Tolvaptan Extension Study in Participants With ADPKD (TEMPO 4/4)

Multi-center, Open-label, Extension Study to Evaluate the Long-term Efficacy and Safety of Oral Tolvaptan Tablet Regimens in Subjects With Autosomal Dominant Polycystic Kidney Disease (ADPKD)

To demonstrate whether tolvaptan modifies ADPKD progression as measured by changes from Baseline (from Study 156-04-251) in total kidney volume (TKV) and renal function.

Study Overview

• Status: Completed
• Conditions: Autosomal Dominant Polycystic Kidney Disease (ADPKD)
• Intervention / Treatment: Drug: Tolvaptan

• Study Type: Interventional
• Enrollment (Actual): 1083
• Phase: Phase 3

Contacts and Locations

Study Locations

• Argentina
  • Buenos Aires, Argentina, C1425APQ
    • Otsuka Investigational Site
  • Cordoba, Argentina, 5000
    • Otsuka Investigational Site
  • Córdoba, Argentina, X5016KEH
    • Otsuka Investigational Site
  • Buenos Aires
    • C.a.b.a., Buenos Aires, Argentina, C1429BWN
      • Otsuka Investigational Site
    • Pilar, Buenos Aires, Argentina, B1629ODT
      • Otsuka Investigational Site
• Australia
  • New South Wales
    • St. Leonards, New South Wales, Australia, 2065
      • Otsuka Investigational Site
    • Westmead, New South Wales, Australia, 2145
      • Otsuka Investigational Site
  • Queensland
    • Woolloongabba, Queensland, Australia, 4102
      • Otsuka Investigational Site
  • South Australia
    • Adelaide, South Australia, Australia, 5000
      • Otsuka Investigational Site
  • Victoria
    • Parkville, Victoria, Australia, 3050
      • Otsuka Investigational Site
  • Western Australia
    • Perth, Western Australia, Australia, 6000
      • Otsuka Investigational Site
• Belgium
  • Brussels, Belgium, 1200
    • Otsuka Investigational Site
  • Brussels, Belgium, 1090
    • Otsuka Investigational Site
  • Gent, Belgium, 9000
    • Otsuka Investigational Site
• Canada
  • Nova Scotia
    • Halifax, Nova Scotia, Canada, B3H 1V8
      • Otsuka Investigational Site
  • Quebec
    • Montreal, Quebec, Canada, H3A1A1
      • Otsuka Investigational Site
    • Montreal, Quebec, Canada, H4J1C5
      • Otsuka Investigational Site
• France
  • Bordeaux, France, 33076
    • Otsuka Investigational Site
  • Caen Cedex, France, 14033
    • Otsuka Investigational Site
  • Lyon Cedex 3, France, 69437
    • Otsuka Investigational Site
  • Paris, France, 75018
    • Otsuka Investigational Site
  • Reims Cedex, France, 51092
    • Otsuka Investigational Site
  • Saint-Etienne Cedex 2, France, 42055
    • Otsuka Investigational Site
  • Toulouse Cedex 09, France, 31059
    • Otsuka Investigational Site
• Germany
  • Dresden, Germany, 01307
    • Otsuka Investigational Site
  • Dusseldorf, Germany, 40210
    • Otsuka Investigational Site
  • Essen, Germany, 45147
    • Otsuka Investigational Site
  • Heidelberg, Germany, 69120
    • Otsuka Investigational Site
  • Nurnberg, Germany, 90471
    • Otsuka Investigational Site
• Italy
  • Bergamo, Italy, 24127
    • Otsuka Investigational Site
  • Milano, Italy, 20132
    • Otsuka Investigational Site
  • Modena, Italy, 41100
    • Otsuka Investigational Site
  • Napoli, Italy, 80131
    • Otsuka Investigational Site
  • Pavia, Italy, 27100
    • Otsuka Investigational Site
• Netherlands
  • Amsterdam, Netherlands, 1081 HV
    • Otsuka Investigational Site
  • Groningen, Netherlands, 9713 GZ
    • Otsuka Investigational Site
• Poland
  • Ciechanów, Poland, 06-400
    • Otsuka Investigational Site
  • Krakow, Poland, 31-501
    • Otsuka Investigational Site
  • Lodz, Poland, 90-153
    • Otsuka Investigational Site
  • Lublin, Poland, 20-954
    • Otsuka Investigational Site
  • Szczecin, Poland, 70-111
    • Otsuka Investigational Site
  • Warszawa, Poland, 04-749
    • Otsuka Investigational Site
  • Wrocław, Poland, 50-556
    • Otsuka Investigational Site
• Romania
  • Bucuresti, Romania, 010731
    • Otsuka Investigational Site
  • Bucuresti, Romania, 022328
    • Otsuka Investigational Site
  • Iasi, Romania, 700504
    • Otsuka Investigational Site
• Russian Federation
  • Kemerovo, Russian Federation, 650029
    • Otsuka Investigational Site
  • St. Petersburg, Russian Federation, 191104
    • Otsuka Investigational Site
  • Tomsk, Russian Federation, 634063
    • Otsuka Investigational Site
