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CompletedNCT02160145Updated Aug 8, 2018Results posted

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 3 interventional study of Tolvaptan (OPC-41061) and Placebo in Chronic Kidney Disease and Autosomal Dominant Polycystic Kidney Disease, sponsored by Otsuka Pharmaceutical Development & Commercialization, Inc.. Completed at 231 sites in 22 countries. Open to participants aged 18 Years to 65 Years. Per ClinicalTrials.gov, last updated 2018-08-08.

Sponsored by Otsuka Pharmaceutical Development & Commercialization, Inc. · Phase 3, Interventional, and Treatment

Phase
Phase 3
Study type
Interventional
Enrollment
1,370
Allocation
Randomized
Ages
18 Years to 65 Years
Sex
All
01

Study summary

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)

Read the 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

02

Conditions studied

  • Chronic Kidney Disease
  • Autosomal Dominant Polycystic Kidney Disease

Keywords

  • Chronic Kidney Disease
  • Autosomal Dominant Polycystic Kidney Disease
03

In context

Arthrogryposis

85 studies on the registry are indexed under Arthrogryposis; 10 are open to participants now.

This study's enrollment of 1,370 is above the median of 66 across 63 interventional studies indexed under Arthrogryposis.

Browse Arthrogryposis studies →

Lead sponsor

Otsuka Pharmaceutical Development & Commercialization, Inc. is the lead sponsor of 289 studies on the registry; 18 are open to participants now.

Of its 104 completed or terminated interventional studies of FDA-regulated products, 69 (66%) have results posted.

Counted across the registry records on this site, refreshed daily.

04

Who can participate

Ages eligible
18 Years to 65 Years
Sexes eligible
All
Accepts healthy volunteers
No

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

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
05

Study design

Phase
Phase 3
Primary purpose
Treatment
Allocation
Randomized
Intervention model
Parallel assignment
Masking
Quadruple (Participant, Care provider, Investigator, Outcomes assessor)
Enrollment
1,370 participants (actual)

Study arms

  • Experimental
    Tolvaptan

    Tolvaptan (OPC-41061)

    Drug: Tolvaptan (OPC-41061)

  • Placebo comparator
    Placebo

    Placebo

    Drug: Placebo

Interventions

  • DrugTolvaptan (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.

  • DrugPlacebo

    Matching placebo tablets will be self-administered orally as split-dose regimens, once upon awakening and another approximately 8 to 9 hours later

06

What researchers measure

Primary outcomes

  1. 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.

    Time frame: Pretreatment baseline to post-treatment follow-up (up to 61 weeks).

Secondary outcomes

  1. 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.

    Time frame: Pretreatment baseline to post-treatment follow-up (up to 61 weeks).

Other outcomes

  1. 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.

    Time frame: Baseline and Months 3, 6, 9 and 12 (End of treatment visit) of the double-blind treatment period, and post-treatment follow-up.

  2. 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.

    Time frame: Baseline and Months 3, 6, 9 and 12 (End of treatment visit) of the double-blind treatment period, and post-treatment follow-up.

07

Results

Posted Aug 8, 2018

Participant flow

First subject first visit: 21 May 2014; Last subject last visit: 18 April 2017. Subjects were recruited from 213 sites in 21 countries. Of 2292 subjects screened, 1519 entered the 6-week run-in period; 23 were placebo run-in failures and 126 were tolvaptan titration/run-in failures.

Prerandomization Single-blind Period
Participant flow — Prerandomization Single-blind Period
MilestoneAll Subjects PrerandomizationTolvaptanPlacebo
Started151900
Treated in placebo run-in151400
Treated in tolvaptan titration/run-in149100
Randomized137000
Completed137000
Not completed14900
Withdrew: Placebo run-in failure2300
Withdrew: Tolvaptan titration/run-in failure12600
Randomized Double-blind Period
Participant flow — Randomized Double-blind Period
MilestoneAll Subjects PrerandomizationTolvaptanPlacebo
Started0683687
On-treatment completers0578637
Off-treatment completers07622
Completed0654659
Not completed02928
Withdrew: Subject decision02120
Withdrew: Lost to follow-up013
Withdrew: Physician decision075

Outcome measures

PrimaryThe 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.

