Trial Outcomes & Findings for Tolvaptan Extension Study in Participants With ADPKD (NCT NCT01214421)

Last Updated: 2021-10-25

Results Overview

Total kidney volume is a measure of disease progression in the ADPKD participants. Kidney volume was assessed in T1-weighted magnetic resonance images collected at each study site and sent to a central reviewing facility. At the central reviewing facility, radiologists used proprietary software to measure the volume of both kidneys in participants continuing from previous study (156-04-251) at Month 24 of this study (156-08-271) comparing change in TKV for the early-treated (those previously treated with tolvaptan) to delayed-treated (those previously treated with placebo). The percent change in the volume of both kidneys combined was analysed using mixed-effect model repeated measures (MMRM) analysis and reported. This outcome measure was analyzed only in the participants enrolled from the previous study - 156-04-251, as pre-specified in the protocol.

Recruitment status

COMPLETED

Study phase

PHASE3

Target enrollment

1083 participants

Primary outcome timeframe

Study Baseline (Prior to Day 1 in Study 156-04-251) to Month 24 in this study (Study 156-08-271)

Results posted on

2021-10-25

Participant Flow

This study was conducted at 106 sites in 13 countries from 26 May 2010 to 29 Feb 2016. Eligible participants with autosomal dominant polycystic kidney disease (ADPKD) or renal impairment who completed previous tolvaptan treatment in studies: 156-04-251 (NCT00428948), 156-04-250 (NCT00413777), 156-06-260, 156-09-284 (NCT01336972), 156-09-285 (NCT01210560), and 156-09-290 (NCT01451827) were enrolled in this open-label study.

All enrolled participants received tolvaptan in this study. Data in this study was collected and reported as per the prior treatment received - tolvaptan (called as early treated) or placebo (called as delayed treated), for study 156-04-251 and all other studies combined.

Participant milestones

Participant milestones
Measure	Tolvaptan (From Study 156-04-251: Tolvaptan, Early Treated) Participants received a daily split-dose of tolvaptan titrated to the maximally tolerated dose, starting daily tolvaptan dose of 45 milligram (mg) in the morning \[AM\]/15 mg in the evening \[PM\] titrated to 60 mg \[AM\]/30 mg \[PM\], then 90 mg \[AM\]/30 mg \[PM\] based on tolerability were given orally twice daily up to Month 24. Participants were previously treated with tolvaptan in previous Study 156-04-251, hence called as Early Treated.	Tolvaptan (From Study 156-04-251: Placebo, Delayed Treated) Participants received a daily split-dose of tolvaptan titrated to the maximally tolerated dose, starting daily tolvaptan dose of 45 mg \[AM\]/15 mg \[PM\] titrated to 60 mg \[AM\]/30 mg \[PM\], then 90 mg \[AM\]/30 mg \[PM\] based on tolerability were given orally twice daily up to Month 24. Participants were previously treated with placebo in the previous Study 156-04-251, hence called as Delayed Treated.	Tolvaptan (From Other Studies: Tolvaptan, Early Treated) Participants received a daily split-dose of tolvaptan titrated to the maximally tolerated dose, starting daily tolvaptan dose of 45 mg \[AM\]/15 mg \[PM\] titrated to 60 mg \[AM\]/30 mg \[PM\], then 90 mg \[AM\]/30 mg \[PM\] based on tolerability were given orally twice daily up to Month 24. Participants were previously treated with tolvaptan in other studies (156-04-250, 156-06-260, 156-09-284, 156-09-285, and 156-09-290), hence called as Early Treated.	Tolvaptan (From Other Studies: Placebo, Delayed Treated) Participants received a daily split-dose of tolvaptan titrated to the maximally tolerated dose, starting daily tolvaptan dose of 45 mg \[AM\]/15 mg \[PM\] titrated to 60 mg \[AM\]/30 mg \[PM\], then 90 mg \[AM\]/30 mg \[PM\] based on tolerability were given orally twice daily up to Month 24. Participants were previously treated with placebo in other studies (156-04-250, 156-06-260, 156-09-284, 156-09-285, and 156-09-290), hence called as Delayed Treated.
Overall Study STARTED	557	314	181	31
Overall Study COMPLETED	507	256	143	22
Overall Study NOT COMPLETED	50	58	38	9

Reasons for withdrawal

Reasons for withdrawal
Measure	Tolvaptan (From Study 156-04-251: Tolvaptan, Early Treated) Participants received a daily split-dose of tolvaptan titrated to the maximally tolerated dose, starting daily tolvaptan dose of 45 milligram (mg) in the morning \[AM\]/15 mg in the evening \[PM\] titrated to 60 mg \[AM\]/30 mg \[PM\], then 90 mg \[AM\]/30 mg \[PM\] based on tolerability were given orally twice daily up to Month 24. Participants were previously treated with tolvaptan in previous Study 156-04-251, hence called as Early Treated.	Tolvaptan (From Study 156-04-251: Placebo, Delayed Treated) Participants received a daily split-dose of tolvaptan titrated to the maximally tolerated dose, starting daily tolvaptan dose of 45 mg \[AM\]/15 mg \[PM\] titrated to 60 mg \[AM\]/30 mg \[PM\], then 90 mg \[AM\]/30 mg \[PM\] based on tolerability were given orally twice daily up to Month 24. Participants were previously treated with placebo in the previous Study 156-04-251, hence called as Delayed Treated.	Tolvaptan (From Other Studies: Tolvaptan, Early Treated) Participants received a daily split-dose of tolvaptan titrated to the maximally tolerated dose, starting daily tolvaptan dose of 45 mg \[AM\]/15 mg \[PM\] titrated to 60 mg \[AM\]/30 mg \[PM\], then 90 mg \[AM\]/30 mg \[PM\] based on tolerability were given orally twice daily up to Month 24. Participants were previously treated with tolvaptan in other studies (156-04-250, 156-06-260, 156-09-284, 156-09-285, and 156-09-290), hence called as Early Treated.	Tolvaptan (From Other Studies: Placebo, Delayed Treated) Participants received a daily split-dose of tolvaptan titrated to the maximally tolerated dose, starting daily tolvaptan dose of 45 mg \[AM\]/15 mg \[PM\] titrated to 60 mg \[AM\]/30 mg \[PM\], then 90 mg \[AM\]/30 mg \[PM\] based on tolerability were given orally twice daily up to Month 24. Participants were previously treated with placebo in other studies (156-04-250, 156-06-260, 156-09-284, 156-09-285, and 156-09-290), hence called as Delayed Treated.
Overall Study Lost to Follow-up	7	3	7	3
Overall Study Adverse Event	16	35	14	3
Overall Study Sponsor Discontinued Site	1	2	0	0
Overall Study Withdrawal Criteria Met	3	0	2	1
Overall Study Physician Decision	2	0	4	0
Overall Study Withdrawal by Subject	21	18	11	2

Baseline Characteristics

Tolvaptan Extension Study in Participants With ADPKD

Baseline characteristics by cohort

Baseline characteristics by cohort
Measure	Tolvaptan (From Study 156-04-251: Tolvaptan, Early Treated) n=557 Participants Participants received a daily split-dose of tolvaptan titrated to the maximally tolerated dose, starting daily tolvaptan dose of 45 mg \[AM\]/15 mg \[PM\] titrated to 60 mg \[AM\]/30 mg \[PM\], then 90 mg \[AM\]/30 mg \[PM\] based on tolerability were given orally twice daily up to Month 24. Participants were previously treated with tolvaptan in previous Study 156-04-251, hence called as Early Treated.	Tolvaptan (From Study 156-04-251: Placebo, Delayed Treated) n=314 Participants Participants received a daily split-dose of tolvaptan titrated to the maximally tolerated dose, starting daily tolvaptan dose of 45 mg \[AM\]/15 mg \[PM\] titrated to 60 mg \[AM\]/30 mg \[PM\], then 90 mg \[AM\]/30 mg \[PM\] based on tolerability were given orally twice daily up to Month 24. Participants were previously treated with placebo in the previous Study 156-04-251, hence called as Delayed Treated.	Tolvaptan (From Other Studies: Tolvaptan, Early Treated) n=181 Participants Participants received a daily split-dose of tolvaptan titrated to the maximally tolerated dose, starting daily tolvaptan dose of 45 mg \[AM\]/15 mg \[PM\] titrated to 60 mg \[AM\]/30 mg \[PM\], then 90 mg \[AM\]/30 mg \[PM\] based on tolerability were given orally twice daily up to Month 24. Participants were previously treated with tolvaptan in other studies (156-04-250, 156-06-260, 156-09-284, 156-09-285, and 156-09-290), hence called as Early Treated.	Tolvaptan (From Other Studies: Placebo, Delayed Treated) n=31 Participants Participants received a daily split-dose of tolvaptan titrated to the maximally tolerated dose, starting daily tolvaptan dose of 45 mg \[AM\]/15 mg \[PM\] titrated to 60 mg \[AM\]/30 mg \[PM\], then 90 mg \[AM\]/30 mg \[PM\] based on tolerability were given orally twice daily up to Month 24. Participants were previously treated with placebo in other studies (156-04-250, 156-06-260, 156-09-284, 156-09-285, and 156-09-290), hence called as Delayed Treated.	Total n=1083 Participants Total of all reporting groups
Sex: Female, Male Male	303 Participants n=5 Participants	158 Participants n=7 Participants	90 Participants n=5 Participants	16 Participants n=4 Participants	567 Participants n=21 Participants
Age, Continuous	42.2 years STANDARD_DEVIATION 6.9 • n=5 Participants	42.5 years STANDARD_DEVIATION 7.2 • n=7 Participants	40.0 years STANDARD_DEVIATION 10.1 • n=5 Participants	35.6 years STANDARD_DEVIATION 8.7 • n=4 Participants	41.7 years STANDARD_DEVIATION 7.8 • n=21 Participants
Sex: Female, Male Female	254 Participants n=5 Participants	156 Participants n=7 Participants	91 Participants n=5 Participants	15 Participants n=4 Participants	516 Participants n=21 Participants
Ethnicity (NIH/OMB) Hispanic or Latino	24 Participants n=5 Participants	19 Participants n=7 Participants	8 Participants n=5 Participants	4 Participants n=4 Participants	55 Participants n=21 Participants
Ethnicity (NIH/OMB) Not Hispanic or Latino	471 Participants n=5 Participants	249 Participants n=7 Participants	172 Participants n=5 Participants	27 Participants n=4 Participants	919 Participants n=21 Participants
Ethnicity (NIH/OMB) Unknown or Not Reported	62 Participants n=5 Participants	46 Participants n=7 Participants	1 Participants n=5 Participants	0 Participants n=4 Participants	109 Participants n=21 Participants
Race/Ethnicity, Customized White/Caucasian	535 Participants n=5 Participants	302 Participants n=7 Participants	169 Participants n=5 Participants	27 Participants n=4 Participants	1033 Participants n=21 Participants
Race/Ethnicity, Customized Black/African American	9 Participants n=5 Participants	2 Participants n=7 Participants	2 Participants n=5 Participants	3 Participants n=4 Participants	16 Participants n=21 Participants
Race/Ethnicity, Customized American Indian or Alaska Native	0 Participants n=5 Participants	0 Participants n=7 Participants	1 Participants n=5 Participants	0 Participants n=4 Participants	1 Participants n=21 Participants
Race/Ethnicity, Customized Asian	3 Participants n=5 Participants	2 Participants n=7 Participants	5 Participants n=5 Participants	0 Participants n=4 Participants	10 Participants n=21 Participants
Race/Ethnicity, Customized Other	10 Participants n=5 Participants	8 Participants n=7 Participants	4 Participants n=5 Participants	1 Participants n=4 Participants	23 Participants n=21 Participants

