Study Design and Baseline Characteristics of the CARDINAL Trial: A Phase 3 Study of Bardoxolone Methyl in Patients with Alport Syndrome

Abstract

<b><i>Introduction:</i></b> Alport syndrome is a rare genetic disorder that affects as many as 60,000 persons in the USA and a total of 103,000 persons (<5 per 10,000) in the European Union [1, 2]. It is the second most common inherited cause of kidney failure and is characterized by progressive loss of kidney function that often leads to end-stage kidney disease. Currently, there are no approved disease-specific agents for therapeutic use. We designed a phase 3 study (CARDINAL; NCT03019185) to evaluate the safety, tolerability, and efficacy of bardoxolone methyl in patients with Alport syndrome. <b><i>Methods:</i></b> The CARDINAL phase 3 study is an international, multicenter, double-blind, placebo-controlled, randomized registrational trial. Eligible patients were of ages 12–70 years with confirmed genetic or histologic diagnosis of Alport syndrome, eGFR 30–90 mL/min/1.73 m<sup>2</sup>, and urinary albumin to creatinine ratio (UACR) ≤3,500 mg/g. Patients with B-type natriuretic peptide values >200 pg/mL at baseline or with significant cardiovascular histories were excluded. Patients were randomized 1:1 to bardoxolone methyl or placebo, with stratification by baseline UACR. <b><i>Results:</i></b> A total of 371 patients were screened, and 157 patients were randomly assigned to receive bardoxolone methyl (<i>n</i> = 77) or placebo (<i>n</i> = 80). The average age at screening was 39.2 years, and 23 (15%) were <18 years of age. Of the randomized population, 146 (93%) had confirmed genetic diagnosis of Alport syndrome, and 62% of patients had X-linked mode of inheritance. Mean baseline eGFR was 62.7 mL/min/1.73 m<sup>2</sup>, and the geometric mean UACR was 141.0 mg/g. The average annual rate of eGFR decline prior to enrollment in the study was −4.9 mL/min/1.73 m<sup>2</sup> despite 78% of the patient population receiving ACE inhibitor (ACEi) or ARB therapy. <b><i>Discussion/Conclusion:</i></b> CARDINAL is one of the largest interventional, randomized controlled trials in Alport syndrome conducted to date. Despite the use of ACEi or ARB, patients were experiencing significant loss of kidney function prior to study entry.

Chronic Inflammation in Chronic Kidney Disease Progression: Role of Nrf2

“…2,59,120,121 As patients with Alport syndrome experience a loss of kidney function despite the use of angiotensin-converting enzyme inhibitors and angiotensin-receptor blockers and there is a documented inflammatory component, the effects of Nrf2 stimulation with bardoxolone methyl are currently investigated in a randomized controlled trial (CARDINAL). 122…”

Single, Double and Triple Blockade of RAAS in Alport Syndrome: Different Tools to Freeze the Evolution of the Disease

“…Thus far, this type of therapeutic approach is to be considered the most effective, pending the results of the most recent studies on more modern therapies. In fact, more recently, studies have focused on new therapeutic options such as Bardoxolone [ 21 ], anti-microRNA-21 [ 22 ], stem cell-based therapies [ 23 ]. Furthermore, a recent innovation is the so-called “exon skipping therapy”, which, in mice with reduced expression of the α5 (IV) chain, has led to remarkable clinical and pathological improvements, including a higher expression of the α5 chain on glomerular and the tubular basement membrane, with better survival [ 24 ].…”

Kidney Cancer and Chronic Kidney Disease: Too Close for Comfort

“…Bardoxolone is an inducer of the Nuclear factor erythroid 2-related factor 2 (NRF2) and was a promising therapeutical agent [ 50 ]. Different clinical trials reported that patients diagnosed with diabetic nephropathy, late stage CKD [ 51 ], glomerulosclerosis and polycystic kidney disease had a significant recovery in GFR when treated with bardoxolone [ 52 ]. NRF2 is a transcription factor central to several regulatory mechanisms in mice models in which this factor is dysregulated or knocked-out; the animals developed glomerular damage and fibrosis leading to the loss of renal function [ 53 ].…”