Polycystic Kidney Disease, Autosomal DominantPhase 3TEMPO3:4NCT00428948
Tolvaptan Phase 3 Efficacy and Safety Study in Autosomal Dominant Polycystic Kidney Disease (ADPKD)
A Phase 3 study testing Tolvaptan in people with Polycystic Kidney Disease, Autosomal Dominant, run by Otsuka Pharmaceutical Development & Commercialization, Inc. at 133 sites in 15 countries.
Trial summary
This study's purpose is to evaluate the long-term safety and efficacy of tolvaptan versus placebo in patients with ADPKD. Read more about this study
- Who is it for?
- Ages 18 to 50 years
- Conditions the study is for
- Polycystic Kidney Disease, Autosomal Dominant
- What is being tested?
- Tolvaptan
- Type of treatment
- Pill or oral medicine
- Could I receive a placebo?
- Yes, some participants may receive a placebo
- How many people
- 1,445 participants
- Where
- 133 sitesin 15 countries
- Study dates
- Jan 2007to Jan 2012
- Phase
- Phase 3
- Are there results?
- Yes, posted in the registrySummary in the doctors' view
Key requirements
Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.
- Ages 18 to 50 years
- All sexes
- No healthy volunteers
- Adult
Who may be able to join
- 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.
Who cannot join
- 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.
Trial locations and contacts
133 sites in 15 countries.
133 sites in 15 countries
United States30 sites
Emory University School of Medicine
Atlanta, Georgia, 30308
John Hopkins School of Medicine
Baltimore, Maryland, 21205
Renal Associates of Baton Rough, L.L.C.
Baton Rouge, Louisiana, 70809
Tufts- New England Medical Center
Boston, Massachusetts, 02111
Beth Israel Deaconess Medical Center
Boston, Massachusetts, 02215
Erie County Medical Center
Buffalo, New York, 14215
University of North Carolina, UNC, Kidney Center
Chapel Hill, North Carolina, 27599
Charleston Nephrology Associates
Charleston, South Carolina, 29405
University of Virginia, Nephrology Clinical Research Center
Charlottesville, Virginia, 22908
Northwestern University
Chicago, Illinois, 60611
Kidney and Hypertension Center
Cincinnati, Ohio, 45220
University Hospitals of Cleveland/Case
Cleveland, Ohio, 44106
University of Colorado Health Sciences Center
Denver, Colorado, 80262
East Carolina University
Greenville, North Carolina, 27834
Nephrology Associates of Westchester
Hawthorne, New York, 10532
Jacksonville Center for Clinical Research
Jacksonville, Florida, 32216
University of Kansas Medical Center
Kansas City, Kansas, 66160
Coastal Clinical Research
Mobile, Alabama, 36608
University of South Alabama
Mobile, Alabama, 36617
Nephrology Associates, P.C.
Nashville, Tennessee, 37205
Vanderbilt University Medical Center
Nashville, Tennessee, 37232-1371
Yale University School of Medicine
New Haven, Connecticut, 06510
The Rogosin Institute
New York, New York, 10021
Columbia University Medical Center
New York, New York, 10032
University of Pennsylvania Medical Center
Philadelphia, Pennsylvania, 19104
Coastal Nephrology Associates Research Center, LLC
Port Charlotte, Florida, 33952
Northwest Renal Clinic, Inc.
