Efficacy and Safety of Tolvaptan in Subjects With Chronic... | NCT02160145

NCT02160145

Status Module

Sponsor/Collaborators Module

Oversight Module

Description Module

Conditions Module

Design Module

Interventional Study Design

Biospecimen

No data available

No data is available for this block.

Arms/Interventions Module

Label	Type	Description	Intervention Names
Tolvaptan	Experimental	Tolvaptan (OPC-41061)	Drug: Tolvaptan (OPC-41061)
Placebo	Placebo Comparator	Placebo	Drug: Placebo

Interventions

Name	Type	Description	Arm Group Labels	Other Names
Tolvaptan (OPC-41061)	Drug	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.

Outcomes Module

Primary Outcomes

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 Outcomes

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.

Other Outcomes

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.

Eligibility Module

Contacts/Locations Module

Facility	Status	City	State	ZIP	Country	Contacts
		Birmingham	Alabama	35294	United States

References Module

Citations

PubMed Identifier	Type	Citation	Retractions
39356039	Derived	St Pierre K, Cashmore BA, Bolignano D, Zoccali C, Ruospo M, Craig JC, Strippoli GF, Mallett AJ, Green SC, Tunnicliffe DJ. Interventions for preventing the progression of autosomal dominant polycystic kidney disease. Cochrane Database Syst Rev. 2024 Oct 2;10(10):CD010294. doi: 10.1002/14651858.CD010294.pub3.
37250503	Derived

IPD Sharing Statement Module

No data available

No data is available for this block.

Results Section

Participant Flow Module

Arm/Group Information

ID	Title	Description
FG000	All Subjects Prerandomization	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.

Baseline Characteristics Module

Outcome Measures Module

Adverse Events Module

More Info Module

Annotation Section

No data available

No data is available for this block.

Document Section

Large Document Module

Type	Includes Protocol	Includes SAP	Includes ICF	Document Label	Document Date	Document Uploaded Date	Document File Name
SAP	No	Yes	No	Statistical Analysis Plan	Mar 31, 2017	May 1, 2018

Derived Section

Miscellaneous Info Module

Submission Tracking

No data available

No data is available for this block.

Condition Browse Module

Intervention Browse Module

Masking Info

FG0001519 subjects
FG0010 subjects
FG0020 subjects

The baseline population consisted of all randomized subjects.

Arm/Group Information

ID	Title	Description
BG000	Tolvaptan	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.
BG001	Placebo	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.
BG002	Total Title

Baseline Measures

Title

Description

Population Description

Parameter Type

Dispersion Type

Unit of Measure

Calculate Percentage

Denominator Units Selected

Denominators

Classes

Age, Continuous

Mean

Standard Deviation

years

Title

Denominators

Categories

Title	Measurements
	BG00047.3± 8.2 BG00147.2± 8.2 BG00247.3± 8.2

Sex: Female, Male

Count of Participants

Participants

Title

Denominators

Categories

Title	Measurements
Female	BG000336 BG001354 BG002

Ethnicity (NIH/OMB)

Count of Participants

Participants

Title

Denominators

Categories

Title	Measurements
Hispanic or Latino	BG00044 BG00135 BG002

Race (NIH/OMB)

Count of Participants

Participants

Title

Denominators

Categories

Title	Measurements
American Indian or Alaska Native	BG0003 BG0011 BG002

Type

Title

Description

Population Description

Reporting Status

Anticipated Posting Date

Parameter Type

Dispersion Type

Unit of Measure

Calculate Percentage

Time Frame

Units Analyzed

Denominator Units Selected

Arm/Group Information

Denominators

Classes

Analyses

Primary

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.

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).

Posted

Least Squares Mean

Standard Error

mL/min/1.73 m^2/year

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

ID	Title	Description
OG000	Tolvaptan	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.
OG001	Placebo	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.

Units	Counts
Participants	OG000668 OG001663

Title

Denominators

Categories

Title	Measurements
	OG000-2.339± 0.240 OG001-3.610± 0.240

Group IDs	Group Description	Statistical Method	Statistical Comment	P-Value	P-Value Comment	Parameter Type	Parameter Value	Dispersion Type	Dispersion Value	Confidence Interval Sides	Confidence Interval %	CI Lower Limit	CI Upper Limit	CI Lower Limit Comment	CI Upper Limit Comment	Estimate Comment	Tested Non-Inferiority	Non-Inferiority Type	Non-Inferiority Comment	Other Analysis Description
OG000 OG001	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.	ANCOVA	Weighted Analysis of Covariance (ANCOVA) with effects of treatment and randomization stratification factors and covariate baseline.	<0.0001	A 2-sided alpha of 0.05 was applied to the primary analysis of the primary endpoint.	Treatment difference	1.271			2-Sided	95	0.859	1.684					Other

Secondary

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.

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.

Posted

Least Squares Mean

Standard Error

mL/min/1.73m^2/year

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

ID	Title	Description
OG000	Tolvaptan	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.
OG001	Placebo

Other Pre-specified

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.

