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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

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ClinicalTrials.gov Identifier: NCT02160145
Recruitment Status : Completed
First Posted : June 10, 2014
Results First Posted : August 8, 2018
Last Update Posted : August 8, 2018
Sponsor:
Information provided by (Responsible Party):
Otsuka Pharmaceutical Development & Commercialization, Inc.

Study Type Interventional
Study Design Allocation: Randomized;   Intervention Model: Parallel Assignment;   Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor);   Primary Purpose: Treatment
Conditions Chronic Kidney Disease
Autosomal Dominant Polycystic Kidney Disease
Interventions Drug: Tolvaptan (OPC-41061)
Drug: Placebo
Enrollment 1370
Recruitment Details 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.
Pre-assignment Details Subjects with Stage 2 - 4 chronic kidney disease (CKD) due to Autosomal Dominant Polycystic Kidney Disease (ADPKD) were stratified by baseline estimated glomerular filtration rate (eGFR) (≤ 45 or > 45 milliliters/minute/ 1.73 square metres [mL/min/1.73 m^2]), by age (≤ 55 or > 55 years), and total kidney volume (≤ 2000 mL, > 2000 mL, or unknown).
Arm/Group Title All Subjects Prerandomization Tolvaptan Placebo
Hide Arm/Group Description

Following screening, the single-blind prerandomization period (Day -42 to Day -1) consisted of:

  1. Placebo Run-in: All subjects received a daily split-dose of placebo (0/0 milligrams [mg]) in a form identical to 15/15 mg tolvaptan split-dose for 1 week.
  2. Tolvaptan Titration: Over 2 weeks all subjects received a split-dose of 30/15 mg (2 x 15mg tablets upon waking, then 1 x 15 mg tablet 8-9 hours later) which was titrated up every 3-4 days to 45/15 mg, then 60/30 mg, and up to a maximum dose of 90/30 mg.
  3. Tolvaptan Run-in: Eligible subjects who tolerated at least 60/30 mg tolvaptan during titration entered the 3-week run-in period and continued on a stable dose of 60/30 mg or 90/30 mg tolvaptan to confirm eligibility and establish prerandomization baseline.

Double-blind Randomized Treatment Period (Day 0 to Month 12): Following randomization subjects continued on the same dose of tolvaptan they received during the tolvaptan run-in period (60/30 mg or 90/30 mg) for a duration of 12 months.

Follow-up Period: A 3-week final follow-up for efficacy analysis.

Double-blind Randomized Treatment Period (Day 0 to Month 12):

Following randomization subjects received placebo tablets matching their tolerated tolvaptan dose during the tolvaptan run-in period (60/30 mg or 90/30 mg) for a duration of 12 months.

Follow-up Period: A 3-week final follow-up for efficacy analysis.

Period Title: Prerandomization Single-blind Period
Started 1519 0 0
Treated in Placebo Run-in 1514 0 0
Treated in Tolvaptan Titration/Run-in 1491 0 0
Randomized 1370 0 0
Completed 1370 0 0
Not Completed 149 0 0
Reason Not Completed
Placebo run-in failure             23             0             0
Tolvaptan titration/run-in failure             126             0             0
Period Title: Randomized Double-blind Period
Started 0 [1] 683 [2] 687 [3]
On-treatment Completers 0 578 637
Off-treatment Completers 0 76 22
Completed [4] 0 654 659
Not Completed 0 29 28
Reason Not Completed
Subject decision             0             21             20
Lost to Follow-up             0             1             3
Physician Decision             0             7             5
[1]
1370 subjects were randomized to receive tolvaptan or placebo in the double-blind period.
[2]
Subjects completed the single-blind period and were randomized to receive tolvaptan.
[3]
Subjects completed the single-blind period and were randomized to receive placebo.
[4]
Completed Month 12 Visit
Arm/Group Title Tolvaptan Placebo Total Title
Hide Arm/Group Description

Double-blind Randomized Treatment Period (Day 0 to Month 12): Following randomization subjects continued on the same dose of tolvaptan they received during the tolvaptan run-in period (60/30 mg or 90/30 mg) for a duration of 12 months.

Follow-up Period: A 3-week final follow-up for efficacy analysis.

Double-blind Randomized Treatment Period (Day 0 to Month 12): Following randomization subjects received placebo tablets matching their tolerated tolvaptan dose during the tolvaptan run-in period (60/30 mg or 90/30 mg) for a duration of 12 months.

Follow-up Period: A 3-week final follow-up for efficacy analysis.

