Published on in Nephrology News
The Division of Nephrology at CHOP is striving to help develop evidence pertaining to novel treatment options for children with chronic kidney disease. One example is the CARDINAL TRIAL led by Kevin Meyers, MBBCh, Assistant Chief of the Division of Nephrology, Director of the Hypertension Clinic and Co-Director of the Lupus Integrated Nephritis Clinic at CHOP. The CARDINAL TRIAL was a Phase 3 international, randomized, double‐blind, placebo‐controlled, registrational, two‐year trial of Bardoxolone (Bard). It was the largest and longest interventional study in patients with Alport syndrome (AS). It enrolled a wide and representative range of patients with AS with an estimated glomerular filtration rate (eGFR) between 30 to 90 mL/min/1.73m^2. Subjects were aged 12 to 70 years. The primary endpoints for the study were on‐treatment change from baseline in eGFR versus placebo at Week 48 and Week 100. The key secondary endpoint was off‐treatment change from baseline in eGFR versus placebo at Week 52 and Week 104 (4 weeks after withdrawal of drug). Ninety-eight percent of patients completed follow‐up through Week 104.
Bard reduced the risk by 50% of a kidney failure event composite defined by ESKD, or confirmed 30% eGFR decline, or confirmed eGFR < 15 mL/min/1.73 m^2. On‐treatment and off‐treatment benefit with Bard compared to the placebo was observed in multiple subgroups and across multiple stages of disease. Specifically, in children there was a reduction in GFR loss of 14.6 +/- 5.7 ml/min/1.73m^2 at week 104 (p=0.004). The urine albumin/creatinine ratio was not significantly different from the placebo at Weeks 100 and 104. Adverse events (AEs) were similar to the placebo group except for mild increase in muscle spasms, mild increase in transaminases and in serum potassium levels. Blood pressure, a sensitive measure of fluid status, was unchanged relative to the placebo. There were no imbalances in AEs associated with fluid status, including hypertension or peripheral edema. There were no serious adverse events (SAEs) of fluid‐overload in patients treated with Bard.
In summary, there was a clinically meaningful improvement in eGFR that reduced risk for kidney failure events by 50%. The persistent efficacy following off‐treatment periods at Week 52 and Week 104 is consistent with a disease modifying effect.