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.

Posted

Mean

Standard Deviation

milliosmole per kilogram (mOSm/kg)

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

ID	Title	Description
OG000	Tolvaptan	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.
OG001	Placebo	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.

Other Pre-specified

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.

Posted

Mean

Standard Deviation

unitless

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

ID	Title	Description
OG000	Tolvaptan	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.
OG001	Placebo	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.

Arm/Groups

ID	Title	Description	Deaths (Affected)	Deaths (At Risk)	Serious Events (Affected)	Serious Events (At Risk)	Other Events (Affected)	Other Events (At Risk)
EG000	Tolvaptan (Single-blind Treatment Period)	The secondary safety population consisted of all subjects who took at least one dose of tolvaptan during the tolvaptan titration/run-in periods.	1	1,491	43	1,491	1,051	1,491
EG001	Tolvaptan (Double-blind Treatment Period)	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.	0	681	85	681	581	681
EG002	Placebo (Double-blind Treatment Period)	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.	1	685	60	685	564	685

Serious Adverse Events

Term	Organ System	Source Vocabulary	Assessment Type	Statistical Information
Angina Pectoris	Cardiac disorders	MedDRA (20.0)	Systematic Assessment	EG0001 events1 affected1,491 at risk EG0010 events0 affected681 at risk EG0020 events0 affected685 at risk
Atrial fibrillation	Cardiac disorders	MedDRA (20.0)	Systematic Assessment	EG0001 events1 affected1,491 at risk EG0011 events1 affected681 at risk EG0021 events1 affected685 at risk
Acute myocardial infarction	Cardiac disorders	MedDRA (20.0)	Systematic Assessment	EG0000 events0 affected1,491 at risk EG0010 events0 affected681 at risk EG0022 events2 affected685 at risk
Aortic valve incompetence	Cardiac disorders	MedDRA (20.0)	Systematic Assessment	EG0000 events0 affected1,491 at risk EG0011 events1 affected681 at risk EG0020 events0 affected685 at risk
Arteriosclerosis coronary artery	Cardiac disorders	MedDRA (20.0)	Systematic Assessment	EG0000 events0 affected1,491 at risk EG0011 events1 affected681 at risk EG0020 events0 affected685 at risk
Mitral valve incompetence	Cardiac disorders	MedDRA (20.0)	Systematic Assessment	EG0000 events0 affected1,491 at risk EG0011 events1 affected681 at risk EG0020 events0 affected685 at risk
Mitral valve prolapse	Cardiac disorders	MedDRA (20.0)	Systematic Assessment	EG0000 events0 affected1,491 at risk EG0011 events1 affected681 at risk EG0020 events0 affected685 at risk
Pericardial effusion	Cardiac disorders	MedDRA (20.0)	Systematic Assessment	EG0000 events0 affected1,491 at risk EG0011 events1 affected681 at risk EG0020 events0 affected685 at risk
Anaemia	Blood and lymphatic system disorders	MedDRA (20.0)	Systematic Assessment	EG0000 events0 affected1,491 at risk EG0011 events1 affected681 at risk EG0020 events0 affected685 at risk
Neutropenia	Blood and lymphatic system disorders	MedDRA (20.0)	Systematic Assessment	EG0000 events0 affected1,491 at risk EG0011 events1 affected681 at risk EG0020 events0 affected685 at risk
Congenital Hepatic Fibrosis	Congenital, familial and genetic disorders	MedDRA (20.0)	Systematic Assessment	EG0000 events0 affected1,491 at risk EG0010 events0 affected681 at risk EG0021 events1 affected685 at risk
Vertigo	Ear and labyrinth disorders	MedDRA (20.0)	Systematic Assessment	EG0001 events1 affected1,491 at risk EG0010 events0 affected681 at risk EG0020 events0 affected685 at risk
Abdominal pain	Gastrointestinal disorders	MedDRA (20.0)	Systematic Assessment	EG0001 events1 affected1,491 at risk EG0011 events1 affected681 at risk EG0020 events0 affected685 at risk
Gastritis	Gastrointestinal disorders	MedDRA (20.0)	Systematic Assessment	EG0001 events1 affected1,491 at risk EG0010 events0 affected681 at risk EG0020 events0 affected685 at risk
Intestinal obstruction	Gastrointestinal disorders	MedDRA (20.0)	Systematic Assessment	EG0001 events1 affected1,491 at risk EG0010 events0 affected681 at risk EG0020 events0 affected685 at risk
Abdominal Hernia	Gastrointestinal disorders	MedDRA (20.0)	Systematic Assessment	EG0000 events0 affected1,491 at risk EG0010 events0 affected681 at risk EG0021 events1 affected685 at risk
