Crizanlizumab with or without hydroxyurea in patients with sickle cell disease (STAND): primary analyses from a placebo-controlled, randomised, double-blind, phase 3 trial.

Background: Crizanlizumab has previously shown efficacy as a potent disease-modifying therapy for alleviating vaso-occlusive crisis in sickle cell disease. The SUSTAIN study showed a reduction of vaso-occlusive crises in patients treated with 5 mg/kg crizanlizumab, compared with placebo. The STAND study aimed to evaluate the efficacy and safety of two doses (5·0 mg/kg and 7·5 mg/kg) of crizanlizumab in sickle cell disease. Herein, we report the primary analysis results of STAND.

Methods: STAND is a phase 3, multicentre, randomised, double-blind study of patients with sickle cell disease aged 12 years and older done at 65 sites in 21 countries. Patients were randomly assigned (1:1:1) to receive either 5·0 mg/kg of crizanlizumab, 7·5 mg/kg of crizanlizumab, or placebo, in addition to standard of care, for 1 year. The primary endpoint was the annualised rate of vaso-occlusive crises leading to a health-care visit over the first-year post-randomisation. The secondary objectives included assessing crizanlizumab's safety. The trial is registered at ClinicalTrials.gov (NCT03814746) and is ongoing.

Findings: Between July 26, 2019, and Aug 31, 2022, 252 patients were enrolled and treated. The primary analysis showed an adjusted annualised rate of vaso-occlusive crises of 2·49 (95% CI 1·90-3·26) in the crizanlizumab 5·0 mg/kg group, 2·04 (1·56-2·65) in the 7·5 mg/kg group, and 2·30 (1·75-3·01) in the placebo group. Ratios of adjusted annualised rates of vaso-occlusive crises leading to health-care visits were 1·08 (95% CI 0·76-1·55, p>0·999) for 5·0 mg/kg and 0·89 (0·62-1·27, p>0·999) for 7·5 mg/kg vs placebo. The incidence of adverse events was similar across treatment groups. Grade 3 or higher adverse events were observed less frequently in the placebo and crizanlizumab 7·5 mg/kg groups (27 [32%] of 85 and 32 [39%] of 83, respectively) than in the 5·0 mg/kg group (47 [56%] of 84). Serious adverse events (all grades) were also less frequent in the placebo and crizanlizumab 7·5 mg/kg groups (26 [31%] and 22 [27%], respectively) than in the 5·0 mg/kg group (35 [42%]).

Interpretation: The STAND study supports the safety and tolerability of crizanlizumab in the treatment of sickle cell disease. The primary analysis showed no significant difference in efficacy between crizanlizumab and placebo. Factors including the COVID-19 pandemic, global enrolment with varied patterns of health-care use and vaso-occlusive crisis management as well as the commercial availability of crizanlizumab might have influenced these results. The safety profile of crizanlizumab was consistent with that in previous reports, without new safety concerns.

Funding: Novartis Pharmaceuticals.