| Protocol No: | ECCT/22/04/01 | Date of Protocol: | 30-03-2021 |
| Study Title: |
An Open-Label Extension Study to Evaluate the Long-Term Safety of Inclacumab Administered to Participants with Sickle Cell Disease Who Have Participated in an Inclacumab Clinical Trial
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| Study Objectives: |
Main Objective
The primary objective of this study is to:
1. evaluate the long-term safety of every 12 week dosing of inclacumab in participants with sickle cell disease (SCD) that have completed a prior inclacumab clinical trial.
The secondary Objective
Additional objectives are to:
1.Evaluate the incidence of vaso-occlusive crises (VOCs), hospitalizations, missed work/school days, red blood cell (RBC)
transfusions, and quality of life (QoL) with long-term use of inclacumab
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| Laymans Summary: |
Sickle cell disease is an inherited blood disorder that causes frequent pain episodes, and multiple organ complications. Currently, there is only one known cure for sickle cell disease which is a bone marrow transplant that is inaccessible for most Kenyans. However, currently most patients are usually on treatments that help control the disease e.g. hydroxyurea and folic acid, or prevent infections e.g. palludrine and Penicillin V, or manage symptoms as they arise e.g. painkillers for pain episodes and blood transfusion for anemia. There is a need for new treatments that help improve the patients’ quality of life.
Pain episodes are mainly caused by the blockage of blood flow to various parts of the body. One of the causes of this blockage includes formation of clots in the blood vessels. A molecule called p-selectin; produced by our bodies contributes to formation of this clots. GBT has developed a drug called inclacumab that prevents the function of p-selectin leading to a reduction in the formation of clots bringing about an overall decrease in pain episodes. The main aim of this study is to assess whether inclacumab is safe for use and if it reduces the number of vaso occlusive crises in patients with sickle cell disease when administered long-term.
A total of 520 participants will be enrolled across 150 clinical sites globally. There will be about 5 sites in Kenya. 3 sites are in Nairobi 1 in Siaya and another one in Eldoret. The sites will enrol this participants following their participation in and receipt of inclacumab in another GBT-sponsored inclacumab clinical study.
Participation in the study is voluntary and those enrolled have the possibility of benefiting from the study. If the drug proves to be efficacious there may be a reduction in the number of pain episodes. Additionally, participants will receive education on the disease. Participation in the study may also benefit health care workers and the local community who are actively involved with sickle cell disease management by providing more information on the treatment of the disease.
There are potential risks associated with participation in the study and are mainly related to the side effects of the investigational product including but not limited to
diarrhoea, vomiting, tiredness, nasal congestion, common cold symptoms and pain in the mouth and throat. Participants will be monitored for any side effects or sickness and if unwell treatment will be provided.
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| Abstract of Study: | Introduction Sickle cell disease is one of the most commonly inherited blood disorders in the world characterized by vaso-occlusive crises, anemia, stroke and multiple organ damage. Vaso-occlusive crises are the most common presentation of sickle cell disease. Vaso-occlusive crises are caused by activation of the endothelial cells, neutrophils, monocytes and platelets by the sickled red blood cells. The activation of these cells leads to their expression of the p-selectin molecule promoting the aggregation and adhesion of these cells to one another and to the endothelial cells leading to clot formation and blockage of the microvascular channels. There is only one known cure of sickle cell disease, which is a hematopoietic stem cell transplant (HSCT). Unfortunately, this intervention is not easily accessible to most patients due to its cost and unavailability in the country. Most patients with sickle cell disease are therefore mainly on supportive treatment. These reasons inform the need for more affordable and accessible treatments. The study participants will have completed a study of inclacumab (originating study) and will receive inclacumab intravenous infusion in this open-label study. They will receive the intravenous treatment every 12 weeks. The mechanism of action of inclacumab is to prevent the action of p-selectin molecule, which reduces adhesion of molecules and leads to a reduction in the episodes of vaso-occlusive crises. The study aims to assess the safety of long-term administration of inclacumab in participants with SCD that have completed an inclacumab clinical trial. During the study period, participants can receive standard of care treatment except for crizanlizumab.
Methodology
Study setting
The study will be carried out in up to 150 global clinical sites with a sample size of 520 participants. There will be approximately 5 sites in Kenya. We have three study sites in different parts of Nairobi, one in Siaya and the last one in Eldoret.
Study design
This study is an open-label extension study to evaluate the safety of long-term treatment with inclacumab in participants with SCD. The study will be available to eligible participants who were enrolled in a prior GBT-Sponsored inclacumab clinical study (originating study). Eligible participants, who continue to receive clinical benefit that outweighs risk, will receive inclacumab every 12 weeks until the participant has access to inclacumab from an alternative source. Given the long half-life of inclacumab (terminal half-life of 21 to 28 days) at the dose to be evaluated in this study, the majority of participants receiving active study drug are expected to maintain target concentrations as required throughout the study period.
INTRODUCTION & JUSTIFICATION
Sickle cell disease is one of the most commonly inherited blood disorders worldwide (Sj et al., 2017). It is estimated that approximately 300,000 children are born with sickle cell disease in the world annually, 75% of whom are from Sub-Saharan Africa (Makani et al., 2013). As there is no systematic neonatal screening program in most public and private facilities, there is no national prevalence data. However, it is estimated that 4% of children born in Western Kenya have sickle cell disease(Wanjiku et al., 2019). The study is being conducted in Kenya due to the high incidence of sickle cell disease in the country.