Abdominal Incarcerated Hernia	Gastrointestinal disorders	MedDRA (20.0)	Systematic Assessment	EG0000 events0 affected1,491 at risk EG0010 events0 affected681 at risk EG0021 events1 affected685 at risk
Abdominal pain lower	Gastrointestinal disorders	MedDRA (20.0)	Systematic Assessment	EG0000 events0 affected1,491 at risk EG0010 events0 affected681 at risk EG0021 events1 affected685 at risk
Gastrointestinal haemorrhage	Gastrointestinal disorders	MedDRA (20.0)	Systematic Assessment	EG0000 events0 affected1,491 at risk EG0011 events1 affected681 at risk EG0021 events1 affected685 at risk
Gastrooesophageal reflux disease	Gastrointestinal disorders	MedDRA (20.0)	Systematic Assessment	EG0000 events0 affected1,491 at risk EG0011 events1 affected681 at risk EG0020 events0 affected685 at risk
Ileus	Gastrointestinal disorders	MedDRA (20.0)	Systematic Assessment	EG0000 events0 affected1,491 at risk EG0010 events0 affected681 at risk EG0021 events1 affected685 at risk
Nausea	Gastrointestinal disorders	MedDRA (20.0)	Systematic Assessment	EG0000 events0 affected1,491 at risk EG0011 events1 affected681 at risk EG0020 events0 affected685 at risk
Pancreatitis acute	Gastrointestinal disorders	MedDRA (20.0)	Systematic Assessment	EG0000 events0 affected1,491 at risk EG0010 events0 affected681 at risk EG0021 events1 affected685 at risk
Swollen tongue	Gastrointestinal disorders	MedDRA (20.0)	Systematic Assessment	EG0000 events0 affected1,491 at risk EG0010 events0 affected681 at risk EG0021 events1 affected685 at risk
Umbilical hernia	Gastrointestinal disorders	MedDRA (20.0)	Systematic Assessment	EG0000 events0 affected1,491 at risk EG0011 events1 affected681 at risk EG0020 events0 affected685 at risk
Fatigue	General disorders	MedDRA (20.0)	Systematic Assessment	EG0001 events1 affected1,491 at risk EG0011 events1 affected681 at risk EG0021 events1 affected685 at risk
Pyrexia	General disorders	MedDRA (20.0)	Systematic Assessment	EG0001 events1 affected1,491 at risk EG0010 events0 affected681 at risk EG0021 events1 affected685 at risk
Thirst	General disorders	MedDRA (20.0)	Systematic Assessment	EG0002 events2 affected1,491 at risk EG0010 events0 affected681 at risk EG0020 events0 affected685 at risk
Cyst rupture	General disorders	MedDRA (20.0)	Systematic Assessment	EG0000 events0 affected1,491 at risk EG0011 events1 affected681 at risk EG0020 events0 affected685 at risk
Non-cardiac chest pain	General disorders	MedDRA (20.0)	Systematic Assessment	EG0000 events0 affected1,491 at risk EG0011 events1 affected681 at risk EG0021 events1 affected685 at risk
Drug-induced liver injury	Hepatobiliary disorders	MedDRA (20.0)	Systematic Assessment	EG0001 events1 affected1,491 at risk EG0010 events0 affected681 at risk EG0020 events0 affected685 at risk
Hepatic function abnormal	Hepatobiliary disorders	MedDRA (20.0)	Systematic Assessment	EG0001 events1 affected1,491 at risk EG0010 events0 affected681 at risk EG0020 events0 affected685 at risk
Cholangitis	Hepatobiliary disorders	MedDRA (20.0)	Systematic Assessment	EG0000 events0 affected1,491 at risk EG0010 events0 affected681 at risk EG0022 events1 affected685 at risk
Cholelithiasis	Hepatobiliary disorders	MedDRA (20.0)	Systematic Assessment	EG0000 events0 affected1,491 at risk EG0011 events1 affected681 at risk EG0020 events0 affected685 at risk
Haemorrhagic hepatic cyst	Hepatobiliary disorders	MedDRA (20.0)	Systematic Assessment	EG0000 events0 affected1,491 at risk EG0010 events0 affected681 at risk EG0021 events1 affected685 at risk
Hepatic cyst	Hepatobiliary disorders	MedDRA (20.0)	Systematic Assessment	EG0000 events0 affected1,491 at risk EG0011 events1 affected681 at risk EG0020 events0 affected685 at risk
Hepatitis toxic	Hepatobiliary disorders	MedDRA (20.0)	Systematic Assessment	EG0000 events0 affected1,491 at risk EG0011 events1 affected681 at risk EG0020 events0 affected685 at risk
Hypertransaminasaemia	Hepatobiliary disorders	MedDRA (20.0)	Systematic Assessment	EG0000 events0 affected1,491 at risk EG0011 events1 affected681 at risk EG0021 events1 affected685 at risk
Liver injury	Hepatobiliary disorders	MedDRA (20.0)	Systematic Assessment	EG0000 events0 affected1,491 at risk EG0011 events1 affected681 at risk EG0020 events0 affected685 at risk
Drug hypersensitivity	Immune system disorders	MedDRA (20.0)	Systematic Assessment	EG0000 events0 affected1,491 at risk EG0010 events0 affected681 at risk EG0021 events1 affected685 at risk
