Tolvaptan Extension Study in Participants With ADPKD

NCT01214421 | Completed Phase 3 Results DMC FDA Drug

• 2 other identifiers: 156-08-2712010-018401-10
• Study Type: interventional
• Target: 1,083
• Locations: 13 countries
• Sites: 97

Brief Summary

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.

Conditions

Autosomal Dominant Polycystic Kidney Disease (ADPKD)

Keywords

Kidney Disease; ADPKD; Autosomal Dominant Polycystic Kidney Disease; Adult Polycystic Kidney Disease

Outcome Measures

Primary Outcomes (1)

• 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 Outcomes (5)

• 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)

  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

  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

  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

  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

  Tolvaptan, Delayed Treated: Baseline to Month 24 in Study 156-08-271; Placebo: Baseline to Month 36 in Study 156-04-251

Study Arms (1)

Tolvaptan

EXPERIMENTAL

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

Interventions

Tolvaptan DRUG

Tablets of 15 or 30 mg

Also known as: OPC-41061, Jinarc

Tolvaptan

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• \- 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 \[either 156-04-251 (NCT00428948) or 156-04-250 (NCT00413777), 156-06-260, 156-09-284 (NCT01336972), 156-09-285 (NCT01210560), and 156-09-290 (NCT01451827)\].

You may not qualify if:

• 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.

Sponsors & Collaborators

• Otsuka Pharmaceutical Development & Commercialization, Inc.: lead

Study Sites (97)

Otsuka Investigational Site

Mobile, Alabama, 36617, United States

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Otsuka Investigational Site

Peoria, Arizona, 85381, United States

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Tempe, Arizona, 85284, United States

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Los Angeles, California, 90025, United States

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Palo Alto, California, 94304, United States

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San Diego, California, 92108, United States

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Aurora, Colorado, 80045, United States

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New Haven, Connecticut, 06510, United States

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Jacksonville, Florida, 32216, United States

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Port Charlotte, Florida, 33952, United States

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Otsuka Investigational Site

Atlanta, Georgia, 30322, United States

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Augusta, Georgia, 30909, United States

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Chicago, Illinois, 60611, United States

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Kansas City, Kansas, 66160, United States

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Baton Rouge, Louisiana, 70808, United States

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Baltimore, Maryland, 21205, United States

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Rockville, Maryland, 20850, United States

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Boston, Massachusetts, 02111, United States

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Detroit, Michigan, 48236, United States

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Minneapolis, Minnesota, 55404, United States

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Rochester, Minnesota, 55905, United States

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Voorhees Township, New Jersey, 08043, United States

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Buffalo, New York, 14215, United States

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Hawthorne, New York, 10532, United States

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Otsuka Investigational Site

New York, New York, 10021, United States

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New York, New York, 10032, United States

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Chapel Hill, North Carolina, 27599, United States

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Cincinnati, Ohio, 45246, United States

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Cleveland, Ohio, 44106, United States

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Portland, Oregon, 97210, United States

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Bethlehem, Pennsylvania, 18017, United States

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Philadelphia, Pennsylvania, 19104, United States

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Anderson, South Carolina, 29621, United States

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Nashville, Tennessee, 37205, United States

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Nashville, Tennessee, 37232, United States

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Arlington, Texas, 76015, United States

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McAllen, Texas, 78503, United States

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Charlottesville, Virginia, 22908, United States

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C.a.b.a., Buenos Aires, C1429BWN, Argentina

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Pilar, Buenos Aires, B1629ODT, Argentina

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Buenos Aires, C1425APQ, Argentina

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Córdoba, 5000, Argentina

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Córdoba, X5016KEH, Argentina

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St Leonards, New South Wales, 2065, Australia

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Westmead, New South Wales, 2145, Australia

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Woolloongabba, Queensland, 4102, Australia

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Adelaide, South Australia, 5000, Australia

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Parkville, Victoria, 3050, Australia

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Perth, Western Australia, 6000, Australia

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Brussels, 1090, Belgium

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Brussels, 1200, Belgium

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Ghent, 9000, Belgium

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Halifax, Nova Scotia, B3H 1V8, Canada

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Montreal, Quebec, H3A1A1, Canada

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Montreal, Quebec, H4J1C5, Canada

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Bordeaux, 33076, France

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Caen, 14033, France

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Lyon, 69437, France

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Paris, 75018, France

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Reims, 51092, France

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Saint-Etienne, 42055, France

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Toulouse, 31059, France

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Dresden, 01307, Germany

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Düsseldorf, 40210, Germany

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Essen, 45147, Germany

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Heidelberg, 69120, Germany

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Nuremberg, 90471, Germany

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Bergamo, 24127, Italy

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Milan, 20132, Italy

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Modena, 41100, Italy

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Napoli, 80131, Italy

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Pavia, 27100, Italy

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Amsterdam, 1081 HV, Netherlands