PRIMARY outcome

Timeframe: Study Baseline (Prior to Day 1 in Study 156-04-251) to Month 24 in this study (Study 156-08-271)

Population: The Efficacy Sample consisted of all enrolled participants who took at least 1 dose of study drug and completed 3 years of study drug treatment in previous Study 156-04-251. Overall number of participants analyzed signifies the number of participants who were evaluable for this outcome measure.

Outcome measures

Outcome measures
Measure	Tolvaptan, Early Treated (From Study 156-04-251: Tolvaptan) n=505 Participants Participants received a daily split-dose of tolvaptan titrated to the maximally tolerated dose, starting daily tolvaptan dose of 45 mg \[AM\]/15 mg \[PM\] titrated to 60 mg \[AM\]/30 mg \[PM\], then 90 mg \[AM\]/30 mg \[PM\] based on tolerability were given orally twice daily up to Month 24. Participants were previously treated with tolvaptan in Study 156-04-251.	Tolvaptan, Delayed Treated (From Study 156-04-251: Placebo) n=267 Participants Participants received a daily split-dose of tolvaptan titrated to the maximally tolerated dose, starting daily tolvaptan dose of 45 mg \[AM\]/15 mg \[PM\] titrated to 60 mg \[AM\]/30 mg \[PM\], then 90 mg \[AM\]/30 mg \[PM\] based on tolerability were given orally twice daily up to Month 24. Participants were previously treated with placebo in Study 156-04-251.
Percent Change From the Baseline in Total Kidney Volume (TKV) for Study 156-04-251 Participants Enrolled in This Study (156-08-271)	28.66 percent change Standard Deviation 26.14	30.58 percent change Standard Deviation 27.21

SECONDARY outcome

Timeframe: Study Baseline (Prior to Day 1 in Study 156-04-251) to Month 24 in this study (Study 156-08-271)

Estimated Glomerular Filtration Rate (eGFR) according to CKD-EPI is calculated using the CKD-EPI equation, expressed as a single equation, is GFR = 141 × min (serum creatinine \[Scr\]/κ, 1)α × max(Scr/κ, 1)\^-1.209 × 0.993 Age × 1.018 (if female) × 1.159 (if black), where Scr is serum creatinine, κ is 0.7 for females and 0.9 for males, α is -0.329 for females and -0.411 for males, min indicates the minimum of Scr/ĸ or 1, and max indicates the maximum of Scr/κ or 1 in participants continuing from previous study (156-04-251) at Month 24 of this study (156-08-271) comparing change in eGFR for the early-treated (those previously treated with tolvaptan) to delayed-treated (those previously treated with placebo). MMRM was used for the analysis. This outcome measure was analyzed only in the participants enrolled from the previous - 156-04-251, as pre-specified in the protocol.

Outcome measures

Outcome measures
Measure	Tolvaptan, Early Treated (From Study 156-04-251: Tolvaptan) n=503 Participants Participants received a daily split-dose of tolvaptan titrated to the maximally tolerated dose, starting daily tolvaptan dose of 45 mg \[AM\]/15 mg \[PM\] titrated to 60 mg \[AM\]/30 mg \[PM\], then 90 mg \[AM\]/30 mg \[PM\] based on tolerability were given orally twice daily up to Month 24. Participants were previously treated with tolvaptan in Study 156-04-251.	Tolvaptan, Delayed Treated (From Study 156-04-251: Placebo) n=263 Participants Participants received a daily split-dose of tolvaptan titrated to the maximally tolerated dose, starting daily tolvaptan dose of 45 mg \[AM\]/15 mg \[PM\] titrated to 60 mg \[AM\]/30 mg \[PM\], then 90 mg \[AM\]/30 mg \[PM\] based on tolerability were given orally twice daily up to Month 24. Participants were previously treated with placebo in Study 156-04-251.
Change From the Baseline in Estimated Glomerular Filtration Rate (eGFR) as Assessed by Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) for Study 156-04-251 Participants Enrolled in This Study (156-08-271)	-16.77 mL/min/1.73 square meters (m^2) Standard Deviation 13.16	-19.92 mL/min/1.73 square meters (m^2) Standard Deviation 16.40

SECONDARY outcome

Timeframe: Study Baseline (Prior to Day 1 in Study 156-08-271) to Month 24 in this study (Study 156-08-271)

Annualized slope of TKV is a measure of renal function and disease progression in ADPKD participants. The annualized slope is calculated as percentage of growth in TKV (measured in mL by MRI) divided by each participant's years of participation for all participants was calculated using MMRM analysis in participants continuing from previous study (156-04-251) at Month 24 of this study (156-08-271) comparing annualized slope of TKV for the early-treated (those previously treated with tolvaptan) to delayed-treated (those previously treated with placebo). This outcome measure was analyzed only in the participants enrolled from the previous study - 156-04-251, as pre-specified in the protocol.

Outcome measures

Outcome measures
Measure	Tolvaptan, Early Treated (From Study 156-04-251: Tolvaptan) n=509 Participants Participants received a daily split-dose of tolvaptan titrated to the maximally tolerated dose, starting daily tolvaptan dose of 45 mg \[AM\]/15 mg \[PM\] titrated to 60 mg \[AM\]/30 mg \[PM\], then 90 mg \[AM\]/30 mg \[PM\] based on tolerability were given orally twice daily up to Month 24. Participants were previously treated with tolvaptan in Study 156-04-251.	Tolvaptan, Delayed Treated (From Study 156-04-251: Placebo) n=268 Participants Participants received a daily split-dose of tolvaptan titrated to the maximally tolerated dose, starting daily tolvaptan dose of 45 mg \[AM\]/15 mg \[PM\] titrated to 60 mg \[AM\]/30 mg \[PM\], then 90 mg \[AM\]/30 mg \[PM\] based on tolerability were given orally twice daily up to Month 24. Participants were previously treated with placebo in Study 156-04-251.
Annualized Slope of Total Kidney Volume (TKV) for Study 156-04-251 Participants Enrolled in Study 156-08-271	6.164 percent change in TKV/participant-years	4.960 percent change in TKV/participant-years

SECONDARY outcome

Timeframe: Study Baseline (Prior to Day 1 in Study 156-08-271) to Month 24 (Study 156-08-271)

Annualized slope of eGFR (CKD-EPI) is a measure of renal function and disease progression in ADPKD participants. The annualized slope of eGFR (CKD-EPI) (divided by each participant's years of participation) for all participants was calculated using MMRM analysis in participants continuing from previous study (156-04-251) at Month 24 of this study (156-08-271) comparing change in TKV for the early-treated (those previously treated with tolvaptan) to delayed-treated (those previously treated with placebo). eGFR was calculated using the Chronic Kidney Disease-Epidemiology (CKD-EPI) formula. This outcome measure was analyzed only in the participants enrolled from the previous study - 156-04-251, as pre-specified in the protocol.

Outcome measures

Outcome measures
Measure	Tolvaptan, Early Treated (From Study 156-04-251: Tolvaptan) n=549 Participants Participants received a daily split-dose of tolvaptan titrated to the maximally tolerated dose, starting daily tolvaptan dose of 45 mg \[AM\]/15 mg \[PM\] titrated to 60 mg \[AM\]/30 mg \[PM\], then 90 mg \[AM\]/30 mg \[PM\] based on tolerability were given orally twice daily up to Month 24. Participants were previously treated with tolvaptan in Study 156-04-251.	Tolvaptan, Delayed Treated (From Study 156-04-251: Placebo) n=304 Participants Participants received a daily split-dose of tolvaptan titrated to the maximally tolerated dose, starting daily tolvaptan dose of 45 mg \[AM\]/15 mg \[PM\] titrated to 60 mg \[AM\]/30 mg \[PM\], then 90 mg \[AM\]/30 mg \[PM\] based on tolerability were given orally twice daily up to Month 24. Participants were previously treated with placebo in Study 156-04-251.
Annualized Slope of eGFR (CKD-EPI) for Study 156-04-251 Participants Enrolled in Study 156-08-271	-3.255 ml/min/1.73m^2/participant-years	-3.142 ml/min/1.73m^2/participant-years

SECONDARY outcome

Timeframe: Tolvaptan, Delayed Treated: Baseline to Month 24 in Study 156-08-271; Placebo: Baseline to Month 36 in Study 156-04-251

Annualized slope of TKV is a measure of renal function and disease progression in ADPKD participants. The annualized slope is calculated as percentage of growth in TKV (measured in mL by MRI) divided by each participant's years of participation, using MMRM analysis to compare annualized slope of TKV for the participants who received placebo in previous study (156-04-251) to annualized slope of TKV for the same participants who received tolvaptan in this study (156-08-271). This outcome measure was analyzed only in the participants enrolled from the previous study - 156-04-251 and who received placebo in the previous study, as pre-specified in the protocol.