Time frame:
Pretreatment baseline to post-treatment follow-up (up to 61 weeks).
Reported as:
Least squares mean · mL/min/1.73 m^2/year
The Mean Annualized Change in eGFR From Pretreatment Baseline to Post-treatment Follow-up.
mL/min/1.73 m^2/yearTolvaptanPlacebo
The Mean Annualized Change in eGFR From Pretreatment Baseline to Post-treatment Follow-up.-2.339 ± 0.240-3.610 ± 0.240
Statistical analysis
  • Tolvaptan vs Placebo · ANCOVA · p = <0.0001 (A 2-sided alpha of 0.05 was applied to the primary analysis of the primary endpoint.) · Treatment difference: 1.271 · 95% CI 0.859 to 1.684Weighted Analysis of Covariance (ANCOVA) with effects of treatment and randomization stratification factors and covariate baseline.
SecondaryMean 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.

Time frame:
Pretreatment baseline to post-treatment follow-up (up to 61 weeks).
Reported as:
Least squares mean · mL/min/1.73m^2/year
Mean Annualized Slope of eGFR Change
mL/min/1.73m^2/yearTolvaptanPlacebo
Mean Annualized Slope of eGFR Change-3.160 ± 0.140-4.170 ± 0.142
Statistical analysis
  • Tolvaptan vs Placebo · Mixed Models Analysis · p = <0.0001 (A two-sided alpha of 0.05 was applied when the primary endpoint reached a two-sided alpha of 0.05.) · Treatment difference: 1.011 · 95% CI 0.618 to 1.403
Other pre-specifiedMean 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.

Time frame:
Baseline and Months 3, 6, 9 and 12 (End of treatment visit) of the double-blind treatment period, and post-treatment follow-up.
Reported as:
Mean · milliosmole per kilogram (mOSm/kg)
Mean Change From Baseline in Urine Osmolality During the Double-blind Treatment Period and Post-treatment Follow-up
milliosmole per kilogram (mOSm/kg)TolvaptanPlacebo
Month 310.2 ± 80.3177.7 ± 124.5
Month 622.9 ± 84.3179.1 ± 126.2
Month 930.4 ± 92.1179.9 ± 125.1
Month1236.9 ± 96.0180.3 ± 121.1
Follow-up162.4 ± 114.0179.5 ± 128.9
Other pre-specifiedMean 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.

Time frame:
Baseline and Months 3, 6, 9 and 12 (End of treatment visit) of the double-blind treatment period, and post-treatment follow-up.
Reported as:
Mean · unitless
Mean Change From Baseline in Urine Specific Gravity During the Double-blind Treatment Period and Post-treatment Follow-up
unitlessTolvaptanPlacebo
Month 30.0001 ± 0.00220.0041 ± 0.0033
Month 60.0003 ± 0.00240.0042 ± 0.0033
Month 90.004 ± 0.00250.0040 ± 0.0032
Month 120.0006 ± 0.00270.0040 ± 0.0033
Follow-up0.0037 ± 0.00310.0040 ± 0.0034

Adverse events

Collected over For the tolvaptan single-blind period: 35 days (Day -35 to Day -1). For the double-blind treatment period: 12 months (Day 0 to 12 months).. Non-serious events are listed at a 5% frequency threshold.

