Tolvaptan Phase 3 Efficacy and Safety Study in Autosomal Dominant Polycystic Kidney Disease (ADPKD) (TEMPO3:4)

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Read our disclaimer for details. Identifier: NCT00428948
Recruitment Status : Completed
First Posted : January 30, 2007
Results First Posted : July 2, 2017
Last Update Posted : July 2, 2017
Otsuka Pharmaceutical Co., Ltd.
Information provided by (Responsible Party):
Otsuka Pharmaceutical Development & Commercialization, Inc.

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

Condition or disease Intervention/treatment Phase
Polycystic Kidney Disease, Autosomal Dominant Drug: Tolvaptan Drug: Placebo Phase 3

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.

Study Type : Interventional  (Clinical Trial)
Actual Enrollment : 1445 participants
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Primary Purpose: Treatment
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 Start Date : January 2007
Actual Primary Completion Date : January 2012
Actual Study Completion Date : January 2012

Resource links provided by the National Library of Medicine

MedlinePlus related topics: Kidney Diseases
Drug Information available for: Tolvaptan

Arm Intervention/treatment
Experimental: 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.
Drug: Tolvaptan
Tolvaptan was supplied as tablets.
Other Names:
  • OPC-41061
  • OPC-156

Placebo Comparator: Placebo
Participants received placebo (upon awakening and 9 hours later) orally for 36 months.
Drug: Placebo
Placebo was supplied as tablets.

Primary Outcome Measures :
  1. Percentage Change Per Year in Total Kidney Volume From Baseline to Month 36 [ Time Frame: Baseline to Month 36 ]
    Kidney volume was assessed in T1-weighted magnetic resonance images collected at each study site and sent to a central reviewing facility. At the central reviewing facility, blinded radiologists used proprietary software to measure the volume of both kidneys.

Secondary Outcome Measures :
  1. Number of ADPKD Clinical Progression Events Per 100 Follow-up Years From Baseline to Month 36 [ Time Frame: Baseline to Month 36 ]
    These ADPKD events in the key secondary Outcome Measure were selected on the basis of their potential relationship to progressing cystogenesis. Reducing the rate of cyst development and expansion would likely slow the progression of ADPKD. The 4 events were: (1) Onset or progression of hypertension (someone is hypertensive if they have > 139 mmHg systolic blood pressure [BP], > 89 mmHg diastolic BP, or if they are taking antihypertensive medication at any BP level); (2) severe renal pain requiring medical intervention; (3) worsening albuminuria (by category, see below); and (4) worsening renal function, defined as a 25% decrease in 1/serum creatinine from Baseline. Albuminuria was assessed using spot urine albumin/creatinine ratio measurements (all measurements in mg/mmol). Categories included normal (< 2.8 female or < 2.0 male), microalbuminuria (2.8-28 female or 2.0-20 male), and overt proteinuria (> 28 female or > 20 male.

  2. Change in Renal Function Per Year From Week 3 to Month 36 [ Time Frame: Week 3 to Month 36 ]
    Renal function was assessed using serum creatinine measurements and was estimated using 1/serum creatinine. The formula for 1/serum creatinine is: 1/Pcr, where Pcr = serum creatinine concentration (mg/dL). The change in renal function per year was based on the slope of change, obtained by regressing renal function data against time by subject.

  3. Change in Mean Arterial Blood Pressure Per Year in Non-hypertensive Participants From Baseline to Month 36 [ Time Frame: Baseline to Month 36 ]
    For participants who were non-hypertensive (systolic BP ≤ 139 mmHg and diastolic BP ≤ 89 mmHg without taking antihypertensive medications) at baseline, mean arterial blood pressure was measured at scheduled clinic visits up to the point of exposure to antihypertensive therapy for any reason. The change in mean arterial blood pressure per year was based on the slope of blood pressure, obtained by regressing blood pressure against time by subject.

  4. Area Under the Concentration-time Curve of Change in Renal Pain From Baseline to Month 36 [ Time Frame: At screening, Baseline, Day 1, every 4 months up to month 36/early tremination (ET), follow-up visit 1 and 2 ]
    Change from baseline in renal pain was assessed by a 0 to 10 pain scale as average area under the concentration-time curve (AUC) between baseline and the last trial visit or the last visit prior to initiating medical (eg, narcotic or anti-nociceptives [eg, tricyclic antidepressants]) or surgical therapy for pain. In the pain scale, score 0 represented no pain at all and score 10 represented the worst pain. A negative change score indicates less pain. AUC of renal pain was derived from renal pain scores within treatment period and was calculated using the trapezoidal rule, by dividing the number of days between the first and last assessment.