Outcome measures

Outcome measures
Measure	Tolvaptan, Early Treated (From Study 156-04-251: Tolvaptan) n=268 Participants Participants received a daily split-dose of tolvaptan titrated to the maximally tolerated dose, starting daily tolvaptan dose of 45 mg \[AM\]/15 mg \[PM\] titrated to 60 mg \[AM\]/30 mg \[PM\], then 90 mg \[AM\]/30 mg \[PM\] based on tolerability were given orally twice daily up to Month 24. Participants were previously treated with tolvaptan in Study 156-04-251.	Tolvaptan, Delayed Treated (From Study 156-04-251: Placebo) n=268 Participants Participants received a daily split-dose of tolvaptan titrated to the maximally tolerated dose, starting daily tolvaptan dose of 45 mg \[AM\]/15 mg \[PM\] titrated to 60 mg \[AM\]/30 mg \[PM\], then 90 mg \[AM\]/30 mg \[PM\] based on tolerability were given orally twice daily up to Month 24. Participants were previously treated with placebo in Study 156-04-251.
Annualized TKV Slope for Study 156-04-251 Placebo Participants Enrolled in Study 156-08-271	4.779 percent change in TKV/participant-years	5.627 percent change in TKV/participant-years

SECONDARY outcome

Timeframe: Tolvaptan, Delayed Treated: Baseline to Month 24 in Study 156-08-271; Placebo: Baseline to Month 36 in Study 156-04-251

Annualized slope of eGFR (CKD-EPI) is a measure of renal function and disease progression in ADPKD participants. The annualized slope of eGFR (calculated using CKD-EPI formula) divided by each participant's years of participation, using MMRM analysis to compare annualized slope of eGFR (CKD-EPI) for the participants who received placebo in previous study (156-04-251) to the annualized slope of eGFR (CKD-EPI) for the same participants who received tolvaptan in this study (156-08-271). This outcome measure was analyzed only in the participants enrolled from the previous study - 156-04-251 who received placebo in previous study and received tolvaptan in this study, as pre-specified in the protocol.

Outcome measures

Outcome measures
Measure	Tolvaptan, Early Treated (From Study 156-04-251: Tolvaptan) n=304 Participants Participants received a daily split-dose of tolvaptan titrated to the maximally tolerated dose, starting daily tolvaptan dose of 45 mg \[AM\]/15 mg \[PM\] titrated to 60 mg \[AM\]/30 mg \[PM\], then 90 mg \[AM\]/30 mg \[PM\] based on tolerability were given orally twice daily up to Month 24. Participants were previously treated with tolvaptan in Study 156-04-251.	Tolvaptan, Delayed Treated (From Study 156-04-251: Placebo) n=304 Participants Participants received a daily split-dose of tolvaptan titrated to the maximally tolerated dose, starting daily tolvaptan dose of 45 mg \[AM\]/15 mg \[PM\] titrated to 60 mg \[AM\]/30 mg \[PM\], then 90 mg \[AM\]/30 mg \[PM\] based on tolerability were given orally twice daily up to Month 24. Participants were previously treated with placebo in Study 156-04-251.
Annualized Slope of Renal Function (eGFRCKD-EPI) for Study 156-04-251 Placebo Participants Enrolled in Study 156-08-271	-3.211 ml/min/1.73m^2/participant-years	-3.572 ml/min/1.73m^2/participant-years

Adverse Events

Tolvaptan (From Study 156-04-251: Tolvaptan, Early Treated)

Serious events: 143 serious events

Other events: 528 other events

Deaths: 5 deaths

Tolvaptan (From Study 156-04-251: Placebo, Delayed Treated)

Serious events: 79 serious events

Other events: 310 other events

Deaths: 0 deaths

Tolvaptan (From Other Studies: Tolvaptan, Early Treated)

Serious events: 34 serious events

Other events: 175 other events

Deaths: 0 deaths

Tolvaptan (From Other Studies: Placebo, Delayed Treated)

Serious events: 5 serious events

Other events: 29 other events

Deaths: 0 deaths

Serious adverse events

Other adverse events

Additional Information

Global Clinical Development

Otsuka Pharmaceutical Development & Commercialization, Inc.

Phone: +1-609-524-6788

Email: [email protected]

Results disclosure agreements

Principal investigator is a sponsor employee Sponsor reserves the right to review results publications prior to public release and can delay such publications for a period greater than 60 days but no more than 120 days from the date that the publication is submitted to the Sponsor for review. Sponsor can require changes to the publication to protect Sponsor's intellectual property rights and/or confidential information and reserves the right to limit publication timing and scope of data published based on the number of study locations.
Publication restrictions are in place

