Trial Outcomes & Findings for Tolvaptan Open-label Pilot Efficacy, Tolerability, and Safety Study in Autosomal Dominant Polycystic Kidney Disease (ADPKD) (NCT NCT00413777)

Last Updated: 2017-07-02

Results Overview

An AE was defined as any new medical problem, or exacerbation of an existing problem, experienced by a participant while enrolled in a study , whether or not it was considered drug-related by the study physician. A treatment-emergent AE (TEAE) was defined as an AE that started after start of study drug treatment; or if the event was continuous from Baseline and was serious, study drug related, or resulted in death, discontinuation.

Recruitment status

COMPLETED

Study phase

PHASE2

Target enrollment

46 participants

Primary outcome timeframe

AEs were recorded from screening (ICF was signed) until 7-Day follow-up

Results posted on

2017-07-02

Participant Flow

A phase 2, multi-center, open-label trial, to determine the safety, tolerability, and efficacy study of split-dose oral regimens of tolvaptan tablets in a range of 30 to 120 mg/d in autosomal dominant polycystic kidney disease (ADPKD) participants.

This was an open-label study with a 30-day Screening period, Titration period (Day 1 to Month 2), Fixed-dose period (Month 2 to Month 36), and Extension period (12 Months).

Participant milestones

Participant milestones
Measure	Tolvaptan 45+15 mg Participants had received tolvaptan tablets of 45+15 mg orally twice daily during the fixed-dose period from Month 2 to Month 36 followed by a planned extension period for an additional 12 Months.	Tolvaptan 60+30 mg Participants had received tolvaptan tablets of 60+30 mg orally twice daily during the fixed-dose period from Month 2 to Month 36 followed by a planned extension period for an additional 12 Months.
Fixed-dose Period STARTED	22	24
Fixed-dose Period COMPLETED	18	21
Fixed-dose Period NOT COMPLETED	4	3
Extension Period STARTED	17	18
Extension Period COMPLETED	17	18
Extension Period NOT COMPLETED	0	0

Reasons for withdrawal

Reasons for withdrawal
Measure	Tolvaptan 45+15 mg Participants had received tolvaptan tablets of 45+15 mg orally twice daily during the fixed-dose period from Month 2 to Month 36 followed by a planned extension period for an additional 12 Months.	Tolvaptan 60+30 mg Participants had received tolvaptan tablets of 60+30 mg orally twice daily during the fixed-dose period from Month 2 to Month 36 followed by a planned extension period for an additional 12 Months.
Fixed-dose Period Lost to Follow-up	1	1
Fixed-dose Period Adverse Event	2	1
Fixed-dose Period Met Withdrawal Criteria	1	0
Fixed-dose Period Withdrew Consent	0	1

Baseline Characteristics

Tolvaptan Open-label Pilot Efficacy, Tolerability, and Safety Study in Autosomal Dominant Polycystic Kidney Disease (ADPKD)

Baseline characteristics by cohort

Baseline characteristics by cohort
Measure	Tolvaptan 45+15 mg n=22 Participants Participants had received tolvaptan tablets of 45+15 mg orally twice daily during the fixed-dose period from Month 2 to Month 36 followed by a planned extension period for an additional 12 Months.	Tolvaptan 60+30 mg n=24 Participants Participants had received tolvaptan tablets of 60+30 mg orally twice daily during the fixed-dose period from Month 2 to Month 36 followed by a planned extension period for an additional 12 Months.	Total n=46 Participants Total of all reporting groups
Age, Continuous	39.3 Years STANDARD_DEVIATION 8.4 • n=5 Participants	43.9 Years STANDARD_DEVIATION 7.8 • n=7 Participants	41.7 Years STANDARD_DEVIATION 8.3 • n=5 Participants
Sex: Female, Male Female	16 Participants n=5 Participants	18 Participants n=7 Participants	34 Participants n=5 Participants
Sex: Female, Male Male	6 Participants n=5 Participants	6 Participants n=7 Participants	12 Participants n=5 Participants

PRIMARY outcome

Timeframe: AEs were recorded from screening (ICF was signed) until 7-Day follow-up

Population: Safety dataset was defined as all participants who consumed at least 1 dose of study medication. Safety variables analyzed included physical examinations, laboratory tests, vital signs, ECG's and AEs.