[Not Specified]
Overall Number of Baseline Participants 683 687 1370
Hide Baseline Analysis Population Description
The baseline population consisted of all randomized subjects.
Age, Continuous  
Mean (Standard Deviation)
Unit of measure:  Years
Number Analyzed 683 participants 687 participants 1370 participants
47.3  (8.2) 47.2  (8.2) 47.3  (8.2)
Sex: Female, Male  
Measure Type: Count of Participants
Unit of measure:  Participants
Number Analyzed 683 participants 687 participants 1370 participants
Female
336
  49.2%
354
  51.5%
690
  50.4%
Male
347
  50.8%
333
  48.5%
680
  49.6%
Ethnicity (NIH/OMB)  
Measure Type: Count of Participants
Unit of measure:  Participants
Number Analyzed 683 participants 687 participants 1370 participants
Hispanic or Latino
44
   6.4%
35
   5.1%
79
   5.8%
Not Hispanic or Latino
632
  92.5%
647
  94.2%
1279
  93.4%
Unknown or Not Reported
7
   1.0%
5
   0.7%
12
   0.9%
Race (NIH/OMB)  
Measure Type: Count of Participants
Unit of measure:  Participants
Number Analyzed 683 participants 687 participants 1370 participants
American Indian or Alaska Native
3
   0.4%
1
   0.1%
4
   0.3%
Asian
22
   3.2%
19
   2.8%
41
   3.0%
Native Hawaiian or Other Pacific Islander
0
   0.0%
0
   0.0%
0
   0.0%
Black or African American
25
   3.7%
23
   3.3%
48
   3.5%
White
626
  91.7%
632
  92.0%
1258
  91.8%
More than one race
0
   0.0%
0
   0.0%
0
   0.0%
Unknown or Not Reported
7
   1.0%
12
   1.7%
19
   1.4%
1.Primary Outcome
Title The Mean Annualized Change in eGFR From Pretreatment Baseline to Post-treatment Follow-up.
Hide Description

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).
Hide Outcome Measure Data
Hide Analysis Population Description
The primary endpoint efficacy population consisted of all subjects who were in the randomized sample, took at least 1 dose of investigational medicinal product (IMP) after randomization, and had a baseline and at least 1 valid post-treatment evaluation in eGFR (i.e at least 1 week off-treatment).
Arm/Group Title Tolvaptan Placebo
Hide Arm/Group Description:

Double-blind Randomized Treatment Period (Day 0 to Month 12): Following randomization subjects continued on the same dose of tolvaptan they received during the tolvaptan run-in period (60/30 mg or 90/30 mg) for a duration of 12 months.

Follow-up Period: A 3-week final follow-up for efficacy analysis.

Double-blind Randomized Treatment Period (Day 0 to Month 12): Following randomization subjects received placebo tablets matching their tolerated tolvaptan dose during the tolvaptan run-in period (60/30 mg or 90/30 mg) for a duration of 12 months.

Follow-up Period: A 3-week final follow-up for efficacy analysis.

Overall Number of Participants Analyzed 668 663
Least Squares Mean (Standard Error)
Unit of Measure: mL/min/1.73 m^2/year
-2.339  (0.240) -3.610  (0.240)
Show Statistical Analysis 1 Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Tolvaptan, Placebo
Comments Tolvaptan versus placebo. Treatment difference in the change of eGFR assessed the efficacy of tolvaptan treatment as compared with placebo in subjects with late-stage CKD due to ADPKD who tolerated tolvaptan during an initial run-in period.
Type of Statistical Test Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value <0.0001
Comments A 2-sided alpha of 0.05 was applied to the primary analysis of the primary endpoint.
Method ANCOVA
Comments Weighted Analysis of Covariance (ANCOVA) with effects of treatment and randomization stratification factors and covariate baseline.
Method of Estimation Estimation Parameter Treatment difference
Estimated Value 1.271
Confidence Interval (2-Sided) 95%
0.859 to 1.684
Estimation Comments [Not Specified]
2.Secondary Outcome
Title Mean Annualized Slope of eGFR Change
Hide Description

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).
Hide Outcome Measure Data
Hide Analysis Population Description
The key secondary endpoint efficacy population consisted of all randomized subjects who took at least 1 dose of IMP after randomization, and have a baseline (average of up to 3 eGFR values observed during screening and placebo run-in periods) and at least 1 post-randomization evaluation in eGFR during the double-blind treatment period.
Arm/Group Title Tolvaptan Placebo
Hide Arm/Group Description:

Double-blind Randomized Treatment Period (Day 0 to Month 12): Following randomization subjects continued on the same dose of tolvaptan they received during the tolvaptan run-in period (60/30 mg or 90/30 mg) for a duration of 12 months.

