Efficacy and Safety of Bardoxolone Methyl in Pediatric Patients with Alport Syndrome in CARDINAL Phase 3 Trial
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Background: Alport syndrome accounts for an estimated 3% of children with end-stage kidney disease in the US (USRDS, 2014). Whereas current management recommendations include the use of renin-angiotensin-aldosterone system inhibitors (RAASi) in patients with proteinuria, no specific therapies have been approved for this disease.
Objective: A Phase 3 study (CARDINAL; NCT03019185) evaluated the safety and efficacy of bardoxolone methyl (Bard) in adult and adolescent patients with Alport syndrome.
Design/Methods: CARDINAL was an international, multicenter, double-blind, placebo-controlled, randomized trial conducted over two years in patients with confirmed diagnosis of Alport syndrome. Patients aged 12 to 70 years old with baseline eGFR 30-90 mL/min/1.73 m2 and urinary albumin to creatinine ratio (UACR) ≤ 3500 mg/g were randomized 1:1 to Bard or placebo. Patients did not receive study drug during a 4-week withdrawal period between Weeks 48 and 52, after which treatment was re-started and continued through Week 100. Efficacy endpoints for all patients were changes from baseline in eGFR in Bard-treated patients relative to placebo at Weeks 48 and 100 (primary) and at Weeks 52 and 104 (key secondary), following a 4-week withdrawal period.
Results: A total of 23 (15%) pediatric patients were randomized in the trial. The average age at screening for these patients was 15.3 years, mean (± SD) baseline eGFR was 69.9 ± 15.4 mL/min/1.73 m2 and mean (± SE) baseline UACR was 230.9 ± 95.8 mg/g. A total of 14 of 23 (61%) patients had an X-linked mode of inheritance, 6 (26%) patients had autosomal disease. Four (17%) patients were female, and 17 (74%) patients received RAASi treatment.
In pediatric patients, Bard treatment resulted in a significantly higher mean change from baseline in on-treatment eGFR compared to placebo at Week 100 (13.8 mL/min/1.73 m2; p = 0.0017), and in off-treatment eGFR compared to placebo at Week 104 (14.6 mL/min/1.73 m2; p = 0.0035), despite mean UACR remaining generally unchanged. Mean body weight in Bard-treated pediatric patients also remained generally unchanged relative to baseline through Week 100. No serious adverse events (AEs) were reported in Bard-treated pediatric patients and reported AEs were consistent with those observed in previous studies.
Conclusion(s): In CARDINAL, the addition of Bard to RAASi in pediatric patients with Alport syndrome and chronic kidney disease appeared to preserve kidney function and was generally well-tolerated.
Presented at the 2021 PAS Virtual Conference
Nephrology | Pediatrics
Warady, Bradley A.; Andreol, Sharon; Chadha, Vimal; Chin, Melanie; Gbadegesin, Rasheed; Gibson, Keisha; Gipson, Debbie; Goldsberry, Angie; Lieberman, Kenneth; Meyer, Colin; Meyers, Kevin; Kandai, Nozu; O'Grady, Megan; Rheault, Michelle; and Kashtan, Clifford, "Efficacy and Safety of Bardoxolone Methyl in Pediatric Patients with Alport Syndrome in CARDINAL Phase 3 Trial" (2021). Posters. 177.