Outcome measures

Outcome measures
Measure	Tolvaptan 45+15 mg n=22 Participants Participants had received tolvaptan tablets of 45+15 mg orally twice daily during the fixed-dose period from Month 2 to Month 36 followed by a planned extension period for an additional 12 Months.	Tolvaptan 60+30 mg n=24 Participants Participants had received tolvaptan tablets of 60+30 mg orally twice daily during the fixed-dose period from Month 2 to Month 36 followed by a planned extension period for an additional 12 Months.
Safety Assessments Based on Vital Signs, Electrocardiogram (ECG's), Clinical Laboratory Tests, Physical Examinations Are Reported as Adverse Events (AEs) Upon Study Physician Discretion. Participants with serious TEAEs	3 participants	8 participants
Safety Assessments Based on Vital Signs, Electrocardiogram (ECG's), Clinical Laboratory Tests, Physical Examinations Are Reported as Adverse Events (AEs) Upon Study Physician Discretion. Participants with severe TEAEs	6 participants	10 participants
Safety Assessments Based on Vital Signs, Electrocardiogram (ECG's), Clinical Laboratory Tests, Physical Examinations Are Reported as Adverse Events (AEs) Upon Study Physician Discretion. Participants discontinued due to AEs	3 participants	1 participants

SECONDARY outcome

Timeframe: Baseline to Month 36

Population: The intent-to-treat (ITT) dataset was defined as a dataset that included data from all participants who enrolled to the study with observations at Baseline and Post Baseline. Observed cases (OC) dataset were used.

Spot urine osmolality at trough was determined for urine samples collected immediately prior to morning dosing for Day 1 (Baseline), Months 2, 6, 12, 24, 36 for all participants. Sample was taken after the first morning's void and was provided as a mid-stream, clean catch sample. During the titration period (Weeks 1, 2, 3 and 4) and at Month 6, additional samples were collected for the preceding day immediately preceding the 2nd daily dose and at bed-time. These samples allowed derivation of an average nadir of spot urine osmolality concentrations at each dose level and while at steady state during extended tolvaptan administration. At the Month 36 visit, participants were given a urine container and brought back the specimen at Extension Day 1. All participants were fasting.

Outcome measures

Outcome measures
Measure	Tolvaptan 45+15 mg n=22 Participants Participants had received tolvaptan tablets of 45+15 mg orally twice daily during the fixed-dose period from Month 2 to Month 36 followed by a planned extension period for an additional 12 Months.	Tolvaptan 60+30 mg n=24 Participants Participants had received tolvaptan tablets of 60+30 mg orally twice daily during the fixed-dose period from Month 2 to Month 36 followed by a planned extension period for an additional 12 Months.
Mean Change From Baseline in Trough Urine Osmolality at Steady State Prior to First Daily Dose. Month 24 (N= 18, 20)	-170.17 mOsm/kg Standard Deviation 272.21	-189.75 mOsm/kg Standard Deviation 229.33
Mean Change From Baseline in Trough Urine Osmolality at Steady State Prior to First Daily Dose. Month 36 (N= 18, 21)	-222.50 mOsm/kg Standard Deviation 229.91	-208.90 mOsm/kg Standard Deviation 194.19
Mean Change From Baseline in Trough Urine Osmolality at Steady State Prior to First Daily Dose. Month 2 (N= 21, 22)	-274.10 mOsm/kg Standard Deviation 223.14	-228.00 mOsm/kg Standard Deviation 238.19
Mean Change From Baseline in Trough Urine Osmolality at Steady State Prior to First Daily Dose. Month 6 (N= 19, 23)	-288.42 mOsm/kg Standard Deviation 219.55	-263.78 mOsm/kg Standard Deviation 221.05
Mean Change From Baseline in Trough Urine Osmolality at Steady State Prior to First Daily Dose. Month 12 (N= 17, 21)	-227.29 mOsm/kg Standard Deviation 226.63	-178.43 mOsm/kg Standard Deviation 228.43