Hypersensitivity	Immune system disorders	MedDRA (20.0)	Systematic Assessment	EG0000 events0 affected1,491 at risk EG0010 events0 affected681 at risk EG0021 events1 affected685 at risk
HIV infection	Infections and infestations	MedDRA (20.0)	Systematic Assessment	EG0001 events1 affected1,491 at risk EG0010 events0 affected681 at risk EG0020 events0 affected685 at risk
Pneumonia	Infections and infestations	MedDRA (20.0)	Systematic Assessment	EG0001 events1 affected1,491 at risk EG0011 events1 affected681 at risk EG0020 events0 affected685 at risk
Pyelonephritis	Infections and infestations	MedDRA (20.0)	Systematic Assessment	EG0001 events1 affected1,491 at risk EG0011 events1 affected681 at risk EG0023 events3 affected685 at risk
Pyelonephritis acute	Infections and infestations	MedDRA (20.0)	Systematic Assessment	EG0001 events1 affected1,491 at risk EG0010 events0 affected681 at risk EG0020 events0 affected685 at risk
Renal cyst infection	Infections and infestations	MedDRA (20.0)	Systematic Assessment	EG0002 events2 affected1,491 at risk EG0012 events2 affected681 at risk EG0021 events1 affected685 at risk
Sinusitis	Infections and infestations	MedDRA (20.0)	Systematic Assessment	EG0001 events1 affected1,491 at risk EG0010 events0 affected681 at risk EG0020 events0 affected685 at risk
Urinary tract infection	Infections and infestations	MedDRA (20.0)	Systematic Assessment	EG0001 events1 affected1,491 at risk EG0014 events3 affected681 at risk EG0020 events0 affected685 at risk
Appendicitis	Infections and infestations	MedDRA (20.0)	Systematic Assessment	EG0000 events0 affected1,491 at risk EG0010 events0 affected681 at risk EG0021 events1 affected685 at risk
Bacteraemia	Infections and infestations	MedDRA (20.0)	Systematic Assessment	EG0000 events0 affected1,491 at risk EG0011 events1 affected681 at risk EG0020 events0 affected685 at risk
Cellulitis	Infections and infestations	MedDRA (20.0)	Systematic Assessment	EG0000 events0 affected1,491 at risk EG0010 events0 affected681 at risk EG0021 events1 affected685 at risk
Diverticulitis	Infections and infestations	MedDRA (20.0)	Systematic Assessment	EG0000 events0 affected1,491 at risk EG0011 events1 affected681 at risk EG0020 events0 affected685 at risk
Enterobacter bacteraemia	Infections and infestations	MedDRA (20.0)	Systematic Assessment	EG0000 events0 affected1,491 at risk EG0010 events0 affected681 at risk EG0021 events1 affected685 at risk
Erysipelas	Infections and infestations	MedDRA (20.0)	Systematic Assessment	EG0000 events0 affected1,491 at risk EG0011 events1 affected681 at risk EG0020 events0 affected685 at risk
Gastroenteritis	Infections and infestations	MedDRA (20.0)	Systematic Assessment	EG0000 events0 affected1,491 at risk EG0011 events1 affected681 at risk EG0021 events1 affected685 at risk
Hepatic cyst infection	Infections and infestations	MedDRA (20.0)	Systematic Assessment	EG0000 events0 affected1,491 at risk EG0010 events0 affected681 at risk EG0021 events1 affected685 at risk
Influenza	Infections and infestations	MedDRA (20.0)	Systematic Assessment	EG0000 events0 affected1,491 at risk EG0011 events1 affected681 at risk EG0020 events0 affected685 at risk
Klebsiella infection	Infections and infestations	MedDRA (20.0)	Systematic Assessment	EG0000 events0 affected1,491 at risk EG0011 events1 affected681 at risk EG0020 events0 affected685 at risk
Otitis media	Infections and infestations	MedDRA (20.0)	Systematic Assessment	EG0000 events0 affected1,491 at risk EG0011 events1 affected681 at risk EG0020 events0 affected685 at risk
Respiratory tract infection	Infections and infestations	MedDRA (20.0)	Systematic Assessment	EG0000 events0 affected1,491 at risk EG0011 events1 affected681 at risk EG0020 events0 affected685 at risk
Rhinovirus infection	Infections and infestations	MedDRA (20.0)	Systematic Assessment	EG0000 events0 affected1,491 at risk EG0010 events0 affected681 at risk EG0021 events1 affected685 at risk
Sepsis	Infections and infestations	MedDRA (20.0)	Systematic Assessment	EG0000 events0 affected1,491 at risk EG0011 events1 affected681 at risk EG0021 events1 affected685 at risk
Tonsillitis	Infections and infestations	MedDRA (20.0)	Systematic Assessment	EG0000 events0 affected1,491 at risk EG0010 events0 affected681 at risk EG0021 events1 affected685 at risk