  5. Number of Hypertensive Events Per 100 Follow-up Years in Non-hypertensive Participants From Baseline to Month 36 [ Time Frame: Baseline to Month 36 ]
    A hypertensive event was defined as a change from non-hypertensive (systolic BP ≤ 139 mmHg and diastolic BP ≤ 89 mmHg without taking antihypertensive medications) status to 1 of 3 conditions: (1) High pre-hypertensive (systolic BP [sBP] > 129 mmHg and/or diastolic BP [dBP] > 84 mmHg), (2) hypertensive (sBP > 139 mmHg and/or dBP > 89 mmHg), or (3) requiring antihypertensive therapy.

  6. Percentage of Participants With a Clinically Sustained Decrease of Blood Pressure Leading to a Sustained Reduction in Antihypertensive Therapy From Baseline to Month 36 [ Time Frame: Baseline to Month 36 ]

Information from the National Library of Medicine

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Ages Eligible for Study:   18 Years to 50 Years   (Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No

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.

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its identifier (NCT number): NCT00428948

  Hide Study Locations
United States, Alabama
Coastal Clinical Research
Mobile, Alabama, United States, 36608
University of South Alabama
Mobile, Alabama, United States, 36617
United States, California
Apex Research of Riverside
Riverside, California, United States, 92503
Stanford University Medical Center
Stanford, California, United States, 94305-5114
United States, Colorado
University of Colorado Health Sciences Center
Denver, Colorado, United States, 80262
United States, Connecticut
Yale University School of Medicine
New Haven, Connecticut, United States, 06510
United States, Florida
Jacksonville Center for Clinical Research
Jacksonville, Florida, United States, 32216
Coastal Nephrology Associates Research Center, LLC
Port Charlotte, Florida, United States, 33952
United States, Georgia
Emory University School of Medicine
Atlanta, Georgia, United States, 30308
United States, Illinois
Northwestern University
Chicago, Illinois, United States, 60611
United States, Kansas
University of Kansas Medical Center
Kansas City, Kansas, United States, 66160
United States, Louisiana
Renal Associates of Baton Rough, L.L.C.
Baton Rouge, Louisiana, United States, 70809
United States, Maryland
John Hopkins School of Medicine
Baltimore, Maryland, United States, 21205
United States, Massachusetts
Tufts- New England Medical Center
Boston, Massachusetts, United States, 02111
Beth Israel Deaconess Medical Center
Boston, Massachusetts, United States, 02215
United States, Minnesota
Mayo Medical Center
Rochester, Minnesota, United States, 55905
United States, New York
Erie County Medical Center
Buffalo, New York, United States, 14215
Nephrology Associates of Westchester
Hawthorne, New York, United States, 10532
The Rogosin Institute
New York, New York, United States, 10021
Columbia University Medical Center
New York, New York, United States, 10032
United States, North Carolina
University of North Carolina, UNC, Kidney Center
Chapel Hill, North Carolina, United States, 27599
East Carolina University
Greenville, North Carolina, United States, 27834
United States, Ohio
Kidney and Hypertension Center
Cincinnati, Ohio, United States, 45220
University Hospitals of Cleveland/Case
Cleveland, Ohio, United States, 44106
United States, Oregon
Northwest Renal Clinic, Inc.
Portland, Oregon, United States, 97210
United States, Pennsylvania
University of Pennsylvania Medical Center
Philadelphia, Pennsylvania, United States, 19104
United States, South Carolina
Charleston Nephrology Associates
Charleston, South Carolina, United States, 29405
United States, Tennessee
Nephrology Associates, P.C.
Nashville, Tennessee, United States, 37205
Vanderbilt University Medical Center
Nashville, Tennessee, United States, 37232-1371
United States, Virginia