Follow-up Period: A 3-week final follow-up for efficacy analysis.

Double-blind Randomized Treatment Period (Day 0 to Month 12): Following randomization subjects received placebo tablets matching their tolerated tolvaptan dose during the tolvaptan run-in period (60/30 mg or 90/30 mg) for a duration of 12 months.

Follow-up Period: A 3-week final follow-up for efficacy analysis.

Overall Number of Participants Analyzed 680 682
Least Squares Mean (Standard Error)
Unit of Measure: mL/min/1.73m^2/year
-3.160  (0.140) -4.170  (0.142)
Show Statistical Analysis 1 Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Tolvaptan, Placebo
Comments Difference in treatment effect was derived from a linear mixed model with effects of treatment, time, treatment ime interaction, acute haemodynamic effect, pretreatment baseline, and randomization stratification factors. An unstructured variance matrix was assumed for the random intercept and time.
Type of Statistical Test Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value <0.0001
Comments A two-sided alpha of 0.05 was applied when the primary endpoint reached a two-sided alpha of 0.05.
Method Mixed Models Analysis
Comments [Not Specified]
Method of Estimation Estimation Parameter Treatment difference
Estimated Value 1.011
Confidence Interval (2-Sided) 95%
0.618 to 1.403
Estimation Comments [Not Specified]
3.Other Pre-specified Outcome
Title Mean Change From Baseline in Urine Osmolality During the Double-blind Treatment Period and Post-treatment Follow-up
Hide Description 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.
Hide Outcome Measure Data
Hide Analysis Population Description
The primary safety population consisted of all subjects who were randomized and took at least 1 dose of IMP after randomization. Only subjects with data available for analysis at the timepoints of testing are presented.
Arm/Group Title Tolvaptan Placebo
Hide Arm/Group Description:

Double-blind Randomized Treatment Period (Day 0 to Month 12): Following randomization subjects continued on the same dose of tolvaptan they received during the tolvaptan run-in period (60/30 mg or 90/30 mg) for a duration of 12 months.

Follow-up Period: A 3-week final follow-up for efficacy analysis.

Double-blind Randomized Treatment Period (Day 0 to Month 12): Following randomization subjects received placebo tablets matching their tolerated tolvaptan dose during the tolvaptan run-in period (60/30 mg or 90/30 mg) for a duration of 12 months.

Follow-up Period: A 3-week final follow-up for efficacy analysis.

Overall Number of Participants Analyzed 681 685
Mean (Standard Deviation)
Unit of Measure: milliosmole per kilogram (mOSm/kg)
Month 3 Number Analyzed 655 participants 664 participants
10.2  (80.3) 177.7  (124.5)
Month 6 Number Analyzed 637 participants 652 participants
22.9  (84.3) 179.1  (126.2)
Month 9 Number Analyzed 625 participants 646 participants
30.4  (92.1) 179.9  (125.1)
Month12 Number Analyzed 629 participants 651 participants
36.9  (96.0) 180.3  (121.1)
Follow-up Number Analyzed 624 participants 650 participants
162.4  (114.0) 179.5  (128.9)
4.Other Pre-specified Outcome
Title Mean Change From Baseline in Urine Specific Gravity During the Double-blind Treatment Period and Post-treatment Follow-up
Hide Description 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.
Hide Outcome Measure Data
Hide Analysis Population Description
The primary safety population consisted of all subjects who were randomized and took at least 1 dose of IMP after randomization. Only subjects with data available for analysis at the timepoints of testing are presented.
Arm/Group Title Tolvaptan Placebo
Hide Arm/Group Description:

Double-blind Randomized Treatment Period (Day 0 to Month 12): Following randomization subjects continued on the same dose of tolvaptan they received during the tolvaptan run-in period (60/30 mg or 90/30 mg) for a duration of 12 months.

Follow-up Period: A 3-week final follow-up for efficacy analysis.

Double-blind Randomized Treatment Period (Day 0 to Month 12): Following randomization subjects received placebo tablets matching their tolerated tolvaptan dose during the tolvaptan run-in period (60/30 mg or 90/30 mg) for a duration of 12 months.

Follow-up Period: A 3-week final follow-up for efficacy analysis.

