Rationale and Design of a Clinical Trial Investigating Tolvaptan Safety and Efficacy in Autosomal Dominant Polycystic Kidney Disease.

Abstract

BACKGROUND:

In TEMPO 3:4, the vasopressin V2-receptor antagonist tolvaptan slowed kidney growth and function decline in autosomal dominant polycystic kidney disease (ADPKD) patients with relatively preserved kidney function.

METHODS:

Prospective, phase 3b, multi-center, randomized-withdrawal, placebo-controlled, double-blind trial of tolvaptan in ADPKD patients with late stage 2 to early stage 4 chronic kidney disease (CKD). The primary endpoint was estimated glomerular filtration rate (eGFR) change from pre-treatment baseline to post-treatment follow-up. Secondary endpoints included annualized eGFR slope, incidence of ADPKD complications, and overall and hepatic safety profiles. Participants were 18-55 year-old ADPKD patients with baseline eGFR ≥25 and ≤65 mL/min/1.73 m2 or 56-65 year-old with eGFR ≥25 and ≤44 mL/min/1.73 m2 and evidence of eGFR decline >2.0 mL/min/1.73 m2 per year. Daily split doses of tolvaptan were titrated to tolerance (30/15, 45/15, 60/30, or 90/30 mg) and maintained for 12 months, after an 8-week pre-randomization period to screen out subjects unable to tolerate at least 60/30 mg for 3 weeks.

RESULTS:

Of 1,495 subjects who entered the tolvaptan titration period, 125 (8.4%) discontinued the study before randomization. One thousand three hundred seventy subjects (684 tolvaptan, 686 placebo) from 213 centers across 21 countries were randomized. Baseline demographics were well balanced across treatment arms. Information collected during the study included eGFR, survey scores (PKD history and outcome), adverse events, vital signs, hematology, urinalysis, and serum chemistry tests.

CONCLUSION:

Replicating Evidence of Preserved Renal Function: An Investigation of Tolvaptan Safety and Efficacy (REPRISE) determines whether tolvaptan administered over 1 year exhibits disease-modifying properties in ADPKD patients with late stage 2 to early stage 4 CKD, which provides an important therapeutic advancement for this difficult-to-treat disease.

• Authors: Vicente E Torres, Olivier Devuyst, Arlene B Chapman, Ron T Gansevoort, Ronald D Perrone, John Ouyang, Jaime D Blais, Frank S Czerwiec, Olga Sergeyeva, REPRISE Trial Investigators
• Journal: American journal of nephrology (Am J Nephrol) Vol. 45 Issue 3 Pg. 257-266 ( 2017) ISSN: 1421-9670 [Electronic] Switzerland
• PMID: 28166521 (Publication Type: Clinical Trial, Phase III, Journal Article, Multicenter Study, Randomized Controlled Trial)
• Copyright: © 2017 S. Karger AG, Basel.

Chemical References

• Benzazepines
• Tolvaptan

Topics

• Adolescent
• Adult
• Aged
• Benzazepines (therapeutic use)
• Double-Blind Method
• Female
• Glomerular Filtration Rate (drug effects)
• Humans
• Kidney (drug effects)
• Male
• Middle Aged
• Patient Safety
• Polycystic Kidney, Autosomal Dominant (drug therapy, physiopathology)
• Prospective Studies
• Renal Insufficiency, Chronic (complications)
• Research Design
• Tolvaptan
• Treatment Outcome
• Young Adult