Efficacy and Safety of Tolvaptan in Subjects With Chronic Kidney Disease Between Late Stage 2 to Early Stage 4 Due to Autosomal Dominant Polycystic Kidney Disease

A Phase 3b, Multi-center, Randomized-withdrawal, Placebo-controlled, Double-blind, Parallel-group Trial to Compare the Efficacy and Safety of Tolvaptan (45 to 120 mg/Day, Split-dose) in Subjects With Chronic Kidney Disease Between Late Stage 2 to Early Stage 4 Due to Autosomal Dominant Polycystic Kidney Disease

The purpose of the study is to determine whether tolvaptan is effective and safe for the treatment of late-stage chronic kidney disease due to autosomal dominant polycystic kidney disease (ADPKD)

Study Overview

• Status: Completed
• Conditions: Chronic Kidney Disease; Autosomal Dominant Polycystic Kidney Disease
• Intervention / Treatment: Drug: Tolvaptan (OPC-41061); Drug: Placebo

Detailed Description

The protocol will extend the understanding of the efficacy and safety of tolvaptan treatment in ADPKD patients with late stage 2 to early stage 4 CKD (chronic kidney disease).

This trial will compare the efficacy of tolvaptan treatment in reducing the annualized change in estimated glomerular filtration rate (eGFR) from pre-treatment baseline to post-treatment follow-up, as compared with placebo, in subjects who tolerate tolvaptan during an initial run-in period. The change in eGFR, calculated by the Chronic Kidney Disease-Epidemiology (CKD-EPI) formula, will provide kidney function data that are complementary to the data demonstrating the benefits previously observed primarily in ADPKD subjects with earlier stages of disease.

Also, it will compare the efficacy of tolvaptan treatment in reducing the decline of annualized eGFR slope, as compared with placebo, in this type of subjects. Finally, it will compare the overall and hepatic safety profile of tolvaptan with placebo and to compare incidence of ADPKD complications (outcomes) during the trial

