Pharmacy and Poisons Board: Applications

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Protocol No:

ECCT/25/03/07

Date of Protocol:

02-02-2024

Study Title:	A phase III, Multicenter, Randomized, Placebo Controlled, Double blind Study to Assess Efficacy and Safety of Crizanlizumab (5 mg/kg) versus placebo, with or without Hydroxyurea/Hydroxycarbamide Therapy, in Adolescent and Adult Sickle Cell Disease Patients with Frequent Vaso-Occlusive Crises
Study Objectives:	Primary Objective: To compare the efficacy of 5 mg/kg of crizanlizumab versus placebo, with or without hydroxyurea/hydroxycarbamide, on the annualized rate of VOCs* that are HCPmanaged (including VOCs leading to management at a health care facility or those managed via remote consultation) over the planned 52-week treatment period in SCD patients aged 12 years and older with a history of frequent VOCs (4-12 events in 12 months prior to the screening visit). Secondary Objective: To compare the efficacy of 5 mg/kg of crizanlizumab versus placebo, with or without hydroxyurea/hydroxycarbamide, on the annualized rate of all VOCs including VOCs that are HCP-managed (including VOCs leading to management at a health care facility or those managed via remote consultation) and VOCs that are self-managed without recommendations from HCP during the event over the planned 52- week treatment period in SCD patients aged 12 years and older with a history of frequent VOCs (4-12 events in the 12 months prior to the screening visit). To evaluate the annualized rate of VOCs by type of management between treatment arms over the planned 52-week treatment period: VOCs that are HCP-managed at a health care facility VOCs that are HCP-managed via remote consultation VOCs that are self-managed without recommendations from HCP during the event VOCs that are HCP-managed via remote consultation or self-managed without recommendations from HCP during the event To evaluate the time to first VOC that is HCPmanaged (including VOCs leading to management at a health care facility or those managed via remote consultation) between treatment arms over the planned 52-week treatment period. To evaluate the proportion of participants free from VOCs that are HCP-managed (including VOCs leading to management at a health care facility or those managed via remote consultation) between treatment arms over the planned 52-week treatment period. To evaluate the duration of VOCs that are HCP managed (including VOCs leading to management at a health care facility or those managed via remote consultation) between treatment arms over the planned 52-week treatment period. To evaluate the safety and immunogenicity of crizanlizumab 5 mg/kg over the 2-year study period. Exploratory Objectives: To explore the efficacy of crizanlizumab 5 mg/kg over the 2-year study period. To explore the proportion of VOCs that are self-managed without recommendations from HCP during the event, versus VOCs that are HCP managed (including VOCs leading to management at a health care facility or those managed via remote consultation) between treatment arms over the planned treatment period of 52 weeks. To explore the proportion of VOCs that are HCP managed via remote consultation versus VOCs that are HCP-managed at a healthcare facility between treatment arms over the planned 52- week treatment period. To explore the incidence rates of all VOCs, VOCs that are HCP-managed at a healthcare facility, VOCs that are HCP-managed via remote consultation, VOCs that are HCP-managed, VOCs that are self-managed without recommendations from HCP during the event, VOCs that are HCP-managed via remote consultation or self-managed without recommendations from HCP during the event, by treatment arm. To explore quality of life in each treatment arm (ASCQ-Me Short Forms: emotional impact, sleep impact, and joint stiffness). To explore healthcare facility resource utilization (inpatient hospital admission, emergency room visit, urgent care/clinic visit, infusion center visit) between treatment arms over the planned 52- week treatment period. To explore the pharmacokinetics (PK) profile of crizanlizumab at 5 mg/kg. To explore the pharmacodynamics (PD) (P selectin inhibition) of crizanlizumab at 5 mg/kg. To explore biomarkers [p-selectin (free and total)] and CRP]. To explore exposure-response relationship
