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)

Abstract

Abstract Background The optimal therapeutic strategies for adult sickle cell disease (SCD) patients with nephropathy remains to be determined. Observational studies suggested that Hydroxyurea (HU), the main disease-modifying therapy, by increasing fetal hemoglobin (HbF), reducing hemolysis and inflammation, may have reno-protective effects. However, robust randomized trial evidence is lacking. Aims To determine the effect of HU on albuminuria after 6 and 12 months compared with placebo in adults SCD patients. Methods SIKAMIC is a phase IIb, multicenter, randomized, double-blind, placebo-controlled trial conducted in 34 sites across France, Senegal, Mali, and Ivory Coast. Among the enrolled patients, 34.3% were recruited in France and 65.7% in Africa. Adults ≥18 years with confirmed HbSS or HbSβ0 genotypes and persistent albuminuria (urine albumin-to-creatinine ratio [UACR] >3 mg/mmol and <100 mg/mmol on three first-morning samples) were eligible. Key exclusion criteria included prior HU administration within 6 months, chronic transfusion, Angiotensin-converting enzyme (ACE) inhibitors or Angiotensin receptors blockers (ARBs) use, and etimated glomerula filtration rate (eGFR) < 60 or ≥ 140 ml/min/1,73m². Patients were randomized for receiving HU 15 mg/kg/day or placebo for 6 months. The primary endpoint was the proportion of patients achieving at least a 30% UACR reduction at M6. Those reaching this threshold could continue blinded treatment up to 12 months, while patients not meeting the criterion were considered non-responders. Secondary endpoints included absolute and relative UACR changes, eGFR changes, and safety. Results Ninety-nine patients were randomized (HU n=51; placebo n=48); 46 (90.2%) and 40 (83.3%) received at least one dose and had post-baseline UACR data. Baseline characteristics were similar between groups (mean age 30.2±9.3 years, 69% female). Due to high intra-patient UACR variability (CV >50% at baseline), median values were analyzed. Median baseline UACR was 7.9 mg/mmol (IQR: 4.9–18.7) (HU) and 10.5 mg/mmol (IQR: 5.3-16.8) (placebo). At Month 6, compared to baseline, the median ACR decreased by 1.2 mg/mmol in the HU group (a 21.0% reduction) and by 1.1 mg/mmol in the placebo group (a 14.4% reduction). The primary endpoint —a ≥30% reduction in UACR at 6 months—was achieved by 39.1% of patients in the HU group and 37.5% in the placebo group (not statistically significant). However, a ≥20% reduction in UACR was significantly more frequent with HU than with placebo (46% vs 25%, p=0.03). At 12 months, the median UACR decreased in both groups, 2.5 mg/mmol (IQR 0.7-4.5) in the HU group and 3.1 mg/mmol (IQR 3.0-8.6) in the placebo group. Additionally, 26% of HU-treated patients achieved a ≥30% reduction in UACR (vs 10% with placebo, p=0.07), and 34.7% achieved a ≥20% reduction (vs 15% with placebo, p=0.04). Median eGFR increased by 4.3 mL/min/1.73m² in the HU group (from 115.7 to 123.5) at M6 and remained stable in the placebo group (124.4 to 125.1). Among responders at M12, eGFR was 116.5 mL/min/1.73m² (HU) versus 123.6 (placebo). Hematologic parameters improved as expected in the HU group : median HbF increased by 9.8% at M6 (vs +0.1% in placebo) and by 11.0% at M12 (vs +1.6% in placebo). Median hemoglobin increased by 11 g/L at M6 (HU) and by 14 g/L at M12 (HU), vs decreases or minimal change in placebo (-2 at M6 and +0.5 g/L at M12). Markers of hemolysis declined accordingly. All serious treatment emergent adverse events (TEAEs) were related to the underlying disease. Five HU and seven placebo patients experienced serious TEAEs. No unexpected safety signals were reported. Conclusion This first randomized, placebo-controlled trial targeting albuminuria in SCD showed that HU led to a ≥30% reduction in nearly 40% of patients at 6 months, consistent with prior data. The high placebo response at 6 months likely reflects regression to the mean and was not sustained at 12 months, where HU's benefit persisted. Notably, imputing patients as non-responders if they did not respond by 6 months—even if they might have between 6 and 12 months—introduces a bias that likely underestimates HU's true effect. These results highlight the potential of HU to improve renal outcomes in SCD.