Upper respiratory tract infection	Infections and infestations	MedDRA (20.0)	Systematic Assessment	EG0000 events0 affected1,491 at risk EG0011 events1 affected681 at risk EG0020 events0 affected685 at risk
Urosepsis	Infections and infestations	MedDRA (20.0)	Systematic Assessment	EG0000 events0 affected1,491 at risk EG0010 events0 affected681 at risk EG0021 events1 affected685 at risk
Accidental overdose	Injury, poisoning and procedural complications	MedDRA (20.0)	Systematic Assessment	EG0001 events1 affected1,491 at risk EG0010 events0 affected681 at risk EG0020 events0 affected685 at risk
Fall	Injury, poisoning and procedural complications	MedDRA (20.0)	Systematic Assessment	EG0000 events0 affected1,491 at risk EG0010 events0 affected681 at risk EG0021 events1 affected685 at risk
Incisional hernia	Injury, poisoning and procedural complications	MedDRA (20.0)	Systematic Assessment	EG0000 events0 affected1,491 at risk EG0013 events1 affected681 at risk EG0020 events0 affected685 at risk
Ligament rupture	Injury, poisoning and procedural complications	MedDRA (20.0)	Systematic Assessment	EG0000 events0 affected1,491 at risk EG0011 events1 affected681 at risk EG0020 events0 affected685 at risk
Meniscus injury	Injury, poisoning and procedural complications	MedDRA (20.0)	Systematic Assessment	EG0000 events0 affected1,491 at risk EG0010 events0 affected681 at risk EG0021 events1 affected685 at risk
Procedural intestinal perforation	Injury, poisoning and procedural complications	MedDRA (20.0)	Systematic Assessment	EG0000 events0 affected1,491 at risk EG0011 events1 affected681 at risk EG0020 events0 affected685 at risk
Road traffic accident	Injury, poisoning and procedural complications	MedDRA (20.0)	Systematic Assessment	EG0000 events0 affected1,491 at risk EG0010 events0 affected681 at risk EG0021 events1 affected685 at risk
Subarachnoid haemorrhage	Injury, poisoning and procedural complications	MedDRA (20.0)	Systematic Assessment	EG0000 events0 affected1,491 at risk EG0011 events1 affected681 at risk EG0023 events3 affected685 at risk
Subdural haematoma	Injury, poisoning and procedural complications	MedDRA (20.0)	Systematic Assessment	EG0000 events0 affected1,491 at risk EG0012 events2 affected681 at risk EG0020 events0 affected685 at risk
Tibia fracture	Injury, poisoning and procedural complications	MedDRA (20.0)	Systematic Assessment	EG0000 events0 affected1,491 at risk EG0010 events0 affected681 at risk EG0021 events1 affected685 at risk
Alanine aminotransferase increased	Investigations	MedDRA (20.0)	Systematic Assessment	EG0004 events4 affected1,491 at risk EG0018 events8 affected681 at risk EG0020 events0 affected685 at risk
Blood creatinine increased	Investigations	MedDRA (20.0)	Systematic Assessment	EG0001 events1 affected1,491 at risk EG0010 events0 affected681 at risk EG0022 events2 affected685 at risk
Liver function test abnormal	Investigations	MedDRA (20.0)	Systematic Assessment	EG0001 events1 affected1,491 at risk EG0013 events3 affected681 at risk EG0020 events0 affected685 at risk
Transaminases increased	Investigations	MedDRA (20.0)	Systematic Assessment	EG0001 events1 affected1,491 at risk EG0013 events2 affected681 at risk EG0020 events0 affected685 at risk
Aspartate aminotransferase increased	Investigations	MedDRA (20.0)	Systematic Assessment	EG0000 events0 affected1,491 at risk EG0013 events3 affected681 at risk EG0020 events0 affected685 at risk
Blood alkaline phosphatase increased	Investigations	MedDRA (20.0)	Systematic Assessment	EG0000 events0 affected1,491 at risk EG0011 events1 affected681 at risk EG0020 events0 affected685 at risk
Blood bicarbonate decreased	Investigations	MedDRA (20.0)	Systematic Assessment	EG0000 events0 affected1,491 at risk EG0010 events0 affected681 at risk EG0021 events1 affected685 at risk
Gamma-glutamyltransferase increased	Investigations	MedDRA (20.0)	Systematic Assessment	EG0000 events0 affected1,491 at risk EG0011 events1 affected681 at risk EG0020 events0 affected685 at risk
Hepatic enzyme increased	Investigations	MedDRA (20.0)	Systematic Assessment	EG0000 events0 affected1,491 at risk EG00112 events11 affected681 at risk EG0021 events1 affected685 at risk
Liver function test increased	Investigations	MedDRA (20.0)	Systematic Assessment	EG0000 events0 affected1,491 at risk EG0017 events4 affected681 at risk EG0022 events2 affected685 at risk