• Study Type: Interventional
• Enrollment (Actual): 1370
• Phase: Phase 3

Contacts and Locations

Study Locations

• Argentina
  • Cordoba, Argentina, X5000JHQ
  • Cordoba, Argentina, X5003DCE
  • Cordoba, Argentina, X5016KEH
  • Buenos Aires
    • Bahia Blanca, Buenos Aires, Argentina, B8000FTD
    • Ciudad Autonoma, Buenos Aires, Argentina, C1093AAS
    • Ciudad Autonoma, Buenos Aires, Argentina, C1119ACN
    • Ciudad Autonoma, Buenos Aires, Argentina, C1425APQ
    • Ciudad Autonoma, Buenos Aires, Argentina, C1429BWN
    • Ciudad Autonoma, Buenos Aires, Argentina, C1431FWO
    • Junin, Buenos Aires, Argentina, 6000
    • Pergamino, Buenos Aires, Argentina, B2700CPM
    • Pilar, Buenos Aires, Argentina, B1629ODT
    • Sarandi, Buenos Aires, Argentina, B1872EEA
• Australia
  • New South Wales
    • Camperdown, New South Wales, Australia, 2050
    • Concord, New South Wales, Australia, 2139
    • New Lambton Heights, New South Wales, Australia, 2305
    • St. Leonards, New South Wales, Australia, 2065
    • Westmead, New South Wales, Australia, 2145
  • Queensland
    • Woolloongabba, Queensland, Australia, 4102
  • South Australia
    • Adelaide, South Australia, Australia, 5000
  • Tasmania
    • Launceston, Tasmania, Australia, 7250
  • Victoria
    • Parkville, Victoria, Australia, 3050
    • Reservoir, Victoria, Australia, 3073
    • Richmond, Victoria, Australia, 3121
  • Western Australia
    • Perth, Western Australia, Australia, 6000
• Belgium
  • Aalst, Belgium, 9300
  • Antwerpen, Belgium, 2650
  • Bruxelles, Belgium, 1200
  • Bruxelles, Belgium, 1090
  • Gent, Belgium, 9000
  • Kortrijk, Belgium, 8500
  • Leuven, Belgium, 3000
  • Liège, Belgium, 400
• Canada
  • Alberta
    • Edmonton, Alberta, Canada, T6G 2B7
  • Newfoundland and Labrador
    • St. John's, Newfoundland and Labrador, Canada, A1B 3V6
  • Ontario
    • Scarborough, Ontario, Canada, M1H 3G4
    • Toronto, Ontario, Canada, M5C 2T2
    • Toronto, Ontario, Canada, M5G 2N2
    • Toronto, Ontario, Canada, M4C 5T2
  • Quebec
    • Greenfield Park, Quebec, Canada, J4V 2H1
    • Montreal, Quebec, Canada, H3A 1A1
    • Montréal, Quebec, Canada, H4J 1C5
• Czechia
  • Brno, Czechia, 625 00
  • Ceske Budejovice, Czechia, 370 01
  • Hradec Kralove, Czechia, 500 05
  • Jihlava, Czechia, 586 33
  • Jilemnice, Czechia, 51401
  • Liberec, Czechia, 460 63
  • Ostrava, Czechia, 708 52
  • Praha 2, Czechia, 128 08
  • Praha 4, Czechia, 140 21
  • Tabor, Czechia, 390 03
• Denmark
  • Aalborg, Denmark, 9100
  • Aarhus C, Denmark, 8000
  • Holstebro, Denmark, 7500
  • Odense C, Denmark, 5000
  • Viborg, Denmark, 8800
• France
  • Finistere
    • Brest cedex 2, Finistere, France, 29609
  • Gironde
    • Bordeaux Cedex, Gironde, France, 33000
  • Haute Garonne
    • Toulouse Cedex 9, Haute Garonne, France, 31059
  • Herault
    • Montpellier cedex 5, Herault, France, 34295
  • Isere
    • Grenoble cedex 9, Isere, France, 38043
  • Loire
    • Saint-Priest-En-Jarez, Loire, France, 42055
  • Marne
    • Reims Cedex, Marne, France, 51090
  • Meurthe Et Moselle
    • Vandoeuvre les Nancy, Meurthe Et Moselle, France, 54511
  • Rhone
    • Lyon Cedex 03, Rhone, France, 69437
    • Pierre-Bénite cedex, Rhone, France, 69495
• Germany
  • Baden Wuerttemberg
    • Heidelberg, Baden Wuerttemberg, Germany, 69120
  • Bayern
    • Muenchen, Bayern, Germany, 81675
    • Nuernberg, Bayern, Germany, 90471
  • Niedersachsen
    • Hannover, Niedersachsen, Germany, 30625
  • Nordrhein Westfalen
    • Duesseldorf, Nordrhein Westfalen, Germany, 40210
    • Essen, Nordrhein Westfalen, Germany, 45147
    • Wiesbaden, Nordrhein Westfalen, Germany, 65191
  • Sachsen
    • Dresden, Sachsen, Germany, 01307
• Hungary
  • Budapest, Hungary, 1032
  • Pecs, Hungary, 7623
  • Szeged, Hungary, 6720