University of Virginia, Nephrology Clinical Research Center
Charlottesville, Virginia, United States, 22908
Instituto de Nefrología, Nefrology SA
Buenos Aires, Argentina, 1425
Hospital Municipal de Vicente Lopez, Dr Bernardo Houssay
Buenos Aires, Argentina, 1602
Hosptial Universitario Austral
Buenos Aires, Argentina, B1664INZ
Sanatorio Allende
Cordoba, Argentina, X5000IUP
Hospital Privado-Centro Medico de Cordoba
Cordoba, Argentina, X5016KEA
Royal Adelaide Hospital
Adelaide, Australia, 5000
Queen Elizebeth Hospital
Adelaide, Australia, 5011
Princess Alexandra Hospital
Brisbane, Australia, 4102
Royal Melbourne Hospital
Melbourne, Australia, 3050
Melbourne Renal Research Group
Melbourne, Australia, 3121
Royal Perth Hospital
Perth, Australia, 6054
Royal North Shore Hospital
Sydney, Australia, 2065
Westmead Hospital
Sydney, Australia, 2145
Ucl-St Luc
Brussels, Belgium, 1200
UZ Brussel
Brussel, Belgium, 1090
UZ Gent
Gent, Belgium, 9000
Canada, Nova Scotia
Queen Elizabeth II Health Science Center, Division of Nephrology
Halifax, Nova Scotia, Canada, B3H1v8
Canada, Quebec
Royal Victoria Hospital
Montreal, Quebec, Canada, H3A1A1
Hospital du Sacre- Coeur de Montreal
Montreal, Quebec, Canada, H4J1C5
Herlev Amtssygehus
Herlev, Denmark, 2730
Odense Universitetshospital
Odense, Denmark, 5000
CHU-Hopital Pellegrin
Bordeaux, France, 33076
CHU - Hôpital Clémenceau
Caen Cedex, France, 14033
Hôpital Edouard Herriot
Lyon Cedex 3, France, 69437
Hôpital de la Conception
Marseille, France, 13005
CHU - Hôpital Lapeyronie
Montpellier, France, 34295
Hopital Bichat-Claude Bernard
Paris, France, 75018
Centre Hospitalier Universitaire
Reims cedex, France, 51092
CHU - Hôpital Nord
Saint-Etienne Cedex 2, France, 42055
Hopital Rangueil
Toulouse Cedex 09, France, 31059
Universitätsklinikum Carl Gustav Carus
Dresden, Germany, 1307
Nephrologische Gemeinschaftspraxis/Dialysezentrum
Düsseldorf, Germany, 40210
Klinik für Nieren- und Hochdruckkrankheiten
Essen, Germany, 45147
Universitätsklinikum Freiburg
Freiburg, Germany, 78106
Universitätskliniken Heidelberg
Heidelberg, Germany, 69120
UH Erlangen/Nürnberg
Nuernberg, Germany, 90471
Ospedali Riuniti di Bergamo
Bergamo, Italy, 24128
Università Vita e Salute, Ospedale San Raffaele
Milano, Italy, 20132
Policlinico di Modena
Modena, Italy, 41100
Napoli, Italy, 80131
IRCCS Fondazione Salvatore Maugeri
Pavia, Italy, 27100
Fujita Health University Hospital
Toyoake, Aichi, Japan, 4701192
Hokkaido University Hospital
Sapporo, Hokkaido, Japan, 608648
Tokai University Hospital
Isehara, Kanagawa, Japan, 2591193
Toranomon Hospital Kajigaya
Kawasaki, Kanagawa, Japan, 2138587
Kitasato University Hospital
Sagamihara, Kanagawa, Japan, 2288555
Tohoku University Hospital
Sendai, Miyagi, Japan, 9808574
Osaka City University Hospital
Osaka-City, Osaka, Japan, 5458586
Osaka University Hospital
Suita, Osaka, Japan, 5650871
Shuwa General Hospital
Kasukabe, Saitama, Japan, 3440035
Saitama Medical Center
Kawagoe, Saitama, Japan, 3508500
Hamamatsu University School of Medicine, University Hospital
Hamamatsu, Shizuoka, Japan, 4313192
Jichi Medical School Hospital
Shimotsuke, Tochigi, Japan, 3290498
Tokyo Medical & Dental University Hospital, Faculty of Medicine
Bunkyo-ku, Tokyo, Japan, 1138519
Nippon Medical School Hospital
Bunkyo-ku, Tokyo, Japan, 1138603
Teikyo University Hospital
Itabashi-ku, Tokyo, Japan, 1738606
Toranomon Hospital
Minato-ku, Tokyo, Japan, 1058470
The Jikei University Hospital
Minato-Ku, Tokyo, Japan, 1058471
Kyorin University Hospital
Mitaka, Tokyo, Japan, 1818611
Tokyo Women's Medical University Hospital
Shinjuku-ku, Tokyo, Japan, 1628666
Chiba University Hospital
Chiba, Japan, 2608677
National Hospital Organization Chiba-East Hospital
Chiba, Japan, 2608712
Kyusyu University Hospital
Fukuoka, Japan, 8128582
Fukushima Medical University Hospital
Fukushima, Japan, 9601295
Hiroshima University Hospital