Prostatic specific antigen increased	Investigations	MedDRA (20.0)	Systematic Assessment	EG0000 events0 affected1,491 at risk EG0010 events0 affected681 at risk EG0021 events1 affected685 at risk
Weight decreased	Investigations	MedDRA (20.0)	Systematic Assessment	EG0000 events0 affected1,491 at risk EG0011 events1 affected681 at risk EG0020 events0 affected685 at risk
Polydipsia	Metabolism and nutrition disorders	MedDRA (20.0)	Systematic Assessment	EG0001 events1 affected1,491 at risk EG0010 events0 affected681 at risk EG0020 events0 affected685 at risk
Hyperglycaemia	Metabolism and nutrition disorders	MedDRA (20.0)	Systematic Assessment	EG0000 events0 affected1,491 at risk EG0010 events0 affected681 at risk EG0021 events1 affected685 at risk
Hypokalaemia	Metabolism and nutrition disorders	MedDRA (20.0)	Systematic Assessment	EG0000 events0 affected1,491 at risk EG0010 events0 affected681 at risk EG0021 events1 affected685 at risk
Hyponatraemia	Metabolism and nutrition disorders	MedDRA (20.0)	Systematic Assessment	EG0000 events0 affected1,491 at risk EG0010 events0 affected681 at risk EG0022 events2 affected685 at risk
Vitamin B complex deficiency	Metabolism and nutrition disorders	MedDRA (20.0)	Systematic Assessment	EG0000 events0 affected1,491 at risk EG0011 events1 affected681 at risk EG0020 events0 affected685 at risk
Back pain	Musculoskeletal and connective tissue disorders	MedDRA (20.0)	Systematic Assessment	EG0001 events1 affected1,491 at risk EG0012 events2 affected681 at risk EG0021 events1 affected685 at risk
Arthritis	Musculoskeletal and connective tissue disorders	MedDRA (20.0)	Systematic Assessment	EG0000 events0 affected1,491 at risk EG0010 events0 affected681 at risk EG0021 events1 affected685 at risk
Cervical spinal stenosis	Musculoskeletal and connective tissue disorders	MedDRA (20.0)	Systematic Assessment	EG0000 events0 affected1,491 at risk EG0010 events0 affected681 at risk EG0021 events1 affected685 at risk
Basal cell carcinoma	Neoplasms benign, malignant and unspecified (incl cysts and polyps)	MedDRA (20.0)	Systematic Assessment	EG0000 events0 affected1,491 at risk EG0010 events0 affected681 at risk EG0022 events2 affected685 at risk
Brain neoplasm benign	Neoplasms benign, malignant and unspecified (incl cysts and polyps)	MedDRA (20.0)	Systematic Assessment	EG0000 events0 affected1,491 at risk EG0010 events0 affected681 at risk EG0021 events1 affected685 at risk
Invasive ductal breast carcinoma	Neoplasms benign, malignant and unspecified (incl cysts and polyps)	MedDRA (20.0)	Systematic Assessment	EG0000 events0 affected1,491 at risk EG0010 events0 affected681 at risk EG0021 events1 affected685 at risk
Meningioma	Neoplasms benign, malignant and unspecified (incl cysts and polyps)	MedDRA (20.0)	Systematic Assessment	EG0000 events0 affected1,491 at risk EG0010 events0 affected681 at risk EG0021 events1 affected685 at risk
Phaeochromocytoma	Neoplasms benign, malignant and unspecified (incl cysts and polyps)	MedDRA (20.0)	Systematic Assessment	EG0000 events0 affected1,491 at risk EG0010 events0 affected681 at risk EG0021 events1 affected685 at risk
Carotid artery aneurysm	Nervous system disorders	MedDRA (20.0)	Systematic Assessment	EG0000 events0 affected1,491 at risk EG0010 events0 affected681 at risk EG0021 events1 affected685 at risk
Cerebral artery thrombosis	Nervous system disorders	MedDRA (20.0)	Systematic Assessment	EG0000 events0 affected1,491 at risk EG0010 events0 affected681 at risk EG0021 events1 affected685 at risk
Cerebrovascular accident	Nervous system disorders	MedDRA (20.0)	Systematic Assessment	EG0000 events0 affected1,491 at risk EG0011 events1 affected681 at risk EG0021 events1 affected685 at risk
Intracranial aneurysm	Nervous system disorders	MedDRA (20.0)	Systematic Assessment	EG0000 events0 affected1,491 at risk EG0011 events1 affected681 at risk EG0021 events1 affected685 at risk
Intracranial pressure increased	Nervous system disorders	MedDRA (20.0)	Systematic Assessment	EG0000 events0 affected1,491 at risk EG0010 events0 affected681 at risk EG0021 events1 affected685 at risk
Transient ischaemic attack	Nervous system disorders	MedDRA (20.0)	Systematic Assessment	EG0000 events0 affected1,491 at risk EG0012 events2 affected681 at risk EG0021 events1 affected685 at risk
Insomnia	Psychiatric disorders	MedDRA (20.0)	Systematic Assessment	EG0001 events1 affected1,491 at risk EG0010 events0 affected681 at risk EG0020 events0 affected685 at risk