• Israel
  • Ashkelon, Israel, 7830604
  • Jerusalem, Israel, 9112001
  • Nahariya, Israel, 22100
  • Petach Tikva, Israel, 4941492
  • Petaẖ Tiqwa, Israel, 4941492
  • Ramat-Gan, Israel, 52621
  • Tel Aviv, Israel, 34239
• Italy
  • Bari, Italy, 70124
  • Bologna, Italy, 40138
  • Lecco, Italy, 23900
  • Milano, Italy, 20122
  • Milano, Italy, 20132
  • Modena, Italy, 41124
  • Napoli, Italy, 80131
  • Pavia, Italy, 27100
  • Ancona
    • Torrette Di Ancona, Ancona, Italy, 60126
  • Brescia
    • Montichiari, Brescia, Italy, 25018
• Netherlands
  • Groningen, Netherlands, 9713 GZ
  • Nijmegen, Netherlands, 6525 GA
• Norway
  • Bergen, Norway, 5021
  • Oslo, Norway, 0424
  • Stavanger, Norway, 4068
• Poland
  • Ciechanow, Poland, 06-400
  • Golub Dobrzyn, Poland, 87-400
  • Kraków, Poland, 31-559
  • Lodz, Poland, 92-213
  • Lublin, Poland, 20-954
  • Warszawa, Poland, 04-749
  • Wroclaw, Poland, 50-556
  • Łódź, Poland, 92-313
• Puerto Rico
  • San Juan, Puerto Rico, 00918
• Romania
  • Bucuresti, Romania, 011794
  • Bucuresti, Romania, 022328
  • Oradea, Romania, 410649
• Russian Federation
  • Krasnoyarsk, Russian Federation, 660062
  • St. Petersburg, Russian Federation, 194044
  • St. Petersburg, Russian Federation, 197110
  • Yaroslavl, Russian Federation, 150062
• South Africa
  • Gauteng
    • Pretoria, Gauteng, South Africa, 0002
  • KwaZulu-Natal
    • Durban, KwaZulu-Natal, South Africa, 4001
  • Western Cape
    • Cape Town, Western Cape, South Africa, 7925
• Spain
  • Ciudad Real, Spain, 13005
  • Madrid, Spain, 28046
  • Madrid, Spain, 28041
  • Sevilla, Spain, 41071
  • Sevilla, Spain, 41009
  • Valencia, Spain, 46017
  • Barcelona
    • L'Hospitalet de Llobregat, Barcelona, Spain, 08907
• Sweden
  • Göteborg, Sweden, 41345
  • Linköping, Sweden, 58185
  • Stockholm, Sweden, 14186
  • Stockholm, Sweden, 141 86
  • Uppsala, Sweden, 75185
  • Örebro, Sweden, 70185
• United Kingdom
  • Swansea, United Kingdom, SA6 6NL
  • Devon
    • Exeter, Devon, United Kingdom, EX2 5DW
  • East Riding Of Yorkshire
    • Hull, East Riding Of Yorkshire, United Kingdom, HU3 2JZ
  • East Sussex
    • Brighton, East Sussex, United Kingdom, BN2 5BE
  • Greater London
    • London, Greater London, United Kingdom, NW3 2QG
  • Greater Manchester
    • Manchester, Greater Manchester, United Kingdom, M13 9WL
    • Salford, Greater Manchester, United Kingdom, M6 8HD
  • Hertfordshire
    • Stevenage, Hertfordshire, United Kingdom, SG1 4AB
  • Highland Region
    • Inverness, Highland Region, United Kingdom, IV2 3UJ
  • Leicestershire
    • Leicester, Leicestershire, United Kingdom, LE5 4PW
  • Lothian Region
    • Edinburgh, Lothian Region, United Kingdom, EH16 4SA
  • Merseyside
    • Liverpool, Merseyside, United Kingdom, L7 8XP
  • North Yorkshire
    • Middlesbrough, North Yorkshire, United Kingdom, TS4 3BW
  • South Yorkshire
    • Sheffield, South Yorkshire, United Kingdom, S5 7AU
  • Staffordshire
    • Stoke-on-Trent, Staffordshire, United Kingdom, ST4 6QG
  • Tyne & Wear
    • Newcastle upon Tyne, Tyne & Wear, United Kingdom, NE7 7DN
  • Warwickshire
    • Coventry, Warwickshire, United Kingdom, CV2 2DX
• United States
  • Alabama
    • Birmingham, Alabama, United States, 35294
    • Huntsville, Alabama, United States, 35805
    • Mobile, Alabama, United States, 36617
  • Arizona
    • Phoenix, Arizona, United States, 85381
    • Tempe, Arizona, United States, 85284
    • Tucson, Arizona, United States, 85745
  • California
    • La Jolla, California, United States, 92037
    • Los Angeles, California, United States, 90025
    • Los Angeles, California, United States, 90022
    • San Francisco, California, United States, 94143
  • Colorado
    • Aurora, Colorado, United States, 80045
    • Denver, Colorado, United States, 80210