Restriction type: OTHER

Serious adverse events
Measure	Tolvaptan (From Study 156-04-251: Tolvaptan, Early Treated) n=557 participants at risk Participants received a daily split-dose of tolvaptan titrated to the maximally tolerated dose, starting daily tolvaptan dose of 45 mg \[AM\]/15 mg \[PM\] titrated to 60 mg \[AM\]/30 mg \[PM\], then 90 mg \[AM\]/30 mg \[PM\] based on tolerability were given orally twice daily up to Month 24. Participants were previously treated with tolvaptan in previous Study 156-04-251, hence called as Early Treated.	Tolvaptan (From Study 156-04-251: Placebo, Delayed Treated) n=314 participants at risk Participants received a daily split-dose of tolvaptan titrated to the maximally tolerated dose, starting daily tolvaptan dose of 45 mg \[AM\]/15 mg \[PM\] titrated to 60 mg \[AM\]/30 mg \[PM\], then 90 mg \[AM\]/30 mg \[PM\] based on tolerability were given orally twice daily up to Month 24. Participants were previously treated with placebo in the previous Study 156-04-251, hence called as Delayed Treated.	Tolvaptan (From Other Studies: Tolvaptan, Early Treated) n=181 participants at risk Participants received a daily split-dose of tolvaptan titrated to the maximally tolerated dose, starting daily tolvaptan dose of 45 mg \[AM\]/15 mg \[PM\] titrated to 60 mg \[AM\]/30 mg \[PM\], then 90 mg \[AM\]/30 mg \[PM\] based on tolerability were given orally twice daily up to Month 24. Participants were previously treated with tolvaptan in other studies (156-04-250, 156-06-260, 156-09-284, 156-09-285, and 156-09-290), hence called as Early Treated.	Tolvaptan (From Other Studies: Placebo, Delayed Treated) n=31 participants at risk Participants received a daily split-dose of tolvaptan titrated to the maximally tolerated dose, starting daily tolvaptan dose of 45 mg \[AM\]/15 mg \[PM\] titrated to 60 mg \[AM\]/30 mg \[PM\], then 90 mg \[AM\]/30 mg \[PM\] based on tolerability were given orally twice daily up to Month 24. Participants were previously treated with placebo in other studies (156-04-250, 156-06-260, 156-09-284, 156-09-285, and 156-09-290), hence called as Delayed Treated.
Nervous system disorders Polyneuropathy	0.18% 1/557 • From the signing of the informed consent form until the end of the study regardless of whether the participants were on or off active study medication (Up to approximately 5 years)	0.00% 0/314 • From the signing of the informed consent form until the end of the study regardless of whether the participants were on or off active study medication (Up to approximately 5 years)	0.00% 0/181 • From the signing of the informed consent form until the end of the study regardless of whether the participants were on or off active study medication (Up to approximately 5 years)	0.00% 0/31 • From the signing of the informed consent form until the end of the study regardless of whether the participants were on or off active study medication (Up to approximately 5 years)
Blood and lymphatic system disorders Anaemia	0.36% 2/557 • From the signing of the informed consent form until the end of the study regardless of whether the participants were on or off active study medication (Up to approximately 5 years)	0.32% 1/314 • From the signing of the informed consent form until the end of the study regardless of whether the participants were on or off active study medication (Up to approximately 5 years)	0.55% 1/181 • From the signing of the informed consent form until the end of the study regardless of whether the participants were on or off active study medication (Up to approximately 5 years)	0.00% 0/31 • From the signing of the informed consent form until the end of the study regardless of whether the participants were on or off active study medication (Up to approximately 5 years)
Blood and lymphatic system disorders Thrombocytopenia	0.00% 0/557 • From the signing of the informed consent form until the end of the study regardless of whether the participants were on or off active study medication (Up to approximately 5 years)	0.00% 0/314 • From the signing of the informed consent form until the end of the study regardless of whether the participants were on or off active study medication (Up to approximately 5 years)	0.55% 1/181 • From the signing of the informed consent form until the end of the study regardless of whether the participants were on or off active study medication (Up to approximately 5 years)	0.00% 0/31 • From the signing of the informed consent form until the end of the study regardless of whether the participants were on or off active study medication (Up to approximately 5 years)
Cardiac disorders Accelerated Idioventricular Rhythm	0.00% 0/557 • From the signing of the informed consent form until the end of the study regardless of whether the participants were on or off active study medication (Up to approximately 5 years)	0.00% 0/314 • From the signing of the informed consent form until the end of the study regardless of whether the participants were on or off active study medication (Up to approximately 5 years)	0.00% 0/181 • From the signing of the informed consent form until the end of the study regardless of whether the participants were on or off active study medication (Up to approximately 5 years)	3.2% 1/31 • From the signing of the informed consent form until the end of the study regardless of whether the participants were on or off active study medication (Up to approximately 5 years)
Cardiac disorders Acute Coronary Syndrome	0.18% 1/557 • From the signing of the informed consent form until the end of the study regardless of whether the participants were on or off active study medication (Up to approximately 5 years)	0.32% 1/314 • From the signing of the informed consent form until the end of the study regardless of whether the participants were on or off active study medication (Up to approximately 5 years)	0.00% 0/181 • From the signing of the informed consent form until the end of the study regardless of whether the participants were on or off active study medication (Up to approximately 5 years)	0.00% 0/31 • From the signing of the informed consent form until the end of the study regardless of whether the participants were on or off active study medication (Up to approximately 5 years)
Cardiac disorders Acute Myocardial Infarction	0.18% 1/557 • From the signing of the informed consent form until the end of the study regardless of whether the participants were on or off active study medication (Up to approximately 5 years)	0.32% 1/314 • From the signing of the informed consent form until the end of the study regardless of whether the participants were on or off active study medication (Up to approximately 5 years)	0.00% 0/181 • From the signing of the informed consent form until the end of the study regardless of whether the participants were on or off active study medication (Up to approximately 5 years)	0.00% 0/31 • From the signing of the informed consent form until the end of the study regardless of whether the participants were on or off active study medication (Up to approximately 5 years)
Cardiac disorders Angina Pectoris	0.00% 0/557 • From the signing of the informed consent form until the end of the study regardless of whether the participants were on or off active study medication (Up to approximately 5 years)	0.00% 0/314 • From the signing of the informed consent form until the end of the study regardless of whether the participants were on or off active study medication (Up to approximately 5 years)	0.55% 1/181 • From the signing of the informed consent form until the end of the study regardless of whether the participants were on or off active study medication (Up to approximately 5 years)	0.00% 0/31 • From the signing of the informed consent form until the end of the study regardless of whether the participants were on or off active study medication (Up to approximately 5 years)
Cardiac disorders Atrial Fibrillation	0.36% 2/557 • From the signing of the informed consent form until the end of the study regardless of whether the participants were on or off active study medication (Up to approximately 5 years)	0.64% 2/314 • From the signing of the informed consent form until the end of the study regardless of whether the participants were on or off active study medication (Up to approximately 5 years)	0.00% 0/181 • From the signing of the informed consent form until the end of the study regardless of whether the participants were on or off active study medication (Up to approximately 5 years)	0.00% 0/31 • From the signing of the informed consent form until the end of the study regardless of whether the participants were on or off active study medication (Up to approximately 5 years)
Cardiac disorders Bradycardia	0.36% 2/557 • From the signing of the informed consent form until the end of the study regardless of whether the participants were on or off active study medication (Up to approximately 5 years)	0.00% 0/314 • From the signing of the informed consent form until the end of the study regardless of whether the participants were on or off active study medication (Up to approximately 5 years)	0.00% 0/181 • From the signing of the informed consent form until the end of the study regardless of whether the participants were on or off active study medication (Up to approximately 5 years)	0.00% 0/31 • From the signing of the informed consent form until the end of the study regardless of whether the participants were on or off active study medication (Up to approximately 5 years)
Cardiac disorders Cardiac Arrest	0.18% 1/557 • From the signing of the informed consent form until the end of the study regardless of whether the participants were on or off active study medication (Up to approximately 5 years)	0.00% 0/314 • From the signing of the informed consent form until the end of the study regardless of whether the participants were on or off active study medication (Up to approximately 5 years)	0.55% 1/181 • From the signing of the informed consent form until the end of the study regardless of whether the participants were on or off active study medication (Up to approximately 5 years)	0.00% 0/31 • From the signing of the informed consent form until the end of the study regardless of whether the participants were on or off active study medication (Up to approximately 5 years)
Cardiac disorders Coronary Artery Disease	0.18% 1/557 • From the signing of the informed consent form until the end of the study regardless of whether the participants were on or off active study medication (Up to approximately 5 years)	0.32% 1/314 • From the signing of the informed consent form until the end of the study regardless of whether the participants were on or off active study medication (Up to approximately 5 years)	0.00% 0/181 • From the signing of the informed consent form until the end of the study regardless of whether the participants were on or off active study medication (Up to approximately 5 years)	0.00% 0/31 • From the signing of the informed consent form until the end of the study regardless of whether the participants were on or off active study medication (Up to approximately 5 years)
Cardiac disorders Myocardial Infarction	0.54% 3/557 • From the signing of the informed consent form until the end of the study regardless of whether the participants were on or off active study medication (Up to approximately 5 years)	0.00% 0/314 • From the signing of the informed consent form until the end of the study regardless of whether the participants were on or off active study medication (Up to approximately 5 years)	0.00% 0/181 • From the signing of the informed consent form until the end of the study regardless of whether the participants were on or off active study medication (Up to approximately 5 years)	0.00% 0/31 • From the signing of the informed consent form until the end of the study regardless of whether the participants were on or off active study medication (Up to approximately 5 years)