Portland, Oregon, 97210
Apex Research of Riverside
Riverside, California, 92503
Mayo Medical Center
Rochester, Minnesota, 55905
Stanford University Medical Center
Stanford, California, 94305-5114
Japan30 sites
Tokyo Medical & Dental University Hospital, Faculty of Medicine
Bunkyo-ku, Tokyo, 1138519
Nippon Medical School Hospital
Bunkyo-ku, Tokyo, 1138603
Chiba University Hospital
Chiba, 2608677
National Hospital Organization Chiba-East Hospital
Chiba, 2608712
Kyusyu University Hospital
Fukuoka, 8128582
Fukushima Medical University Hospital
Fukushima, 9601295
Hamamatsu University School of Medicine, University Hospital
Hamamatsu, Shizuoka, 4313192
Hiroshima University Hospital
Hiroshima, 7348551
Tokai University Hospital
Isehara, Kanagawa, 2591193
Shuwa General Hospital
Kasukabe, Saitama, 3440035
Saitama Medical Center
Kawagoe, Saitama, 3508500
Toranomon Hospital Kajigaya
Kawasaki, Kanagawa, 2138587
Kumamoto Univeristy Hospital
Kumamoto, 8608556
Kyoto University Hospital
Kyoto, 6068507
National Hospital Organization Kyoto Medical Center
Kyoto, 612-8555
Toranomon Hospital
Minato-ku, Tokyo, 1058470
The Jikei University Hospital
Minato-Ku, Tokyo, 1058471
Kyorin University Hospital
Mitaka, Tokyo, 1818611
Niigata University Medical & Dental Hospital
Niigata, 9518520
Osaka City University Hospital
Osaka, Osaka, 5458586
Ohno Memorial Hospital
Osaka, 5500015
Kitasato University Hospital
Sagamihara, Kanagawa, 2288555
Saitama Medical Center Jichi Medical University
Saitama, 3308503
Hokkaido University Hospital
Sapporo, Hokkaido, 608648
Tohoku University Hospital
Sendai, Miyagi, 9808574
Jichi Medical School Hospital
Shimotsuke, Tochigi, 3290498
Tokyo Women's Medical University Hospital
Shinjuku-ku, Tokyo, 1628666
Osaka University Hospital
Suita, Osaka, 5650871
Teikyo University Hospital
tabashi City, Tokyo, 1738606
Fujita Health University Hospital
Toyoake, Aichi-ken, 4701192
Poland11 sites
Oddział Nefrologiczny Stacja Dializ
Ciechanów, 06-400
Akademickie Centrum Kliniczne AMG
Gdansk, 80-952
Samodzielny Publiczny Szpital Kliniczny nr 1, Akademickie Centrum Kliniczne AMG
Gdansk, 80-952
Samodzielny Publiczny Zaklad Opieki Zdrowotnej, Szpital Uniwersytecki w Krakowie
Krakow, 31-501
SOP ZOZ Uniwersytecki Szpital Kliniczny
Lodz, 90-153
Samodzielny Publiczny Szpital Kliniczny nr 4 w Lublinie
Lublin, 20-954
Klinika Chorób Wewnętrznych i Nefrologii
Warsaw, 02-507
Szpital Praski p.w. Przemienienia Panskiego, Samodzielny Publiczny Zaklad Opieki Zdrowotnej
Warsaw, 03-401
Szpital Praski, Samodzielny Publiczny ZOZ
Warsaw, 03-401
Międzyleski Szpital Specjalistyczny w Warszawie
Warsaw, 04-749
Akademicki Szpital Kliniczny im J Mikulicza Radeckiego
Wroclaw, 50-417
United Kingdom11 sites
Belfast City Hospital
Belfast, BT9 7AB
Oueen Elizabeth Hospital
Birmingham, B15 2TH
Sussex Renal Unit Royal Sussex County Hospital
Brighton, BN2 5BE
Uhcw Mhs Trust
Coventry, CV2 2DX
Royal Infirmary
Edinburgh, EH16 4SA
Raigmore Hospital
Inverness, IV2 3UJ
Royal Free and University College Medical School
London, NW3 2PF
King's College Hospital
London, SE5-9RS
St. George's Hospital
London, SW170RE
Royal Hallamshire Hospital
Sheffield, S5 7AU
Morriston Hospital
Swansea, SA6 6NL
France9 sites
CHU-Hopital Pellegrin
Bordeaux, 33076
CHU - Hôpital Clémenceau
Caen, 14033
Hôpital Edouard Herriot
Lyon, 69437
Hôpital de la Conception
Marseille, 13005
CHU - Hôpital Lapeyronie
Montpellier, 34295
Hopital Bichat-Claude Bernard
Paris, 75018
Centre Hospitalier Universitaire
Reims, 51092
CHU - Hôpital Nord
Saint-Etienne, 42055
Hopital Rangueil
Toulouse, 31059
Australia8 sites
Royal Adelaide Hospital
Adelaide, 5000
Queen Elizebeth Hospital
Adelaide, 5011