• United Kingdom
  • Belfast, United Kingdom, BT9 7AB
    • Otsuka Investigational Site
  • Birmingham, United Kingdom, B15 2TH
    • Otsuka Investigational Site
  • Brighton, United Kingdom, BN2 5BE
    • Otsuka Investigational Site
  • Coventry, United Kingdom, CV2 2DX
    • Otsuka Investigational Site
  • Edinburgh, United Kingdom, EH16 4SA
    • Otsuka Investigational Site
  • Inverness, United Kingdom, IV2 3UJ
    • Otsuka Investigational Site
  • London, United Kingdom, NW3 2QG
    • Otsuka Investigational Site
  • London, United Kingdom, SW17 0QT
    • Otsuka Investigational Site
  • London, United Kingdom, SE5 9RS
    • Otsuka Investigational Site
  • Swansea, United Kingdom, SA6 6NL
    • Otsuka Investigational Site
• United States
  • Alabama
    • Mobile, Alabama, United States, 36617
      • Otsuka Investigational Site
  • Arizona
    • Peoria, Arizona, United States, 85381
      • Otsuka Investigational Site
    • Tempe, Arizona, United States, 85284
      • Otsuka Investigational Site
  • California
    • Los Angeles, California, United States, 90025
      • Otsuka Investigational Site
    • Palo Alto, California, United States, 94304
      • Otsuka Investigational Site
    • San Diego, California, United States, 92108
      • Otsuka Investigational Site
  • Colorado
    • Aurora, Colorado, United States, 80045
      • Otsuka Investigational Site
  • Connecticut
    • New Haven, Connecticut, United States, 06510
      • Otsuka Investigational Site
  • Florida
    • Jacksonville, Florida, United States, 32216
      • Otsuka Investigational Site
    • Port Charlotte, Florida, United States, 33952
      • Otsuka Investigational Site
  • Georgia
    • Atlanta, Georgia, United States, 30322
      • Otsuka Investigational Site
    • Augusta, Georgia, United States, 30909
      • Otsuka Investigational Site
  • Illinois
    • Chicago, Illinois, United States, 60611
      • Otsuka Investigational Site
  • Kansas
    • Kansas City, Kansas, United States, 66160
      • Otsuka Investigational Site
  • Louisiana
    • Baton Rouge, Louisiana, United States, 70808
      • Otsuka Investigational Site
  • Maryland
    • Baltimore, Maryland, United States, 21205
      • Otsuka Investigational Site
    • Rockville, Maryland, United States, 20850
      • Otsuka Investigational Site
  • Massachusetts
    • Boston, Massachusetts, United States, 02111
      • Otsuka Investigational Site
  • Michigan
    • Detroit, Michigan, United States, 48236
      • Otsuka Investigational Site
  • Minnesota
    • Minneapolis, Minnesota, United States, 55404
      • Otsuka Investigational Site
    • Rochester, Minnesota, United States, 55905
      • Otsuka Investigational Site
  • New Jersey
    • Voorhees, New Jersey, United States, 08043
      • Otsuka Investigational Site
  • New York
    • Buffalo, New York, United States, 14215
      • Otsuka Investigational Site
    • Hawthorne, New York, United States, 10532
      • Otsuka Investigational Site
    • New York, New York, United States, 10021
      • Otsuka Investigational Site
    • New York, New York, United States, 10032
      • Otsuka Investigational Site
  • North Carolina
    • Chapel Hill, North Carolina, United States, 27599
      • Otsuka Investigational Site
  • Ohio
    • Cincinnati, Ohio, United States, 45246
      • Otsuka Investigational Site
    • Cleveland, Ohio, United States, 44106
      • Otsuka Investigational Site
  • Oregon
    • Portland, Oregon, United States, 97210
      • Otsuka Investigational Site
  • Pennsylvania
    • Bethlehem, Pennsylvania, United States, 18017
      • Otsuka Investigational Site
    • Philadelphia, Pennsylvania, United States, 19104
      • Otsuka Investigational Site
  • South Carolina
    • Anderson, South Carolina, United States, 29621
      • Otsuka Investigational Site
  • Tennessee
    • Nashville, Tennessee, United States, 37205
      • Otsuka Investigational Site
    • Nashville, Tennessee, United States, 37232
      • Otsuka Investigational Site
  • Texas
    • Arlington, Texas, United States, 76015
      • Otsuka Investigational Site
    • McAllen, Texas, United States, 78503
      • Otsuka Investigational Site
  • Virginia
    • Charlottesville, Virginia, United States, 22908
      • Otsuka Investigational Site