Overall Number of Participants Analyzed 681 685
Mean (Standard Deviation)
Unit of Measure: unitless
Month 3 Number Analyzed 654 participants 662 participants
0.0001  (0.0022) 0.0041  (0.0033)
Month 6 Number Analyzed 638 participants 649 participants
0.0003  (0.0024) 0.0042  (0.0033)
Month 9 Number Analyzed 623 participants 641 participants
0.004  (0.0025) 0.0040  (0.0032)
Month 12 Number Analyzed 635 participants 648 participants
0.0006  (0.0027) 0.0040  (0.0033)
Follow-up Number Analyzed 620 participants 653 participants
0.0037  (0.0031) 0.0040  (0.0034)
Time Frame 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).
Adverse Event Reporting Description Treatment emergent adverse events (AEs) were collected, defined as an AE that started after IMP treatment or an AE that was continuous from baseline and was serious, IMP related or resulted in death, discontinuation, interruption or reduction of IMP treatment.
 
Arm/Group Title Tolvaptan (Single-blind Treatment Period) Tolvaptan (Double-blind Treatment Period) Placebo (Double-blind Treatment Period)
Hide Arm/Group Description The secondary safety population consisted of all subjects who took at least one dose of tolvaptan during the tolvaptan titration/run-in periods. The tolvaptan primary safety population consisted of all subjects who were randomized in the double-blind treatment period and who took at least one dose of tolvaptan after randomization. The placebo primary safety population consisted of all subjects who were randomized in the double-blind treatment period and who took at least one dose of placebo after randomization.
All-Cause Mortality
Tolvaptan (Single-blind Treatment Period) Tolvaptan (Double-blind Treatment Period) Placebo (Double-blind Treatment Period)
Affected / at Risk (%) Affected / at Risk (%) Affected / at Risk (%)
Total   1/1491 (0.07%)      0/681 (0.00%)      1/685 (0.15%)    
Show Serious Adverse Events Hide Serious Adverse Events
Tolvaptan (Single-blind Treatment Period) Tolvaptan (Double-blind Treatment Period) Placebo (Double-blind Treatment Period)
Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events
Total   43/1491 (2.88%)      85/681 (12.48%)      60/685 (8.76%)    
Blood and lymphatic system disorders       
Anaemia  1  0/1491 (0.00%)  0 1/681 (0.15%)  1 0/685 (0.00%)  0
Neutropenia  1  0/1491 (0.00%)  0 1/681 (0.15%)  1 0/685 (0.00%)  0
Cardiac disorders       
Angina Pectoris  1  1/1491 (0.07%)  1 0/681 (0.00%)  0 0/685 (0.00%)  0
Atrial fibrillation  1  1/1491 (0.07%)  1 1/681 (0.15%)  1 1/685 (0.15%)  1
Acute myocardial infarction  1  0/1491 (0.00%)  0 0/681 (0.00%)  0 2/685 (0.29%)  2
Aortic valve incompetence  1  0/1491 (0.00%)  0 1/681 (0.15%)  1 0/685 (0.00%)  0
Arteriosclerosis coronary artery  1  0/1491 (0.00%)  0 1/681 (0.15%)  1 0/685 (0.00%)  0
Mitral valve incompetence  1  0/1491 (0.00%)  0 1/681 (0.15%)  1 0/685 (0.00%)  0
Mitral valve prolapse  1  0/1491 (0.00%)  0 1/681 (0.15%)  1 0/685 (0.00%)  0
Pericardial effusion  1  0/1491 (0.00%)  0 1/681 (0.15%)  1 0/685 (0.00%)  0
Congenital, familial and genetic disorders       