Adverse event summary by group
GroupDeathsSeriousOther
Tolvaptan (Single-blind Treatment Period)1/1,491 (0.1%)43/1,491 (2.9%)1,051/1,491 (70.5%)
Tolvaptan (Double-blind Treatment Period)0/681 (0%)85/681 (12.5%)581/681 (85.3%)
Placebo (Double-blind Treatment Period)1/685 (0.1%)60/685 (8.8%)564/685 (82.3%)
Most frequent serious events
Showing 10 of 130
Most frequent serious events
EventTolvaptan (Single-blind Treatment Period)Tolvaptan (Double-blind Treatment Period)Placebo (Double-blind Treatment Period)
Hepatic enzyme increasedInvestigations0/149111/6811/685
Alanine aminotransferase increasedInvestigations4/14918/6810/685
Liver function test increasedInvestigations0/14914/6812/685
Urinary tract infectionInfections and infestations1/14913/6810/685
Liver function test abnormalInvestigations1/14913/6810/685
Aspartate aminotransferase increasedInvestigations0/14913/6810/685
Renal cyst haemorrhageRenal and urinary disorders2/14913/6812/685
PyelonephritisInfections and infestations1/14911/6813/685
Subarachnoid haemorrhageInjury, poisoning and procedural complications0/14911/6813/685
Renal impairmentRenal and urinary disorders1/14912/6813/685
Most frequent other events
Showing 10 of 17
Most frequent other events
EventTolvaptan (Single-blind Treatment Period)Tolvaptan (Double-blind Treatment Period)Placebo (Double-blind Treatment Period)
PolyuriaRenal and urinary disorders475/149136/68111/685
ThirstGeneral disorders430/14910/6810/685
NocturiaRenal and urinary disorders308/14910/6810/685
Renal painRenal and urinary disorders0/1491113/681130/685
Viral upper respiratory tract infectionInfections and infestations0/149172/68184/685
HypertensionVascular disorders0/149173/68179/685
PolydipsiaMetabolism and nutrition disorders146/14910/6810/685
Dry mouthGastrointestinal disorders132/14910/6810/685
Upper respiratory tract infectionInfections and infestations0/149159/68158/685
HeadacheNervous system disorders0/149155/68159/685

Baseline characteristics

The baseline population consisted of all randomized subjects.

Age, Continuous
Age, Continuous(years)TolvaptanPlaceboTotal Title
Mean47.3 ± 8.247.2 ± 8.247.3 ± 8.2
Sex: Female, Male
Sex: Female, Male(Participants)TolvaptanPlaceboTotal Title
Female336354690
Male347333680
Ethnicity (NIH/OMB)
Ethnicity (NIH/OMB)(Participants)TolvaptanPlaceboTotal Title
Hispanic or Latino443579
Not Hispanic or Latino6326471279
Unknown or Not Reported7512
Race (NIH/OMB)
Race (NIH/OMB)(Participants)TolvaptanPlaceboTotal Title
American Indian or Alaska Native314
Asian221941
Native Hawaiian or Other Pacific Islander000
Black or African American252348
White6266321258
More than one race000
Unknown or Not Reported71219
08