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (ADULT, OLDER_ADULT)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

- Participants who had successfully completed a Phase 1, 2, or 3 tolvaptan ADPKD or renal impairment study, with a confirmed diagnosis of ADPKD from prior studies [either 156-04-251 (NCT00428948) or 156-04-250 (NCT00413777), 156-06-260, 156-09-284 (NCT01336972), 156-09-285 (NCT01210560), and 156-09-290 (NCT01451827)].

Exclusion Criteria:

• Participants unable to provide written informed consent.
• Participants (men or women) would not adhere to the reproductive precautions as outlined in the Informed Consent Form.
• Participants (women only) with a positive urine pregnancy test.
• Participants who were pregnant or breast-feeding.
• Participants unable to take oral medications.
• Participants who had allergic reactions to tolvaptan or chemically related structures such as benzazepines (benzazepril, conivaptan, fenoldopam mesylate, or mirtazapine).
• Participants with disorders in thirst recognition or an inability to access fluids.
• Participants with critical electrolyte imbalances, as determined by the investigator
• Participants with or at risk of significant hypovolemia, as determined by investigator.
• Participants with significant anemia, as determined by investigator.
• Participants with a history of substance abuse (within the last 3 years).
• Participants who were taking other experimental (that is, non-marketed) therapies or were participating in another clinical drug or device study; participating in the off-drug follow-up period of another ADPKD trial with tolvaptan was permitted.
• Participants unable to complete magnetic resonance imaging (MRI) assessments (for example, participants with ferro-magnetic prostheses, aneurysm clips, severe claustrophobia).
• Participants who had taken a vasopressin antagonist (outside of previous participation in a tolvaptan study).
• Participants unable to comply with anti-hypertensive or other important medical therapy.
• Participants with advanced diabetes.
• Participants who were taking medications or had an illness that could confound endpoint assessments (including taking approved therapies for the purpose of affecting polycystic kidney disease [PKD] cysts).

Study Plan

How is the study designed?

Design Details

• Primary Purpose: TREATMENT
• Allocation: NA
• Interventional Model: SINGLE_GROUP
• Masking: NONE

Number of Arms

1

Arms and Interventions

Participant Group / Arm

Intervention / Treatment

EXPERIMENTAL: Tolvaptan; Participants received a daily split-dose of tolvaptan titrated to the maximally tolerated dose, starting daily tolvaptan dose of 45 milligrams (mg) in the morning [AM]/15 mg in the evening [PM] titrated to 60 mg [AM]/30 mg [PM], then 90 mg [AM]/30 mg [PM] based on tolerability were given orally twice daily until the last participant originating from prior studies (either 156-04-251 or 156-04-250, 156-06-260, 156-09-284, 156-09-285, and 156-09-290) who was eligible for efficacy analysis completed the Month 24.