Congenital Hepatic Fibrosis  1  0/1491 (0.00%)  0 0/681 (0.00%)  0 1/685 (0.15%)  1
Ear and labyrinth disorders       
Vertigo  1  1/1491 (0.07%)  1 0/681 (0.00%)  0 0/685 (0.00%)  0
Gastrointestinal disorders       
Abdominal pain  1  1/1491 (0.07%)  1 1/681 (0.15%)  1 0/685 (0.00%)  0
Gastritis  1  1/1491 (0.07%)  1 0/681 (0.00%)  0 0/685 (0.00%)  0
Intestinal obstruction  1  1/1491 (0.07%)  1 0/681 (0.00%)  0 0/685 (0.00%)  0
Abdominal Hernia  1  0/1491 (0.00%)  0 0/681 (0.00%)  0 1/685 (0.15%)  1
Abdominal Incarcerated Hernia  1  0/1491 (0.00%)  0 0/681 (0.00%)  0 1/685 (0.15%)  1
Abdominal pain lower  1  0/1491 (0.00%)  0 0/681 (0.00%)  0 1/685 (0.15%)  1
Gastrointestinal haemorrhage  1  0/1491 (0.00%)  0 1/681 (0.15%)  1 1/685 (0.15%)  1
Gastrooesophageal reflux disease  1  0/1491 (0.00%)  0 1/681 (0.15%)  1 0/685 (0.00%)  0
Ileus  1  0/1491 (0.00%)  0 0/681 (0.00%)  0 1/685 (0.15%)  1
Nausea  1  0/1491 (0.00%)  0 1/681 (0.15%)  1 0/685 (0.00%)  0
Pancreatitis acute  1  0/1491 (0.00%)  0 0/681 (0.00%)  0 1/685 (0.15%)  1
Swollen tongue  1  0/1491 (0.00%)  0 0/681 (0.00%)  0 1/685 (0.15%)  1
Umbilical hernia  1  0/1491 (0.00%)  0 1/681 (0.15%)  1 0/685 (0.00%)  0
General disorders       
Fatigue  1  1/1491 (0.07%)  1 1/681 (0.15%)  1 1/685 (0.15%)  1
Pyrexia  1  1/1491 (0.07%)  1 0/681 (0.00%)  0 1/685 (0.15%)  1
Thirst  1  2/1491 (0.13%)  2 0/681 (0.00%)  0 0/685 (0.00%)  0
Cyst rupture  1  0/1491 (0.00%)  0 1/681 (0.15%)  1 0/685 (0.00%)  0
Non-cardiac chest pain  1  0/1491 (0.00%)  0 1/681 (0.15%)  1 1/685 (0.15%)  1
Hepatobiliary disorders       
Drug-induced liver injury  1  1/1491 (0.07%)  1 0/681 (0.00%)  0 0/685 (0.00%)  0
Hepatic function abnormal  1  1/1491 (0.07%)  1 0/681 (0.00%)  0 0/685 (0.00%)  0
Cholangitis  1  0/1491 (0.00%)  0 0/681 (0.00%)  0 1/685 (0.15%)  2
Cholelithiasis  1  0/1491 (0.00%)  0 1/681 (0.15%)  1 0/685 (0.00%)  0
Haemorrhagic hepatic cyst  1  0/1491 (0.00%)  0 0/681 (0.00%)  0 1/685 (0.15%)  1
Hepatic cyst  1  0/1491 (0.00%)  0 1/681 (0.15%)  1 0/685 (0.00%)  0
Hepatitis toxic  1  0/1491 (0.00%)  0 1/681 (0.15%)  1 0/685 (0.00%)  0
Hypertransaminasaemia  1  0/1491 (0.00%)  0 1/681 (0.15%)  1 1/685 (0.15%)  1
Liver injury  1  0/1491 (0.00%)  0 1/681 (0.15%)  1 0/685 (0.00%)  0
Immune system disorders       
Drug hypersensitivity  1  0/1491 (0.00%)  0 0/681 (0.00%)  0 1/685 (0.15%)  1
Hypersensitivity  1  0/1491 (0.00%)  0 0/681 (0.00%)  0 1/685 (0.15%)  1
Infections and infestations       
HIV infection  1  1/1491 (0.07%)  1 0/681 (0.00%)  0 0/685 (0.00%)  0
Pneumonia  1  1/1491 (0.07%)  1 1/681 (0.15%)  1 0/685 (0.00%)  0
Pyelonephritis  1  1/1491 (0.07%)  1 1/681 (0.15%)  1 3/685 (0.44%)  3
Pyelonephritis acute  1  1/1491 (0.07%)  1 0/681 (0.00%)  0 0/685 (0.00%)  0
Renal cyst infection  1  2/1491 (0.13%)  2 2/681 (0.29%)  2 1/685 (0.15%)  1
Sinusitis  1  1/1491 (0.07%)  1 0/681 (0.00%)  0 0/685 (0.00%)  0
Urinary tract infection  1  1/1491 (0.07%)  1 3/681 (0.44%)  4 0/685 (0.00%)  0
Appendicitis  1  0/1491 (0.00%)  0 0/681 (0.00%)  0 1/685 (0.15%)  1
Bacteraemia  1  0/1491 (0.00%)  0 1/681 (0.15%)  1 0/685 (0.00%)  0
Cellulitis  1  0/1491 (0.00%)  0 0/681 (0.00%)  0 1/685 (0.15%)  1
