Tolvaptan Phase 3 Efficacy and Safety Study in Autosomal Dominant Polycystic Kidney Disease (ADPKD)
NCT ID: NCT00428948
Last Updated: 2017-07-02
Study Results
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View full resultsBasic Information
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COMPLETED
PHASE3
1445 participants
INTERVENTIONAL
2007-01-31
2012-01-31
Brief Summary
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Detailed Description
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During the 3-week titration phase, tolvaptan or placebo was titrated in weekly intervals from lowest to highest tolerated levels given in split-dose regimens of 45/15 mg, 60/30 mg and 90/30 mg orally upon awakening and approximately 9 hours later. As soon as a subject could not tolerate a given dose, the titration phase was over and the maintenance phase began at the dose level tolerated. The maintenance phase lasted to Month 36. Subjects were able to titrate down at any point during the study. Subjects were able to titrate up during the maintenance phase with Medical Monitor approval.
Conditions
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Study Design
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RANDOMIZED
PARALLEL
TREATMENT
QUADRUPLE
Study Groups
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Tolvaptan
Participants received the highest tolerated split-dose regimen (upon awakening and 9 hours later) of tolvaptan 45/15 mg, 60/30 mg, or 90/30 mg orally for 36 months.
Tolvaptan
Tolvaptan was supplied as tablets.
Placebo
Participants received placebo (upon awakening and 9 hours later) orally for 36 months.
Placebo
Placebo was supplied as tablets.
Interventions
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Tolvaptan
Tolvaptan was supplied as tablets.
Placebo
Placebo was supplied as tablets.
Other Intervention Names
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Eligibility Criteria
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Inclusion Criteria
* Adult subjects with a diagnosis of ADPKD. A diagnosis of ADPKD (age 18 or 20-50) required several cysts in each kidney (3 if by sonography, 5 if by CT or MRI) in those with a family history of ADPKD and 10 cysts (by any radiologic method) in each kidney and exclusion of other cystic kidney diseases if there was no family history.
* Willingness to comply with reproductive precautions, if female.
* Estimated creatinine clearance ≥ 60 mL/min. Estimated from serum creatinine during screening using Cockcroft-Gault with correction for gender and race, where possible.
* Rapidly progressive kidney growth (total volume ≥ 750 cc) by magnetic resonance imaging (MRI) at randomization.
Exclusion Criteria
* Currently taking medication for purpose of affecting PKD cysts.
* Women who are breast feeding and females of childbearing potential who are not using acceptable contraceptive methods.
* In the opinion of the study investigator or sponsor may present a safety risk or confound study objectives.
* Patients who are unlikely to adequately comply with study procedures.
* Patients having contraindications to MRI.
* Patients taking medications or having any illnesses likely to affect ADPKD outcomes.
18 Years
50 Years
ALL
No
Sponsors
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Otsuka Pharmaceutical Co., Ltd.
INDUSTRY
Otsuka Pharmaceutical Development & Commercialization, Inc.
INDUSTRY
Responsible Party
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Principal Investigators
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Vicente Torres, MD, PhD
Role: PRINCIPAL_INVESTIGATOR
Mayo Medical Center
Frank Czerwiec, MD, PhD
Role: STUDY_DIRECTOR
Otsuka Pharmaceutical Development and Commercialization, Inc.
Osamu Sato
Role: STUDY_DIRECTOR
Otsuka Pharmaceutical Corporation, Ltd. Japan
Locations
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Coastal Clinical Research
Mobile, Alabama, United States
University of South Alabama
Mobile, Alabama, United States
Apex Research of Riverside
Riverside, California, United States
Stanford University Medical Center
Stanford, California, United States
University of Colorado Health Sciences Center
Denver, Colorado, United States
Yale University School of Medicine
New Haven, Connecticut, United States
Jacksonville Center for Clinical Research
Jacksonville, Florida, United States
Coastal Nephrology Associates Research Center, LLC
Port Charlotte, Florida, United States
Emory University School of Medicine
Atlanta, Georgia, United States
Northwestern University
Chicago, Illinois, United States
University of Kansas Medical Center
Kansas City, Kansas, United States
Renal Associates of Baton Rough, L.L.C.
