Steadfast: A Randomized, Multicenter, Open-Label, Phase II Study Comparing the Effect of Crizanlizumab Plus Standard of Care (SoC) Versus Soc Alone on Renal Function in Patients with Chronic Kidney Disease Due to Sickle Cell Nephropathy

Background: Sickle cell disease (SCD), an inherited group of blood disorders, places patients at risk of complications in multiple organs including the kidneys. These complications are mostly driven by vaso-occlusion and hemolysis, with vaso-occlusive crises (VOCs) the hallmark of the disease.

‘Sickle cell nephropathy’ (SCN) is used to describe the renal complications of SCD; manifestations include hyperfiltration and progressive renal impairment. Patients with SCN can develop chronic kidney disease (CKD), defined as abnormalities in kidney structure or function which persist for >3 months. Approximately 12% of patients with SCD progress to end-stage kidney disease (Powars et al. Medicine 2005). The current standard of care (SoC) for CKD due to SCN typically consists of angiotensin-converting enzyme inhibitors (ACEI), angiotensin-receptor blockers (ARBs), and/or hydroxyurea/hydroxycarbamide (HU/HC).

P-selectin contributes to vaso-occlusion by mediating cell-to-cell interactions between endothelial cells, sickled red blood cells, and leukocytes. Preclinical studies have demonstrated that P-selectin expression increases in response to renal ischemia-reperfusion injury (Zizzi et al. J Pediatr Surg 1997).

Crizanlizumab, a humanized monoclonal antibody that binds to P-selectin, is approved in the USA and other countries to reduce the frequency of VOCs in patients aged ≥16 years with SCD. In SUSTAIN, crizanlizumab significantly reduced the median annualized rate of VOCs by 45.3% vs placebo (Ataga et al. N Engl J Med 2017). The aim of the Phase II STEADFAST study (NCT04053764, EUDRACT no. 2018-003608-38, Bartolucci et al. EHA25; Abstr PB2362) is to determine whether crizanlizumab, in combination with SoC, has a reno-protective effect in SCD patients with CKD.

Methods: STEADFAST will enroll ~170 patients aged ≥16 years with CKD due to SCD (HbSS or HbSβ⁰-thalassemia genotypes). Eligible patients will have an estimated glomerular filtration rate (eGFR) of ≥45 to ≤130 mL/min/1.73 m² (females) or ≤140 mL/min/1.73 m² (males) based on the CKD-Epidemiology Collaboration formula and an albumin-to-creatinine ratio (ACR) of ≥100 to <2000 mg/g. Prior to study entry, patients must have previously received ≥1 SoC for CKD due to SCD for ≥3 months (ACEI and/or ARBs) or ≥6 months (HU/HC), have been on a stable dose of SoC ≥3 months, and plan to maintain the same dose and schedule of SoC until study end. Patients with a history of stem cell transplant, evidence of acute kidney injury within 3 months of study entry, or those receiving renal replacement therapy will be excluded.

Patients will be randomized 1:1 to receive crizanlizumab 5.0 mg/kg (intravenous infusion over 30 min on Day 1 of Week 1, followed by a second dose 2 weeks later, then every 4 weeks) and their usual SoC or their usual SoC alone (Figure).

The primary endpoint is the proportion of patients with ≥30% decrease from baseline in ACR at 12 months. A logistic regression model including treatment effects and stratification factors will be utilized and the test (based on the log-odds ratio estimated by the model) will be performed at a 1-sided significance level of 0.025. Secondary endpoints include mean change in ACR from baseline to 3, 6, 9, and 12 months, the percentage change in eGFR from baseline to 3, 6, 9, and 12 months, the proportion of patients with a protein-to-creatinine ratio (PCR) improvement (≥20% decrease) at 12 months compared with baseline, the proportion of patients with a stable PCR (within ±20% change from baseline) at 12 months, and the proportion of patients with progression of CKD (based on pre-defined eGFR decline and ACR increase) from baseline to 12 months. To minimize variability of ACR measurements, three urine samples (first morning void [FMV] on the day before study visit, FMV on the day of study visit, and during study visit [third sample not required to be FMV]) will be collected. Exploratory endpoints include assessments of renal and cardiac biomarkers at 3, 6, 9, and 12 months.

Results: The STEADFAST study is ongoing and 15 sites in eight countries are ready for recruitment: Brazil (4 sites), Spain (3 sites), Turkey and the UK (2 sites each), and France, Greece, the Netherlands and the USA (1 site each).

Conclusion: CKD is a severe and common complication of SCD. The Phase II STEADFAST study has been designed to evaluate whether crizanlizumab, in combination with SoC, can reduce albuminuria and slow CKD progression.