Diverticulitis  1  0/1491 (0.00%)  0 1/681 (0.15%)  1 0/685 (0.00%)  0
Enterobacter bacteraemia  1  0/1491 (0.00%)  0 0/681 (0.00%)  0 1/685 (0.15%)  1
Erysipelas  1  0/1491 (0.00%)  0 1/681 (0.15%)  1 0/685 (0.00%)  0
Gastroenteritis  1  0/1491 (0.00%)  0 1/681 (0.15%)  1 1/685 (0.15%)  1
Hepatic cyst infection  1  0/1491 (0.00%)  0 0/681 (0.00%)  0 1/685 (0.15%)  1
Influenza  1  0/1491 (0.00%)  0 1/681 (0.15%)  1 0/685 (0.00%)  0
Klebsiella infection  1  0/1491 (0.00%)  0 1/681 (0.15%)  1 0/685 (0.00%)  0
Otitis media  1  0/1491 (0.00%)  0 1/681 (0.15%)  1 0/685 (0.00%)  0
Respiratory tract infection  1  0/1491 (0.00%)  0 1/681 (0.15%)  1 0/685 (0.00%)  0
Rhinovirus infection  1  0/1491 (0.00%)  0 0/681 (0.00%)  0 1/685 (0.15%)  1
Sepsis  1  0/1491 (0.00%)  0 1/681 (0.15%)  1 1/685 (0.15%)  1
Tonsillitis  1  0/1491 (0.00%)  0 0/681 (0.00%)  0 1/685 (0.15%)  1
Upper respiratory tract infection  1  0/1491 (0.00%)  0 1/681 (0.15%)  1 0/685 (0.00%)  0
Urosepsis  1  0/1491 (0.00%)  0 0/681 (0.00%)  0 1/685 (0.15%)  1
Injury, poisoning and procedural complications       
Accidental overdose  1  1/1491 (0.07%)  1 0/681 (0.00%)  0 0/685 (0.00%)  0
Fall  1  0/1491 (0.00%)  0 0/681 (0.00%)  0 1/685 (0.15%)  1
Incisional hernia  1  0/1491 (0.00%)  0 1/681 (0.15%)  3 0/685 (0.00%)  0
Ligament rupture  1  0/1491 (0.00%)  0 1/681 (0.15%)  1 0/685 (0.00%)  0
Meniscus injury  1  0/1491 (0.00%)  0 0/681 (0.00%)  0 1/685 (0.15%)  1
Procedural intestinal perforation  1  0/1491 (0.00%)  0 1/681 (0.15%)  1 0/685 (0.00%)  0
Road traffic accident  1  0/1491 (0.00%)  0 0/681 (0.00%)  0 1/685 (0.15%)  1
Subarachnoid haemorrhage  1  0/1491 (0.00%)  0 1/681 (0.15%)  1 3/685 (0.44%)  3
Subdural haematoma  1  0/1491 (0.00%)  0 2/681 (0.29%)  2 0/685 (0.00%)  0
Tibia fracture  1  0/1491 (0.00%)  0 0/681 (0.00%)  0 1/685 (0.15%)  1
Investigations       
Alanine aminotransferase increased  1  4/1491 (0.27%)  4 8/681 (1.17%)  8 0/685 (0.00%)  0
Blood creatinine increased  1  1/1491 (0.07%)  1 0/681 (0.00%)  0 2/685 (0.29%)  2
Liver function test abnormal  1  1/1491 (0.07%)  1 3/681 (0.44%)  3 0/685 (0.00%)  0
Transaminases increased  1  1/1491 (0.07%)  1 2/681 (0.29%)  3 0/685 (0.00%)  0
Aspartate aminotransferase increased  1  0/1491 (0.00%)  0 3/681 (0.44%)  3 0/685 (0.00%)  0
Blood alkaline phosphatase increased  1  0/1491 (0.00%)  0 1/681 (0.15%)  1 0/685 (0.00%)  0
Blood bicarbonate decreased  1  0/1491 (0.00%)  0 0/681 (0.00%)  0 1/685 (0.15%)  1
Gamma-glutamyltransferase increased  1  0/1491 (0.00%)  0 1/681 (0.15%)  1 0/685 (0.00%)  0
Hepatic enzyme increased  1  0/1491 (0.00%)  0 11/681 (1.62%)  12 1/685 (0.15%)  1
Liver function test increased  1  0/1491 (0.00%)  0 4/681 (0.59%)  7 2/685 (0.29%)  2
Prostatic specific antigen increased  1  0/1491 (0.00%)  0 0/681 (0.00%)  0 1/685 (0.15%)  1
Weight decreased  1  0/1491 (0.00%)  0 1/681 (0.15%)  1 0/685 (0.00%)  0
Metabolism and nutrition disorders       
Polydipsia  1  1/1491 (0.07%)  1 0/681 (0.00%)  0 0/685 (0.00%)  0
Hyperglycaemia  1  0/1491 (0.00%)  0 0/681 (0.00%)  0 1/685 (0.15%)  1
Hypokalaemia  1  0/1491 (0.00%)  0 0/681 (0.00%)  0 1/685 (0.15%)  1