Baton Rouge, Louisiana, United States
John Hopkins School of Medicine
Baltimore, Maryland, United States
Tufts- New England Medical Center
Boston, Massachusetts, United States
Beth Israel Deaconess Medical Center
Boston, Massachusetts, United States
Mayo Medical Center
Rochester, Minnesota, United States
Erie County Medical Center
Buffalo, New York, United States
Nephrology Associates of Westchester
Hawthorne, New York, United States
The Rogosin Institute
New York, New York, United States
Columbia University Medical Center
New York, New York, United States
University of North Carolina, UNC, Kidney Center
Chapel Hill, North Carolina, United States
East Carolina University
Greenville, North Carolina, United States
Kidney and Hypertension Center
Cincinnati, Ohio, United States
University Hospitals of Cleveland/Case
Cleveland, Ohio, United States
Northwest Renal Clinic, Inc.
Portland, Oregon, United States
University of Pennsylvania Medical Center
Philadelphia, Pennsylvania, United States
Charleston Nephrology Associates
Charleston, South Carolina, United States
Nephrology Associates, P.C.
Nashville, Tennessee, United States
Vanderbilt University Medical Center
Nashville, Tennessee, United States
University of Virginia, Nephrology Clinical Research Center
Charlottesville, Virginia, United States
Instituto de Nefrología, Nefrology SA
Buenos Aires, , Argentina
Hospital Municipal de Vicente Lopez, Dr Bernardo Houssay
Buenos Aires, , Argentina
Hosptial Universitario Austral
Buenos Aires, , Argentina
Sanatorio Allende
Córdoba, , Argentina
Hospital Privado-Centro Medico de Cordoba
Córdoba, , Argentina
Royal Adelaide Hospital
Adelaide, , Australia
Queen Elizebeth Hospital
Adelaide, , Australia
Princess Alexandra Hospital
Brisbane, , Australia
Royal Melbourne Hospital
Melbourne, , Australia
Melbourne Renal Research Group
Melbourne, , Australia
Royal Perth Hospital
Perth, , Australia
Royal North Shore Hospital
Sydney, , Australia
Westmead Hospital
Sydney, , Australia
UZ Brussel
Brussels, , Belgium
Ucl-St Luc
Brussels, , Belgium
UZ Gent
Ghent, , Belgium
Queen Elizabeth II Health Science Center, Division of Nephrology
Halifax, Nova Scotia, Canada
Royal Victoria Hospital
Montreal, Quebec, Canada
Hospital du Sacre- Coeur de Montreal
Montreal, Quebec, Canada
Herlev Amtssygehus
Herlev, , Denmark
Odense Universitetshospital
Odense, , Denmark
CHU-Hopital Pellegrin
Bordeaux, , France
CHU - Hôpital Clémenceau
Caen, , France
Hôpital Edouard Herriot
Lyon, , France
Hôpital de la Conception
Marseille, , France
CHU - Hôpital Lapeyronie
Montpellier, , France
Hopital Bichat-Claude Bernard
Paris, , France
Centre Hospitalier Universitaire
Reims, , France
CHU - Hôpital Nord
Saint-Etienne, , France
Hopital Rangueil
Toulouse, , France
Universitätsklinikum Carl Gustav Carus
Dresden, , Germany
Nephrologische Gemeinschaftspraxis/Dialysezentrum
Düsseldorf, , Germany
Klinik für Nieren- und Hochdruckkrankheiten
Essen, , Germany
Universitätsklinikum Freiburg
Freiburg im Breisgau, , Germany
Universitätskliniken Heidelberg
Heidelberg, , Germany
UH Erlangen/Nürnberg
Nuremberg, , Germany
Ospedali Riuniti di Bergamo
Bergamo, , Italy
Università Vita e Salute, Ospedale San Raffaele
Milan, , Italy
Policlinico di Modena
Modena, , Italy
Policlinico
Napoli, , Italy
IRCCS Fondazione Salvatore Maugeri
Pavia, , Italy
Fujita Health University Hospital
Toyoake, Aichi-ken, Japan
Hokkaido University Hospital
Sapporo, Hokkaido, Japan
Tokai University Hospital
Isehara, Kanagawa, Japan
Toranomon Hospital Kajigaya
Kawasaki, Kanagawa, Japan
Kitasato University Hospital
Sagamihara, Kanagawa, Japan
