Clinical trial NCT00428948: Tolvaptan Phase 3 Efficacy and Safety Study in Autosomal Dominant Polycystic Kidney Disease (ADPKD)
Official title: A Phase 3, Multi-center, Double-blind, Placebo-controlled, Parallel-arm Trial to Determine Long-term Safety and Efficacy of Oral Tolvaptan Tablets Regimens in Adult Subjects With Autosomal Dominant Polycystic Kidney Disease
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE3
Conditions: Polycystic Kidney Disease, Autosomal Dominant
Keywords: ADPKD
Polycystic
kidney
ADPKD (Autosomal Dominant Polycystic Kidney Disease)
Lead sponsor: Otsuka Pharmaceutical Development & Commercialization, Inc.
Sponsor class: INDUSTRY
Collaborators: name: Otsuka Pharmaceutical Co., Ltd.
First posted: 2007-01-30
Enrollment: 1445
Sex: ALL
Minimum age (years): 18
Maximum age (years): 50
Standard ages: ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief summary: This study's purpose is to evaluate the long-term safety and efficacy of tolvaptan versus placebo in patients with ADPKD.

Detailed description: This study evaluated whether or not tolvaptan is potentially beneficial, while maintaining an adequate safety profile, by reducing the rate of total kidney volume increase, while impacting the onset, severity, and progression of other important consequences of ADPKD.

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.

Eligibility criteria: Inclusion Criteria:

* Legal adult age and able to give Informed Consent.
* 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:

* Prior exposure to tolvaptan or other experimental PKD therapies.
* 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.