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Groningen, 9713 GZ, Netherlands

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Ciechanów, 06-400, Poland

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Krakow, 31-501, Poland

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Lodz, 90-153, Poland

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Lublin, 20-954, Poland

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Szczecin, 70-111, Poland

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Warsaw, 04-749, Poland

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Wroclaw, 50-556, Poland

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Bucharest, 010731, Romania

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Bucharest, 022328, Romania

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Otsuka Investigational Site

Iași, 700504, Romania

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Otsuka Investigational Site

Kemerovo, 650029, Russia

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Saint Petersburg, 191104, Russia

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Tomsk, 634063, Russia

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Belfast, BT9 7AB, United Kingdom

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Birmingham, B15 2TH, United Kingdom

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Brighton, BN2 5BE, United Kingdom

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Coventry, CV2 2DX, United Kingdom

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Edinburgh, EH16 4SA, United Kingdom

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Inverness, IV2 3UJ, United Kingdom

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London, NW3 2QG, United Kingdom

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London, SE5 9RS, United Kingdom

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London, SW17 0QT, United Kingdom

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Swansea, SA6 6NL, United Kingdom

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Related Publications (6)

• Lioudis 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.

  PMID: 37349694 DERIVED

• Chebib FT, Zhou X, Garbinsky D, Davenport E, Nunna S, Oberdhan D, Fernandes A. Tolvaptan and Kidney Function Decline in Older Individuals With Autosomal Dominant Polycystic Kidney Disease: A Pooled Analysis of Randomized Clinical Trials and Observational Studies. Kidney Med. 2023 Apr 14;5(6):100639. doi: 10.1016/j.xkme.2023.100639. eCollection 2023 Jun.

  PMID: 37250503 DERIVED

• Alpers DH, Lewis JH, Hunt CM, Freston JW, Torres VE, Li H, Wang W, Hoke ME, Roth SE, Westcott-Baker L, Estilo A. Clinical Pattern of Tolvaptan-Associated Liver Injury in Trial Participants With Autosomal Dominant Polycystic Kidney Disease (ADPKD): An Analysis of Pivotal Clinical Trials. Am J Kidney Dis. 2023 Mar;81(3):281-293.e1. doi: 10.1053/j.ajkd.2022.08.012. Epub 2022 Sep 30.

  PMID: 36191725 DERIVED

• 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.

  PMID: 31014270 DERIVED

• 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.

  PMID: 24470398 DERIVED

• 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.

  PMID: 21757630 DERIVED

MeSH Terms

Conditions

Polycystic Kidney, Autosomal Dominant; Kidney Diseases

Interventions

Tolvaptan

Condition Hierarchy (Ancestors)

Polycystic Kidney Diseases; Kidney Diseases, Cystic; Urologic Diseases; Female Urogenital Diseases; Female Urogenital Diseases and Pregnancy Complications; Urogenital Diseases; Male Urogenital Diseases; Abnormalities, Multiple; Congenital Abnormalities; Congenital, Hereditary, and Neonatal Diseases and Abnormalities; Ciliopathies; Genetic Diseases, Inborn

Intervention Hierarchy (Ancestors)

Benzazepines; Heterocyclic Compounds, 2-Ring; Heterocyclic Compounds, Fused-Ring; Heterocyclic Compounds

Limitations and Caveats

The trial did not meet its primary endpoint as both groups showed similar decreases in the rate of TKV growth due in part to unforeseen limitations in the trial design. However, early-treatment resulted in cumulative improvements in renal function.

Results Point of Contact

• Title: Global Clinical Development
• Organization: Otsuka Pharmaceutical Development & Commercialization, Inc.

clinicaltransparency@otsuka-us.com

+1-609-524-6788

Study Officials

• Study Director

  Otsuka Pharmaceutical Development & Commercialization, Inc.

  STUDY DIRECTOR

Publication Agreements

• PI is Sponsor Employee: No
• Restriction Type: OTHER
• Restrictive Agreement: Yes

Study Design

• Study Type: interventional
• Phase: phase 3
• Allocation: NA
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: SINGLE GROUP
• Sponsor Type: INDUSTRY
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: September 26, 2010
• First Posted: October 5, 2010
• Study Start: May 26, 2010
• Primary Completion: February 29, 2016
• Study Completion: February 29, 2016
• Last Updated: October 25, 2021
• Results First Posted: October 25, 2021

Record last verified: 2021-09

Data Sharing

• IPD Sharing: Will share
• Shared Documents: STUDY PROTOCOL, SAP, CSR
• 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.
• Access Criteria: Otsuka will share data on the Vivli data sharing platform which can be found here: https://vivli.org/ourmember/Otsuka/

Locations

GB (10); BE (3); FR (7); NL (2); AU (6); US (38); RO (3); CA (3); RU (3); IT (5); AR (5); PL (7); DE (5)