SECONDARY outcome

Timeframe: Baseline to Month 24

Population: The ITT dataset was defined as a dataset that included data from all participants who enrolled to the study with observations at Baseline and Post Baseline. OC dataset were used.

Urine osmolality at steady state (after at least 4 days of dosing) including "absolute trough" prior to the second daily dose. Samples for this assessment were taken as closely coincident to PK blood sample as practical. During Weeks 1, 2, 3 and 4 of the Titration Period and at Month 6, additional samples were collected for the preceding day immediately preceding the second daily dose. These samples allowed derivation of an average nadir of spot urine osmolality concentrations at each dose level and while at steady state during extended tolvaptan administration.

Outcome measures

Outcome measures
Measure	Tolvaptan 45+15 mg n=20 Participants Participants had received tolvaptan tablets of 45+15 mg orally twice daily during the fixed-dose period from Month 2 to Month 36 followed by a planned extension period for an additional 12 Months.	Tolvaptan 60+30 mg n=24 Participants Participants had received tolvaptan tablets of 60+30 mg orally twice daily during the fixed-dose period from Month 2 to Month 36 followed by a planned extension period for an additional 12 Months.
Mean Change From Baseline in Trough Urine Osmolality at Steady State Prior to Second Daily Dose. Month 2 (N= 21, 21)	-263.95 mOsm/kg Standard Deviation 220.40	-298.71 mOsm/kg Standard Deviation 257.53
Mean Change From Baseline in Trough Urine Osmolality at Steady State Prior to Second Daily Dose. Month 6 (N= 19, 23)	-321.78 mOsm/kg Standard Deviation 242.53	-294.13 mOsm/kg Standard Deviation 215.95
Mean Change From Baseline in Trough Urine Osmolality at Steady State Prior to Second Daily Dose. Month 12 (N= 16, 20)	-288.20 mOsm/kg Standard Deviation 216.85	-234.65 mOsm/kg Standard Deviation 238.82
Mean Change From Baseline in Trough Urine Osmolality at Steady State Prior to Second Daily Dose. Month 24 (N= 1, 7)	-405.00 mOsm/kg Standard Deviation NA The standard deviation value was not available or not determined.	-227.14 mOsm/kg Standard Deviation 334.13

SECONDARY outcome

Timeframe: Baseline to Month 24

Population: The ITT dataset was defined as a dataset that included data from all participants who enrolled to the study with observations at Baseline and Post Baseline. OC dataset were used.

Urine osmolality at steady state (after at least 4 days of dosing) including "average of troughs" (the mean urine osmolality prior to bedtime). Samples for this assessment were to be taken as closely coincident to PK blood sample as practical. During Weeks 1, 2, 3 and 4 of the Titration Period and at Month 6, additional samples were collected for the preceding day at bedtime. These samples allowed derivation of an average nadir of spot urine osmolality concentrations at each dose level and while at steady state during extended tolvaptan administration.