Tohoku University Hospital
Sendai, Miyagi, Japan
Osaka City University Hospital
Osaka, Osaka, Japan
Osaka University Hospital
Suita, Osaka, Japan
Shuwa General Hospital
Kasukabe, Saitama, Japan
Saitama Medical Center
Kawagoe, Saitama, Japan
Hamamatsu University School of Medicine, University Hospital
Hamamatsu, Shizuoka, Japan
Jichi Medical School Hospital
Shimotsuke, Tochigi, Japan
Tokyo Medical & Dental University Hospital, Faculty of Medicine
Bunkyo-ku, Tokyo, Japan
Nippon Medical School Hospital
Bunkyo-ku, Tokyo, Japan
Teikyo University Hospital
Itabashi-ku, Tokyo, Japan
Toranomon Hospital
Minato-ku, Tokyo, Japan
The Jikei University Hospital
Minato-Ku, Tokyo, Japan
Kyorin University Hospital
Mitaka, Tokyo, Japan
Tokyo Women's Medical University Hospital
Shinjuku-ku, Tokyo, Japan
Chiba University Hospital
Chiba, , Japan
National Hospital Organization Chiba-East Hospital
Chiba, , Japan
Kyusyu University Hospital
Fukuoka, , Japan
Fukushima Medical University Hospital
Fukushima, , Japan
Hiroshima University Hospital
Hiroshima, , Japan
Kumamoto Univeristy Hospital
Kumamoto, , Japan
Kyoto University Hospital
Kyoto, , Japan
National Hospital Organization Kyoto Medical Center
Kyoto, , Japan
Niigata University Medical & Dental Hospital
Niigata, , Japan
Ohno Memorial Hospital
Osaka, , Japan
Saitama Medical Center Jichi Medical University
Saitama, , Japan
VU Medisch Centrum
Amsterdam, , Netherlands
UMCG Groningen
Groningen, , Netherlands
Oddział Nefrologiczny Stacja Dializ
Ciechanów, , Poland
Akademickie Centrum Kliniczne AMG
Gdansk, , Poland
Samodzielny Publiczny Szpital Kliniczny nr 1, Akademickie Centrum Kliniczne AMG
Gdansk, , Poland
Samodzielny Publiczny Zaklad Opieki Zdrowotnej, Szpital Uniwersytecki w Krakowie
Krakow, , Poland
SOP ZOZ Uniwersytecki Szpital Kliniczny
Lodz, , Poland
Samodzielny Publiczny Szpital Kliniczny nr 4 w Lublinie
Lublin, , Poland
Klinika Chorób Wewnętrznych i Nefrologii
Warsaw, , Poland
Szpital Praski p.w. Przemienienia Panskiego, Samodzielny Publiczny Zaklad Opieki Zdrowotnej
Warsaw, , Poland
Szpital Praski, Samodzielny Publiczny ZOZ
Warsaw, , Poland
Międzyleski Szpital Specjalistyczny w Warszawie
Warsaw, , Poland
Akademicki Szpital Kliniczny im J Mikulicza Radeckiego
Wroclaw, , Poland
Spitalul Clinic de Nefrologie Dr. Carol Davila
Bucharest, , Romania
Institutul Clinic Fundeni
Bucharest, , Romania
Spitalul Clinic "C.I.Parhon"
Iași, , Romania
Kemerovo Medical Academy, Regional Clinical Hospital
Kemerovo, , Russia
City Clinical Hospital #52
Moscow, , Russia
City Mariinskiy Hospital
Saint Petersburg, , Russia
Leningrad Regional Clinical Hospital
Saint Petersburg, , Russia
Tomsk Regional Clinical Hospital
Tomsk, , Russia
Belfast City Hospital
Belfast, , United Kingdom
Oueen Elizabeth Hospital
Birmingham, , United Kingdom
Sussex Renal Unit Royal Sussex County Hospital
Brighton, , United Kingdom
Uhcw Mhs Trust
Coventry, , United Kingdom
Royal Infirmary
Edinburgh, , United Kingdom
Raigmore Hospital
Inverness, , United Kingdom
Royal Free and University College Medical School
London, , United Kingdom
King's College Hospital
London, , United Kingdom
St. George's Hospital
London, , United Kingdom
Royal Hallamshire Hospital
Sheffield, , United Kingdom
Morriston Hospital
Swansea, , United Kingdom
Countries
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References
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Gattone VH 2nd, Wang X, Harris PC, Torres VE. Inhibition of renal cystic disease development and progression by a vasopressin V2 receptor antagonist. Nat Med. 2003 Oct;9(10):1323-6. doi: 10.1038/nm935. Epub 2003 Sep 21.