Sickle cell disease (SCD) is an autosomal recessive disease characterized by chronic haemolysis, inflammation and vaso-occlusion presenting as recurrent pain episodes (variously termed sickle cell-related pain crises or VOCs), multi-organ dysfunction, and early death (Kato, 2018).
vaso-occlusion in SCD is driven by a series of complex and often redundant receptor–ligand interactions involved in the adhesion of circulating cells to the damaged endothelium and exposed sub-endothelium. Extensive research demonstrates that P-selectin mediated cellular interactions with sickled red blood cells (RBCs), leukocytes and platelets play a crucial role in the pathophysiology of vaso-occlusion in SCD. Blocking P-selectin-mediated cellular interactions reduces vaso-occlusion in animal models. Taken together, these data led to the hypothesis that blocking P-selectin could reduce the risk of VOCs in SCD patients.
Results from a randomized, placebo-controlled Phase 2b trial of crizanlizumab, a humanized monoclonal antibody in SCD, bolstered the hypothesis that blocking the interaction of P-selectin with its receptors could prevent vaso-occlusion and VOCs (Ataga, 2017). In summary, there is a high unmet need for treatment options in SCD and there is a scientific rationale, supported by clinical data, that p-selectin inhibition has the potential to reduce the risk for acute vaso-occlusions.
JUSTIFICATION/RATIONALE
Allogeneic HSCT remains the only curative therapy for sickle cell disease. It is however unavailable for most patients due to its high cost and it being available only in high income countries. It is also associated with various transplant complications (Kassim and Sharma 2017). Three therapies, hydroxyurea (HU [DROXIA®, 2017]; (also known as hydroxycarbamide), L-glutamine (ENDARI, 2017) and crizanlizumab (ADAKVEO®, 2019), have been approved by the Food and Drug Administration (FDA) and the European Medicines Agency (EMA) to reduce VOCs in patients with SCD (Charache, 1995; Niihara, 2018; Ataga, 2017). The effectiveness of HU is impaired by low compliance rates and frequent discontinuations in treatment (Shah, 2019) while L-glutamine provides a modest 25% reduction in annual VOC rates (Niihara, 2018).
Crizanlizumab is a monoclonal antibody directed against human P-Selectin and is administered as an infusion every 4 weeks whereas inclacumab is to be administered every 12 weeks. The 4-week administration of crizanlizumab is a potential barrier to continued adherence to lifelong therapy because patients need to travel more frequently to an infusion centre to receive treatment. This regimen extracts a higher cost on patient and caregiver productivity and frequent intravenous infusions generally attract extra costs Version No: * Date of Protocol * Study Drug* Route(s) of Administration * Disease condition being investigated * Product Type * Name of manufacturer Manufacturing site address Phone Email Manufacturing activities at site If others, specify Country of manufacture to the patient. (Saini, 2009; Richter, 2003). It has also been shown that less frequent dosing results in better adherence to medication (Saini, 2009; Richter, 2003).
Inclacumab has a similar mechanism of action as crizanlizumab. Previous studies on inhibition of p-selectin through crizanlizumab, have demonstrated it to be efficacious and safe for use in SCD patients. Additionally, the dose selected is 30mg/kg every 12 weeks and from previous studies, population PK simulations project that the inclacumab dose regimen of 30 mg/kg Q12W will maintain concentrations above 10 μg/mL throughout the study period in the majority of participants, thereby maximizing the pharmacology required for effective reduction of VOC in the SCD population. The 12-week dosing for inclacumab offers a potential benefit over the 4-week dosing of crizanlizumab and this could increase patient adherence to treatment, reduce the costs of patient and caregiver productivity, leading to a reduction in the overall health costs. Treatments with stable standard of care are allowed except for crizanlizumab because it has a similar mechanism of action as the study drug and would confound the interpretation of this data.
In summary, despite the recent availability of new options to treat VOCs, an unmet medical need exists to further reduce the frequency of VOCs while reducing patient burden and enhancing patient adherence to therapy.
NULL HYPOTHESIS
There is no null hypothesis.
OBJECTIVES
Primary objective
1. To evaluate the long-term safety of every 12-week dosing of inclacumab in participants with SCD that have completed a prior inclacumab clinical trial.
Additional objectives
2.To evaluate the incidence of VOCs, hospitalizations, missed work/school days, RBC transfusions, and quality of life (QoL) with long-term use of inclacumab.
STUDY DESIGN
This study is a multicenter,global,open-label extention,designed to assess the safety of long-term treatment with inclacumab in participants with SCD.
Participants must have completed participation in their originating clinical study and must meet the entry criteria for this study to be eligible for enrolment. Eligible participants will receive Inclacumab 30 mg/kg administered IV Q12W; if they continue to receive clinical benefit that outweighs the risk, until the participant has access to inclacumab from an alternative source (e.g., through commercialization or a managed-access program).
All participants will undergo safety and outcome assessments at Baseline (Day 1), Week 6, and every 12 weeks thereafter. Visits to the clinical site for infusion of study drug will occur at Baseline (Day 1) and every 12 weeks (Weeks 12, 24, 36, 48, etc.).
Despite this being an open-label study, Investigators, study site staff, the Sponsor’s study staff, the Sponsor’s clinical CRO, and study participants will remain blinded to the randomized treatment assignments, as applicable, from the originating GBT-Sponsored inclacumab study. During the study, access to participants’ treatment assignment from the originating study will be limited to DMC members and service providers supporting DMC reviews, including the independent Data Coordinating Centre, until the database from the originating study is locked and primary endpoint analysis is complete. If a need arises for unblinding of the originating GBT-Sponsored inclacumab study, the instruction for unblinding as outlined in the originating study protocol will be followed.
A Data Monitoring Committee (DMC) will regularly review the totality of accumulated safety data from all ongoing inclacumab studies on an ongoing, unblinded basis with additional emphasis on adolescent participants. DMC review will continue until the originating studies have been completed and the randomization assignments are unblinded. Details will be provided in the DMC Charter.
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