Laymans Summary:	Sickle cell disease is one of the most common blood disease in the world that is passed down from generation to another and is characterized by frequent pain episodes, reduced blood levels as well as multiple organ damage. Painful episodes are the most common presentation of sickle cell disease. These are caused by activation of different components of blood triggered by the sickled red blood cells. The activation of these blood components leads to their expression of the p-selectin molecule found in blood which promotes sticking together of cells to each other resulting in blockage of blood vessels. Painful episodes are a clinical hallmark of SCD and cause considerable acute and chronic reduction in quality of life as well as death. L-glutamine and Hyrdoxyurea have been approved by the food and drug administration to reduce VOCs in patients with SCD. Crizanlizumab is a potent and selective IgG2 (immunoglobulin G2) kappa humanized monoclonal antibody that binds to human P-selectin with high affinity, blocking its interaction with its ligands, including P-selectin glycoprotein ligand 1 (PSGL-1). Extensive pre-clinical data have established P-selectin as a key mediator of VOC in SCD (Matsui et al 2001) and suggest that blockade of P-selectin could eliminate or reduce VOC. This study is a drug clinical trial sponsored by Norvatis Research and Development and is to be implemented at KEMRI CRDR Siaya Clinical Research Annex by Professor Videlis Nduba as the Principal Investigators alongside Dr. Mercy Mwale and Dr. Mike Odoyo as the Sub-investigators. This study will be conducted in many sites globally in a randomized manner where a participant will either get inactive or active form of treatment as assigned by the Investigator or designee through a system generated method provided by sponsor. Both the participants as well as the study staff will not know the treatment administered to the participant. It is a Phase 3 study comparing crizanlizumab 5 mg/kg to inactive form of treatment with or without simultaneous use of Hydroxyurea/Hydroxycarbamide treatment in adolescent and adult SCD patients who experience frequent painful episodes. The study will include participants aged 12 years and older with confirmed diagnosis of SCD (all variants of sickle cell disease are eligible) who have experienced at least 4-12 painful episodes that are Healthcare professional-managed (including painful episodes leading to management at a health care facility or those managed via remote consultation) within the 12 months prior to the screening visit. Participants may receive Hydroxyurea/Hydroxycarbamide as standard of care. Globally 315 participants will be enrolled. Kenya has been allocated 30 participants to be competitively enrolled among 6 sites sites which are: Getrude’s Children’s Hospital; International Cancer Institute; KEMRI Kondele Children’s Hospital; CREATES Ahero Clinical Ahero and Victoria Biomedical Research. Therefore, at least 5 participants will be enrolled by the Siaya site. For every 3 participants enrolled into the study, 2 will receive crizanlizumab 5mg/kg whereas 1 will receive the inactive form of treatment. Central assignment of the treatment arm will be grouped according to simultaneous Hydroxyurea/Hydroxycarbamide usage (yes/no) and region (South America, North America, and sub- Saharan Africa) at baseline. There is a potential side effect of infusion related reaction with the administration of crizanlizumab that has been observed so far. Data from this study will be used to evaluate the effect of crizanlizumab versus inactive form of treatment, with or without concurrent Hydroxyurea/Hydroxycarbamide treatment, on painful episodes rate in SCD patients aged 12 years and older who experience frequent painful episodes. The study will be conducted according to the protocol, guidelines established by the ICH for GCP in clinical studies. The study protocol, informed consent forms, electronic case report forms and site specific protocol will be submitted to the regulatory bodies as required, and once approval is received from the Ethics Committee and Pharmacy and Poisons Board of Kenya , the site will be initiated and activated.
Abstract of Study:	Trial Design: This is a Phase III multicenter, randomized, double-blind, placebo-controlled study to assess the efficacy and safety of crizanlizumab 5 mg/kg versus placebo, with or without concurrent HU/HC therapy in patients with SCD who experience frequent VOCs (4-12 events in the 12 months prior to the screening visit). Purpose of the study: The main purpose of this study is to determine whether crizanlizumab may reduce the number of VOCs when compared to placebo, with or without standard of care medications in adolescent and adult SCD patients with frequent VOCs leading to healthcare visits. The study duration will be approximately 2 years. Study Rationale: Crizanlizumab was first approved in the USA (BLA 761128) under the trade name Adakveo® on 15-Nov-2019. This BLA approval was based on the