| Protocol No: | ECCT/21/12/07 | Date of Protocol: | 08-03-2021 |
| Study Title: | A Randomized, Double-blind, Placebo-controlled, Multicenter Study of a Single Dose of Inclacumab to Reduce Re-admission in Participants with Sickle Cell Disease and Recurrent Vaso-occlusive Crises. |
| Study Objectives: |
The primary objective of this study:
Is to evaluate the safety and efficacy of a single dose of inclacumab compared to placebo to reduce the incidence of readmission to a healthcare facility for a vaso-occlusive crisis (VOC) after an admission for an index VOC in participants with sickle cell disease (SCD).
Secondary Objectives
Additional objectives of the study are to evaluate the pharmacokinetics (PK) and pharmacodynamics (PD) of inclacumab, the presence of antidrug antibodies (ADAs), and changes in quality of life (QOL).
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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 bone marrow transplantation that is inaccessible for most Kenyans. Most patients however 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 low blood levels 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 these clots. This study drug under investigation i.e inclacumab prevents the function of p-selectin leading to the reduction of clots resulting in overall decrease in pain episodes. The main aim of this study is to assess whether inclacumab is able to reduce re admission among patients with sickle cell disease and recurrent vaso occlusive crises. A total of 280 participants will be enrolled across 60 sites. There will be about 4 sites in Kenya. Enrolled for this study is competative world wide. Initially participants above 16 years will be enrolled in the study but after the data monitoring committee reviews the data and deems that the drug is safe then participants aged 12 to 15 years of age will be enrolled into the study. These participants must have experienced a pain episode that required hospital admission. They will randomly be assigned to either the treatment arm or the arm without the active drug also called placebo. They will be followed up for a period of 90 days after which they will be provided an opportunity to enroll in the open-label extension (OLE) study where they will be given inclacumab. 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 and readmissions. 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 diarrhea, 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. |
| 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 crisis is the most common presentation of sickle cell disease. Vaso-occlusive crisis is 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 the hematopoietic stem cell transplant (HSCT) that 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 be randomly allocated to either a placebo or inclacumab treatment arm in the ratio of 1:1. In this study, participants will receive a single intravenous dose of the study drug will be administered on Day 1. The mechanism of action is to counter the action of p-selectin molecule leading to reduced adhesion of molecules hence reduced episodes of vaso-occlusive crises. The study aims to assess the safety and efficacy of inclacumab as compared to placebo to reduce the incidence of re-admission to a healthcare facility for a vaso-occlusive crisis (VOC) after an admission for an index VOC in participants with sickle cell disease (SCD). During the study period participants can receive standard of care treatment except for crizanlizumab. This care may be provided on site or at their preferred facility. On site participant will be assessed for any adverse events or SAEs. Those who are unwell will be managed appropriately irrespective of their treatment arm.
Methodology
Study setting
The study will be carried out in approximately 60 sites across the globe with a sample size of 280 participants. There will be approximately 4 sites in Kenya. We have 4 study sites: Eldoret International cancer centre whose PI is Prof. Chite , Strathmore medical centre whose PI is Prof Ogutu and KEMRI_CRDR Nairobi located at the KNH complex, and in Siaya located at the Siaya County Referral Hospital grounds whose PI is Dr. Nduba.
Study Design
The study is a randomized placebo-controlled, double blind, multicenter, parallel-group study to assess the safety and efficacy of a single dose of inclacumab in reducing the rate of re-admission to a healthcare facility for a VOC after an index VOC. The index VOC is any VOC that required admission to a healthcare facility and treatment with parenteral pain medication. Randomization may occur upto 5 days after the index VOC has resolved.On the day of randomization participant will be given a single dose of the study drug (treatment or placebo), afterwhich they will be followed up for a period of 90 days. Following completion of the visits each participant irrespective of their treatment arm will be given the opportunity to enroll into the open label extension study where they will be given inclacumab.
Expected results
Crizanlizumab has been shown to be safe and reduce painful episodes in patients with sickle cell disease. Having a similar mechanism of action as inclacumab that is inhibition of p-selectin, it is thought that it will reduce the rate of readmission and recurrent vaso occlusive crises in patients with sickle cell disease.
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). There is currently insufficient data on the prevalence of sickle cell disease in Kenya but 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 hemolysis, 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 subendothelium. 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. By contrast, blocking P-selectin-mediated cellular interactions or reducing the levels of P-selectin reduces or eliminates vasoocclusion 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).
JUSTIFICATION/RATIONALE
Allogeneic HSCT remains the only curative therapy for sickle cell disease. It is however unavailable for most of 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 treatment discontinuation (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 administered every 12 weeks. This is potentially limiting in continued adherence to lifelong therapy as patients need to travel to an infusion center in order to receive treatment. This extracts a cost on patient and caregiver productivity and frequent intravenous infusions generally attract extra costs 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 as a single dose and from previous studies population PK simulations project that this dose will maintain concentrations above 10 μg/mL throughout the 90-day study period in the majority of participants, thereby attaining levels required for an effective and sustained reduction of re-admissions due to a VOC in the SCD population.
This study uses placebo as a comparator on the background of standard of care (SOC) treatment for a VOC. Placebo was chosen as the control because it is necessary to determine the safety and efficacy of inclacumab by allowing efficacy to be estimated controlling for background VOCs with SOC and safety signals to be distinguished from adverse events (AEs) occurring due to SCD. 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. In addition, there is a need for an “on demand” therapy to prevent re-admissions for patients that do not require or are unable to adhere to chronic therapy.
NULL HYPOTHESIS
Inclacumab is non superior to placebo in reducing the incidence of re-admission for a vaso-occlusive crisis following an admission for an index vaso-occlusive crisis.
OBJECTIVES
Primary objective
1. To evaluate the safety and efficacy of a single dose of inclacumab to reduce the incidence of re-admission to a healthcare facility for a VOC after an admission for an index VOC in participants with SCD.
Additional objectives
2. To evaluate the PK and PD of inclacumab,
3. To evaluate the presence of anti-drug antibodies (ADAs), and
4. To evaluate the changes in quality of life (QOL).
STUDY DESIGN
This study will assess the safety and efficacy of inclacumab in reducing the frequency of re-admissions due to VOCs after an index VOC in approximately 280 adult and adolescent participants (≥ 12 years of age) with SCD. Initial enrollment will include participants’ ≥ 16 years of age until the independent Data Monitoring Committee (DMC) determines that adequate safety and PK data support the enrollment of participants 12 to 15 years of age.
Eligible participants will be randomized with a 1:1 ratio into one of two treatment arms as follows: • Inclacumab 30 mg/kg administered IV; or • Placebo administered IV. At the time of randomization, participants will be stratified by Baseline Hydroxyurea (HU) use (yes; no), number of VOCs (2 to 4; 5 to 10) in the preceding 12 months, and geographic region (North America; rest of world).
All participants will undergo safety, efficacy, and PK/PD assessments at Baseline and Day 91. An additional visit at Day 46 will occur for safety, PK, and PD monitoring. The incidence of VOC events will be collected every 4 weeks, with participants contacted by phone at Day 31 and Day 61.
Following completion of the Day 91 visit, eligible participants will be given the option to enroll in an open-label extension (OLE) study (under a separate protocol) to receive inclacumab. Participants will receive their first dose in the OLE study on the same Day 91 visit. Participants enrolling in the OLE study will not be required to return to clinic for the Day 161 visit. Safety, efficacy, and PK/PD assessments will occur on Day 161 for participants not enrolling into the OLE study. The 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. Details will be provided in the DMC Charter.
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