A Study to Investigate the Efficacy and Safety of Crizanlizumab (5 mg/kg) Compared With Placebo in Adolescent and Adult Sickle Cell Disease Patients Who Experience Frequent Vaso-Occlusive Crises (SPARKLE)

Study CSEG101A2303 (SPARKLE) is a Phase III, multicenter, randomized, double-blind study to assess efficacy and safety of crizanlizumab 5 mg/kg versus placebo, with or without hydroxyurea/ hydroxycarbamide therapy (HU/HC), in Sickle Cell Disease patients aged 12 years and older with frequent vaso-occlusive crises (4-12 events in 12 months prior to the screening visit).

Participants will be randomized in a 2:1 ratio to the crizanlizumab 5 mg/kg or placebo treatment arm. Central randomization will be stratified by concomitant HU/HC usage (yes/no) and region (South America, North America, and sub-Saharan Africa) at baseline.

Participants receive Crizanlizumab (SEG101) at 5.0 mg/kg and standard of care.

Biological: Crizanlizumab

Participants receive the placebo drug and standard of care.

Drug: Placebo

Crizanlizumab is supplied in single use 10 mL glass vials at a concentration of 10 mg/mL. One vial contains 100 mg of crizanlizumab. This is a concentrate for solution for IV infusion.

Placebo is supplied in single use 10 mL glass vials at a concentration of 0 mg/mL. This is a concentrate for solution for IV infusion.

Time frame: 1 year

Vaso oclusive crisis (VOC) is defined as a pain crisis (acute onset of pain for which there is no other medically determined explanation other than vaso-occlusion) lasting for at least 4 hours which is treated as per local guidelines with standard of care therapy used to treat VOC. Acute chest syndrome (ACS), priapism and hepatic or splenic sequestration will be considered VOC in this study.

VOCs included are those HCP-managed in a healthcare facility and HCP-managed via remote consultation.

Annualized rate of VOC events = (Number of VOC events \* 365)/(number of days in the observation period).

Observation period = time from date of randomization to minimum of (last dose date until treatment discontinuation + 27 days, date of initiation or discontinuation of HU/HC or L-Glutamine (or other therapies such as Voxelotor and erythropoietin therapies to treat SCD and/or to prevent/reduce VOCs), date of randomization + 365 days).

Time frame: 1 year

VOCs can be categorized as those HCP-managed in a healthcare facility, HCP-managed via remote consultation, or self-managed without recommendations from HCP during the event.

Annualized rate of VOC events = (Number of VOC events \* 365)/(number of days in the observation period).

To capture VOC events that are self-managed, and in order to avoid VOC recall bias and to make sure the pain events are captured in real-time, a cloud-based application will be used and setup an account for each participant.

Time frame: 1 year

Vaso oclusive crisis (VOC) is defined as a pain crisis lasting for at least 4 hours which is treated as per local guidelines with standard of care therapy. Acute chest syndrome (ACS), priapism and hepatic or splenic sequestration will be considered VOC in this study.

VOCs can be categorized as those HCP-managed in a healthcare facility, HCP-managed via remote consultation, or self-managed without recommendations from HCP during the event.

Annualized rate of VOC is the number of VOC events during a year period.

Time frame: 1 year

VOC is defined as a pain crisis lasting for at least 4 hours which is treated as per local guidelines with standard of care therapy. ACS, priapism and hepatic or splenic sequestration will be considered VOC in this study.

VOCs included are those HCP-managed in a healthcare facility and HCP-managed via remote consultation.

Time to first occurrence of VOC that is HCP-managed (either at a health care facility or via remote consultation) is defined as the time from the date of randomization to the date of the first occurrence of the VOC.

Time frame: 1 year

To assess the number of participants free from VOCs leading to healthcare visit.

VOC is defined as a pain crisis lasting for at least 4 hours which is treated as per local guidelines with standard of care therapy. ACS, priapism and hepatic or splenic sequestration will be considered VOC in this study. A participant is free from VOC if they do not have a VOC crisis.

Time frame: 1 year

VOC is defined as a pain crisis lasting for at least 4 hours which is treated as per local guidelines with standard of care therapy. ACS, priapism and hepatic or splenic sequestration will be considered VOC in this study.

Duration of HCP-managed VOC is defined as end date of the VOC - start date of the VOC + 1 day.

Time frame: 2 years

Immunogenicity: measurement of anti-drug antibodies (ADA) to crizanlizumab.

Time frame: 2 years

Incidence and severity of AEs and SAEs by treatment group, including changes in vital signs, electrocardiograms (ECGs), and laboratory results qualifying and reported as AEs.

Time frame: Baseline, 2 years

Assessment of safety of SEG101

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