Patients with Alport syndrome who met the inclusion and exclusion criteria were randomized 1:1 to receive either bardoxolone methyl or placebo. Randomization was stratified by baseline UACR (≤300 mg/g, 300 to ≤1,000 mg/g, and 1,000 to ≤3,500 mg/g). Patients randomized to placebo remained on placebo throughout the study, undergoing sham dose titration. The target maximum bardoxolone methyl dose was determined by baseline proteinuria status. Adult patients started once-daily dosing by receiving 5 mg for the first week, and dose escalated to 10 mg at week 2, to 20 mg at week 4, and lastly to 30 mg at week 6 (only if baseline UACR >300 mg/g). Patients <18 years of age started bardoxolone methyl dosing at 5 mg every other day for the first week, followed by 5 mg once daily at week 2, and then increased dosage every 2 weeks following the same aforementioned dose-titration scheme based on baseline UACR at weeks 2, 4, and 6 to achieve the same target doses as adult patients.

All patients in the study follow the same visit and assessment schedule (Fig. (Fig.1).1). Following randomization on day 1, patients are assessed in-person at weeks 1, 2, 4, 6, 8, 12, 24, 36, 48, 52, 64, 76, 88, 100, and 104 and by telephone contact on days 3, 10, 21, 31, 38, and 45. Study drug is discontinued for 4 weeks between weeks 48 and 52. Patients restart treatment at week 52 at the same dose received at week 48, and patients continue study drug treatment through week 100. At week 100 visit study, the drug was discontinued again for 4 weeks, and a follow-up visit is scheduled at week 104.

CARDINAL trial design. UACR, urinary albumin to creatinine ratio; Bard, bardoxolone methyl; eGFR, estimated glomerular filtration rate; F/U, follow-up; ScrA, screening visit A; ScrB, screening visit B; W/D, withdrawal.

We calculated eGFR using the Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) equation or Bedside Schwartz equation for patients under the age of 18 at the time of consent. Pediatric patients who turned 18 during the conduct of the trial continued to have eGFR calculated with the Bedside Schwartz equation. Clinical lab evaluations, including eGFR, were assessed at each in-person visit. We collected historical eGFR data from all patients for a period of up to 5 years prior to study entry to estimate the annualized change in eGFR. We converted all historical serum creatinine values to mg/dL in order to calculate eGFR according to the appropriate equation using the patient age at laboratory collection for adult patients, or patient height at screening for pediatric patients. Historical serum creatinine and corresponding eGFR values were considered part of a patient's medical history and distinct from central lab assessments collected as part of the trial. We collected first morning void urine samples for UACR at screening and every 4 weeks until week 12 and every 12 weeks thereafter until the end of treatment; UACR was also assessed at weeks 52 and 104 following a 4-week study drug withdrawal period. We conducted pure tone audiology tests at day 1 and weeks 48 and 100 to assess changes in hearing, also an exploratory outcome.

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