Document Detail


Tolvaptan in patients with autosomal dominant polycystic kidney disease.
MedLine Citation:
PMID:  23121377     Owner:  NLM     Status:  MEDLINE    
Abstract/OtherAbstract:
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;
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Publication Detail:
Type:  Clinical Trial, Phase III; Journal Article; Multicenter Study; Randomized Controlled Trial; Research Support, Non-U.S. Gov't     Date:  2012-11-03
Journal Detail:
Title:  The New England journal of medicine     Volume:  367     ISSN:  1533-4406     ISO Abbreviation:  N. Engl. J. Med.     Publication Date:  2012 Dec 
Date Detail:
Created Date:  2012-12-20     Completed Date:  2013-01-02     Revised Date:  2013-09-08    
Medline Journal Info:
Nlm Unique ID:  0255562     Medline TA:  N Engl J Med     Country:  United States    
Other Details:
Languages:  eng     Pagination:  2407-18     Citation Subset:  AIM; IM    
Affiliation:
Division of Nephrology and Hypertension, Department of Internal Medicine, Mayo Clinic, Rochester, MN 55905, USA. torres.vicente@mayo.edu
Data Bank Information
Bank Name/Acc. No.:
ClinicalTrials.gov/NCT00428948
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MeSH Terms
Descriptor/Qualifier:
Adolescent
Adult
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
Receptors, Vasopressin / antagonists & inhibitors*
Sodium / blood
Young Adult
Grant Support
ID/Acronym/Agency:
R01 DK044863/DK/NIDDK NIH HHS
Chemical
Reg. No./Substance:
0/Benzazepines; 0/Receptors, Vasopressin; 150683-30-0/tolvaptan; 7440-23-5/Sodium
Investigator
Investigator/Affiliation:
P Gross / ; B Schulze / ; D Bichet / ; D Chauveau / ; P Peeters / ; M Voiculescu / ; P Manunta / ; J Tuazon / ; T Watnick / ; S Goral / ; S Horie / ; K Nutahara / ; V Torres / ; A Chapman / ; O Devuyst / ; R Gansevoort / ; E Higashihara / ; R Perrone / ; J Ouyang / ; F Czerwiec / ; S Goldstein / ; B Cowley / ; M Fukagawa / ; R Torra / ; L J Wei / ; T Cook / ; R Toto / ; R Agarwal / ; P August / ; G Bakris / ; S Beddhu / ; H Corwin / ; L Ruilope / ; G Rosa-Diez / ; J De La Fuente / ; R Martin / ; P Massari / ; P Novoa / ; M Rial / ; A Wasserman / ; R Faull / ; I Fraser / ; D Johnson / ; E Pedagagos / ; M Lian / ; C Pollock / ; B Cooper / ; G Rangan / ; G Russ / ; S McDonald / ; M Thomas / ; D Khoo / ; R Walker / ; O Devuyst / ; Y Pirson / ; P Peeters / ; V Laecke / ; P Van der Niepen / ; J Sennesael / ; P Barre / ; A Alam / ; D Bichet / ; S Soroka / ; H Dieperink / ; S Strandgaard / ; L Juhl Petersen / ; F Berthoux / ; F Berthoux / ; B Canaud / ; A Gontiers-Picard / ; D Chauveau / ; A Huart / ; C Combe / ; Y Delmas / ; B Dussol / ; F Berthoux / ; M Laville / ; F Guebre-Egziabher / ; F Mignon / ; C Michel / ; P Rieu / ; N Noel / ; J P Ryckelynck / ; T Lobbedez / ; F H Dellanna / ; W Kleophas / ; P Gross / ; T Feldkamp / ; O Witzke / ; J Nurnberger / ; B D Schulze / ; R Zeltner / ; G Walz / ; M Zeier / ; C Sommerer / ; S Bianchi / ; G Capasso / ; N Miranda / ; R Magistroni / ; P Manunta / ; M