Tolvaptan in patients with autosomal dominant polycystic kidney disease.

Abstract

BACKGROUND:

The course of autosomal dominant polycystic kidney disease (ADPKD) is often associated with pain, hypertension, and kidney failure. Preclinical studies indicated that vasopressin V(2)-receptor antagonists inhibit cyst growth and slow the decline of kidney function.

METHODS:

In this phase 3, multicenter, double-blind, placebo-controlled, 3-year trial, we randomly assigned 1445 patients, 18 to 50 years of age, who had ADPKD with a total kidney volume of 750 ml or more and an estimated creatinine clearance of 60 ml per minute or more, in a 2:1 ratio to receive tolvaptan, a V(2)-receptor antagonist, at the highest of three twice-daily dose regimens that the patient found tolerable, or placebo. The primary outcome was the annual rate of change in the total kidney volume. Sequential secondary end points included a composite of time to clinical progression (defined as worsening kidney function, kidney pain, hypertension, and albuminuria) and rate of kidney-function decline.

RESULTS:

Over a 3-year period, the increase in total kidney volume in the tolvaptan group was 2.8% per year (95% confidence interval [CI], 2.5 to 3.1), versus 5.5% per year in the placebo group (95% CI, 5.1 to 6.0; P<0.001). The composite end point favored tolvaptan over placebo (44 vs. 50 events per 100 follow-up-years, P=0.01), with lower rates of worsening kidney function (2 vs. 5 events per 100 person-years of follow-up, P<0.001) and kidney pain (5 vs. 7 events per 100 person-years of follow-up, P=0.007). Tolvaptan was associated with a slower decline in kidney function (reciprocal of the serum creatinine level, -2.61 [mg per milliliter](-1) per year vs. -3.81 [mg per milliliter](-1) per year; P<0.001). There were fewer ADPKD-related adverse events in the tolvaptan group but more events related to aquaresis (excretion of electrolyte-free water) and hepatic adverse events unrelated to ADPKD, contributing to a higher discontinuation rate (23%, vs. 14% in the placebo group).

CONCLUSIONS:

Tolvaptan, as compared with placebo, slowed the increase in total kidney volume and the decline in kidney function over a 3-year period in patients with ADPKD but was associated with a higher discontinuation rate, owing to adverse events. (Funded by Otsuka Pharmaceuticals and Otsuka Pharmaceutical Development and Commercialization; TEMPO 3:4 ClinicalTrials.gov number, NCT00428948.).

• Authors: Vicente E Torres, Arlene B Chapman, Olivier Devuyst, Ron T Gansevoort, Jared J Grantham, Eiji Higashihara, Ronald D Perrone, Holly B Krasa, John Ouyang, Frank S Czerwiec, TEMPO 3:4 Trial Investigators
• Journal: The New England journal of medicine (N Engl J Med) Vol. 367 Issue 25 Pg. 2407-18 (Dec 20 2012) ISSN: 1533-4406 [Electronic] United States
• PMID: 23121377 (Publication Type: Clinical Trial, Phase III, Journal Article, Multicenter Study, Randomized Controlled Trial, Research Support, Non-U.S. Gov't)

Chemical References

• Antidiuretic Hormone Receptor Antagonists
• Benzazepines
• Tolvaptan
• Sodium

Topics

• Adolescent
• Adult
• Antidiuretic Hormone Receptor Antagonists
• Benzazepines (adverse effects, therapeutic use)
• Double-Blind Method
• Female
• Glomerular Filtration Rate (drug effects)
• Humans
• Kidney (drug effects, pathology, physiopathology)
• Male
• Middle Aged
• Organ Size (drug effects)
• Polycystic Kidney, Autosomal Dominant (drug therapy, pathology, physiopathology)
• Sodium (blood)
• Tolvaptan
• Young Adult