Outcome measures

Outcome measures
Measure	Tolvaptan 45+15 mg n=19 Participants Participants had received tolvaptan tablets of 45+15 mg orally twice daily during the fixed-dose period from Month 2 to Month 36 followed by a planned extension period for an additional 12 Months.	Tolvaptan 60+30 mg n=24 Participants Participants had received tolvaptan tablets of 60+30 mg orally twice daily during the fixed-dose period from Month 2 to Month 36 followed by a planned extension period for an additional 12 Months.
Mean Change From Baseline in Trough Urine Osmolality at Steady State Prior to Bedtime. Month 2 (N= 21, 22)	-275.00 mOsm/kg Standard Deviation 219.37	-291.09 mOsm/kg Standard Deviation 194.88
Mean Change From Baseline in Trough Urine Osmolality at Steady State Prior to Bedtime. Month 6 (N= 19, 23)	-327.41 mOsm/kg Standard Deviation 217.15	-301.83 mOsm/kg Standard Deviation 210.55
Mean Change From Baseline in Trough Urine Osmolality at Steady State Prior to Bedtime. Month 12 (16, 18)	-283.21 mOsm/kg Standard Deviation 230.81	-245.83 mOsm/kg Standard Deviation 234.46
Mean Change From Baseline in Trough Urine Osmolality at Steady State Prior to Bedtime. Month 24 (N= 1, 7)	-263.00 mOsm/kg Standard Deviation NA The standard deviation value was not available or not determined.	-246.00 mOsm/kg Standard Deviation 208.50

SECONDARY outcome

Timeframe: Baseline to Month 36

Population: The ITT dataset was defined as a dataset that included data from all participants who enrolled to the study with observations at Baseline and Post Baseline. OC dataset were used.

Total Kidney Volume (TKV) was assessed by the central magnetic resonance imaging (MRI) rater.

Outcome measures

Outcome measures
Measure	Tolvaptan 45+15 mg n=22 Participants Participants had received tolvaptan tablets of 45+15 mg orally twice daily during the fixed-dose period from Month 2 to Month 36 followed by a planned extension period for an additional 12 Months.	Tolvaptan 60+30 mg n=24 Participants Participants had received tolvaptan tablets of 60+30 mg orally twice daily during the fixed-dose period from Month 2 to Month 36 followed by a planned extension period for an additional 12 Months.
Percent Change From Baseline in Renal Volume. Month 2 (N= 21, 24)	-1.0 Percentage change per month Standard Deviation 5.2	-1.3 Percentage change per month Standard Deviation 5.3
Percent Change From Baseline in Renal Volume. Month 12 (N= 18, 22)	0.3 Percentage change per month Standard Deviation 6.0	2.4 Percentage change per month Standard Deviation 6.6
Percent Change From Baseline in Renal Volume. Month 24 (N= 18, 21)	4.6 Percentage change per month Standard Deviation 8.4	1.0 Percentage change per month Standard Deviation 8.3
Percent Change From Baseline in Renal Volume. Month 36 (N= 18, 20)	9.9 Percentage change per month Standard Deviation 11.8	5.3 Percentage change per month Standard Deviation 10.0

SECONDARY outcome

Timeframe: Baseline to Month 36

Population: The ITT dataset was defined as a dataset that included data from all participants who enrolled to the study with observations at Baseline and Post Baseline. OC dataset were used.

GFR was estimated using reciprocal serum creatinine formula. The formula does not adjust for body weight or height, but this may be done to normalize to body surface area. The formula for reciprocal Serum creatinine is: 1/Pcr. (Pcr = serum creatinine concentration \[mg/dL\]). Clinic weight scales were calibrated at least yearly.