Drug: Tolvaptan; Tablets of 15 or 30 mg; Other Names: OPC-41061; Jinarc

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Percent Change From the Baseline in Total Kidney Volume (TKV) for Study 156-04-251 Participants Enrolled in This Study (156-08-271)	Total kidney volume is a measure of disease progression in the ADPKD participants. 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, radiologists used proprietary software to measure the volume of both kidneys in participants continuing from previous study (156-04-251) at Month 24 of this study (156-08-271) comparing change in TKV for the early-treated (those previously treated with tolvaptan) to delayed-treated (those previously treated with placebo). The percent change in the volume of both kidneys combined was analysed using mixed-effect model repeated measures (MMRM) analysis and reported. This outcome measure was analyzed only in the participants enrolled from the previous study - 156-04-251, as pre-specified in the protocol.	Study Baseline (Prior to Day 1 in Study 156-04-251) to Month 24 in this study (Study 156-08-271)

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Change From the Baseline in Estimated Glomerular Filtration Rate (eGFR) as Assessed by Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) for Study 156-04-251 Participants Enrolled in This Study (156-08-271)	Estimated Glomerular Filtration Rate (eGFR) according to CKD-EPI is calculated using the CKD-EPI equation, expressed as a single equation, is GFR = 141 × min (serum creatinine [Scr]/κ, 1)α × max(Scr/κ, 1)^-1.209 × 0.993 Age × 1.018 (if female) × 1.159 (if black), where Scr is serum creatinine, κ is 0.7 for females and 0.9 for males, α is -0.329 for females and -0.411 for males, min indicates the minimum of Scr/ĸ or 1, and max indicates the maximum of Scr/κ or 1 in participants continuing from previous study (156-04-251) at Month 24 of this study (156-08-271) comparing change in eGFR for the early-treated (those previously treated with tolvaptan) to delayed-treated (those previously treated with placebo). MMRM was used for the analysis. This outcome measure was analyzed only in the participants enrolled from the previous - 156-04-251, as pre-specified in the protocol.	Study Baseline (Prior to Day 1 in Study 156-04-251) to Month 24 in this study (Study 156-08-271)
Annualized Slope of Total Kidney Volume (TKV) for Study 156-04-251 Participants Enrolled in Study 156-08-271	Annualized slope of TKV is a measure of renal function and disease progression in ADPKD participants. The annualized slope is calculated as percentage of growth in TKV (measured in mL by MRI) divided by each participant's years of participation for all participants was calculated using MMRM analysis in participants continuing from previous study (156-04-251) at Month 24 of this study (156-08-271) comparing annualized slope of TKV for the early-treated (those previously treated with tolvaptan) to delayed-treated (those previously treated with placebo). This outcome measure was analyzed only in the participants enrolled from the previous study - 156-04-251, as pre-specified in the protocol.	Study Baseline (Prior to Day 1 in Study 156-08-271) to Month 24 in this study (Study 156-08-271)
Annualized Slope of eGFR (CKD-EPI) for Study 156-04-251 Participants Enrolled in Study 156-08-271	Annualized slope of eGFR (CKD-EPI) is a measure of renal function and disease progression in ADPKD participants. The annualized slope of eGFR (CKD-EPI) (divided by each participant's years of participation) for all participants was calculated using MMRM analysis in participants continuing from previous study (156-04-251) at Month 24 of this study (156-08-271) comparing change in TKV for the early-treated (those previously treated with tolvaptan) to delayed-treated (those previously treated with placebo). eGFR was calculated using the Chronic Kidney Disease-Epidemiology (CKD-EPI) formula. This outcome measure was analyzed only in the participants enrolled from the previous study - 156-04-251, as pre-specified in the protocol.	Study Baseline (Prior to Day 1 in Study 156-08-271) to Month 24 (Study 156-08-271)
Annualized TKV Slope for Study 156-04-251 Placebo Participants Enrolled in Study 156-08-271	Annualized slope of TKV is a measure of renal function and disease progression in ADPKD participants. The annualized slope is calculated as percentage of growth in TKV (measured in mL by MRI) divided by each participant's years of participation, using MMRM analysis to compare annualized slope of TKV for the participants who received placebo in previous study (156-04-251) to annualized slope of TKV for the same participants who received tolvaptan in this study (156-08-271). This outcome measure was analyzed only in the participants enrolled from the previous study - 156-04-251 and who received placebo in the previous study, as pre-specified in the protocol.	Tolvaptan, Delayed Treated: Baseline to Month 24 in Study 156-08-271; Placebo: Baseline to Month 36 in Study 156-04-251
Annualized Slope of Renal Function (eGFRCKD-EPI) for Study 156-04-251 Placebo Participants Enrolled in Study 156-08-271	Annualized slope of eGFR (CKD-EPI) is a measure of renal function and disease progression in ADPKD participants. The annualized slope of eGFR (calculated using CKD-EPI formula) divided by each participant's years of participation, using MMRM analysis to compare annualized slope of eGFR (CKD-EPI) for the participants who received placebo in previous study (156-04-251) to the annualized slope of eGFR (CKD-EPI) for the same participants who received tolvaptan in this study (156-08-271). This outcome measure was analyzed only in the participants enrolled from the previous study - 156-04-251 who received placebo in previous study and received tolvaptan in this study, as pre-specified in the protocol.	Tolvaptan, Delayed Treated: Baseline to Month 24 in Study 156-08-271; Placebo: Baseline to Month 36 in Study 156-04-251