Hiroshima, Japan, 7348551
Kumamoto Univeristy Hospital
Kumamoto, Japan, 8608556
Kyoto University Hospital
Kyoto, Japan, 6068507
National Hospital Organization Kyoto Medical Center
Kyoto, Japan, 612-8555
Niigata University Medical & Dental Hospital
Niigata, Japan, 9518520
Ohno Memorial Hospital
Osaka, Japan, 5500015
Saitama Medical Center Jichi Medical University
Saitama, Japan, 3308503
VU Medisch Centrum
Amsterdam, Netherlands, 1081 HV
UMCG Groningen
Groningen, Netherlands, 9713 GZ
Oddział Nefrologiczny Stacja Dializ
Ciechanow, Poland, 06-400
Akademickie Centrum Kliniczne AMG
Gdansk, Poland, 80-952
Samodzielny Publiczny Szpital Kliniczny nr 1, Akademickie Centrum Kliniczne AMG
Gdansk, Poland, 80-952
Samodzielny Publiczny Zaklad Opieki Zdrowotnej, Szpital Uniwersytecki w Krakowie
Krakow, Poland, 31-501
SOP ZOZ Uniwersytecki Szpital Kliniczny
Lodz, Poland, 90-153
Samodzielny Publiczny Szpital Kliniczny nr 4 w Lublinie
Lublin, Poland, 20-954
Klinika Chorób Wewnętrznych i Nefrologii
Warsaw, Poland, 02-507
Międzyleski Szpital Specjalistyczny w Warszawie
Warsaw, Poland, 04-749
Szpital Praski p.w. Przemienienia Panskiego, Samodzielny Publiczny Zaklad Opieki Zdrowotnej
Warszawa, Poland, 03-401
Szpital Praski, Samodzielny Publiczny ZOZ
Warszawa, Poland, 03-401
Akademicki Szpital Kliniczny im J Mikulicza Radeckiego
Wroclaw, Poland, 50-417
Spitalul Clinic de Nefrologie Dr. Carol Davila
Bucharest, Romania, 10731
Institutul Clinic Fundeni
Bucharest, Romania, 22328
Spitalul Clinic "C.I.Parhon"
Iasi, Romania, 700503
Russian Federation
Kemerovo Medical Academy, Regional Clinical Hospital
Kemerovo, Russian Federation, 650061
City Clinical Hospital #52
Moscow, Russian Federation, 123060
City Mariinskiy Hospital
St. Petersburg, Russian Federation, 191104
Leningrad Regional Clinical Hospital
St.-Petersburg, Russian Federation, 194291
Tomsk Regional Clinical Hospital
Tomsk, Russian Federation, 634063
United Kingdom
Belfast City Hospital
Belfast, United Kingdom, BT9 7AB
Oueen Elizabeth Hospital
Birmingham, United Kingdom, B15 2TH
Sussex Renal Unit Royal Sussex County Hospital
Brighton, United Kingdom, BN2 5BE
Uhcw Mhs Trust
Coventry, United Kingdom, CV2 2DX
Royal Infirmary
Edinburgh, United Kingdom, EH16 4SA
Raigmore Hospital
Inverness, United Kingdom, IV2 3UJ
Royal Free and University College Medical School
London, United Kingdom, NW3 2PF
King's College Hospital
London, United Kingdom, SE5-9RS
St. George's Hospital
London, United Kingdom, SW170RE
Royal Hallamshire Hospital
Sheffield, United Kingdom, S5 7AU
Morriston Hospital
Swansea, United Kingdom, SA6 6NL
Sponsors and Collaborators
Otsuka Pharmaceutical Development & Commercialization, Inc.
Otsuka Pharmaceutical Co., Ltd.
Principal Investigator: Vicente Torres, MD, PhD Mayo Medical Center
Study Director: Frank Czerwiec, MD, PhD Otsuka Pharmaceutical Development and Commercialization, Inc.
Study Director: Osamu Sato Otsuka Pharmaceutical Corporation, Ltd. Japan


Publications automatically indexed to this study by Identifier (NCT Number):
Responsible Party: Otsuka Pharmaceutical Development & Commercialization, Inc. Identifier: NCT00428948     History of Changes
Other Study ID Numbers: 156-04-251
2006-002768-24 ( EudraCT Number )
First Posted: January 30, 2007    Key Record Dates
Results First Posted: July 2, 2017
Last Update Posted: July 2, 2017
Last Verified: May 2017

Keywords provided by Otsuka Pharmaceutical Development & Commercialization, Inc.:
ADPKD (Autosomal Dominant Polycystic Kidney Disease)

Additional relevant MeSH terms:
Kidney Diseases
Polycystic Kidney Diseases
Polycystic Kidney, Autosomal Dominant
Urologic Diseases
Kidney Diseases, Cystic
Abnormalities, Multiple
Congenital Abnormalities
Genetic Diseases, Inborn
Antidiuretic Hormone Receptor Antagonists
Molecular Mechanisms of Pharmacological Action
Natriuretic Agents
Physiological Effects of Drugs