Study locations

231 sites
  • Birmingham, Alabama 35294, United States
  • Huntsville, Alabama 35805, United States
  • Mobile, Alabama 36617, United States
  • Phoenix, Arizona 85381, United States
  • Tempe, Arizona 85284, United States
  • Tucson, Arizona 85745, United States
  • La Jolla, California 92037, United States
  • Los Angeles, California 90022, United States
  • Los Angeles, California 90025, United States
  • San Francisco, California 94143, United States
  • Aurora, Colorado 80045, United States
  • Denver, Colorado 80210, United States
  • New Haven, Connecticut 06520, United States
  • Hudson, Florida 34667, United States
  • Jacksonville, Florida 32216, United States
  • Miami, Florida 33150, United States
  • Ocala, Florida 34471, United States
  • Port Charlotte, Florida 33952, United States
  • Tampa, Florida 33614, United States
  • Atlanta, Georgia 30322, United States
  • Augusta, Georgia 30909, United States
  • Meridian, Idaho 83642, United States
  • Chicago, Illinois 60637, United States
  • Kansas City, Kansas 66160, United States
  • Wichita, Kansas 67214, United States
  • Baton Rouge, Louisiana 70808, United States
  • Lafayette, Louisiana 70503, United States
  • Baltimore, Maryland 21201, United States
  • Greenbelt, Maryland 20770, United States
  • Rockville, Maryland 20850, United States
  • Wheaton, Maryland 20906, United States
  • Boston, Massachusetts 02215, United States
  • Springfield, Massachusetts 01107, United States
  • Detroit, Michigan 48202, United States
  • Kalamazoo, Michigan 49007, United States
  • Pontiac, Michigan 48341, United States
  • Roseville, Michigan 48066, United States
  • Minneapolis, Minnesota 55404, United States
  • Rochester, Minnesota 55905, United States
  • Saint Louis, Missouri 63110, United States
  • Las Vegas, Nevada 89128, United States
  • Reno, Nevada 89511, United States
  • Eatontown, New Jersey 07724, United States
  • Voorhees, New Jersey 08043, United States
  • Buffalo, New York 14215, United States
  • Mineola, New York 11501, United States
  • New York, New York 10016, United States
  • New York, New York 10021, United States
  • New York, New York 10032, United States
  • Rosedale, New York 11422, United States
  • Asheville, North Carolina 28801, United States
  • Chapel Hill, North Carolina 27599-7155, United States
  • Charlotte, North Carolina 28207, United States
  • Winston-Salem, North Carolina 27103, United States
  • Fargo, North Dakota 58122, United States
  • Grand Forks, North Dakota 58201, United States
  • Akron, Ohio 44302, United States
  • Cincinnati, Ohio 45206, United States
  • Cleveland, Ohio 44106, United States
  • Cleveland, Ohio 44195, United States
  • Columbus, Ohio 43210, United States
  • Portland, Oregon 98686, United States
  • Bethlehem, Pennsylvania 18017, United States
  • Doylestown, Pennsylvania 18901, United States
  • Philadelphia, Pennsylvania 19104, United States
  • Charleston, South Carolina 29425, United States
  • Columbia, South Carolina 29203, United States
  • Orangeburg, South Carolina 29118, United States
  • Knoxville, Tennessee 39723, United States
  • Nashville, Tennessee 37205, United States
  • Nashville, Tennessee 37232, United States
  • Arlington, Texas 76015, United States
  • Houston, Texas 77030-3411, United States
  • Houston, Texas 77030, United States
  • McAllen, Texas 78503, United States
  • Burlington, Vermont 05401, United States
  • Arlington, Virginia 22205, United States
  • Charlottesville, Virginia 22908, United States
  • Norfolk, Virginia 23507, United States
  • Wenatchee, Washington 98801, United States
  • Morgantown, West Virginia 26506, United States
  • La Crosse, Wisconsin 54601, United States
  • Bahia Blanca, Buenos Aires B8000FTD, Argentina
  • Ciudad Autonoma, Buenos Aires C1093AAS, Argentina
  • Ciudad Autonoma, Buenos Aires C1119ACN, Argentina
  • Ciudad Autonoma, Buenos Aires C1425APQ, Argentina
  • Ciudad Autonoma, Buenos Aires C1429BWN, Argentina
  • Ciudad Autonoma, Buenos Aires C1431FWO, Argentina
  • Junin, Buenos Aires 6000, Argentina
  • Pergamino, Buenos Aires B2700CPM, Argentina
  • Pilar, Buenos Aires B1629ODT, Argentina
  • Sarandi, Buenos Aires B1872EEA, Argentina
  • Cordoba, X5000JHQ, Argentina
  • Cordoba, X5003DCE, Argentina
  • Cordoba, X5016KEH, Argentina
  • Camperdown, New South Wales 2050, Australia
  • Concord, New South Wales 2139, Australia
  • New Lambton Heights, New South Wales 2305, Australia
  • St. Leonards, New South Wales 2065, Australia
  • Westmead, New South Wales 2145, Australia

Showing the first 100 of 231 sites across 22 countries.

09

References and documents

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. PubMed 31014270 ↗
  • 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. PubMed 29105594 ↗

Study documents

  • Statistical analysis plan · Mar 31, 2017
  • Study protocol · Mar 26, 2015

Documents are hosted by the registry — open the source record to download them.

10

Updates

Tracking since Sep 25, 2026
No changes since tracking began. The registry record was last updated on Aug 8, 2018, before this site started recording changes on Sep 25, 2026. Its history is on ClinicalTrials.gov ↗
11

Registry details

Key details

Study ID
NCT02160145
Lead sponsor
Otsuka Pharmaceutical Development & Commercialization, Inc.
Responsible party
Sponsor
First posted
Jun 10, 2014
Start date
May 2014
Primary completion
Apr 18, 2017
Completion
Apr 18, 2017
Results posted
Aug 8, 2018
Last update
Aug 8, 2018

Oversight

Data monitoring committee
Yes
View the source record on ClinicalTrials.gov ↗

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