Crizanlizumab, a P-selectin blocker, has been approved by the US Food and Drug Administration to reduce the frequency of vaso-occlusive crises (VOCs) in adults and pediatric patients aged 16 years and older with sickle cell disease (SCD). The approval was based on the Phase II SUSTAIN trial, in which crizanlizumab 5.0 mg/kg significantly reduced the median annualized rate of VOCs versus placebo and showed a favorable safety profile (Ataga KI et al. N Engl J Med 2017). In addition, the clinical benefits with crizanlizumab were further evidenced from open label (SOLACE-Adults and SOLACE Kids) and real-world (MAP data registries) studies. However, in the Phase III STAND trial, crizanlizumab (5.0 mg/kg or 7.5 mg/kg) did not show superiority over placebo in reducing the annualized rate of VOCs leading to a healthcare visit (Abboud MR et al. Lancet Haematol. 2025). The conflicting results between the SUSTAIN and STAND trials may be due to the COVID-19 pandemic and geographic differences among patients, which could have affected healthcare access, leading to underreporting of VOCs thereby diluting the treatment effect.

To address the conflicting findings from SUSTAIN and STAND trials and to confirm the efficacy of crizanlizumab, the SPARKLE trial (ClinicalTrials.gov: NCT06439082) was designed. This Phase III, multicenter, randomized, placebo-controlled, double-blind, 52-week study will evaluate the efficacy and safety of crizanlizumab versus placebo, with or without Hydroxyurea/Hydroxycarbamide (HU/HC), in reducing the frequency of VOCs in patients with SCD experiencing frequent VOCs. Participants will be randomized (2:1) to receive either crizanlizumab 5.0 mg/kg or placebo intravenously as loading doses on Week 1 Day 1 and Week 3 Day 1, followed by maintenance doses every four weeks for 52 weeks. Stratification will be based on HU/HC use (yes/no) and region (South America, North America, and sub-Saharan Africa) at enrollment. Eligible participants are adults and adolescents aged ≥12 years with confirmed diagnosis of SCD and have experienced 4 to 12 VOCs in the previous 12 months; those with VOCs outside this range will be excluded.

The primary endpoint is the annualized rate of healthcare professional (HCP)-managed VOCs, (i.e., VOCs managed at a health care facility or via remote consultation) in each treatment arm over 52 weeks. Key secondary endpoint is the annualized rate of all VOCs (HCP-managed and self-managed without HCP recommendations) captured in real time via a cloud-based app. Other secondary endpoints include time to first HCP-managed VOC, proportion of participants free from HCP-managed VOCs, and duration of HCP-managed VOCs in each treatment arm over 52 weeks. Safety assessments include treatment-emergent adverse events (AEs), AEs of special interest (infusion related reactions, infections [serious, non-serious and opportunistic infections]) and tolerability.

The primary endpoint will be analyzed using negative binomial regression model, adjusting for treatment group, and stratification factors with the log time as offset. Annualized VOC rate estimated with 95% confidence intervals will be reported. The same analysis methods will be applied for secondary endpoints, with an additional stratified Wilcoxon rank-sum test conducted using stratification factors (concomitant HU/HC usage and region). Safety data will be summarized descriptively.

This study differs from previous studies in patient eligibility (required higher baseline rate of VOCs), a redefined VOC endpoint (pain crisis lasting ≥4 hours, treated per local standard-of-care guidelines), and use of a novel cloud-based application to measure self-managed VOCs. The app aims to differentiate between HCP- and self-managed VOCs, using structured symptom-reporting workflow to minimize recall bias via continuous tracking and documentation from initial self-care to HCP involvement. Participants will log pain episodes via smartphones or a web portal at onset and will remain open until they report resolution or seek medical assistance, after which data will be transferred to the electronic capture system.

Patient recruitment is ongoing, with approximately 315 participants expected to enroll. Study completion is anticipated by 2030.In conclusion, the SPARKLE study may offer valuable insights into the clinical effectiveness of crizanlizumab in reducing both HCP managed and total VOCs (HCP- and self-managed), offering an alternative to current HU/HC therapies.

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2025
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