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

• 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: Otsuka Pharmaceutical Development & Commercialization, Inc.
• 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

Participant Flow

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
Arm/Group Description	Following screening, the single-blind prerandomization period (Day -42 to Day -1) consisted of: 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.; 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.; 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

Baseline Characteristics

Arm/Group Title		Tolvaptan	Placebo	Total Title
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
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%

Outcome Measures

1. Primary Outcome

Title	The Mean Annualized Change in eGFR From Pretreatment Baseline to Post-treatment Follow-up.
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).

Outcome Measure Data

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
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)

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
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).

Outcome Measure Data

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
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)

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
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.

Outcome Measure Data

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
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
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.

Outcome Measure Data

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
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)

Adverse Events

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)
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%)
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
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

Limitations and Caveats

[Not Specified]

More Information

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
• EMail: clinicaltransparency@otsuka-us.com

Publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):

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.

• Responsible Party: Otsuka Pharmaceutical Development & Commercialization, Inc.
• ClinicalTrials.gov Identifier: NCT02160145
• 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