Outcome measures

Outcome measures
Measure	Tolvaptan 45+15 mg n=22 Participants Participants had received tolvaptan tablets of 45+15 mg orally twice daily during the fixed-dose period from Month 2 to Month 36 followed by a planned extension period for an additional 12 Months.	Tolvaptan 60+30 mg n=24 Participants Participants had received tolvaptan tablets of 60+30 mg orally twice daily during the fixed-dose period from Month 2 to Month 36 followed by a planned extension period for an additional 12 Months.
Change From Pre-dose Baseline in Renal Function Estimated by Glomerular Filtration Rate (GFR). Month 6 (N= 19, 21)	-0.03 dL/mg Standard Deviation 0.10	-0.01 dL/mg Standard Deviation 0.12
Change From Pre-dose Baseline in Renal Function Estimated by Glomerular Filtration Rate (GFR). Month 9 (N= 18, 23)	-0.01 dL/mg Standard Deviation 0.12	-0.03 dL/mg Standard Deviation 0.13
Change From Pre-dose Baseline in Renal Function Estimated by Glomerular Filtration Rate (GFR). Month 28 (N= 18, 21)	-0.07 dL/mg Standard Deviation 0.10	-0.02 dL/mg Standard Deviation 0.14
Change From Pre-dose Baseline in Renal Function Estimated by Glomerular Filtration Rate (GFR). Month 32 (N= 18, 21)	-0.09 dL/mg Standard Deviation 0.14	-0.06 dL/mg Standard Deviation 0.12
Change From Pre-dose Baseline in Renal Function Estimated by Glomerular Filtration Rate (GFR). Month 36 (N= 18, 21)	-0.07 dL/mg Standard Deviation 0.11	-0.06 dL/mg Standard Deviation 0.13
Change From Pre-dose Baseline in Renal Function Estimated by Glomerular Filtration Rate (GFR). Month 2 (N= 22, 24)	-0.09 dL/mg Standard Deviation 0.11	-0.05 dL/mg Standard Deviation 0.13
Change From Pre-dose Baseline in Renal Function Estimated by Glomerular Filtration Rate (GFR). Month 12 (N= 17, 22)	-0.03 dL/mg Standard Deviation 0.11	-0.01 dL/mg Standard Deviation 0.18
Change From Pre-dose Baseline in Renal Function Estimated by Glomerular Filtration Rate (GFR). Month 16 (N= 18, 21)	-0.06 dL/mg Standard Deviation 0.12	-0.02 dL/mg Standard Deviation 0.12
Change From Pre-dose Baseline in Renal Function Estimated by Glomerular Filtration Rate (GFR). Month 20 (N= 18, 21)	-0.06 dL/mg Standard Deviation 0.10	-0.03 dL/mg Standard Deviation 0.15
Change From Pre-dose Baseline in Renal Function Estimated by Glomerular Filtration Rate (GFR). Month 24 (N= 18, 20)	-0.04 dL/mg Standard Deviation 0.10	-0.02 dL/mg Standard Deviation 0.13

SECONDARY outcome

Timeframe: Baseline to Months 2, 6, 12, 24, 36, Extension Day 1, Extension Month 12

Spot urine osmolality at trough was determined for urine samples collected immediately prior to morning dosing for Day 1 (Baseline), Months 2, 6, 12, 24, 36, Extension Day 1, and Extension Month 12 for all participants. Sample was taken after the first morning's void and was provided as a mid-stream, clean catch sample. During the titration period (Weeks 1, 2, 3 and 4) and at Month 6, additional samples were collected for the preceding day immediately preceding the 2nd daily dose and at bed-time. These samples allowed derivation of an average nadir of spot urine osmolality concentrations at each dose level and while at steady state during extended tolvaptan administration. At the Month 36 visit, participants were given a urine container and brought back the specimen at Extension Day 1. All participants were fasting.

