DUET: A Phase 2 Study Evaluating the Efficacy and Safety of Sparsentan in Patients with FSGS.

BACKGROUND: We evaluated and compared the effects of sparsentan, a dual endothelin type A (ETA) and angiotensin II type 1 receptor antagonist, with those of the angiotensin II type 1 receptor antagonist irbesartan in patients with primary FSGS. METHODS: In this phase 2, randomized, double-blind, active-control Efficacy and Safety of Sparsentan (RE-021), a Dual Endothelin Receptor and Angiotensin Receptor Blocker, in Patients with Focal Segmental Glomerulosclerosis (FSGS): A Randomized, Double-blind, Active-Control, Dose-Escalation Study (DUET), patients aged 8-75 years with biopsy-proven FSGS, eGFR>30 ml/min per 1.73 m2, and urinary protein-to-creatinine ratio (UP/C) ≥1.0 g/g received sparsentan (200, 400, or 800 mg/d) or irbesartan (300 mg/d) for 8 weeks, followed by open-label sparsentan only. End points at week 8 were reduction from baseline in UP/C (primary) and proportion of patients achieving FSGS partial remission end point (FPRE) (UP/C: ≤1.5 g/g and >40% reduction [secondary]). RESULTS: Of 109 patients randomized, 96 received study drugs and had baseline and week 8 UP/C measurements. Sparsentan-treated patients had greater reductions in UP/C than irbesartan-treated patients did when all doses (45% versus 19%; P=0.006) or the 400 and 800 mg doses (47% versus 19%; P=0.01) were pooled for analysis. The FSGS partial remission end point was achieved in 28% of sparsentan-treated and 9% of irbesartan-treated patients (P=0.04). After 8 weeks of treatment, BP was reduced with sparsentan but not irbesartan, and eGFR was stable with both treatments. Overall, the incidence of adverse events was similar between groups. Hypotension and edema were more common among sparsentan-treated patients but did not result in study withdrawals. CONCLUSIONS: Patients with FSGS achieved significantly greater reductions in proteinuria after 8 weeks of sparsentan versus irbesartan. Sparsentan was safe and well tolerated.

Real-World Experience With Avacopan in Antineutrophil Cytoplasmic Autoantibody-Associated Vasculitis.

Introduction: Postmarketing data on outcomes of avacopan use in antineutrophil cytoplasmic autoantibody (ANCA)-associated vasculitis (AAV) are lacking. Methods: We performed a multicenter retrospective analysis of 92 patients with newly diagnosed or relapsing AAV who received therapy with avacopan. The coprimary outcome measures were clinical remission at 26 and 52 weeks. We use descriptive statistics and univariate logistic regression to assess outcomes and predictors of remission, respectively. Results: Of the 92 patients, 23% (n = 21) had a baseline estimated glomerular filtration rate (eGFR) < 15 ml/min per 1.73 m2 and 10% on kidney replacement therapy at baseline. Among those with kidney involvement, mean (SD) enrollment eGFR was 33 (27) ml/min per 1.73 m2 with a mean (SD) change of +12 (25) and +20 (23) ml/min per 1.73 m2 at weeks 26 and 52, respectively. In addition to avacopan, 47% of patients received combination therapy of rituximab and low-dose cyclophosphamide, and 14% of patients received plasma exchange (PLEX). After induction, the median (interquartile range [IQR]) time to start avacopan was 3.6 (2.1-7.7) weeks, and the median time to discontinue prednisone after starting avacopan was 5.6 (3.3-9.5) weeks. Clinical remission was achieved in 90% of patients at week 26 and 84% of patients at week 52. Of the patients, 20% stopped avacopan due to adverse events, with the most common being elevated serum aminotransferases (4.3%). Conclusion: A high rate of remission and an acceptable safety profile were observed with the use of avacopan in the treatment of AAV in this postmarketing analysis, including the populations excluded from the ADVOCATE trial.

A Randomized Crossover Trial of Dietary Sodium Restriction in Stage 3-4 CKD.

BACKGROUND AND OBJECTIVES: Patients with chronic kidney disease (CKD) are often volume expanded and hypertensive. Few controlled studies have assessed the effects of a sodium-restricted diet (SRD) in CKD. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS: We conducted a randomized crossover trial to evaluate the effect of SRD (target <2 g sodium per day) versus usual diet on hydration status (by bioelectrical impedance spectroscopy) and blood pressure (BP) between May of 2009 and May of 2013. A total of 58 adults with stage 3-4 CKD were enrolled from two academic sites: University of Michigan (n=37) and University of North Carolina at Chapel Hill (n=21); 60% were men, 43% were diabetic, 93% were hypertensive, and mean age was 61 years. Participants followed SRD or usual diet for 4 weeks, followed by a 2-week washout period and a 4-week crossover phase. During the SRD, dieticians provided counseling every 2 weeks, using motivational interviewing techniques. RESULTS: Whole-body extracellular volume and calf intracellular volume decreased by 1.02 L (95% confidence interval [95% CI], -1.48 to -0.56; P<0.001) and -0.06 L (95% CI, -0.12 to -0.01; P=0.02), respectively, implying decreased fluid content on the SRD compared with usual diet. Significant reductions in urinary sodium (-57.3 mEq/24 h; 95% CI, -81.8 to -32.9), weight (-2.3 kg; 95% CI, -3.2 to -1.5), and 24-hour systolic BP (-10.8 mmHg; 95% CI, -17.0 to -4.6) were also observed (all P<0.01). Albumin-to-creatinine ratio did not change significantly and mean serum creatinine increased slightly (0.1 mg/dl; 95% CI, -0.01 to 0.2; P=0.06). No period or carryover effects were observed. Results were similar when analyzed from phase 1 only before crossover, although P values were modestly larger because of the loss of power. CONCLUSIONS: In this randomized crossover trial, implementation of SRD in patients with CKD stage 3-4 resulted in clinically and statistically significant improvement in BP and hydration status. This simple dietary intervention merits a larger trial in CKD to evaluate effects on major clinical outcomes.