Alport syndrome, a rare and serious hereditary disease with no approved pharmacological therapy, is caused by mutations in the genes encoding type IV collagen that result in structural defects of the glomerular basement membrane resulting in inflammation, remodeling, fibrosis, and loss of kidney function. Through induction of Nrf2 and suppression of NF-κB, bardoxolone methyl (Bard) and related analogs improve renal function, reduce inflammation, and prevent fibrosis in multiple animal models of renal injury and disease. In previous clinical studies that enrolled over 2,600 patients, including primarily patients with chronic kidney disease (CKD) caused by type 2 diabetes, Bard improved estimated and measured GFR as assessed by inulin clearance. A Phase 2/3 trial was designed to test the hypothesis that Bard will improve renal function in patients with Alport syndrome. The Phase 2/3 trial of the Efficacy and Safety of Bardoxolone Methyl in Patients with Alport Syndrome (CARDINAL NCT03019185) is a double-blind, randomized, placebo-controlled, multinational, multicenter study that will enroll approximately 150 patients on stable RAAS blockade, ages 12 to 70 years with confirmed genetic or histologic diagnosis of Alport syndrome, eGFR values between 30 to 90 mL/min/1.73 m2, and albumin to creatinine ratio ≤ 3500 mg/g. Patients with brain natriuretic peptide (BNP) values > 200 pg/mL at baseline or with significant cardiovascular histories, including left ventricular ejection fraction < 40% (based on echocardiogram), are excluded. The primary efficacy endpoint will be the change from baseline in eGFR in Bard-treated patients relative to placebo after 48 weeks of treatment. The key secondary endpoint will be the change from baseline in eGFR in Bard-treated patients relative to placebo at Week 52 following a 4-week drug treatment withdrawal period. The 4 week withdrawal period represents 17 half-lives of the drug and is associated with 1) sub-therapeutic serum Bard concentrations, 2) return to baseline of pharmacodynamic markers of Nrf2 activation, 3) and loss of pharmacologic activity. All patients enrolled in the study will be followed for two years. The open-label Phase 2 portion of the CARDINAL trial enrolled 30 subjects and showed that Bard significantly increased eGFR in patients with Alport syndrome after 12 weeks of treatment and these improvements were sustained for up to 48 weeks (+10.4 mL/min/1.73 m2; n=25; p<0.0001). Bard also resulted in a significant retained benefit of +4.1 mL/min/1.73 m2 4 weeks post-drug withdrawal. Urinary albumin to creatinine ratios were not significantly different from baseline at Weeks 48 or 52. The Phase 3 portion enrolled 157 patients and data are not yet available. Initial 1-year data from the Phase 2 portion of CARDINAL, in particular the retained benefit after Bard is stopped, support that the mechanism by which Bard increases eGFR is not harmful and may even suggest disease-modifying activity in patients with Alport syndrome. The Phase 3 portion of CARDINAL is the first randomized, placebo-controlled trial to test the hypothesis that Bard will slow the progression of CKD in patients with Alport syndrome.