Torres VE, Wang X, Qian Q, Somlo S, Harris PC, Gattone VH 2nd. Effective treatment of an orthologous model of autosomal dominant polycystic kidney disease. Nat Med. 2004 Apr;10(4):363-4. doi: 10.1038/nm1004. Epub 2004 Feb 29.
Torres VE, Meijer E, Bae KT, Chapman AB, Devuyst O, Gansevoort RT, Grantham JJ, Higashihara E, Perrone RD, Krasa HB, Ouyang JJ, Czerwiec FS. Rationale and design of the TEMPO (Tolvaptan Efficacy and Safety in Management of Autosomal Dominant Polycystic Kidney Disease and its Outcomes) 3-4 Study. Am J Kidney Dis. 2011 May;57(5):692-9. doi: 10.1053/j.ajkd.2010.11.029. Epub 2011 Feb 17.
Torres VE, Chapman AB, Devuyst O, Gansevoort RT, Grantham JJ, Higashihara E, Perrone RD, Krasa HB, Ouyang J, Czerwiec FS; TEMPO 3:4 Trial Investigators. Tolvaptan in patients with autosomal dominant polycystic kidney disease. N Engl J Med. 2012 Dec 20;367(25):2407-18. doi: 10.1056/NEJMoa1205511. Epub 2012 Nov 3.
Watkins PB, Lewis JH, Kaplowitz N, Alpers DH, Blais JD, Smotzer DM, Krasa H, Ouyang J, Torres VE, Czerwiec FS, Zimmer CA. Clinical Pattern of Tolvaptan-Associated Liver Injury in Subjects with Autosomal Dominant Polycystic Kidney Disease: Analysis of Clinical Trials Database. Drug Saf. 2015 Nov;38(11):1103-13. doi: 10.1007/s40264-015-0327-3.
Kher A. Tolvaptan in autosomal dominant polycystic kidney disease. N Engl J Med. 2013 Mar 28;368(13):1257-8. doi: 10.1056/NEJMc1300762. No abstract available.
Spital A. Tolvaptan in autosomal dominant polycystic kidney disease. N Engl J Med. 2013 Mar 28;368(13):1257. doi: 10.1056/NEJMc1300762. No abstract available.
Torres VE, Gansevoort RT, Czerwiec FS. Tolvaptan in autosomal dominant polycystic kidney disease. N Engl J Med. 2013 Mar 28;368(13):1259. doi: 10.1056/NEJMc1300762. No abstract available.
Jouret F, Krzesinski JM. Tolvaptan in autosomal dominant polycystic kidney disease. N Engl J Med. 2013 Mar 28;368(13):1258-9. doi: 10.1056/NEJMc1300762. No abstract available.
Sexton DJ. Tolvaptan in autosomal dominant polycystic kidney disease. N Engl J Med. 2013 Mar 28;368(13):1258. doi: 10.1056/NEJMc1300762. No abstract available.
St Pierre K, Cashmore BA, Bolignano D, Zoccali C, Ruospo M, Craig JC, Strippoli GF, Mallett AJ, Green SC, Tunnicliffe DJ. Interventions for preventing the progression of autosomal dominant polycystic kidney disease. Cochrane Database Syst Rev. 2024 Oct 2;10(10):CD010294. doi: 10.1002/14651858.CD010294.pub3.
Ivaturi V, Gobburu J, Leslie B, Wang X, Jadhav P. Urine Osmolality Is a Potential Marker of Longer-Term Efficacy of Tolvaptan in Autosomal Dominant Polycystic Kidney Disease: A Post Hoc Analysis. Kidney360. 2024 Jul 1;5(7):996-1001. doi: 10.34067/KID.0000000000000485. Epub 2024 Jun 10.