Primary outcomes:
measure: Percentage Change Per Year in Total Kidney Volume From Baseline to Month 36
timeFrame: Baseline to Month 36
Secondary outcomes:
measure: Number of ADPKD Clinical Progression Events Per 100 Follow-up Years From Baseline to Month 36
timeFrame: Baseline to Month 36
measure: Change in Renal Function Per Year From Week 3 to Month 36
timeFrame: Week 3 to Month 36
measure: Change in Mean Arterial Blood Pressure Per Year in Non-hypertensive Participants From Baseline to Month 36
timeFrame: Baseline to Month 36
measure: Area Under the Concentration-time Curve of Change in Renal Pain From Baseline to Month 36
timeFrame: At screening, Baseline, Day 1, every 4 months up to month 36/early tremination (ET), follow-up visit 1 and 2
measure: Number of Hypertensive Events Per 100 Follow-up Years in Non-hypertensive Participants From Baseline to Month 36
timeFrame: Baseline to Month 36
measure: Percentage of Participants With a Clinically Sustained Decrease of Blood Pressure Leading to a Sustained Reduction in Antihypertensive Therapy From Baseline to Month 36
timeFrame: Baseline to Month 36
Other outcomes:
Locations:
city: Mobile
country: United States
facility: Coastal Clinical Research
state: Alabama
city: Mobile
country: United States
facility: University of South Alabama
state: Alabama
city: Riverside
country: United States
facility: Apex Research of Riverside
state: California
city: Stanford
country: United States
facility: Stanford University Medical Center
state: California
city: Denver
country: United States
facility: University of Colorado Health Sciences Center
state: Colorado
city: New Haven
country: United States
facility: Yale University School of Medicine
state: Connecticut
city: Jacksonville
country: United States
facility: Jacksonville Center for Clinical Research
state: Florida
city: Port Charlotte
country: United States
facility: Coastal Nephrology Associates Research Center, LLC
state: Florida
city: Atlanta
country: United States
facility: Emory University School of Medicine
state: Georgia
city: Chicago
country: United States
facility: Northwestern University
state: Illinois
city: Kansas City
country: United States
facility: University of Kansas Medical Center
state: Kansas
city: Baton Rouge
country: United States
facility: Renal Associates of Baton Rough, L.L.C.
state: Louisiana
city: Baltimore
country: United States
facility: John Hopkins School of Medicine
state: Maryland
city: Boston
country: United States
facility: Tufts- New England Medical Center
state: Massachusetts
city: Boston
country: United States
facility: Beth Israel Deaconess Medical Center
state: Massachusetts
city: Rochester
country: United States
facility: Mayo Medical Center
state: Minnesota
city: Buffalo
country: United States
facility: Erie County Medical Center
state: New York
city: Hawthorne
country: United States
facility: Nephrology Associates of Westchester
state: New York
city: New York
country: United States
facility: The Rogosin Institute
state: New York
city: New York
country: United States
facility: Columbia University Medical Center
state: New York
city: Chapel Hill
country: United States
facility: University of North Carolina, UNC, Kidney Center
state: North Carolina
city: Greenville
country: United States
facility: East Carolina University
state: North Carolina
city: Cincinnati
country: United States
facility: Kidney and Hypertension Center
state: Ohio
city: Cleveland
country: United States
facility: University Hospitals of Cleveland/Case
state: Ohio
city: Portland
country: United States
facility: Northwest Renal Clinic, Inc.
state: Oregon
city: Philadelphia
country: United States
facility: University of Pennsylvania Medical Center
state: Pennsylvania
city: Charleston
country: United States
facility: Charleston Nephrology Associates
state: South Carolina
city: Nashville
country: United States
facility: Nephrology Associates, P.C.
state: Tennessee
city: Nashville
country: United States
facility: Vanderbilt University Medical Center
state: Tennessee
city: Charlottesville
country: United States
facility: University of Virginia, Nephrology Clinical Research Center
state: Virginia
city: Buenos Aires
country: Argentina
facility: Instituto de Nefrología, Nefrology SA
city: Buenos Aires
country: Argentina
facility: Hospital Municipal de Vicente Lopez, Dr Bernardo Houssay
city: Buenos Aires
country: Argentina
facility: Hosptial Universitario Austral
city: Cordoba
country: Argentina
facility: Sanatorio Allende
city: Cordoba
country: Argentina
facility: Hospital Privado-Centro Medico de Cordoba
city: Adelaide
country: Australia
facility: Royal Adelaide Hospital
city: Adelaide
country: Australia
facility: Queen Elizebeth Hospital
city: Brisbane
country: Australia
facility: Princess Alexandra Hospital
city: Melbourne
country: Australia
facility: Royal Melbourne Hospital
city: Melbourne
country: Australia
facility: Melbourne Renal Research Group
city: Perth
country: Australia
facility: Royal Perth Hospital
city: Sydney
country: Australia
facility: Royal North Shore Hospital
city: Sydney
country: Australia
facility: Westmead Hospital
city: Brussels
country: Belgium
facility: Ucl-St Luc
city: Brussel
country: Belgium
facility: UZ Brussel
city: Gent
country: Belgium
facility: UZ Gent
city: Halifax
country: Canada
facility: Queen Elizabeth II Health Science Center, Division of Nephrology
state: Nova Scotia
city: Montreal
country: Canada
facility: Royal Victoria Hospital
state: Quebec
city: Montreal
country: Canada
facility: Hospital du Sacre- Coeur de Montreal
state: Quebec
city: Herlev
country: Denmark
facility: Herlev Amtssygehus
city: Odense
country: Denmark
facility: Odense Universitetshospital
city: Bordeaux
country: France
facility: CHU-Hopital Pellegrin
city: Caen Cedex
country: France
facility: CHU - Hôpital Clémenceau
city: Lyon Cedex 3
country: France
facility: Hôpital Edouard Herriot
city: Marseille
country: France
facility: Hôpital de la Conception
city: Montpellier
country: France
facility: CHU - Hôpital Lapeyronie
city: Paris
country: France
facility: Hopital Bichat-Claude Bernard
city: Reims cedex
country: France
facility: Centre Hospitalier Universitaire
city: Saint-Etienne Cedex 2
country: France
facility: CHU - Hôpital Nord
city: Toulouse Cedex 09
country: France
facility: Hopital Rangueil
city: Dresden
country: Germany
facility: Universitätsklinikum Carl Gustav Carus
city: Düsseldorf
country: Germany
facility: Nephrologische Gemeinschaftspraxis/Dialysezentrum
city: Essen
country: Germany
facility: Klinik für Nieren- und Hochdruckkrankheiten
city: Freiburg
country: Germany
facility: Universitätsklinikum Freiburg
city: Heidelberg
country: Germany
facility: Universitätskliniken Heidelberg
city: Nuernberg
country: Germany
facility: UH Erlangen/Nürnberg
city: Bergamo
country: Italy
