Background/Aims: Vitamin D insufficiency drives secondary hyperparathyroidism (SHPT) and is associated with increased cardiovascular mortality in patients with chronic kidney disease (CKD). SHPT is poorly addressed by current vitamin D repletion options. The present study evaluated a novel investigational vitamin D repletion therapy: a modified-release (MR) formulation of calcifediol designed to raise serum 25-hydroxyvitamin D in a gradual manner to minimize the induction of CYP24 and, thereby, improve the SHPT control. Methods: This randomized, double-blind, placebo-controlled trial evaluated MR calcifediol in CKD subjects (n = 78) with plasma intact parathyroid hormone (iPTH) >70 pg/ml and serum total 25-hydroxyvitamin D <30 ng/ml. Subjects received daily treatment for six weeks with oral MR calcifediol (30, 60 or 90 µg) or a placebo. Results: More than 90% of subjects treated with MR calcifediol achieved serum 25-hydroxyvitamin D levels ≥30 ng/ml versus 3% of subjects treated with placebo (p < 0.0001). Mean plasma iPTH decreased from baseline (140.3 pg/ml) by 20.9 ± 6.2% (SE), 32.8 ± 5.7 and 39.3 ± 4.3% in the 30, 60 and 90 µg dose groups, respectively, and increased 17.2 ± 7.8% in the pooled placebo group (p < 0.005). No clinically significant safety concerns arose during MR calcifediol treatment. Conclusion: Oral MR calcifediol appears safe and highly effective in treating SHPT associated with vitamin D insufficiency in CKD.

<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 (&#x3c;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 m², and urinary albumin to creatinine ratio (UACR) ≤3,500 mg/g. Patients with B-type natriuretic peptide values &#x3e;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 &#x3c;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 m², 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 m² 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.

Background: Treating hyperphosphatemia is a tenet of dialysis care. This trial assessed the safety and efficacy of tenapanor for the management of hyperphosphatemia. Methods: In this 52-week phase 3 study (NCT03427125), participants receiving maintenance dialysis with both hyperphosphatemia (serum phosphorus 6.0-10.0 mg/dl) and a 1.5 mg/dl increase following phosphate binder washout were randomized (3:1) to tenapanor 30 mg twice daily for 26 weeks (randomized treatment period) or sevelamer carbonate (52-week safety control). Participants completing 26 weeks' treatment with tenapanor were re-randomized (1:1) to tenapanor or placebo for 12 weeks (randomized withdrawal period) and were eligible to enter the 14-week safety extension period. With input from the US Food and Drug Administration, the primary efficacy endpoint was the difference in the change in serum phosphorus from the end of the randomized treatment period to the end of the randomized withdrawal period among participants who achieved ≥1.2 mg/dl decrease in serum phosphorus during the randomized treatment period (efficacy analysis set). Efficacy was also evaluated in the intention-to-treat (ITT) analysis set. Results: Of 564 eligible participants randomized to receive tenapanor (n=423) or sevelamer carbonate (n=141) during the randomized treatment period, 255 (60%) in the tenapanor group subsequently were re-randomized to tenapanor (n=128) or placebo (n=127) during the randomized withdrawal period. In the efficacy analysis set (n=131), the difference in estimated mean change in serum phosphorus level between tenapanor and placebo from the beginning to the end of the randomized withdrawal period was −1.4 mg/dl (P<0.0001); in the ITT analysis set (n=243), the estimated mean difference was −0.7 mg/dl (P=0.002). Loosened stools were the most frequently reported adverse event (53% during the randomized treatment period). Serious adverse events were reported more frequently for participants treated with sevelamer carbonate (16-23% across the three study periods) compared with tenapanor (11-17%). Conclusions: Tenapanor reduced serum phosphorus concentrations and maintained control of serum phosphorus in participants receiving maintenance dialysis, with an acceptable safety and tolerability profile.

Background and objectivesAlport syndrome is an inherited disease characterized by progressive loss of kidney function. We aimed to evaluate the safety and efficacy of bardoxolone methyl in patients with Alport syndrome.Design, setting, participants, & measurementsWe randomly assigned patients with Alport syndrome, ages 12–70 years and eGFR 30–90 ml/min per 1.73 m2, to bardoxolone methyl (n=77) or placebo (n=80). Primary efficacy end points were change from baseline in eGFR at weeks 48 and 100. Key secondary efficacy end points were change from baseline in eGFR at weeks 52 and 104, after an intended 4 weeks off treatment. Safety was assessed by monitoring for adverse events and change from baseline in vital signs, 12-lead electrocardiograms, laboratory measurements (including, but not limited to, aminotransferases, urinary albumin-creatinine ratio, magnesium, and B-type natriuretic peptide), and body weight.ResultsPatients randomized to bardoxolone methyl experienced preservation in eGFR relative to placebo at 48 and 100 weeks (between-group differences: 9.2 [97.5% confidence interval, 5.1 to 13.4;P<0.001] and 7.4 [95% confidence interval, 3.1 to 11.7;P=0.0008] ml/min per 1.73 m2, respectively). After a 4-week off-treatment period, corresponding mean differences in eGFR were 5.4 (97.5% confidence interval, 1.8 to 9.1;P<0.001) and 4.4 (95% confidence interval, 0.7 to 8.1;P=0.02) ml/min per 1.73 m2at 52 and 104 weeks, respectively. In apost hocanalysis with no imputation of missing eGFR data, the difference at week 104 was not statistically significant (1.5 [95% confidence interval, −1.9 to 4.9] ml/min per 1.73 m2). Discontinuations from treatment were more frequent among patients randomized to bardoxolone methyl; most discontinuations were due to protocol-specified criteria being met for increases in serum transaminases. Serious adverse events were more frequent among patients randomized to placebo. Three patients in each group developed kidney failure.ConclusionsIn adolescent and adult patients with Alport syndrome receiving standard of care, treatment with bardoxolone methyl resulted in preservation in eGFR relative to placebo after a 2-year study period; off-treatment results using all available data were not significantly different.Clinical Trial registry name and registration number:A Phase 2/3 Trial of the Efficacy and Safety of Bardoxolone Methyl in Patients with Alport Syndrome - CARDINAL (CARDINAL),NCT03019185