Mochizuki T, Matsukawa M, Tanaka T, Jiang H. Initial eGFR Changes Predict Response to Tolvaptan in ADPKD. Kidney360. 2024 Apr 1;5(4):522-528. doi: 10.34067/KID.0000000000000404. Epub 2024 Feb 28.
Gobburu J, Ivaturi V, Wang X, Shoaf SE, Jadhav P, Perrone RD. Comparing Effects of Tolvaptan and Instruction to Increase Water Consumption in ADPKD: Post Hoc Analysis of TEMPO 3:4. Kidney360. 2023 Dec 1;4(12):1702-1707. doi: 10.34067/KID.0000000000000302. Epub 2023 Nov 21.
Lioudis M, Zhou X, Davenport E, Nunna S, Krasa HB, Oberdhan D, Fernandes AW. Effects of tolvaptan discontinuation in patients with autosomal dominant polycystic kidney disease: a post hoc pooled analysis. BMC Nephrol. 2023 Jun 22;24(1):182. doi: 10.1186/s12882-023-03247-6.
Alpers DH, Lewis JH, Hunt CM, Freston JW, Torres VE, Li H, Wang W, Hoke ME, Roth SE, Westcott-Baker L, Estilo A. Clinical Pattern of Tolvaptan-Associated Liver Injury in Trial Participants With Autosomal Dominant Polycystic Kidney Disease (ADPKD): An Analysis of Pivotal Clinical Trials. Am J Kidney Dis. 2023 Mar;81(3):281-293.e1. doi: 10.1053/j.ajkd.2022.08.012. Epub 2022 Sep 30.
Nowak KL, Steele C, Gitomer B, Wang W, Ouyang J, Chonchol MB. Overweight and Obesity and Progression of ADPKD. Clin J Am Soc Nephrol. 2021 Jun;16(6):908-915. doi: 10.2215/CJN.16871020. Epub 2021 Jun 11.
Heida JE, Gansevoort RT, Torres VE, Devuyst O, Perrone RD, Lee J, Li H, Ouyang J, Chapman AB. The Effect of Tolvaptan on BP in Polycystic Kidney Disease: A Post Hoc Analysis of the TEMPO 3:4 Trial. J Am Soc Nephrol. 2021 Jul;32(7):1801-1812. doi: 10.1681/ASN.2020101512. Epub 2021 Apr 22.
Bennett H, McEwan P, Hamilton K, O'Reilly K. Modelling the long-term benefits of tolvaptan therapy on renal function decline in autosomal dominant polycystic kidney disease: an exploratory analysis using the ADPKD outcomes model. BMC Nephrol. 2019 Apr 23;20(1):136. doi: 10.1186/s12882-019-1290-5.
McEwan P, Bennett Wilton H, Ong ACM, Orskov B, Sandford R, Scolari F, Cabrera MV, Walz G, O'Reilly K, Robinson P. A model to predict disease progression in patients with autosomal dominant polycystic kidney disease (ADPKD): the ADPKD Outcomes Model. BMC Nephrol. 2018 Feb 13;19(1):37. doi: 10.1186/s12882-017-0804-2.
Torres VE, Chapman AB, Devuyst O, Gansevoort RT, Perrone RD, Dandurand A, Ouyang J, Czerwiec FS, Blais JD; TEMPO 4:4 Trial Investigators. Multicenter, open-label, extension trial to evaluate the long-term efficacy and safety of early versus delayed treatment with tolvaptan in autosomal dominant polycystic kidney disease: the TEMPO 4:4 Trial. Nephrol Dial Transplant. 2018 Mar 1;33(3):477-489. doi: 10.1093/ndt/gfx043.
Muto S, Kawano H, Higashihara E, Narita I, Ubara Y, Matsuzaki T, Ouyang J, Torres VE, Horie S. The effect of tolvaptan on autosomal dominant polycystic kidney disease patients: a subgroup analysis of the Japanese patient subset from TEMPO 3:4 trial. Clin Exp Nephrol. 2015 Oct;19(5):867-77. doi: 10.1007/s10157-015-1086-2. Epub 2015 Feb 7.
Other Identifiers
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2006-002768-24
Identifier Type: EUDRACT_NUMBER
Identifier Source: secondary_id
156-04-251
Identifier Type: -
Identifier Source: org_study_id
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