Confusional state	Psychiatric disorders	MedDRA (20.0)	Systematic Assessment	EG0000 events0 affected1,491 at risk EG0010 events0 affected681 at risk EG0021 events1 affected685 at risk
Acute kidney injury	Renal and urinary disorders	MedDRA (20.0)	Systematic Assessment	EG0002 events2 affected1,491 at risk EG0012 events2 affected681 at risk EG0021 events1 affected685 at risk
Chronic kidney disease	Renal and urinary disorders	MedDRA (20.0)	Systematic Assessment	EG0001 events1 affected1,491 at risk EG0011 events1 affected681 at risk EG0020 events0 affected685 at risk
Nephrolithiasis	Renal and urinary disorders	MedDRA (20.0)	Systematic Assessment	EG0001 events1 affected1,491 at risk EG0010 events0 affected681 at risk EG0021 events1 affected685 at risk
Haematuria	Renal and urinary disorders	MedDRA (20.0)	Systematic Assessment	EG0000 events0 affected1,491 at risk EG0011 events1 affected681 at risk EG0022 events2 affected685 at risk
Nocturia	Renal and urinary disorders	MedDRA (20.0)	Systematic Assessment	EG0003 events3 affected1,491 at risk EG0010 events0 affected681 at risk EG0020 events0 affected685 at risk
Pollakiuria	Renal and urinary disorders	MedDRA (20.0)	Systematic Assessment	EG0002 events2 affected1,491 at risk EG0010 events0 affected681 at risk EG0020 events0 affected685 at risk
Polyuria	Renal and urinary disorders	MedDRA (20.0)	Systematic Assessment	EG0004 events4 affected1,491 at risk EG0010 events0 affected681 at risk EG0020 events0 affected685 at risk
Renal colic	Renal and urinary disorders	MedDRA (20.0)	Systematic Assessment	EG0001 events1 affected1,491 at risk EG0010 events0 affected681 at risk EG0020 events0 affected685 at risk
Renal cyst haemorrhage	Renal and urinary disorders	MedDRA (20.0)	Systematic Assessment	EG0002 events2 affected1,491 at risk EG0013 events3 affected681 at risk EG0022 events2 affected685 at risk
Renal impairment	Renal and urinary disorders	MedDRA (20.0)	Systematic Assessment	EG0001 events1 affected1,491 at risk EG0012 events2 affected681 at risk EG0023 events3 affected685 at risk
Renal pain	Renal and urinary disorders	MedDRA (20.0)	Systematic Assessment	EG0001 events1 affected1,491 at risk EG0011 events1 affected681 at risk EG0023 events3 affected685 at risk
Ureteric obstruction	Renal and urinary disorders	MedDRA (20.0)	Systematic Assessment	EG0001 events1 affected1,491 at risk EG0010 events0 affected681 at risk EG0020 events0 affected685 at risk
Renal haemorrhage	Renal and urinary disorders	MedDRA (20.0)	Systematic Assessment	EG0000 events0 affected1,491 at risk EG0010 events0 affected681 at risk EG0021 events1 affected685 at risk
Vaginal haemorrhage	Reproductive system and breast disorders	MedDRA (20.0)	Systematic Assessment	EG0000 events0 affected1,491 at risk EG0011 events1 affected681 at risk EG0020 events0 affected685 at risk
Pulmonary embolism	Respiratory, thoracic and mediastinal disorders	MedDRA (20.0)	Systematic Assessment	EG0001 events1 affected1,491 at risk EG0012 events2 affected681 at risk EG0020 events0 affected685 at risk
Cough	Respiratory, thoracic and mediastinal disorders	MedDRA (20.0)	Systematic Assessment	EG0000 events0 affected1,491 at risk EG0011 events1 affected681 at risk EG0020 events0 affected685 at risk
Epistaxis	Respiratory, thoracic and mediastinal disorders	MedDRA (20.0)	Systematic Assessment	EG0000 events0 affected1,491 at risk EG0011 events1 affected681 at risk EG0020 events0 affected685 at risk
Rash	Skin and subcutaneous tissue disorders	MedDRA (20.0)	Systematic Assessment	EG0001 events1 affected1,491 at risk EG0010 events0 affected681 at risk EG0020 events0 affected685 at risk
Rash pruritic	Skin and subcutaneous tissue disorders	MedDRA (20.0)	Systematic Assessment	EG0000 events0 affected1,491 at risk EG0011 events1 affected681 at risk EG0020 events0 affected685 at risk
Rash Maculo-papular	Skin and subcutaneous tissue disorders	MedDRA (20.0)	Systematic Assessment	EG0001 events1 affected1,491 at risk EG0010 events0 affected681 at risk EG0020 events0 affected685 at risk
Hypertension	Vascular disorders	MedDRA (20.0)	Systematic Assessment	EG0001 events1 affected1,491 at risk EG0010 events0 affected681 at risk EG0021 events1 affected685 at risk
Aortic dissection	Vascular disorders	MedDRA (20.0)	Systematic Assessment	EG0000 events0 affected1,491 at risk EG0011 events1 affected681 at risk EG0020 events0 affected685 at risk