Outcome measures

Outcome measures
Measure	Tolvaptan 45+15 mg n=17 Participants Participants had received tolvaptan tablets of 45+15 mg orally twice daily during the fixed-dose period from Month 2 to Month 36 followed by a planned extension period for an additional 12 Months.	Tolvaptan 60+30 mg n=18 Participants Participants had received tolvaptan tablets of 60+30 mg orally twice daily during the fixed-dose period from Month 2 to Month 36 followed by a planned extension period for an additional 12 Months.
Mean Change From Baseline in Trough Urine Osmolality at Steady State Prior to First Daily Dose- Extension. Month 2 (N= 17, 17)	-328.06 mOsm/kg Standard Deviation 207.05	-176.88 mOsm/kg Standard Deviation 225.54
Mean Change From Baseline in Trough Urine Osmolality at Steady State Prior to First Daily Dose- Extension. Month 6 (N= 17, 18)	-270.94 mOsm/kg Standard Deviation 200.29	-223.50 mOsm/kg Standard Deviation 211.61
Mean Change From Baseline in Trough Urine Osmolality at Steady State Prior to First Daily Dose- Extension. Month 12 (N= 16, 17)	-234.56 mOsm/kg Standard Deviation 232.01	-155.65 mOsm/kg Standard Deviation 242.53
Mean Change From Baseline in Trough Urine Osmolality at Steady State Prior to First Daily Dose- Extension. Extension Day 1 (N= 17, 17)	-54.59 mOsm/kg Standard Deviation 236.96	-157.18 mOsm/kg Standard Deviation 229.19
Mean Change From Baseline in Trough Urine Osmolality at Steady State Prior to First Daily Dose- Extension. Extension Month 12 (N= 17, 18)	-115.59 mOsm/kg Standard Deviation 278.19	-202.44 mOsm/kg Standard Deviation 227.92
Mean Change From Baseline in Trough Urine Osmolality at Steady State Prior to First Daily Dose- Extension. Month 24 (N= 17, 17)	-164.06 mOsm/kg Standard Deviation 279.32	-160.06 mOsm/kg Standard Deviation 196.50
Mean Change From Baseline in Trough Urine Osmolality at Steady State Prior to First Daily Dose- Extension. Month 36 (N= 17, 18)	-234.71 mOsm/kg Standard Deviation 230.90	-196.33 mOsm/kg Standard Deviation 175.23

SECONDARY outcome

Timeframe: Baseline to Month 24

Population: The ITT dataset was defined as a dataset that included data from all participants who enrolled to the study with observations at Baseline and Post Baseline. OC dataset were used.

Outcome measures

Outcome measures
Measure	Tolvaptan 45+15 mg n=16 Participants Participants had received tolvaptan tablets of 45+15 mg orally twice daily during the fixed-dose period from Month 2 to Month 36 followed by a planned extension period for an additional 12 Months.	Tolvaptan 60+30 mg n=18 Participants Participants had received tolvaptan tablets of 60+30 mg orally twice daily during the fixed-dose period from Month 2 to Month 36 followed by a planned extension period for an additional 12 Months.
Mean Change From Baseline in Trough Urine Osmolality at Steady State Prior to Second Daily Dose- Extension. Month 2 (N= 17, 17)	-281.63 mOsm/kg Standard Deviation 235.90	-254.82 mOsm/kg Standard Deviation 217.14
Mean Change From Baseline in Trough Urine Osmolality at Steady State Prior to Second Daily Dose- Extension. Month 6 (N= 17, 18)	-305.25 mOsm/kg Standard Deviation 223.90	-261.61 mOsm/kg Standard Deviation 201.49
Mean Change From Baseline in Trough Urine Osmolality at Steady State Prior to Second Daily Dose- Extension. Month 12 (N= 16, 16)	-288.20 mOsm/kg Standard Deviation 216.85	-190.69 mOsm/kg Standard Deviation 201.16
Mean Change From Baseline in Trough Urine Osmolality at Steady State Prior to Second Daily Dose- Extension. Month 24 (N= 1, 6)	-405.00 mOsm/kg Standard Deviation NA The standard deviation value was not available or not determined.	-120.50 mOsm/kg Standard Deviation 196.05

SECONDARY outcome

Timeframe: Baseline to Month 24

Population: The ITT dataset was defined as a dataset that included data from all participants who enrolled to the study with observations at Baseline and Post Baseline. OC dataset were used.