Princess Alexandra Hospital
Brisbane, 4102
Royal Melbourne Hospital
Melbourne, 3050
Melbourne Renal Research Group
Melbourne, 3121
Royal Perth Hospital
Perth, 6054
Royal North Shore Hospital
Sydney, 2065
Westmead Hospital
Sydney, 2145
Germany6 sites
Universitätsklinikum Carl Gustav Carus
Dresden, 1307
Nephrologische Gemeinschaftspraxis/Dialysezentrum
Düsseldorf, 40210
Klinik für Nieren- und Hochdruckkrankheiten
Essen, 45147
Universitätsklinikum Freiburg
Freiburg im Breisgau, 78106
Universitätskliniken Heidelberg
Heidelberg, 69120
UH Erlangen/Nürnberg
Nuremberg, 90471
Argentina5 sites
Instituto de Nefrología, Nefrology SA
Buenos Aires, 1425
Hospital Municipal de Vicente Lopez, Dr Bernardo Houssay
Buenos Aires, 1602
Hosptial Universitario Austral
Buenos Aires, B1664INZ
Sanatorio Allende
Córdoba, X5000IUP
Hospital Privado-Centro Medico de Cordoba
Córdoba, X5016KEA
Italy5 sites
Ospedali Riuniti di Bergamo
Bergamo, 24128
Università Vita e Salute, Ospedale San Raffaele
Milan, 20132
Policlinico di Modena
Modena, 41100
Policlinico
Naples, 80131
IRCCS Fondazione Salvatore Maugeri
Pavia, 27100
Russia5 sites
Kemerovo Medical Academy, Regional Clinical Hospital
Kemerovo, 650061
City Clinical Hospital #52
Moscow, 123060
City Mariinskiy Hospital
Saint Petersburg, 191104
Leningrad Regional Clinical Hospital
Saint Petersburg, 194291
Tomsk Regional Clinical Hospital
Tomsk, 634063
Belgium3 sites
UZ Brussel
Brussels, 1090
Ucl-St Luc
Brussels, 1200
UZ Gent
Ghent, 9000
Canada3 sites
Queen Elizabeth II Health Science Center, Division of Nephrology
Halifax, Nova Scotia, B3H1v8
Royal Victoria Hospital
Montreal, Quebec, H3A1A1
Hospital du Sacre- Coeur de Montreal
Montreal, Quebec, H4J1C5
Romania3 sites
Spitalul Clinic de Nefrologie Dr. Carol Davila
Bucharest, 10731
Institutul Clinic Fundeni
Bucharest, 22328
Spitalul Clinic "C.I.Parhon"
Iași, 700503
Denmark2 sites
Herlev Amtssygehus
Herlev, 2730
Odense Universitetshospital
Odense, 5000
Netherlands2 sites
VU Medisch Centrum
Amsterdam, 1081 HV
UMCG Groningen
Groningen, 9713 GZ
About this study
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
This study's purpose is to evaluate the long-term safety and efficacy of tolvaptan versus placebo in patients with ADPKD.
Read the 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.
- Being tested
- Tolvaptan, Placebo
- Keywords
- ADPKD, Polycystic, kidney, ADPKD (Autosomal Dominant Polycystic Kidney Disease)
- Medical subject headings
- Polycystic Kidney, Autosomal Dominant
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
TolvaptanDrug
Also called OPC-41061, OPC-156
Tolvaptan was supplied as tablets.
PlaceboDrug
Placebo was supplied as tablets.
| Study group | Role | What they receive |
|---|---|---|
| Tolvaptan | Experimental | 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. Receives: Drug: Tolvaptan |
| Placebo | Placebo comparator | Participants received placebo (upon awakening and 9 hours later) orally for 36 months. Receives: Drug: Placebo |
What is being measured
The primary outcome is the main question the study is designed to answer.
Percentage Change Per Year in Total Kidney Volume From 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.
Measured: Baseline to Month 36
Secondary outcomes (6)
Number of ADPKD Clinical Progression Events Per 100 Follow-up Years From 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.
Measured: Baseline to Month 36
Change in Renal Function Per Year From 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.
Measured: Week 3 to Month 36
Change in Mean Arterial Blood Pressure Per Year in Non-hypertensive Participants From 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.