Cardiac disorders Myocardial Ischaemia	0.00% 0/557 • From the signing of the informed consent form until the end of the study regardless of whether the participants were on or off active study medication (Up to approximately 5 years)	0.32% 1/314 • From the signing of the informed consent form until the end of the study regardless of whether the participants were on or off active study medication (Up to approximately 5 years)	0.00% 0/181 • From the signing of the informed consent form until the end of the study regardless of whether the participants were on or off active study medication (Up to approximately 5 years)	0.00% 0/31 • From the signing of the informed consent form until the end of the study regardless of whether the participants were on or off active study medication (Up to approximately 5 years)
Cardiac disorders Palpitations	0.18% 1/557 • From the signing of the informed consent form until the end of the study regardless of whether the participants were on or off active study medication (Up to approximately 5 years)	0.00% 0/314 • From the signing of the informed consent form until the end of the study regardless of whether the participants were on or off active study medication (Up to approximately 5 years)	0.00% 0/181 • From the signing of the informed consent form until the end of the study regardless of whether the participants were on or off active study medication (Up to approximately 5 years)	0.00% 0/31 • From the signing of the informed consent form until the end of the study regardless of whether the participants were on or off active study medication (Up to approximately 5 years)
Cardiac disorders Pericarditis	0.36% 2/557 • From the signing of the informed consent form until the end of the study regardless of whether the participants were on or off active study medication (Up to approximately 5 years)	0.32% 1/314 • From the signing of the informed consent form until the end of the study regardless of whether the participants were on or off active study medication (Up to approximately 5 years)	0.00% 0/181 • From the signing of the informed consent form until the end of the study regardless of whether the participants were on or off active study medication (Up to approximately 5 years)	0.00% 0/31 • From the signing of the informed consent form until the end of the study regardless of whether the participants were on or off active study medication (Up to approximately 5 years)
Cardiac disorders Prinzmetal Angina	0.00% 0/557 • From the signing of the informed consent form until the end of the study regardless of whether the participants were on or off active study medication (Up to approximately 5 years)	0.32% 1/314 • From the signing of the informed consent form until the end of the study regardless of whether the participants were on or off active study medication (Up to approximately 5 years)	0.00% 0/181 • From the signing of the informed consent form until the end of the study regardless of whether the participants were on or off active study medication (Up to approximately 5 years)	0.00% 0/31 • From the signing of the informed consent form until the end of the study regardless of whether the participants were on or off active study medication (Up to approximately 5 years)
Cardiac disorders Sinus Arrhythmia	0.18% 1/557 • From the signing of the informed consent form until the end of the study regardless of whether the participants were on or off active study medication (Up to approximately 5 years)	0.00% 0/314 • From the signing of the informed consent form until the end of the study regardless of whether the participants were on or off active study medication (Up to approximately 5 years)	0.00% 0/181 • From the signing of the informed consent form until the end of the study regardless of whether the participants were on or off active study medication (Up to approximately 5 years)	0.00% 0/31 • From the signing of the informed consent form until the end of the study regardless of whether the participants were on or off active study medication (Up to approximately 5 years)
Cardiac disorders Tachycardia	0.18% 1/557 • From the signing of the informed consent form until the end of the study regardless of whether the participants were on or off active study medication (Up to approximately 5 years)	0.00% 0/314 • From the signing of the informed consent form until the end of the study regardless of whether the participants were on or off active study medication (Up to approximately 5 years)	0.00% 0/181 • From the signing of the informed consent form until the end of the study regardless of whether the participants were on or off active study medication (Up to approximately 5 years)	0.00% 0/31 • From the signing of the informed consent form until the end of the study regardless of whether the participants were on or off active study medication (Up to approximately 5 years)
Congenital, familial and genetic disorders Congenital Cystic Kidney Disease	0.18% 1/557 • From the signing of the informed consent form until the end of the study regardless of whether the participants were on or off active study medication (Up to approximately 5 years)	0.00% 0/314 • From the signing of the informed consent form until the end of the study regardless of whether the participants were on or off active study medication (Up to approximately 5 years)	0.00% 0/181 • From the signing of the informed consent form until the end of the study regardless of whether the participants were on or off active study medication (Up to approximately 5 years)	0.00% 0/31 • From the signing of the informed consent form until the end of the study regardless of whether the participants were on or off active study medication (Up to approximately 5 years)
Ear and labyrinth disorders Vertigo	0.00% 0/557 • From the signing of the informed consent form until the end of the study regardless of whether the participants were on or off active study medication (Up to approximately 5 years)	0.32% 1/314 • From the signing of the informed consent form until the end of the study regardless of whether the participants were on or off active study medication (Up to approximately 5 years)	0.00% 0/181 • From the signing of the informed consent form until the end of the study regardless of whether the participants were on or off active study medication (Up to approximately 5 years)	0.00% 0/31 • From the signing of the informed consent form until the end of the study regardless of whether the participants were on or off active study medication (Up to approximately 5 years)
Endocrine disorders Goitre	0.18% 1/557 • From the signing of the informed consent form until the end of the study regardless of whether the participants were on or off active study medication (Up to approximately 5 years)	0.00% 0/314 • From the signing of the informed consent form until the end of the study regardless of whether the participants were on or off active study medication (Up to approximately 5 years)	0.00% 0/181 • From the signing of the informed consent form until the end of the study regardless of whether the participants were on or off active study medication (Up to approximately 5 years)	0.00% 0/31 • From the signing of the informed consent form until the end of the study regardless of whether the participants were on or off active study medication (Up to approximately 5 years)
Endocrine disorders Hypothyroidism	0.18% 1/557 • From the signing of the informed consent form until the end of the study regardless of whether the participants were on or off active study medication (Up to approximately 5 years)	0.00% 0/314 • From the signing of the informed consent form until the end of the study regardless of whether the participants were on or off active study medication (Up to approximately 5 years)	0.00% 0/181 • From the signing of the informed consent form until the end of the study regardless of whether the participants were on or off active study medication (Up to approximately 5 years)	0.00% 0/31 • From the signing of the informed consent form until the end of the study regardless of whether the participants were on or off active study medication (Up to approximately 5 years)
Eye disorders Cataract	0.18% 1/557 • From the signing of the informed consent form until the end of the study regardless of whether the participants were on or off active study medication (Up to approximately 5 years)	0.32% 1/314 • From the signing of the informed consent form until the end of the study regardless of whether the participants were on or off active study medication (Up to approximately 5 years)	0.00% 0/181 • From the signing of the informed consent form until the end of the study regardless of whether the participants were on or off active study medication (Up to approximately 5 years)	0.00% 0/31 • From the signing of the informed consent form until the end of the study regardless of whether the participants were on or off active study medication (Up to approximately 5 years)
Eye disorders Retinal Detachment	0.00% 0/557 • From the signing of the informed consent form until the end of the study regardless of whether the participants were on or off active study medication (Up to approximately 5 years)	0.32% 1/314 • From the signing of the informed consent form until the end of the study regardless of whether the participants were on or off active study medication (Up to approximately 5 years)	0.00% 0/181 • From the signing of the informed consent form until the end of the study regardless of whether the participants were on or off active study medication (Up to approximately 5 years)	0.00% 0/31 • From the signing of the informed consent form until the end of the study regardless of whether the participants were on or off active study medication (Up to approximately 5 years)
Gastrointestinal disorders Abdominal Hernia	0.18% 1/557 • From the signing of the informed consent form until the end of the study regardless of whether the participants were on or off active study medication (Up to approximately 5 years)	0.64% 2/314 • From the signing of the informed consent form until the end of the study regardless of whether the participants were on or off active study medication (Up to approximately 5 years)	0.00% 0/181 • From the signing of the informed consent form until the end of the study regardless of whether the participants were on or off active study medication (Up to approximately 5 years)	0.00% 0/31 • From the signing of the informed consent form until the end of the study regardless of whether the participants were on or off active study medication (Up to approximately 5 years)
Gastrointestinal disorders Abdominal Pain	0.18% 1/557 • From the signing of the informed consent form until the end of the study regardless of whether the participants were on or off active study medication (Up to approximately 5 years)	0.64% 2/314 • From the signing of the informed consent form until the end of the study regardless of whether the participants were on or off active study medication (Up to approximately 5 years)	0.00% 0/181 • From the signing of the informed consent form until the end of the study regardless of whether the participants were on or off active study medication (Up to approximately 5 years)	0.00% 0/31 • From the signing of the informed consent form until the end of the study regardless of whether the participants were on or off active study medication (Up to approximately 5 years)