Collaborators and Investigators

• Sponsor: Otsuka Pharmaceutical Development & Commercialization, Inc.

Publications and helpful links

General Publications

• 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.
• Thimmappa ND, Blumenfeld JD, Cerilles MA, Dunning A, Donahue SL, Bobb WO, Zhang HL, Prince MR. Cisterna chyli in autosomal dominant polycystic kidney disease. J Magn Reson Imaging. 2015 Jan;41(1):142-8. doi: 10.1002/jmri.24527. Epub 2014 Jan 27.
• Blumenfeld JD, Tepler J, Mauer A, Coller B, Bichet DG, Smith B. Tolvaptan inhibition of desmopressin effects on coagulation factors in a patient with decreased von Willebrand factor and polycystic kidney disease. Blood. 2011 Jul 14;118(2):474-6. doi: 10.1182/blood-2011-04-347328. No abstract available.

Study record dates

Study Major Dates

• Study Start (ACTUAL): May 26, 2010
• Primary Completion (ACTUAL): February 29, 2016
• Study Completion (ACTUAL): February 29, 2016

Study Registration Dates

• First Submitted: September 26, 2010
• First Submitted That Met QC Criteria: October 1, 2010
• First Posted (ESTIMATE): October 5, 2010

Study Record Updates

• Last Update Posted (ACTUAL): October 25, 2021
• Last Update Submitted That Met QC Criteria: September 27, 2021
• Last Verified: September 1, 2021

More Information

Terms related to this study

• Keywords: ADPKD; Kidney Disease; Autosomal Dominant Polycystic Kidney Disease; Adult Polycystic Kidney Disease
• Additional Relevant MeSH Terms: Urologic Diseases; Congenital Abnormalities; Genetic Diseases, Inborn; Joint Diseases; Musculoskeletal Diseases; Muscular Diseases; Musculoskeletal Abnormalities; Abnormalities, Multiple; Kidney Diseases, Cystic; Ciliopathies; Kidney Diseases; Polycystic Kidney Diseases; Polycystic Kidney, Autosomal Dominant; Arthrogryposis; Physiological Effects of Drugs; Molecular Mechanisms of Pharmacological Action; Natriuretic Agents; Antidiuretic Hormone Receptor Antagonists; Tolvaptan
• Other Study ID Numbers: 156-08-271; 2010-018401-10 (EUDRACT_NUMBER)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: YES
• IPD Plan Description: Anonymized Individual participant data (IPD) that underlie the results of this study will be shared with researchers to achieve aims pre-specified in a methodologically sound research proposal. Small studies with less than 25 participants are excluded from data sharing.
• IPD Sharing Time Frame: Data will be available after marketing approval in global markets or beginning 1-3 years following article publication. There is no end date to the availability of the data.
• IPD Sharing Access Criteria: Otsuka will share data on the Vivli data sharing platform which can be found here: https://vivli.org/ourmember/Otsuka/
• IPD Sharing Supporting Information Type: STUDY_PROTOCOL; SAP; CSR

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No