Measured: Baseline to Month 36
Area Under the Concentration-time Curve of Change in Renal Pain From Baseline to Month 36
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.
Measured: 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
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.
Measured: 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
Measured: Baseline to Month 36
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted30 Jan 2007 (estimated)
- Study startJan 2007
- Primary completionJan 2012
- Study completionJan 2012
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Posted resultsParticipant flow, outcome measures and adverse events reported by the sponsor.
- Publications (22)Papers the sponsor has linked to this study.
- Other trials for Polycystic Kidney Disease, Autosomal DominantStudies of the same condition, open and under way.
- More trials run by Otsuka Pharmaceutical Development & Commercialization, Inc.The sponsor's other registered studies.
- What the trial phases meanHow a treatment moves from first tests in people to approval.
More details
For doctors and researchers: how the study is designed, who runs it, and its registry IDs.
Study design
- Study type
- Interventional
- Phase
- Phase 3
- Primary purpose
- Treatment
- Allocation
- Randomised
- Intervention model
- Parallel groups
- Masking
- Quadruple blind
- Who is masked
- Participant, Care provider, Investigator, Outcomes assessor
- Enrolment
- 1,445 participants (actual)
Sponsor and investigators
- Sponsor type
- Industry (pharma, biotech, devices)
- Collaborators
- Otsuka Pharmaceutical Co., Ltd.
- Responsible party
- Sponsor
- Investigators
- Vicente Torres, MD, PhD, Principal investigator, Mayo Medical CenterFrank Czerwiec, MD, PhD, Study director, Otsuka Pharmaceutical Development & Commercialization, Inc.Osamu Sato, Study director, Otsuka Pharmaceutical Corporation, Ltd. Japan
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT00428948
- Sponsor's protocol ID
- 156-04-251
- Other IDs
- 2006-002768-24
- Acronym
- TEMPO3:4
- Status last verified
- May 2017
- First submitted
- 26 Jan 2007
- Last updated
- 2 Jul 2017
- Results posted
- Yes, on ClinicalTrials.gov
- Data monitoring committee
- Yes
Publications
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.
PubMed 14502283Torres 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.
PubMed 14991049Torres 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.
PubMed 21333426Torres 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.
PubMed 23121377Watkins 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.
PubMed 26188764Kher 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.
PubMed 23534570Spital 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.
PubMed 23534569Torres 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.
PubMed 23534568Jouret 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.
PubMed 23534572Sexton 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.
PubMed 23534571St 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.
PubMed 39356039Ivaturi 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.
PubMed 38857379Mochizuki 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.
PubMed 38414126Gobburu 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.
PubMed 37986188Lioudis 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.
PubMed 37349694
Study at a glance
From the registry record, last updated by the sponsor on 2 Jul 2017. Recruitment status is as the sponsor reported it: confirm with the study team.
- 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
- ClinicalTrials.gov ID
- NCT00428948
- Acronym / sponsor ID
- TEMPO3:4 / 156-04-251
- Keywords
- ADPKD, Polycystic, kidney, ADPKD (Autosomal Dominant Polycystic Kidney Disease)
- Phase
- Phase 3
- Study type
- Interventional
- Recruitment status
- Completed
- Enrolment
- 1,445 participants (actual)
- Lead sponsor
- Otsuka Pharmaceutical Development & Commercialization, Inc.Industry (pharma, biotech, devices)
- Collaborators
- Otsuka Pharmaceutical Co., Ltd.
- Study start
- Jan 2007
- Primary completion
- Jan 2012 (actual)
- Study completion
- Jan 2012 (actual)
- First posted
- 30 Jan 2007 (estimated)
- Results
- Posted 2 Jul 2017
Clinical summary
The research question as the sponsor registered it. This describes what the study plans to test, not what it found.
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.
Study design
- Primary purpose
- Treatment
- Allocation
- Randomised
- Intervention model
- Parallel groups
- Masking
- Quadruple blind (participant, care provider, investigator, outcomes assessor)
- Number of arms
- 2
| Arm | Type | Receives |
|---|---|---|
| Tolvaptan | Experimental | Drug: TolvaptanParticipants 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. |
| Placebo | Placebo comparator | Drug: PlaceboParticipants received placebo (upon awakening and 9 hours later) orally for 36 months. |
Who may qualify
- Ages
- 18 to 50 years
- Sex
- All
- Healthy volunteers
- Not accepted
- Age groups
- Adult
Key inclusion criteria (5 listed)
- 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.