Gastrointestinal disorders Abdominal Pain Lower	0.18% 1/557 • From the signing of the informed consent form until the end of the study regardless of whether the participants were on or off active study medication (Up to approximately 5 years)	0.00% 0/314 • From the signing of the informed consent form until the end of the study regardless of whether the participants were on or off active study medication (Up to approximately 5 years)	0.00% 0/181 • From the signing of the informed consent form until the end of the study regardless of whether the participants were on or off active study medication (Up to approximately 5 years)	0.00% 0/31 • From the signing of the informed consent form until the end of the study regardless of whether the participants were on or off active study medication (Up to approximately 5 years)
Gastrointestinal disorders Abdominal Pain Upper	0.18% 1/557 • From the signing of the informed consent form until the end of the study regardless of whether the participants were on or off active study medication (Up to approximately 5 years)	0.32% 1/314 • From the signing of the informed consent form until the end of the study regardless of whether the participants were on or off active study medication (Up to approximately 5 years)	0.00% 0/181 • From the signing of the informed consent form until the end of the study regardless of whether the participants were on or off active study medication (Up to approximately 5 years)	0.00% 0/31 • From the signing of the informed consent form until the end of the study regardless of whether the participants were on or off active study medication (Up to approximately 5 years)
Gastrointestinal disorders Gastritis Erosive	0.18% 1/557 • From the signing of the informed consent form until the end of the study regardless of whether the participants were on or off active study medication (Up to approximately 5 years)	0.00% 0/314 • From the signing of the informed consent form until the end of the study regardless of whether the participants were on or off active study medication (Up to approximately 5 years)	0.00% 0/181 • From the signing of the informed consent form until the end of the study regardless of whether the participants were on or off active study medication (Up to approximately 5 years)	0.00% 0/31 • From the signing of the informed consent form until the end of the study regardless of whether the participants were on or off active study medication (Up to approximately 5 years)
Gastrointestinal disorders Gastrooesophageal Reflux Disease	0.00% 0/557 • From the signing of the informed consent form until the end of the study regardless of whether the participants were on or off active study medication (Up to approximately 5 years)	0.32% 1/314 • From the signing of the informed consent form until the end of the study regardless of whether the participants were on or off active study medication (Up to approximately 5 years)	0.00% 0/181 • From the signing of the informed consent form until the end of the study regardless of whether the participants were on or off active study medication (Up to approximately 5 years)	0.00% 0/31 • From the signing of the informed consent form until the end of the study regardless of whether the participants were on or off active study medication (Up to approximately 5 years)
Gastrointestinal disorders Haemorrhoids	0.18% 1/557 • From the signing of the informed consent form until the end of the study regardless of whether the participants were on or off active study medication (Up to approximately 5 years)	0.00% 0/314 • From the signing of the informed consent form until the end of the study regardless of whether the participants were on or off active study medication (Up to approximately 5 years)	0.00% 0/181 • From the signing of the informed consent form until the end of the study regardless of whether the participants were on or off active study medication (Up to approximately 5 years)	0.00% 0/31 • From the signing of the informed consent form until the end of the study regardless of whether the participants were on or off active study medication (Up to approximately 5 years)
Gastrointestinal disorders Ileus Paralytic	0.18% 1/557 • From the signing of the informed consent form until the end of the study regardless of whether the participants were on or off active study medication (Up to approximately 5 years)	0.00% 0/314 • From the signing of the informed consent form until the end of the study regardless of whether the participants were on or off active study medication (Up to approximately 5 years)	0.00% 0/181 • From the signing of the informed consent form until the end of the study regardless of whether the participants were on or off active study medication (Up to approximately 5 years)	0.00% 0/31 • From the signing of the informed consent form until the end of the study regardless of whether the participants were on or off active study medication (Up to approximately 5 years)
Gastrointestinal disorders Inguinal Hernia	0.90% 5/557 • From the signing of the informed consent form until the end of the study regardless of whether the participants were on or off active study medication (Up to approximately 5 years)	0.96% 3/314 • From the signing of the informed consent form until the end of the study regardless of whether the participants were on or off active study medication (Up to approximately 5 years)	0.00% 0/181 • From the signing of the informed consent form until the end of the study regardless of whether the participants were on or off active study medication (Up to approximately 5 years)	0.00% 0/31 • From the signing of the informed consent form until the end of the study regardless of whether the participants were on or off active study medication (Up to approximately 5 years)
Gastrointestinal disorders Intestinal Fistula	0.00% 0/557 • From the signing of the informed consent form until the end of the study regardless of whether the participants were on or off active study medication (Up to approximately 5 years)	0.32% 1/314 • From the signing of the informed consent form until the end of the study regardless of whether the participants were on or off active study medication (Up to approximately 5 years)	0.00% 0/181 • From the signing of the informed consent form until the end of the study regardless of whether the participants were on or off active study medication (Up to approximately 5 years)	0.00% 0/31 • From the signing of the informed consent form until the end of the study regardless of whether the participants were on or off active study medication (Up to approximately 5 years)
Gastrointestinal disorders Large Intestine Polyp	0.18% 1/557 • From the signing of the informed consent form until the end of the study regardless of whether the participants were on or off active study medication (Up to approximately 5 years)	0.00% 0/314 • From the signing of the informed consent form until the end of the study regardless of whether the participants were on or off active study medication (Up to approximately 5 years)	0.00% 0/181 • From the signing of the informed consent form until the end of the study regardless of whether the participants were on or off active study medication (Up to approximately 5 years)	0.00% 0/31 • From the signing of the informed consent form until the end of the study regardless of whether the participants were on or off active study medication (Up to approximately 5 years)
Gastrointestinal disorders Localised Intraabdominal Fluid Collection	0.18% 1/557 • From the signing of the informed consent form until the end of the study regardless of whether the participants were on or off active study medication (Up to approximately 5 years)	0.00% 0/314 • From the signing of the informed consent form until the end of the study regardless of whether the participants were on or off active study medication (Up to approximately 5 years)	0.00% 0/181 • From the signing of the informed consent form until the end of the study regardless of whether the participants were on or off active study medication (Up to approximately 5 years)	0.00% 0/31 • From the signing of the informed consent form until the end of the study regardless of whether the participants were on or off active study medication (Up to approximately 5 years)
Gastrointestinal disorders Oesophagitis	0.00% 0/557 • From the signing of the informed consent form until the end of the study regardless of whether the participants were on or off active study medication (Up to approximately 5 years)	0.32% 1/314 • From the signing of the informed consent form until the end of the study regardless of whether the participants were on or off active study medication (Up to approximately 5 years)	0.00% 0/181 • From the signing of the informed consent form until the end of the study regardless of whether the participants were on or off active study medication (Up to approximately 5 years)	0.00% 0/31 • From the signing of the informed consent form until the end of the study regardless of whether the participants were on or off active study medication (Up to approximately 5 years)
Gastrointestinal disorders Pancreatitis Acute	0.18% 1/557 • From the signing of the informed consent form until the end of the study regardless of whether the participants were on or off active study medication (Up to approximately 5 years)	0.32% 1/314 • From the signing of the informed consent form until the end of the study regardless of whether the participants were on or off active study medication (Up to approximately 5 years)	0.00% 0/181 • From the signing of the informed consent form until the end of the study regardless of whether the participants were on or off active study medication (Up to approximately 5 years)	0.00% 0/31 • From the signing of the informed consent form until the end of the study regardless of whether the participants were on or off active study medication (Up to approximately 5 years)
Gastrointestinal disorders Pancreatitis Necrotising	0.18% 1/557 • From the signing of the informed consent form until the end of the study regardless of whether the participants were on or off active study medication (Up to approximately 5 years)	0.00% 0/314 • From the signing of the informed consent form until the end of the study regardless of whether the participants were on or off active study medication (Up to approximately 5 years)	0.00% 0/181 • From the signing of the informed consent form until the end of the study regardless of whether the participants were on or off active study medication (Up to approximately 5 years)	0.00% 0/31 • From the signing of the informed consent form until the end of the study regardless of whether the participants were on or off active study medication (Up to approximately 5 years)
Gastrointestinal disorders Umbilical Hernia	0.18% 1/557 • From the signing of the informed consent form until the end of the study regardless of whether the participants were on or off active study medication (Up to approximately 5 years)	0.32% 1/314 • From the signing of the informed consent form until the end of the study regardless of whether the participants were on or off active study medication (Up to approximately 5 years)	0.00% 0/181 • From the signing of the informed consent form until the end of the study regardless of whether the participants were on or off active study medication (Up to approximately 5 years)	0.00% 0/31 • From the signing of the informed consent form until the end of the study regardless of whether the participants were on or off active study medication (Up to approximately 5 years)