Bracale / ; G Remuzzi / ; S Rota / ; G Villa / ; P Tilocca / ; K Asahi / ; T Kato / ; M Endo / ; T Umezono / ; Y Fujigaki / ; A Kato / ; A Fukatsu / ; H Hasegawa / ; Y Tayama / ; M Hasegawa / ; S Horie / ; T Hosoya / ; K Hanaoka / ; N Iehara / ; A Fukatsu / ; Y Iino / ; S Tsuruoka / ; E Imai / ; Y Isaka / ; E Imai / ; E Ishimura / ; S Ito / ; H Sato / ; K Kamata / ; H Sakamoto / ; K Kamura / ; T Kato / ; E Kusano / ; S Muto / ; M Kuwahara / ; A Matsubara / ; N Yorioka / ; T Mochizuki / ; S Muto / ; S Horie / ; I Narita / ; Y Naya / ; N Nihei / ; N Yukio / ; S Nishio / ; K Nitta / ; K Tsuchiya / ; K Nutahara / ; M Okamura / ; S Sasaki / ; T Rai / ; K Seta / ; A Sugawara / ; S Shibazaki / ; A Sugawara / ; S Sugiyama / ; K Tabei / ; K Takaichi / ; K Tomita / ; K Kitamura / ; Y Tsukamoto / ; K Tsuruya / ; T Nakano / ; Y Ubara / ; T Watanabe / ; T Yamamoto / ; N Yorioka / ; K Yoshida / ; D Ishii / ; Y Yuzawa / ; M Hasegawa / ; R Gansevoort / ; E Meijer / ; M Vervloet / ; K Ciechanowski / ; M Wisniewska / ; M Gutowska-Jablonska / ; M Marcinkowska-Królewicz / ; W Klatko / ; T Wiśniewski / ; M Klinger / ; M Krajewska / ; A Ksiazek / ; G Orłowska / ; R Malecki / ; J Gontarek-Kacprzak / ; M Nowicki / ; A Makówka / ; B Rutkowski / ; W Wołyniec / ; A Rydzewski / ; W Sulowicz / ; P Jasik / ; A Covic / ; C Volovat / ; G Mircescu / ; L Petrescu / ; M Voiculescu / ; R Bobeica / ; O Barbarash / ; L Chesnokova / ; S Borovoy / ; L Demina / ; G Shostka / ; M Idovu / ; L Tkalich / ; O Geynits / ; N Tomilina / ; L Foggensteiner / ; S Holt / ; J Kingswood / ; S Lambie / ; R Peel / ; I MacDougall / ; B Tucker / ; I MacPhee / ; A Maxwell / ; H Brown / ; A Mikhail / ; L Bastin / ; N Turner / ; J Neary / ; D Wheeler / ; P Maxwell / ; M Wilkie / ; A Ong / ; D Zehnder / ; N Aldridge / ; S Adler / ; M Klein / ; D Battle / ; W Bennett / ; B Berger / ; K Dell / ; J Blumenfeld / ; S Donahue / ; P Bolin / ; R Browder / ; A Perry / ; A Chapman / ; F Rahbari Oskoui / ; M Culpepper / ; N Dahl / ; C Edelstein / ; L Clegg / ; D Fischer / ; S Goral / ; M Kaplan / ; K Kaveh / ; R Pankhaniya / ; M Koren / ; K Mansur / ; R Lafayette / ; W Bibb Lamar / ; J Lee / ; R Mahnensmith / ; P Nachman / ; A Mottl / ; R Perrone / ; D Miskulin / ; J Petersen / ; J Radhakrishnan / ; M Roppolo / ; M Basireddy / ; M Rosner / ; W K Bolton / ; G Schulman / ; L Steed / ; W M Bennett / ; T Steinman / ; V Torres / ; M Hogan / ; J Tuazon / ; R Venuto / ; T Watnick / ; S Turban / ; F Winklhofer /
Comments/Corrections
Comment In:
N Engl J Med. 2013 Mar 28;368(13):1258   [PMID:  23534571 ]
N Engl J Med. 2013 Mar 28;368(13):1259   [PMID:  23534568 ]
N Engl J Med. 2013 Mar 28;368(13):1258-9   [PMID:  23534572 ]
N Engl J Med. 2013 Mar 28;368(13):1257   [PMID:  23534569 ]
Nat Rev Nephrol. 2013 Jan;9(1):1   [PMID:  23183839 ]
N Engl J Med. 2012 Dec 20;367(25):2440-2   [PMID:  23121376 ]
Urology. 2013 Apr;81(4):705-6   [PMID:  23375912 ]
N Engl J Med. 2013 Mar 28;368(13):1257-8   [PMID:  23534570 ]

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