Double-Blind Randomized Study to Evaluate the Effect of Hydroxycarbamide on Albuminuria in Adults with Sickle Cell Disease: Sikamic (SIklos on Kidney Function and AlbuMInuria Clinical Trial)

Background

Sickle cell disease (SCD) is associated with a high frequency of chronic kidney disease, which is an independent risk factor for mortality in this population. SCD-associated nephropathy (SCAN) is an emerging concern, characterized by significant albuminuria and progressive deterioration of renal function with a prevalence of up to 26% to 68% in SCD adult patients (Falk 1992, Powars 2005, Yeruva 2016, Ataga 202). Because of rapid decline of estimated glomerular filtration rate (eGFR) is a frequent finding in this population (Derebail 2019, Ataga KI 2021), early diagnosis of SCAN and identification of associated clinical and biologic risk factors are crucial for initiating kidney-protective therapy at early stages of renal impairment.

Albuminuria serves as a relevant biomarker for detecting early glomerular damage in SCD patients (Audard 2017). To date, Hydroxycarbamide (HU) remains the cornerstone treatment for managing SCD patients, and its efficacy is primarily attributed to its ability to increase fetal hemoglobin (HbF) levels (Segal 2008).

Several observational studies conducted in adult SCD patients have shown that HU may have renal protective effects, making it a promising therapeutic option, but until now, randomized clinical trials confirming this hypothesis are missing (Bartolucci 2015, Laurin 2014).

Method

SIKAMIC (SIklos on Kidney Function and AlbuMInuria Clinical Trial) is an international (France and Africa), phase IIb, double-blind, randomized, placebo-controlled study. The main objective is to assess the effect of HU on albuminuria levels in SCD adult patients after 6 months of treatment.

Eligible patients are of the SS or Sβ0 genotype with a mean albuminuria value (assessed by albumin-to-creatinine ratio: ACR) above 3 and less than 100 mg/mmol, on three urine samples taken one day apart. Patients should not have received HU treatment within the previous 6 months and should not be taking conventional kidney-protecting measures (ACE inhibitors or ARA2) and having blood transfusion in the last 3 months. Patient with an eGFR rate < 60 and ≥ 140 ml/min/1,73m² are excluded from the study.

Patients receive either HU at a dosage of 15mg/kg/day or placebo for 6 months, and responders (patient achieving at least a 30% decrease of the ACR baseline at 6 months) have the option to continue the study for an additional six months.

Recruitment started in August 2019 in France and in October 2021 in Africa and was extended until June 2023 due to challenge in finding HU-Naïve patients. The end of the study is planned in June 2024 with safety monitoring conducted by an Independent Data Monitoring Committee throughout.

Results

During the recruitment period, 179 patients were screened, 99 were randomized, 34 in France, 65 in Africa (Senegal: 31, Mali: 23, Ivory Coast: 11) (Figure 1). The main reason for screen failure was mean ACR < 3mg/mmol. Two patients were excluded from the analysis due to non-compliance with exclusion criteria.

Among the 97 patients analyzed, 32 completed the study by June 30, 2023, while 46 were still ongoing treatment, and 19 withdrew before the end of the 6 months follow-up period. The study includes a higher proportion of women (68%), which can be attributed to challenges faced in conducting semen analysis in African countries and the hesitancy to initiate HU treatment without prior semen analysis. The mean age at enrolment was 29.7 ± 9.2 years. Recruitment significantly improved after opening African sites.

The study encountered several difficulties, primarily stemming from the challenge of finding HU-naïve patients in France and the high rate of screen failure attributed to non-expected ACR measurement variability and eGFR outside the accepted limits. No safety issues were reported, with 15 well-known adverse events related to HU occurring in 11 patients. Results of the study are expected by the end of 2024.

Conclusion

This study is the first randomized placebo-controlled study investigating the effect of HU on albuminuria in SCD patients. By employing a complex and robust study design, with ACR measurements at multiple time points, the study will provide valuable insights into the impact of HU on albuminuria levels. Moreover, the collaboration with African countries has highlighted the significance of considering country-specific factors and fostering partnerships to address the unique challenges faced by patients in these regions.