Key exclusion criteria (7 listed)
- 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.
Eligibility is decided by the study team after screening; this overview does not establish that a patient qualifies. Full inclusion and exclusion criteria.
Interventions
| Intervention | Type | Arms |
|---|---|---|
| TolvaptanAlso: OPC-41061, OPC-156Tolvaptan was supplied as tablets. | Drug | Tolvaptan |
| PlaceboPlacebo was supplied as tablets. | Drug | Placebo |
Primary outcome
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.
6 secondary outcomes
Number of ADPKD Clinical Progression Events Per 100 Follow-up Years From Baseline to Month 36
Time frame: Baseline to Month 36
Change in Renal Function Per Year From Week 3 to Month 36
Time frame: 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
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
Number of Hypertensive Events Per 100 Follow-up Years in Non-hypertensive Participants From Baseline to Month 36
Time frame: 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
Results and safety
Loading the posted results from ClinicalTrials.gov…
Research links
- Official record on ClinicalTrials.govLast updated by the sponsor 2 Jul 2017.
- Posted resultsParticipant flow, baseline, all outcome measures and adverse events.
- Background: PubMed 14502283Gattone 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.
- Background: PubMed 14991049Torres 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.
- Background: PubMed 21333426Torres 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.
- Background: PubMed 23121377Torres 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.
- Background: PubMed 26188764Watkins 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.
- Background: PubMed 23534570Kher 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.
- Background: PubMed 23534569Spital 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.
- Background: PubMed 23534568Torres 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.
- Background: PubMed 23534572Jouret 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.
- Background: PubMed 23534571Sexton 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.
- Derived from this study: PubMed 39356039St 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.
- Derived from this study: PubMed 38857379Ivaturi 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.
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Referral and contact
AzTrials does not enrol participants or take referrals. Contact the study team or a site listed below; they decide who can take part. This study is not recruiting at the moment.
Vicente Torres, MD, PhD principal investigator
Mayo Medical Center
Frank Czerwiec, MD, PhD study director
Otsuka Pharmaceutical Development & Commercialization, Inc.
Osamu Sato study director
Otsuka Pharmaceutical Corporation, Ltd. Japan
133 sites in 15 countries: see every site and its status.
Questions about this trial
What is this clinical trial studying?
A Phase 3 study testing Tolvaptan in people with Polycystic Kidney Disease, Autosomal Dominant, run by Otsuka Pharmaceutical Development & Commercialization, Inc. at 133 sites in 15 countries.
The full registered description is in the About this study section and the official record.
Who may be eligible to take part?
The sponsor lists 5 inclusion and 7 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.
Is this clinical trial currently recruiting?
The record says: finished, as of the sponsor's last update on 2 Jul 2017. Status can change between updates, so confirm with the study contact before making plans.
Where is the study taking place?
The record lists 133 sites in United States, Japan, Poland, United Kingdom, France and 10 more countries. Whether a site is taking part right now should be confirmed with that site. See every site.
What are the possible benefits and risks?
They depend on the study and the treatment, and no study can promise a benefit. Some participants in this study may receive a placebo. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.
What does this phase mean?
Phase 3 studies compare the treatment with the current standard treatment or a placebo in a large group, to confirm how well it works and watch for side effects.
Not every study follows the same path, and some studies (observational studies, device studies) have no phase.
Are results available for this study?
Yes. Results are posted in the registry (first posted 2 Jul 2017). A summary is in the For doctors view, and the full results are on ClinicalTrials.gov.
How can a doctor refer a patient or contact the research team?
The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.
What does the primary outcome measure?
Percentage Change Per Year in Total Kidney Volume From Baseline to Month 36 (time frame: Baseline to Month 36). It is what the study was designed to measure, not a finding.
Where can I read the original study information?
On the ClinicalTrials.gov record for NCT00428948, which also lists 22 linked publications.
Does a listing mean the treatment is approved or proven to work?
No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.
How often is this information updated?
AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 2 Jul 2017.