Hyponatraemia  1  0/1491 (0.00%)  0 0/681 (0.00%)  0 2/685 (0.29%)  2
Vitamin B complex deficiency  1  0/1491 (0.00%)  0 1/681 (0.15%)  1 0/685 (0.00%)  0
Musculoskeletal and connective tissue disorders       
Back pain  1  1/1491 (0.07%)  1 2/681 (0.29%)  2 1/685 (0.15%)  1
Arthritis  1  0/1491 (0.00%)  0 0/681 (0.00%)  0 1/685 (0.15%)  1
Cervical spinal stenosis  1  0/1491 (0.00%)  0 0/681 (0.00%)  0 1/685 (0.15%)  1
Neoplasms benign, malignant and unspecified (incl cysts and polyps)       
Basal cell carcinoma  1  0/1491 (0.00%)  0 0/681 (0.00%)  0 2/685 (0.29%)  2
Brain neoplasm benign  1  0/1491 (0.00%)  0 0/681 (0.00%)  0 1/685 (0.15%)  1
Invasive ductal breast carcinoma  1  0/1491 (0.00%)  0 0/681 (0.00%)  0 1/685 (0.15%)  1
Meningioma  1  0/1491 (0.00%)  0 0/681 (0.00%)  0 1/685 (0.15%)  1
Phaeochromocytoma  1  0/1491 (0.00%)  0 0/681 (0.00%)  0 1/685 (0.15%)  1
Nervous system disorders       
Carotid artery aneurysm  1  0/1491 (0.00%)  0 0/681 (0.00%)  0 1/685 (0.15%)  1
Cerebral artery thrombosis  1  0/1491 (0.00%)  0 0/681 (0.00%)  0 1/685 (0.15%)  1
Cerebrovascular accident  1  0/1491 (0.00%)  0 1/681 (0.15%)  1 1/685 (0.15%)  1
Intracranial aneurysm  1  0/1491 (0.00%)  0 1/681 (0.15%)  1 1/685 (0.15%)  1
Intracranial pressure increased  1  0/1491 (0.00%)  0 0/681 (0.00%)  0 1/685 (0.15%)  1
Transient ischaemic attack  1  0/1491 (0.00%)  0 2/681 (0.29%)  2 1/685 (0.15%)  1
Psychiatric disorders       
Insomnia  1  1/1491 (0.07%)  1 0/681 (0.00%)  0 0/685 (0.00%)  0
Confusional state  1  0/1491 (0.00%)  0 0/681 (0.00%)  0 1/685 (0.15%)  1
Renal and urinary disorders       
Acute kidney injury  1  2/1491 (0.13%)  2 2/681 (0.29%)  2 1/685 (0.15%)  1
Chronic kidney disease  1  1/1491 (0.07%)  1 1/681 (0.15%)  1 0/685 (0.00%)  0
Nephrolithiasis  1  1/1491 (0.07%)  1 0/681 (0.00%)  0 1/685 (0.15%)  1
Haematuria  1  0/1491 (0.00%)  0 1/681 (0.15%)  1 2/685 (0.29%)  2
Nocturia  1  3/1491 (0.20%)  3 0/681 (0.00%)  0 0/685 (0.00%)  0
Pollakiuria  1  2/1491 (0.13%)  2 0/681 (0.00%)  0 0/685 (0.00%)  0
Polyuria  1  4/1491 (0.27%)  4 0/681 (0.00%)  0 0/685 (0.00%)  0
Renal colic  1  1/1491 (0.07%)  1 0/681 (0.00%)  0 0/685 (0.00%)  0
Renal cyst haemorrhage  1  2/1491 (0.13%)  2 3/681 (0.44%)  3 2/685 (0.29%)  2
Renal impairment  1  1/1491 (0.07%)  1 2/681 (0.29%)  2 3/685 (0.44%)  3
Renal pain  1  1/1491 (0.07%)  1 1/681 (0.15%)  1 3/685 (0.44%)  3
Ureteric obstruction  1  1/1491 (0.07%)  1 0/681 (0.00%)  0 0/685 (0.00%)  0
Renal haemorrhage  1  0/1491 (0.00%)  0 0/681 (0.00%)  0 1/685 (0.15%)  1
Reproductive system and breast disorders       
Vaginal haemorrhage  1  0/1491 (0.00%)  0 1/681 (0.15%)  1 0/685 (0.00%)  0
Respiratory, thoracic and mediastinal disorders       
Pulmonary embolism  1  1/1491 (0.07%)  1 2/681 (0.29%)  2 0/685 (0.00%)  0
Cough  1  0/1491 (0.00%)  0 1/681 (0.15%)  1 0/685 (0.00%)  0
Epistaxis  1  0/1491 (0.00%)  0 1/681 (0.15%)  1 0/685 (0.00%)  0
Skin and subcutaneous tissue disorders       
Rash  1  1/1491 (0.07%)  1 0/681 (0.00%)  0 0/685 (0.00%)  0
Rash pruritic  1  0/1491 (0.00%)  0 1/681 (0.15%)  1 0/685 (0.00%)  0
