Sickle cell disease is an inherited blood disorder affecting red blood cells. These cells become sickle-shaped and have difficulty passing through small blood vessels. Additionally, in sickle cell disease blood vessels are damaged and sticky due to the ongoing chronic inflammation. This may lead to obstruction of blood vessels (vaso-occlusion), causing acute episodes of pain and organ damage. Patients with sickle cell disease have higher levels of protein called P-selectin. This protein makes both the blood vessels and certain blood cells stick to each other. The study drug, Crizanlizumab is a drug that binds to and inhibits P-selectin. The main purpose of this study is to determine whether Crizanlizumab may reduce the number of pain episodes when compared to placebo (IV solution without the study drug, also called dummy drug) in adolescent and adult patients with SCD who experience frequent pain episodes. 10-20 study participants will be enrolled at The International Cancer Institute, selected from the pool of patients managed at the facility and referred from its collaborating institutions.

A total of 315 participants will be enrolled globally in 60 participating sites, on a competitive basis. Participants will be allocated by chance into one of the two treatment arms, in a 2:1 ratio, to receive the study drug or the inactive drug(placebo). In both cases, participants will continue with their routine treatment as per the standard of care. During the treatment period, participation will include hospital/clinic visits, physical examinations, and taking blood and other samples. Patients will be required to visit the clinic at least once every month for 2 years. Some of the risks of participating in the study include mild to severe side effects of the study drugs. These will be closely monitored by the study team. Although the study drug may or may not benefit the participants, information learned may help guide the treatment of other patients with a similar condition in future. The results of the study will be shared openly and information on the trial provided to healthcare professionals and to the public, at scientific congresses, in clinical trial registries, and in peer-reviewed journals. The results will also be shared with the study participants. 

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 of the Protocol v00 for more details on sample size determination).