results from the Phase II Study CSEG101A2201 (SUSTAIN), a 52-week, randomized, placebo-controlled study (N=198) of crizanlizumab 2.5 and 5 mg/kg. In Study A2201, a vasoocclusive crises (VOC) was defined as an acute episode of pain with no other cause than a vasoocclusion, which required a visit to a medical facility and treatment with oral or parenteral opioids or parenteral non-steroidal anti-inflammatory drugs (NSAIDs). This included both uncomplicated VOCs as well as complicated VOCs such as acute chest syndrome, hepatic sequestration, splenic sequestration, and priapism. These visits required a visit to a medical facility. An uncomplicated crisis was defined as a VOC that was not classified as acute chest syndrome, hepatic sequestration, splenic sequestration, priapism, and which did not lead to death. Treatment with crizanlizumab 5 mg/kg in Study A2201 resulted in a median annual rate of VOCs leading to a healthcare visit that was 45.3% lower than the median annual rate with placebo, which was statistically significant (p=0.010). The median annual rate of uncomplicated crises and median number of days hospitalized were 62.9% and 41.8% lower than in the placebo group, respectively. These constitute meaningful reductions in the frequency of VOCs and hospitalizations that can be expected to have a significant impact on quality of life (QoL), morbidity and mortality in patients with SCD. Study CSEG101A2301 is an ongoing Phase III, multicenter, randomized, double-blind study to assess efficacy and safety of two doses of crizanlizumab (5 mg/kg and 7.5 mg/kg) versus placebo, with or without hydroxyurea/ hydroxycarbamide therapy (HU/HC), in adolescent and adult patients with SCD. VOC was defined the same way as previously noted in the SUSTAIN trial. In Dec-2022, the results of the primary analysis of Study CSEG101A2301 did not show evidence of superiority of either dose of crizanlizumab (5 mg/kg or 7.5 mg/kg) over placebo on the primary or key secondary endpoints and therefore are not consistent with the results from Study CSEG101A2201. While the endpoint of VOC leading to a healthcare visit reflects a key aim of treatment in SCD, i.e., prevention/reduction of VOCs, it is important to note that it is dependent on patients making the decision to go or not go to the hospital. The different results in Study CSEG101A2301 compared with Study CSEG101A2201 could be due to various factors/differences between the studies, including but not limited to: The impact of the COVID-19 global pandemic, which may have caused a masking effect/reduction in reporting of VOCs as well as a potential reduction in triggers for VOCs in Study CSEG101A2301. Differences in the geographic location of participating patients, thereby factoring in the differences in healthcare utilization: patients were located primarily in the USA in Study CSEG101A2201 vs. globally dispersed in Study CSEG101A2301. Thus, while the initial randomized, placebo-controlled trial (Study CSEG101A2201), the open label studies (Study SEG101A2202, Study SEG101B2201 and Study SEG101AUS05) and real-world data (MAP data and registries) have all demonstrated clinical benefit with crizanlizumab, the second, randomized, placebo-controlled Study CSEG101A2301 did not. The current study (Study CSEG101A2303; hereafter referred to as Study A2303), a randomized, placebo-controlled Phase III study, was developed to overcome the uncertainties raised by the conflicting results of Studies CSEG101A2301 and CSEG101A2201. The purpose of this study is to compare the efficacy of crizanlizumab (5 mg/kg) versus placebo, with or without HU/HC in adolescent and adult SCD patients with frequent VOCs (4 to 12 per year) that are Health care practitioner-managed (including VOCs leading to management at a health care facility or those managed via remote consultation). Data from this study will be used to evaluate the effect of crizanlizumab versus placebo, with or without concurrent HU/HC therapy, on VOC rate in SCD patients aged 12 years and older who experience frequent VOCs. Study Population: The study will include participants aged 12 years and older with confirmed diagnosis of SCD (all genotypes are eligible) who have experienced at least 4-12 VOCs that are HCP-managed (including VOCs leading to management at a health care facility or those managed via remote consultation) within the 12 months prior to the screening visit. Participants may receive HU/HC as a standard of care. This study plans to enroll 315 participants. Participants will be randomized in a 2:1 ratio to the crizanlizumab 5 mg/kg or placebo treatment arm (see Section 9.9 of the Protocol v00 for more details on sample size determination).