 12-week Double-blind Period, participants entered the “Open-label” Period. During this period, the participants and researchers knew that all participants were taking voxelotor. • Voxelotor Group: Participants who took voxelotor in the Double-blind Period continued to take voxelotor. • Delayed Voxelotor Group: Participants who took placebo during the Double-blind Period were switched to start voxelotor. Participants took voxelotor for at least 12 weeks while continuing wound care for their leg ulcers according to the study plan. Participants who completed the 12- week treatment in the Open-label Period could keep taking voxelotor as long as they were receiving clinical benefit as observed by the researchers. Throughout the study, researchers checked on the participants’ health and asked them how they were feeling. The Sponsor ran this study at 19 locations in 3 countries: Brazil, Kenya, and Nigeria. It began on 30 May 2022 and ended on 22 October 2024. The study included participants who were at least 12 years old with SCD and had at least 1 leg ulcer. • A total of 50 boys/men and 38 girls/women participated. • All participants were between the ages of 12 and 54 years. Study participants were in the study for about 34 weeks (8 months). The study ran for about 2 years and 4 months before the Sponsor stopped the study. This study stopped early and was not completed as planned |
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| Abstract of Study: |
Sickle cell disease (SCD) is an inherited blood disorder caused by a point mutation in the β globin gene resulting in the formation of “sickle hemoglobin” (HbS), which polymerizes in the deoxygenated state and leads to red blood cell (RBC) sickling.
Leg ulcers are a common complication of SCD, particularly among individuals with the more severe genotypes. Global prevalence of leg ulcers in the SCD population varies geographically, with estimates of 14% to 18% in the United States (US) and Europe, 10% to 30% in sub-Saharan Africa, and 30% to 40% in Jamaica and Brazil. There is a large unmet need for effective treatment for leg ulcers. In a Cochrane review of 5 randomized trials of interventions for treating leg ulcers in patients with SCD, none of the therapies resulted in complete ulcer healing (Marti-Carvajal, 2014). Current management of SCD leg ulcers relies primarily on the practice approach used for other cutaneous ulcers, involving debridement, wet to dry dressings, and topical agents.
Voxelotor (previously GBT440) is an HbS polymerization inhibitor that binds to HbS with a 1:1 stoichiometry and exhibits preferential partitioning to RBCs. The binding increases HbS-oxygen (O2) affinity, stabilizing the oxyhemoglobin (oxyHb) state and inhibiting polymerization. Findings from the HOPE trial (study GBT440-031) suggest that voxelotor may be an effective treatment for leg ulcers.
The effect of voxelotor on leg ulcer healing and safety will be assessed in participants 12 years of age and older with SCD and active leg ulcer(s) in this study. The study will be conducted in approximately 80 eligible participants at approximately 10 global clinical trial sites. In our site we plan to recruit at least 20 patients. The primary objective of this study is to assess the effect of voxelotor and SOC compared to placebo and SOC on leg ulcer healing in participants ≥ 12 years of age with SCD. The secondary objectives of this study are to evaluate the effect of voxelotor and SOC compared to placebo and SOC on • Time to resolution of target ulcer(s) • Change in total surface area(s) of target ulcer(s) • Incidence of new ulcers.
The proportion of participants achieving resolution of the target ulcer will measure the primary endpoint. The analysis will use a
Cochran-Mantel-Haenszel (CMH) test to compare voxelotor + SOC with placebo + SOC groups, stratified by target ulcer size and target ulcer duration. For the time to resolution, a stratified log-rank test will be used to compare the treatment groups. A Cox regression model will be used to estimate the hazard ratio between voxelotor +SOC and placebo + SOC groups, as appropriate. Exploratory endpoints will be summarized by descriptive statistics. Safety Analysis will be performed on all participants receiving at least 1 dose of study drug.
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