Other adverse events
Measure	Tolvaptan (From Study 156-04-251: Tolvaptan, Early Treated) n=557 participants at risk Participants received a daily split-dose of tolvaptan titrated to the maximally tolerated dose, starting daily tolvaptan dose of 45 mg \[AM\]/15 mg \[PM\] titrated to 60 mg \[AM\]/30 mg \[PM\], then 90 mg \[AM\]/30 mg \[PM\] based on tolerability were given orally twice daily up to Month 24. Participants were previously treated with tolvaptan in previous Study 156-04-251, hence called as Early Treated.	Tolvaptan (From Study 156-04-251: Placebo, Delayed Treated) n=314 participants at risk Participants received a daily split-dose of tolvaptan titrated to the maximally tolerated dose, starting daily tolvaptan dose of 45 mg \[AM\]/15 mg \[PM\] titrated to 60 mg \[AM\]/30 mg \[PM\], then 90 mg \[AM\]/30 mg \[PM\] based on tolerability were given orally twice daily up to Month 24. Participants were previously treated with placebo in the previous Study 156-04-251, hence called as Delayed Treated.	Tolvaptan (From Other Studies: Tolvaptan, Early Treated) n=181 participants at risk Participants received a daily split-dose of tolvaptan titrated to the maximally tolerated dose, starting daily tolvaptan dose of 45 mg \[AM\]/15 mg \[PM\] titrated to 60 mg \[AM\]/30 mg \[PM\], then 90 mg \[AM\]/30 mg \[PM\] based on tolerability were given orally twice daily up to Month 24. Participants were previously treated with tolvaptan in other studies (156-04-250, 156-06-260, 156-09-284, 156-09-285, and 156-09-290), hence called as Early Treated.	Tolvaptan (From Other Studies: Placebo, Delayed Treated) n=31 participants at risk Participants received a daily split-dose of tolvaptan titrated to the maximally tolerated dose, starting daily tolvaptan dose of 45 mg \[AM\]/15 mg \[PM\] titrated to 60 mg \[AM\]/30 mg \[PM\], then 90 mg \[AM\]/30 mg \[PM\] based on tolerability were given orally twice daily up to Month 24. Participants were previously treated with placebo in other studies (156-04-250, 156-06-260, 156-09-284, 156-09-285, and 156-09-290), hence called as Delayed Treated.
Infections and infestations Sinusitis	7.2% 40/557 • From the signing of the informed consent form until the end of the study regardless of whether the participants were on or off active study medication (Up to approximately 5 years)	6.1% 19/314 • From the signing of the informed consent form until the end of the study regardless of whether the participants were on or off active study medication (Up to approximately 5 years)	7.2% 13/181 • From the signing of the informed consent form until the end of the study regardless of whether the participants were on or off active study medication (Up to approximately 5 years)	3.2% 1/31 • From the signing of the informed consent form until the end of the study regardless of whether the participants were on or off active study medication (Up to approximately 5 years)
Blood and lymphatic system disorders Anaemia	6.3% 35/557 • From the signing of the informed consent form until the end of the study regardless of whether the participants were on or off active study medication (Up to approximately 5 years)	6.4% 20/314 • From the signing of the informed consent form until the end of the study regardless of whether the participants were on or off active study medication (Up to approximately 5 years)	7.2% 13/181 • From the signing of the informed consent form until the end of the study regardless of whether the participants were on or off active study medication (Up to approximately 5 years)	0.00% 0/31 • From the signing of the informed consent form until the end of the study regardless of whether the participants were on or off active study medication (Up to approximately 5 years)
Gastrointestinal disorders Abdominal Pain	6.6% 37/557 • From the signing of the informed consent form until the end of the study regardless of whether the participants were on or off active study medication (Up to approximately 5 years)	4.8% 15/314 • From the signing of the informed consent form until the end of the study regardless of whether the participants were on or off active study medication (Up to approximately 5 years)	7.2% 13/181 • From the signing of the informed consent form until the end of the study regardless of whether the participants were on or off active study medication (Up to approximately 5 years)	0.00% 0/31 • From the signing of the informed consent form until the end of the study regardless of whether the participants were on or off active study medication (Up to approximately 5 years)
Gastrointestinal disorders Abdominal Pain Upper	4.1% 23/557 • From the signing of the informed consent form until the end of the study regardless of whether the participants were on or off active study medication (Up to approximately 5 years)	5.1% 16/314 • From the signing of the informed consent form until the end of the study regardless of whether the participants were on or off active study medication (Up to approximately 5 years)	2.2% 4/181 • From the signing of the informed consent form until the end of the study regardless of whether the participants were on or off active study medication (Up to approximately 5 years)	0.00% 0/31 • From the signing of the informed consent form until the end of the study regardless of whether the participants were on or off active study medication (Up to approximately 5 years)
Gastrointestinal disorders Constipation	4.1% 23/557 • From the signing of the informed consent form until the end of the study regardless of whether the participants were on or off active study medication (Up to approximately 5 years)	8.0% 25/314 • From the signing of the informed consent form until the end of the study regardless of whether the participants were on or off active study medication (Up to approximately 5 years)	4.4% 8/181 • From the signing of the informed consent form until the end of the study regardless of whether the participants were on or off active study medication (Up to approximately 5 years)	3.2% 1/31 • From the signing of the informed consent form until the end of the study regardless of whether the participants were on or off active study medication (Up to approximately 5 years)
Gastrointestinal disorders Diarrhoea	10.8% 60/557 • From the signing of the informed consent form until the end of the study regardless of whether the participants were on or off active study medication (Up to approximately 5 years)	9.6% 30/314 • From the signing of the informed consent form until the end of the study regardless of whether the participants were on or off active study medication (Up to approximately 5 years)	7.2% 13/181 • From the signing of the informed consent form until the end of the study regardless of whether the participants were on or off active study medication (Up to approximately 5 years)	6.5% 2/31 • From the signing of the informed consent form until the end of the study regardless of whether the participants were on or off active study medication (Up to approximately 5 years)
Gastrointestinal disorders Dry Mouth	8.1% 45/557 • From the signing of the informed consent form until the end of the study regardless of whether the participants were on or off active study medication (Up to approximately 5 years)	14.0% 44/314 • From the signing of the informed consent form until the end of the study regardless of whether the participants were on or off active study medication (Up to approximately 5 years)	13.8% 25/181 • From the signing of the informed consent form until the end of the study regardless of whether the participants were on or off active study medication (Up to approximately 5 years)	12.9% 4/31 • From the signing of the informed consent form until the end of the study regardless of whether the participants were on or off active study medication (Up to approximately 5 years)
Gastrointestinal disorders Dyspepsia	5.2% 29/557 • From the signing of the informed consent form until the end of the study regardless of whether the participants were on or off active study medication (Up to approximately 5 years)	4.8% 15/314 • From the signing of the informed consent form until the end of the study regardless of whether the participants were on or off active study medication (Up to approximately 5 years)	4.4% 8/181 • From the signing of the informed consent form until the end of the study regardless of whether the participants were on or off active study medication (Up to approximately 5 years)	0.00% 0/31 • From the signing of the informed consent form until the end of the study regardless of whether the participants were on or off active study medication (Up to approximately 5 years)
Gastrointestinal disorders Gastrooesophageal Reflux Disease	4.3% 24/557 • From the signing of the informed consent form until the end of the study regardless of whether the participants were on or off active study medication (Up to approximately 5 years)	3.5% 11/314 • From the signing of the informed consent form until the end of the study regardless of whether the participants were on or off active study medication (Up to approximately 5 years)	5.5% 10/181 • From the signing of the informed consent form until the end of the study regardless of whether the participants were on or off active study medication (Up to approximately 5 years)	6.5% 2/31 • From the signing of the informed consent form until the end of the study regardless of whether the participants were on or off active study medication (Up to approximately 5 years)
Gastrointestinal disorders Nausea	7.5% 42/557 • From the signing of the informed consent form until the end of the study regardless of whether the participants were on or off active study medication (Up to approximately 5 years)	10.2% 32/314 • From the signing of the informed consent form until the end of the study regardless of whether the participants were on or off active study medication (Up to approximately 5 years)	12.2% 22/181 • From the signing of the informed consent form until the end of the study regardless of whether the participants were on or off active study medication (Up to approximately 5 years)	6.5% 2/31 • From the signing of the informed consent form until the end of the study regardless of whether the participants were on or off active study medication (Up to approximately 5 years)
Gastrointestinal disorders Vomiting	5.7% 32/557 • From the signing of the informed consent form until the end of the study regardless of whether the participants were on or off active study medication (Up to approximately 5 years)	4.8% 15/314 • From the signing of the informed consent form until the end of the study regardless of whether the participants were on or off active study medication (Up to approximately 5 years)	5.0% 9/181 • From the signing of the informed consent form until the end of the study regardless of whether the participants were on or off active study medication (Up to approximately 5 years)	6.5% 2/31 • From the signing of the informed consent form until the end of the study regardless of whether the participants were on or off active study medication (Up to approximately 5 years)
General disorders Fatigue	9.5% 53/557 • From the signing of the informed consent form until the end of the study regardless of whether the participants were on or off active study medication (Up to approximately 5 years)	17.2% 54/314 • From the signing of the informed consent form until the end of the study regardless of whether the participants were on or off active study medication (Up to approximately 5 years)	17.7% 32/181 • From the signing of the informed consent form until the end of the study regardless of whether the participants were on or off active study medication (Up to approximately 5 years)	6.5% 2/31 • From the signing of the informed consent form until the end of the study regardless of whether the participants were on or off active study medication (Up to approximately 5 years)
General disorders Oedema Peripheral	9.2% 51/557 • From the signing of the informed consent form until the end of the study regardless of whether the participants were on or off active study medication (Up to approximately 5 years)	10.2% 32/314 • From the signing of the informed consent form until the end of the study regardless of whether the participants were on or off active study medication (Up to approximately 5 years)	5.0% 9/181 • From the signing of the informed consent form until the end of the study regardless of whether the participants were on or off active study medication (Up to approximately 5 years)	3.2% 1/31 • From the signing of the informed consent form until the end of the study regardless of whether the participants were on or off active study medication (Up to approximately 5 years)
General disorders Thirst	46.9% 261/557 • From the signing of the informed consent form until the end of the study regardless of whether the participants were on or off active study medication (Up to approximately 5 years)	51.3% 161/314 • From the signing of the informed consent form until the end of the study regardless of whether the participants were on or off active study medication (Up to approximately 5 years)	44.2% 80/181 • From the signing of the informed consent form until the end of the study regardless of whether the participants were on or off active study medication (Up to approximately 5 years)	41.9% 13/31 • From the signing of the informed consent form until the end of the study regardless of whether the participants were on or off active study medication (Up to approximately 5 years)
Infections and infestations Bronchitis	5.4% 30/557 • From the signing of the informed consent form until the end of the study regardless of whether the participants were on or off active study medication (Up to approximately 5 years)	5.4% 17/314 • From the signing of the informed consent form until the end of the study regardless of whether the participants were on or off active study medication (Up to approximately 5 years)	2.2% 4/181 • From the signing of the informed consent form until the end of the study regardless of whether the participants were on or off active study medication (Up to approximately 5 years)	3.2% 1/31 • From the signing of the informed consent form until the end of the study regardless of whether the participants were on or off active study medication (Up to approximately 5 years)
Infections and infestations Gastroenteritis	5.6% 31/557 • From the signing of the informed consent form until the end of the study regardless of whether the participants were on or off active study medication (Up to approximately 5 years)	6.4% 20/314 • From the signing of the informed consent form until the end of the study regardless of whether the participants were on or off active study medication (Up to approximately 5 years)	5.0% 9/181 • From the signing of the informed consent form until the end of the study regardless of whether the participants were on or off active study medication (Up to approximately 5 years)	6.5% 2/31 • From the signing of the informed consent form until the end of the study regardless of whether the participants were on or off active study medication (Up to approximately 5 years)
Infections and infestations Gastroenteritis Viral	2.2% 12/557 • From the signing of the informed consent form until the end of the study regardless of whether the participants were on or off active study medication (Up to approximately 5 years)	2.2% 7/314 • From the signing of the informed consent form until the end of the study regardless of whether the participants were on or off active study medication (Up to approximately 5 years)	3.3% 6/181 • From the signing of the informed consent form until the end of the study regardless of whether the participants were on or off active study medication (Up to approximately 5 years)	6.5% 2/31 • From the signing of the informed consent form until the end of the study regardless of whether the participants were on or off active study medication (Up to approximately 5 years)
Infections and infestations Influenza	7.5% 42/557 • From the signing of the informed consent form until the end of the study regardless of whether the participants were on or off active study medication (Up to approximately 5 years)	8.0% 25/314 • From the signing of the informed consent form until the end of the study regardless of whether the participants were on or off active study medication (Up to approximately 5 years)	9.9% 18/181 • From the signing of the informed consent form until the end of the study regardless of whether the participants were on or off active study medication (Up to approximately 5 years)	3.2% 1/31 • From the signing of the informed consent form until the end of the study regardless of whether the participants were on or off active study medication (Up to approximately 5 years)
Infections and infestations Nasopharyngitis	14.9% 83/557 • From the signing of the informed consent form until the end of the study regardless of whether the participants were on or off active study medication (Up to approximately 5 years)	17.5% 55/314 • From the signing of the informed consent form until the end of the study regardless of whether the participants were on or off active study medication (Up to approximately 5 years)	9.9% 18/181 • From the signing of the informed consent form until the end of the study regardless of whether the participants were on or off active study medication (Up to approximately 5 years)	12.9% 4/31 • From the signing of the informed consent form until the end of the study regardless of whether the participants were on or off active study medication (Up to approximately 5 years)