Other Adverse Events

Term	Organ System	Source Vocabulary	Assessment Type	Statistical Information
Dry mouth	Gastrointestinal disorders	MedDRA (20.0)	Systematic Assessment	EG000134 events132 affected1,491 at risk EG0010 events0 affected681 at risk EG0020 events0 affected685 at risk
Diarrhoea	Gastrointestinal disorders	MedDRA (20.0)	Systematic Assessment	EG0000 events0 affected1,491 at risk EG00154 events47 affected681 at risk EG00225 events23 affected685 at risk
Thirst	General disorders	MedDRA (20.0)	Systematic Assessment	EG000453 events430 affected1,491 at risk EG0010 events0 affected681 at risk EG0020 events0 affected685 at risk
Fatigue	General disorders	MedDRA (20.0)	Systematic Assessment	EG0000 events0 affected1,491 at risk EG00149 events46 affected681 at risk EG00227 events24 affected685 at risk
Oedema peripheral	General disorders	MedDRA (20.0)	Systematic Assessment	EG0000 events0 affected1,491 at risk EG00137 events30 affected681 at risk EG00250 events45 affected685 at risk
Upper respiratory tract infection	Infections and infestations	MedDRA (20.0)	Systematic Assessment	EG0000 events0 affected1,491 at risk EG00170 events59 affected681 at risk EG00271 events58 affected685 at risk
Urinary tract infection	Infections and infestations	MedDRA (20.0)	Systematic Assessment	EG0000 events0 affected1,491 at risk EG00148 events39 affected681 at risk EG00265 events55 affected685 at risk
Viral upper respiratory tract infection	Infections and infestations	MedDRA (20.0)	Systematic Assessment	EG0000 events0 affected1,491 at risk EG00198 events72 affected681 at risk EG002111 events84 affected685 at risk
Blood creatinine increased	Investigations	MedDRA (20.0)	Systematic Assessment	EG0000 events0 affected1,491 at risk EG00158 events46 affected681 at risk EG00256 events46 affected685 at risk
Polydipsia	Metabolism and nutrition disorders	MedDRA (20.0)	Systematic Assessment	EG000147 events146 affected1,491 at risk EG0010 events0 affected681 at risk EG0020 events0 affected685 at risk
Back pain	Musculoskeletal and connective tissue disorders	MedDRA (20.0)	Systematic Assessment	EG0000 events0 affected1,491 at risk EG00137 events34 affected681 at risk EG00246 events41 affected685 at risk
Headache	Nervous system disorders	MedDRA (20.0)	Systematic Assessment	EG0000 events0 affected1,491 at risk EG00166 events55 affected681 at risk EG00265 events59 affected685 at risk
Nocturia	Renal and urinary disorders	MedDRA (20.0)	Systematic Assessment	EG000319 events308 affected1,491 at risk EG0010 events0 affected681 at risk EG0020 events0 affected685 at risk
Polyuria	Renal and urinary disorders	MedDRA (20.0)	Systematic Assessment	EG000488 events475 affected1,491 at risk EG00138 events36 affected681 at risk EG00211 events11 affected685 at risk
Haematuria	Renal and urinary disorders	MedDRA (20.0)	Systematic Assessment	EG0000 events0 affected1,491 at risk EG00152 events37 affected681 at risk EG00242 events35 affected685 at risk
Renal pain	Renal and urinary disorders	MedDRA (20.0)	Systematic Assessment	EG0000 events0 affected1,491 at risk EG001158 events113 affected681 at risk EG002174 events130 affected685 at risk
Hypertension	Vascular disorders	MedDRA (20.0)	Systematic Assessment	EG0000 events0 affected1,491 at risk EG00188 events73 affected681 at risk EG00296 events79 affected685 at risk

ID	Term
D051436	Renal Insufficiency, Chronic
D016891	Polycystic Kidney, Autosomal Dominant

Ancestor Terms

ID	Term
D051437	Renal Insufficiency
D007674	Kidney Diseases
D014570	Urologic Diseases
D052776	Female Urogenital Diseases
D005261	Female Urogenital Diseases and Pregnancy Complications
D000091642	Urogenital Diseases
D052801	Male Urogenital Diseases
D002908	Chronic Disease
D020969	Disease Attributes
D010335	Pathologic Processes
D013568	Pathological Conditions, Signs and Symptoms
D007690	Polycystic Kidney Diseases
D052177	Kidney Diseases, Cystic
D000015	Abnormalities, Multiple
D000013	Congenital Abnormalities
D009358	Congenital, Hereditary, and Neonatal Diseases and Abnormalities
D000072661	Ciliopathies
D030342	Genetic Diseases, Inborn

ID	Term
D000077602	Tolvaptan

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.

ID	Term
D001552	Benzazepines
D006574	Heterocyclic Compounds, 2-Ring
D000072471	Heterocyclic Compounds, Fused-Ring
D006571	Heterocyclic Compounds