  • Connecticut
    • New Haven, Connecticut, United States, 06520
  • Florida
    • Hudson, Florida, United States, 34667
    • Jacksonville, Florida, United States, 32216
    • Miami, Florida, United States, 33150
    • Ocala, Florida, United States, 34471
    • Port Charlotte, Florida, United States, 33952
    • Tampa, Florida, United States, 33614
  • Georgia
    • Atlanta, Georgia, United States, 30322
    • Augusta, Georgia, United States, 30909
  • Idaho
    • Meridian, Idaho, United States, 83642
  • Illinois
    • Chicago, Illinois, United States, 60637
  • Kansas
    • Kansas City, Kansas, United States, 66160
    • Wichita, Kansas, United States, 67214
  • Louisiana
    • Baton Rouge, Louisiana, United States, 70808
    • Lafayette, Louisiana, United States, 70503
  • Maryland
    • Baltimore, Maryland, United States, 21201
    • Greenbelt, Maryland, United States, 20770
    • Rockville, Maryland, United States, 20850
    • Wheaton, Maryland, United States, 20906
  • Massachusetts
    • Boston, Massachusetts, United States, 02215
    • Springfield, Massachusetts, United States, 01107
  • Michigan
    • Detroit, Michigan, United States, 48202
    • Kalamazoo, Michigan, United States, 49007
    • Pontiac, Michigan, United States, 48341
    • Roseville, Michigan, United States, 48066
  • Minnesota
    • Minneapolis, Minnesota, United States, 55404
    • Rochester, Minnesota, United States, 55905
  • Missouri
    • Saint Louis, Missouri, United States, 63110
  • Nevada
    • Las Vegas, Nevada, United States, 89128
    • Reno, Nevada, United States, 89511
  • New Jersey
    • Eatontown, New Jersey, United States, 07724
    • Voorhees, New Jersey, United States, 08043
  • New York
    • Buffalo, New York, United States, 14215
    • Mineola, New York, United States, 11501
    • New York, New York, United States, 10016
    • New York, New York, United States, 10032
    • New York, New York, United States, 10021
    • Rosedale, New York, United States, 11422
  • North Carolina
    • Asheville, North Carolina, United States, 28801
    • Chapel Hill, North Carolina, United States, 27599-7155
    • Charlotte, North Carolina, United States, 28207
    • Winston-Salem, North Carolina, United States, 27103
  • North Dakota
    • Fargo, North Dakota, United States, 58122
    • Grand Forks, North Dakota, United States, 58201
  • Ohio
    • Akron, Ohio, United States, 44302
    • Cincinnati, Ohio, United States, 45206
    • Cleveland, Ohio, United States, 44195
    • Cleveland, Ohio, United States, 44106
    • Columbus, Ohio, United States, 43210
  • Oregon
    • Portland, Oregon, United States, 98686
  • Pennsylvania
    • Bethlehem, Pennsylvania, United States, 18017
    • Doylestown, Pennsylvania, United States, 18901
    • Philadelphia, Pennsylvania, United States, 19104
  • South Carolina
    • Charleston, South Carolina, United States, 29425
    • Columbia, South Carolina, United States, 29203
    • Orangeburg, South Carolina, United States, 29118
  • Tennessee
    • Knoxville, Tennessee, United States, 39723
    • Nashville, Tennessee, United States, 37232
    • Nashville, Tennessee, United States, 37205
  • Texas
    • Arlington, Texas, United States, 76015
    • Houston, Texas, United States, 77030
    • Houston, Texas, United States, 77030-3411
    • McAllen, Texas, United States, 78503
  • Vermont
    • Burlington, Vermont, United States, 05401
  • Virginia
    • Arlington, Virginia, United States, 22205
    • Charlottesville, Virginia, United States, 22908
    • Norfolk, Virginia, United States, 23507
  • Washington
    • Wenatchee, Washington, United States, 98801
  • West Virginia
    • Morgantown, West Virginia, United States, 26506
  • Wisconsin
    • La Crosse, Wisconsin, United States, 54601