Infections and infestations Upper Respiratory Tract Infection	11.0% 61/557 • From the signing of the informed consent form until the end of the study regardless of whether the participants were on or off active study medication (Up to approximately 5 years)	11.1% 35/314 • From the signing of the informed consent form until the end of the study regardless of whether the participants were on or off active study medication (Up to approximately 5 years)	15.5% 28/181 • From the signing of the informed consent form until the end of the study regardless of whether the participants were on or off active study medication (Up to approximately 5 years)	6.5% 2/31 • From the signing of the informed consent form until the end of the study regardless of whether the participants were on or off active study medication (Up to approximately 5 years)
Infections and infestations Urinary Tract Infection	11.0% 61/557 • From the signing of the informed consent form until the end of the study regardless of whether the participants were on or off active study medication (Up to approximately 5 years)	10.5% 33/314 • From the signing of the informed consent form until the end of the study regardless of whether the participants were on or off active study medication (Up to approximately 5 years)	8.8% 16/181 • From the signing of the informed consent form until the end of the study regardless of whether the participants were on or off active study medication (Up to approximately 5 years)	12.9% 4/31 • From the signing of the informed consent form until the end of the study regardless of whether the participants were on or off active study medication (Up to approximately 5 years)
Investigations Aspartate Aminotransferase Increased	3.4% 19/557 • From the signing of the informed consent form until the end of the study regardless of whether the participants were on or off active study medication (Up to approximately 5 years)	1.6% 5/314 • From the signing of the informed consent form until the end of the study regardless of whether the participants were on or off active study medication (Up to approximately 5 years)	3.9% 7/181 • From the signing of the informed consent form until the end of the study regardless of whether the participants were on or off active study medication (Up to approximately 5 years)	6.5% 2/31 • From the signing of the informed consent form until the end of the study regardless of whether the participants were on or off active study medication (Up to approximately 5 years)
Investigations Blood Creatinine Increased	17.2% 96/557 • From the signing of the informed consent form until the end of the study regardless of whether the participants were on or off active study medication (Up to approximately 5 years)	12.4% 39/314 • From the signing of the informed consent form until the end of the study regardless of whether the participants were on or off active study medication (Up to approximately 5 years)	11.0% 20/181 • From the signing of the informed consent form until the end of the study regardless of whether the participants were on or off active study medication (Up to approximately 5 years)	6.5% 2/31 • From the signing of the informed consent form until the end of the study regardless of whether the participants were on or off active study medication (Up to approximately 5 years)
Metabolism and nutrition disorders Decreased Appetitie	0.90% 5/557 • From the signing of the informed consent form until the end of the study regardless of whether the participants were on or off active study medication (Up to approximately 5 years)	4.1% 13/314 • From the signing of the informed consent form until the end of the study regardless of whether the participants were on or off active study medication (Up to approximately 5 years)	6.6% 12/181 • From the signing of the informed consent form until the end of the study regardless of whether the participants were on or off active study medication (Up to approximately 5 years)	3.2% 1/31 • From the signing of the informed consent form until the end of the study regardless of whether the participants were on or off active study medication (Up to approximately 5 years)
Metabolism and nutrition disorders Gout	6.3% 35/557 • From the signing of the informed consent form until the end of the study regardless of whether the participants were on or off active study medication (Up to approximately 5 years)	2.9% 9/314 • From the signing of the informed consent form until the end of the study regardless of whether the participants were on or off active study medication (Up to approximately 5 years)	3.3% 6/181 • From the signing of the informed consent form until the end of the study regardless of whether the participants were on or off active study medication (Up to approximately 5 years)	0.00% 0/31 • From the signing of the informed consent form until the end of the study regardless of whether the participants were on or off active study medication (Up to approximately 5 years)
Metabolism and nutrition disorders Hyperuricaemia	6.6% 37/557 • From the signing of the informed consent form until the end of the study regardless of whether the participants were on or off active study medication (Up to approximately 5 years)	4.8% 15/314 • From the signing of the informed consent form until the end of the study regardless of whether the participants were on or off active study medication (Up to approximately 5 years)	1.1% 2/181 • From the signing of the informed consent form until the end of the study regardless of whether the participants were on or off active study medication (Up to approximately 5 years)	6.5% 2/31 • From the signing of the informed consent form until the end of the study regardless of whether the participants were on or off active study medication (Up to approximately 5 years)
Metabolism and nutrition disorders Polydipsia	11.1% 62/557 • From the signing of the informed consent form until the end of the study regardless of whether the participants were on or off active study medication (Up to approximately 5 years)	16.2% 51/314 • From the signing of the informed consent form until the end of the study regardless of whether the participants were on or off active study medication (Up to approximately 5 years)	21.0% 38/181 • From the signing of the informed consent form until the end of the study regardless of whether the participants were on or off active study medication (Up to approximately 5 years)	19.4% 6/31 • From the signing of the informed consent form until the end of the study regardless of whether the participants were on or off active study medication (Up to approximately 5 years)
Metabolism and nutrition disorders Vitamin D Deficiency	6.1% 34/557 • From the signing of the informed consent form until the end of the study regardless of whether the participants were on or off active study medication (Up to approximately 5 years)	5.1% 16/314 • From the signing of the informed consent form until the end of the study regardless of whether the participants were on or off active study medication (Up to approximately 5 years)	7.2% 13/181 • From the signing of the informed consent form until the end of the study regardless of whether the participants were on or off active study medication (Up to approximately 5 years)	12.9% 4/31 • From the signing of the informed consent form until the end of the study regardless of whether the participants were on or off active study medication (Up to approximately 5 years)
Musculoskeletal and connective tissue disorders Arthralgia	10.2% 57/557 • From the signing of the informed consent form until the end of the study regardless of whether the participants were on or off active study medication (Up to approximately 5 years)	5.1% 16/314 • From the signing of the informed consent form until the end of the study regardless of whether the participants were on or off active study medication (Up to approximately 5 years)	7.2% 13/181 • From the signing of the informed consent form until the end of the study regardless of whether the participants were on or off active study medication (Up to approximately 5 years)	3.2% 1/31 • From the signing of the informed consent form until the end of the study regardless of whether the participants were on or off active study medication (Up to approximately 5 years)
Musculoskeletal and connective tissue disorders Back Pain	10.8% 60/557 • From the signing of the informed consent form until the end of the study regardless of whether the participants were on or off active study medication (Up to approximately 5 years)	12.7% 40/314 • From the signing of the informed consent form until the end of the study regardless of whether the participants were on or off active study medication (Up to approximately 5 years)	8.3% 15/181 • From the signing of the informed consent form until the end of the study regardless of whether the participants were on or off active study medication (Up to approximately 5 years)	0.00% 0/31 • From the signing of the informed consent form until the end of the study regardless of whether the participants were on or off active study medication (Up to approximately 5 years)
Musculoskeletal and connective tissue disorders Muscle Spasms	5.0% 28/557 • From the signing of the informed consent form until the end of the study regardless of whether the participants were on or off active study medication (Up to approximately 5 years)	5.7% 18/314 • From the signing of the informed consent form until the end of the study regardless of whether the participants were on or off active study medication (Up to approximately 5 years)	2.8% 5/181 • From the signing of the informed consent form until the end of the study regardless of whether the participants were on or off active study medication (Up to approximately 5 years)	3.2% 1/31 • From the signing of the informed consent form until the end of the study regardless of whether the participants were on or off active study medication (Up to approximately 5 years)
Musculoskeletal and connective tissue disorders Pain In Extremity	6.8% 38/557 • From the signing of the informed consent form until the end of the study regardless of whether the participants were on or off active study medication (Up to approximately 5 years)	3.5% 11/314 • From the signing of the informed consent form until the end of the study regardless of whether the participants were on or off active study medication (Up to approximately 5 years)	3.9% 7/181 • From the signing of the informed consent form until the end of the study regardless of whether the participants were on or off active study medication (Up to approximately 5 years)	6.5% 2/31 • From the signing of the informed consent form until the end of the study regardless of whether the participants were on or off active study medication (Up to approximately 5 years)
Nervous system disorders Dizziness	5.4% 30/557 • From the signing of the informed consent form until the end of the study regardless of whether the participants were on or off active study medication (Up to approximately 5 years)	11.5% 36/314 • From the signing of the informed consent form until the end of the study regardless of whether the participants were on or off active study medication (Up to approximately 5 years)	7.2% 13/181 • From the signing of the informed consent form until the end of the study regardless of whether the participants were on or off active study medication (Up to approximately 5 years)	3.2% 1/31 • From the signing of the informed consent form until the end of the study regardless of whether the participants were on or off active study medication (Up to approximately 5 years)
Nervous system disorders Headache	13.5% 75/557 • From the signing of the informed consent form until the end of the study regardless of whether the participants were on or off active study medication (Up to approximately 5 years)	17.8% 56/314 • From the signing of the informed consent form until the end of the study regardless of whether the participants were on or off active study medication (Up to approximately 5 years)	11.0% 20/181 • From the signing of the informed consent form until the end of the study regardless of whether the participants were on or off active study medication (Up to approximately 5 years)	6.5% 2/31 • From the signing of the informed consent form until the end of the study regardless of whether the participants were on or off active study medication (Up to approximately 5 years)
Renal and urinary disorders Haematuria	8.4% 47/557 • From the signing of the informed consent form until the end of the study regardless of whether the participants were on or off active study medication (Up to approximately 5 years)	11.5% 36/314 • From the signing of the informed consent form until the end of the study regardless of whether the participants were on or off active study medication (Up to approximately 5 years)	7.2% 13/181 • From the signing of the informed consent form until the end of the study regardless of whether the participants were on or off active study medication (Up to approximately 5 years)	12.9% 4/31 • From the signing of the informed consent form until the end of the study regardless of whether the participants were on or off active study medication (Up to approximately 5 years)
Renal and urinary disorders Nocturia	26.0% 145/557 • From the signing of the informed consent form until the end of the study regardless of whether the participants were on or off active study medication (Up to approximately 5 years)	35.4% 111/314 • From the signing of the informed consent form until the end of the study regardless of whether the participants were on or off active study medication (Up to approximately 5 years)	51.9% 94/181 • From the signing of the informed consent form until the end of the study regardless of whether the participants were on or off active study medication (Up to approximately 5 years)	54.8% 17/31 • From the signing of the informed consent form until the end of the study regardless of whether the participants were on or off active study medication (Up to approximately 5 years)
Renal and urinary disorders Pollakiuria	5.4% 30/557 • From the signing of the informed consent form until the end of the study regardless of whether the participants were on or off active study medication (Up to approximately 5 years)	7.6% 24/314 • From the signing of the informed consent form until the end of the study regardless of whether the participants were on or off active study medication (Up to approximately 5 years)	11.0% 20/181 • From the signing of the informed consent form until the end of the study regardless of whether the participants were on or off active study medication (Up to approximately 5 years)	12.9% 4/31 • From the signing of the informed consent form until the end of the study regardless of whether the participants were on or off active study medication (Up to approximately 5 years)
Renal and urinary disorders Polyuria	41.5% 231/557 • From the signing of the informed consent form until the end of the study regardless of whether the participants were on or off active study medication (Up to approximately 5 years)	55.7% 175/314 • From the signing of the informed consent form until the end of the study regardless of whether the participants were on or off active study medication (Up to approximately 5 years)	61.3% 111/181 • From the signing of the informed consent form until the end of the study regardless of whether the participants were on or off active study medication (Up to approximately 5 years)	71.0% 22/31 • From the signing of the informed consent form until the end of the study regardless of whether the participants were on or off active study medication (Up to approximately 5 years)
Renal and urinary disorders Renal Cyst Ruptured	0.54% 3/557 • From the signing of the informed consent form until the end of the study regardless of whether the participants were on or off active study medication (Up to approximately 5 years)	0.64% 2/314 • From the signing of the informed consent form until the end of the study regardless of whether the participants were on or off active study medication (Up to approximately 5 years)	1.1% 2/181 • From the signing of the informed consent form until the end of the study regardless of whether the participants were on or off active study medication (Up to approximately 5 years)	9.7% 3/31 • From the signing of the informed consent form until the end of the study regardless of whether the participants were on or off active study medication (Up to approximately 5 years)
Renal and urinary disorders Renal Pain	26.4% 147/557 • From the signing of the informed consent form until the end of the study regardless of whether the participants were on or off active study medication (Up to approximately 5 years)	28.7% 90/314 • From the signing of the informed consent form until the end of the study regardless of whether the participants were on or off active study medication (Up to approximately 5 years)	23.8% 43/181 • From the signing of the informed consent form until the end of the study regardless of whether the participants were on or off active study medication (Up to approximately 5 years)	22.6% 7/31 • From the signing of the informed consent form until the end of the study regardless of whether the participants were on or off active study medication (Up to approximately 5 years)