Rash Maculo-papular  1  1/1491 (0.07%)  1 0/681 (0.00%)  0 0/685 (0.00%)  0
Vascular disorders       
Hypertension  1  1/1491 (0.07%)  1 0/681 (0.00%)  0 1/685 (0.15%)  1
Aortic dissection  1  0/1491 (0.00%)  0 1/681 (0.15%)  1 0/685 (0.00%)  0
1
Term from vocabulary, MedDRA (20.0)
Indicates events were collected by systematic assessment
Show Other (Not Including Serious) Adverse Events Hide Other (Not Including Serious) Adverse Events
Frequency Threshold for Reporting Other Adverse Events 5%
Tolvaptan (Single-blind Treatment Period) Tolvaptan (Double-blind Treatment Period) Placebo (Double-blind Treatment Period)
Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events
Total   1051/1491 (70.49%)      581/681 (85.32%)      564/685 (82.34%)    
Gastrointestinal disorders       
Dry mouth  1  132/1491 (8.85%)  134 0/681 (0.00%)  0 0/685 (0.00%)  0
Diarrhoea  1  0/1491 (0.00%)  0 47/681 (6.90%)  54 23/685 (3.36%)  25
General disorders       
Thirst  1  430/1491 (28.84%)  453 0/681 (0.00%)  0 0/685 (0.00%)  0
Fatigue  1  0/1491 (0.00%)  0 46/681 (6.75%)  49 24/685 (3.50%)  27
Oedema peripheral  1  0/1491 (0.00%)  0 30/681 (4.41%)  37 45/685 (6.57%)  50
Infections and infestations       
Upper respiratory tract infection  1  0/1491 (0.00%)  0 59/681 (8.66%)  70 58/685 (8.47%)  71
Urinary tract infection  1  0/1491 (0.00%)  0 39/681 (5.73%)  48 55/685 (8.03%)  65
Viral upper respiratory tract infection  1  0/1491 (0.00%)  0 72/681 (10.57%)  98 84/685 (12.26%)  111
Investigations       
Blood creatinine increased  1  0/1491 (0.00%)  0 46/681 (6.75%)  58 46/685 (6.72%)  56
Metabolism and nutrition disorders       
Polydipsia  1  146/1491 (9.79%)  147 0/681 (0.00%)  0 0/685 (0.00%)  0
Musculoskeletal and connective tissue disorders       
Back pain  1  0/1491 (0.00%)  0 34/681 (4.99%)  37 41/685 (5.99%)  46
Nervous system disorders       
Headache  1  0/1491 (0.00%)  0 55/681 (8.08%)  66 59/685 (8.61%)  65
Renal and urinary disorders       
Nocturia  1  308/1491 (20.66%)  319 0/681 (0.00%)  0 0/685 (0.00%)  0
Polyuria  1  475/1491 (31.86%)  488 36/681 (5.29%)  38 11/685 (1.61%)  11
Haematuria  1  0/1491 (0.00%)  0 37/681 (5.43%)  52 35/685 (5.11%)  42
Renal pain  1  0/1491 (0.00%)  0 113/681 (16.59%)  158 130/685 (18.98%)  174
Vascular disorders       
Hypertension  1  0/1491 (0.00%)  0 73/681 (10.72%)  88 79/685 (11.53%)  96
1
Term from vocabulary, MedDRA (20.0)
Indicates events were collected by systematic assessment
Certain Agreements
Principal Investigators are NOT employed by the organization sponsoring the study.
There IS an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.
Results Point of Contact
Name/Title: Global Clinical Devlopment
Organization: Otsuka Pharmaceutical Development & Commercialization, Inc.
Phone: 609 524 6788
Responsible Party: Otsuka Pharmaceutical Development & Commercialization, Inc.
ClinicalTrials.gov Identifier: NCT02160145     History of Changes
Other Study ID Numbers: 156-13-210
First Submitted: June 6, 2014
First Posted: June 10, 2014
Results First Submitted: May 1, 2018
Results First Posted: August 8, 2018
Last Update Posted: August 8, 2018