facility: Ospedali Riuniti di Bergamo
city: Milano
country: Italy
facility: Università Vita e Salute, Ospedale San Raffaele
city: Modena
country: Italy
facility: Policlinico di Modena
city: Napoli
country: Italy
facility: Policlinico
city: Pavia
country: Italy
facility: IRCCS Fondazione Salvatore Maugeri
city: Toyoake
country: Japan
facility: Fujita Health University Hospital
state: Aichi
city: Sapporo
country: Japan
facility: Hokkaido University Hospital
state: Hokkaido
city: Isehara
country: Japan
facility: Tokai University Hospital
state: Kanagawa
city: Kawasaki
country: Japan
facility: Toranomon Hospital Kajigaya
state: Kanagawa
city: Sagamihara
country: Japan
facility: Kitasato University Hospital
state: Kanagawa
city: Sendai
country: Japan
facility: Tohoku University Hospital
state: Miyagi
city: Osaka-City
country: Japan
facility: Osaka City University Hospital
state: Osaka
city: Suita
country: Japan
facility: Osaka University Hospital
state: Osaka
city: Kasukabe
country: Japan
facility: Shuwa General Hospital
state: Saitama
city: Kawagoe
country: Japan
facility: Saitama Medical Center
state: Saitama
city: Hamamatsu
country: Japan
facility: Hamamatsu University School of Medicine, University Hospital
state: Shizuoka
city: Shimotsuke
country: Japan
facility: Jichi Medical School Hospital
state: Tochigi
city: Bunkyo-ku
country: Japan
facility: Tokyo Medical & Dental University Hospital, Faculty of Medicine
state: Tokyo
city: Bunkyo-ku
country: Japan
facility: Nippon Medical School Hospital
state: Tokyo
city: Itabashi-ku
country: Japan
facility: Teikyo University Hospital
state: Tokyo
city: Minato-ku
country: Japan
facility: Toranomon Hospital
state: Tokyo
city: Minato-Ku
country: Japan
facility: The Jikei University Hospital
state: Tokyo
city: Mitaka
country: Japan
facility: Kyorin University Hospital
state: Tokyo
city: Shinjuku-ku
country: Japan
facility: Tokyo Women's Medical University Hospital
state: Tokyo
city: Chiba
country: Japan
facility: Chiba University Hospital
city: Chiba
country: Japan
facility: National Hospital Organization Chiba-East Hospital
city: Fukuoka
country: Japan
facility: Kyusyu University Hospital
city: Fukushima
country: Japan
facility: Fukushima Medical University Hospital
city: Hiroshima
country: Japan
facility: Hiroshima University Hospital
city: Kumamoto
country: Japan
facility: Kumamoto Univeristy Hospital
city: Kyoto
country: Japan
facility: Kyoto University Hospital
city: Kyoto
country: Japan
facility: National Hospital Organization Kyoto Medical Center
city: Niigata
country: Japan
facility: Niigata University Medical & Dental Hospital
city: Osaka
country: Japan
facility: Ohno Memorial Hospital
city: Saitama
country: Japan
facility: Saitama Medical Center Jichi Medical University
city: Amsterdam
country: Netherlands
facility: VU Medisch Centrum
city: Groningen
country: Netherlands
facility: UMCG Groningen
city: Ciechanow
country: Poland
facility: Oddział Nefrologiczny Stacja Dializ
city: Gdansk
country: Poland
facility: Akademickie Centrum Kliniczne AMG
city: Gdansk
country: Poland
facility: Samodzielny Publiczny Szpital Kliniczny nr 1, Akademickie Centrum Kliniczne AMG
city: Krakow
country: Poland
facility: Samodzielny Publiczny Zaklad Opieki Zdrowotnej, Szpital Uniwersytecki w Krakowie
city: Lodz
country: Poland
facility: SOP ZOZ Uniwersytecki Szpital Kliniczny
city: Lublin
country: Poland
facility: Samodzielny Publiczny Szpital Kliniczny nr 4 w Lublinie
city: Warsaw
country: Poland
facility: Klinika Chorób Wewnętrznych i Nefrologii
city: Warsaw
country: Poland
facility: Międzyleski Szpital Specjalistyczny w Warszawie
city: Warszawa
country: Poland
facility: Szpital Praski p.w. Przemienienia Panskiego, Samodzielny Publiczny Zaklad Opieki Zdrowotnej
city: Warszawa
country: Poland
facility: Szpital Praski, Samodzielny Publiczny ZOZ
city: Wroclaw
country: Poland
facility: Akademicki Szpital Kliniczny im J Mikulicza Radeckiego
city: Bucharest
country: Romania
facility: Spitalul Clinic de Nefrologie Dr. Carol Davila
city: Bucharest
country: Romania
facility: Institutul Clinic Fundeni
city: Iasi
country: Romania
facility: Spitalul Clinic "C.I.Parhon"
city: Kemerovo
country: Russian Federation
facility: Kemerovo Medical Academy, Regional Clinical Hospital
city: Moscow
country: Russian Federation
facility: City Clinical Hospital #52
city: St. Petersburg
country: Russian Federation
facility: City Mariinskiy Hospital
city: St.-Petersburg
country: Russian Federation
facility: Leningrad Regional Clinical Hospital
city: Tomsk
country: Russian Federation
facility: Tomsk Regional Clinical Hospital
city: Belfast
country: United Kingdom
facility: Belfast City Hospital
city: Birmingham
country: United Kingdom
facility: Oueen Elizabeth Hospital
city: Brighton
country: United Kingdom
facility: Sussex Renal Unit Royal Sussex County Hospital
city: Coventry
country: United Kingdom
facility: Uhcw Mhs Trust
city: Edinburgh
country: United Kingdom
facility: Royal Infirmary
city: Inverness
country: United Kingdom
facility: Raigmore Hospital
city: London
country: United Kingdom
facility: Royal Free and University College Medical School
city: London
country: United Kingdom
facility: King's College Hospital
city: London
country: United Kingdom
facility: St. George's Hospital
city: Sheffield
country: United Kingdom
facility: Royal Hallamshire Hospital
city: Swansea
country: United Kingdom
facility: Morriston Hospital
Study officials:
affiliation: Mayo Medical Center
name: Vicente Torres, MD, PhD
role: PRINCIPAL_INVESTIGATOR
affiliation: Otsuka Pharmaceutical Development and Commercialization, Inc.
name: Frank Czerwiec, MD, PhD
role: STUDY_DIRECTOR
affiliation: Otsuka Pharmaceutical Corporation, Ltd. Japan
name: Osamu Sato
role: STUDY_DIRECTOR
References:
citation: 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.
citation: 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.
citation: 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.
citation: 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.
citation: 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.
citation: 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.
citation: 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.
citation: 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.
citation: 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.
citation: 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.
citation: 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.
citation: 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.
citation: 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.
citation: 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.
citation: 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.
citation: 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.