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 16 years to 63 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

• Male and female subjects with eGFR between 25-65 mL/min/1.73m2 (if aged 18 to55) or eGFR between 25-44 mL/min/1.73m2 (if aged 56 to <66)
• Tolvaptan naïve
• Diagnosis of ADPKD by modified pei-Ravine criteria 1) 3 cysts per kidney by sonography or 5 cysts by CT or MRI with family history of ADPKD or 2) 10 cysts per kidney by any radiologic method and exclusion of other cystic kidney diseases if without family history

Exclusion Criteria:

• Women of childbearing potential who do not agree to practice 2 different methods of birth control or remain abstinent during the trial and for 30 days after the last dose of Investigational medicinal product (IMP)
• Women who are breast-feeding and/or who have a positive pregnancy test prior to receiving IMP
• Need for chronic diuretic use
• Hepatic impairment or liver function abnormalities other than that expected for ADPKD with typical cystic liver disease
• Advanced diabetes, evidence of additional significant renal disease, renal cancer, single kidney, recent renal surgery or acute kidney injury
• Contraindications to required trial assessments
• Medical history or medical findings inconsistent with safety or compliance with trial assessments

Study Plan

How is the study designed?

Design Details

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

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Placebo Comparator: Placebo	Drug: Placebo; Matching placebo tablets will be self-administered orally as split-dose regimens, once upon awakening and another approximately 8 to 9 hours later
Experimental: Tolvaptan; Tolvaptan (OPC-41061)	Drug: Tolvaptan (OPC-41061); Tolvaptan tablets (15 or 30 mg) will be self-administered orally as split-dose regimens, once upon awakening and another approximately 8 to 9 hours later.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
The Mean Annualized Change in eGFR From Pretreatment Baseline to Post-treatment Follow-up.	The mean annualized change in eGFR was calculated using the Chronic Kidney Disease-Epidemiology (CKD-EPI) formula from pretreatment baseline to post-treatment follow-up, annualized (divided) by each subject's trial duration. The baseline for the primary endpoint was defined as the average of up to 3 eGFR values observed during the screening and placebo run-in periods.	Pretreatment baseline to post-treatment follow-up (up to 61 weeks).

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Mean Annualized Slope of eGFR Change	To compare the efficacy of tolvaptan treatment in reducing the decline of annualized eGFR slope, as compared with placebo, in subjects with late-stage CKD due to ADPKD who tolerated tolvaptan during an initial run-in period, the annualized rate of eGFR change was derived from each individual subject's eGFR slope using the CKD-EPI formula. The annualized eGFR change slope was derived from all eGFR observations from placebo-run-in, tolvaptan run-in, double-blind treatment and post-treatment follow-up periods using the linear mixed model of analysis. The mean annualized slope of eGFR change is presented.	Pretreatment baseline to post-treatment follow-up (up to 61 weeks).

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
Mean Change From Baseline in Urine Osmolality During the Double-blind Treatment Period and Post-treatment Follow-up	The mean change from baseline in urine osmolality for the double-blind treatment period collection timepoints and post-treatment follow-up are presented. Baseline was defined as the last evaluation prior to post-randomization dosing.	Baseline and Months 3, 6, 9 and 12 (End of treatment visit) of the double-blind treatment period, and post-treatment follow-up.
Mean Change From Baseline in Urine Specific Gravity During the Double-blind Treatment Period and Post-treatment Follow-up	The mean change from baseline in urine specific gravity for the double-blind treatment period collection timepoints and post-treatment follow up are presented. Baseline was defined as the last evaluation prior to post-randomization dosing.	Baseline and Months 3, 6, 9 and 12 (End of treatment visit) of the double-blind treatment period, and post-treatment follow-up.

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.
• Torres VE, Chapman AB, Devuyst O, Gansevoort RT, Perrone RD, Koch G, Ouyang J, McQuade RD, Blais JD, Czerwiec FS, Sergeyeva O; REPRISE Trial Investigators. Tolvaptan in Later-Stage Autosomal Dominant Polycystic Kidney Disease. N Engl J Med. 2017 Nov 16;377(20):1930-1942. doi: 10.1056/NEJMoa1710030. Epub 2017 Nov 4.

Study record dates

Study Major Dates

• Study Start: May 1, 2014
• Primary Completion (Actual): April 18, 2017
• Study Completion (Actual): April 18, 2017

Study Registration Dates

• First Submitted: June 6, 2014
• First Submitted That Met QC Criteria: June 6, 2014
• First Posted (Estimate): June 10, 2014

Study Record Updates

• Last Update Posted (Actual): August 8, 2018
• Last Update Submitted That Met QC Criteria: July 13, 2018
• Last Verified: July 1, 2018

More Information

Terms related to this study

• Keywords: Chronic Kidney Disease; Autosomal Dominant Polycystic Kidney Disease
• Additional Relevant MeSH Terms: Urologic Diseases; Congenital Abnormalities; Renal Insufficiency; Genetic Diseases, Inborn; Joint Diseases; Musculoskeletal Diseases; Muscular Diseases; Musculoskeletal Abnormalities; Abnormalities, Multiple; Kidney Diseases, Cystic; Ciliopathies; Kidney Diseases; Renal Insufficiency, Chronic; 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: 156-13-210