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

May 30, 2017 updated by: Otsuka Pharmaceutical Development & Commercialization, Inc.

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

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

Study Overview

Status

Completed

Conditions

Intervention / Treatment

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

Enrollment (Actual)

1445

Phase

  • Phase 3

Contacts and Locations

This section provides the contact details for those conducting the study, and information on where this study is being conducted.

Study Locations

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

Participation Criteria

Researchers look for people who fit a certain description, called eligibility criteria. Some examples of these criteria are a person's general health condition or prior treatments.

Eligibility Criteria

Ages Eligible for Study

18 years to 50 years (Adult)

Accepts Healthy Volunteers

No

Genders Eligible for Study

All

Description

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.

Study Plan

This section provides details of the study plan, including how the study is designed and what the study is measuring.

How is the study designed?

Design Details

  • Primary Purpose: Treatment
  • Allocation: Randomized
  • Interventional Model: Parallel Assignment
  • Masking: Quadruple

Arms and Interventions

Participant Group / 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.

What is the study measuring?

Primary Outcome Measures

Outcome Measure
Measure Description
Time Frame
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.
Baseline to Month 36

Secondary Outcome Measures

Outcome Measure
Measure Description
Time Frame
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.
Baseline to Month 36
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.
Week 3 to Month 36
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.
Baseline to Month 36
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.
At screening, Baseline, Day 1, every 4 months up to month 36/early tremination (ET), follow-up visit 1 and 2
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.
Baseline to Month 36
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
Baseline to Month 36

Collaborators and Investigators

This is where you will find people and organizations involved with this study.

Sponsor

Otsuka Pharmaceutical Development & Commercialization, Inc.

Collaborators

Otsuka Pharmaceutical Co., Ltd.

Investigators

  • 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 and helpful links

The person responsible for entering information about the study voluntarily provides these publications. These may be about anything related to the study.

General Publications

Study record dates

These dates track the progress of study record and summary results submissions to ClinicalTrials.gov. Study records and reported results are reviewed by the National Library of Medicine (NLM) to make sure they meet specific quality control standards before being posted on the public website.

Study Major Dates

Study Start

January 1, 2007

Primary Completion (Actual)

January 1, 2012

Study Completion (Actual)

January 1, 2012

Study Registration Dates

First Submitted

January 26, 2007

First Submitted That Met QC Criteria

January 29, 2007

First Posted (Estimate)

January 30, 2007

Study Record Updates

Last Update Posted (Actual)

July 2, 2017

Last Update Submitted That Met QC Criteria

May 30, 2017

Last Verified

May 1, 2017

More Information

Terms related to this study

Keywords

Additional Relevant MeSH Terms

Other Study ID Numbers

  • 156-04-251
  • 2006-002768-24 (EudraCT Number)

This information was retrieved directly from the website clinicaltrials.gov without any changes. If you have any requests to change, remove or update your study details, please contact register@clinicaltrials.gov. As soon as a change is implemented on clinicaltrials.gov, this will be updated automatically on our website as well.

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