Outcome measures

Outcome measures
Measure	Tolvaptan 45+15 mg n=15 Participants Participants had received tolvaptan tablets of 45+15 mg orally twice daily during the fixed-dose period from Month 2 to Month 36 followed by a planned extension period for an additional 12 Months.	Tolvaptan 60+30 mg n=18 Participants Participants had received tolvaptan tablets of 60+30 mg orally twice daily during the fixed-dose period from Month 2 to Month 36 followed by a planned extension period for an additional 12 Months.
Mean Change From Baseline in Trough Urine Osmolality at Steady State Prior to Bedtime- Extension. Month 2 (N= 17, 17)	-322.27 mOsm/kg Standard Deviation 207.32	-258.88 mOsm/kg Standard Deviation 174.51
Mean Change From Baseline in Trough Urine Osmolality at Steady State Prior to Bedtime- Extension. Month 6 (N= 17, 18)	-309.73 mOsm/kg Standard Deviation 225.40	-264.50 mOsm/kg Standard Deviation 180.12
Mean Change From Baseline in Trough Urine Osmolality at Steady State Prior to Bedtime- Extension. Month 12 (16, 15)	-283.21 mOsm/kg Standard Deviation 230.81	-206.00 mOsm/kg Standard Deviation 200.36
Mean Change From Baseline in Trough Urine Osmolality at Steady State Prior to Bedtime- Extension. Month 24 (N= 1, 6)	-263.00 mOsm/kg Standard Deviation NA The standard deviation value was not available or not determined.	-187.50 mOsm/kg Standard Deviation 153.04

SECONDARY outcome

Timeframe: Baseline to Months 2, 12, 24, 36, Extension Day 1, Extension Month 12

Population: The ITT dataset was defined as a dataset that included data from all participants who enrolled to the study with observations at Baseline and Post Baseline. OC dataset were used.

TKV was assessed by the central magnetic resonance imaging (MRI) rater.

Outcome measures

Outcome measures
Measure	Tolvaptan 45+15 mg n=17 Participants Participants had received tolvaptan tablets of 45+15 mg orally twice daily during the fixed-dose period from Month 2 to Month 36 followed by a planned extension period for an additional 12 Months.	Tolvaptan 60+30 mg n=18 Participants Participants had received tolvaptan tablets of 60+30 mg orally twice daily during the fixed-dose period from Month 2 to Month 36 followed by a planned extension period for an additional 12 Months.
Percent Change From Baseline in Renal Volume-Extension. Month 2 (N= 17, 18)	-1.3 Percentage change per month Standard Deviation 5.4	-1.4 Percentage change per month Standard Deviation 3.9
Percent Change From Baseline in Renal Volume-Extension. Month 12 (N= 17, 18)	-0.7 Percentage change per month Standard Deviation 4.5	1.9 Percentage change per month Standard Deviation 5.7
Percent Change From Baseline in Renal Volume-Extension. Month 24 (N= 17, 18)	3.2 Percentage change per month Standard Deviation 6.0	0.2 Percentage change per month Standard Deviation 7.2
Percent Change From Baseline in Renal Volume-Extension. Month 36 (N= 17, 18)	7.9 Percentage change per month Standard Deviation 8.7	3.8 Percentage change per month Standard Deviation 7.4
Percent Change From Baseline in Renal Volume-Extension. Extension Day 1 (N= 17, 18)	14.1 Percentage change per month Standard Deviation 10.5	8.4 Percentage change per month Standard Deviation 7.9
Percent Change From Baseline in Renal Volume-Extension. Extension Month 12 (N= 17, 18)	15.7 Percentage change per month Standard Deviation 12.7	10.7 Percentage change per month Standard Deviation 10.4

SECONDARY outcome

Timeframe: Baseline to Months 2, 6, 9, 12, 16, 20, 24, 28, 32, 36, Extension Day 1, Extension Month 12

Population: The ITT dataset was defined as a dataset that included data from all participants who enrolled to the study with observations at Baseline and Post Baseline. OC dataset were used.

Outcome measures

Outcome measures
Measure	Tolvaptan 45+15 mg n=17 Participants Participants had received tolvaptan tablets of 45+15 mg orally twice daily during the fixed-dose period from Month 2 to Month 36 followed by a planned extension period for an additional 12 Months.	Tolvaptan 60+30 mg n=18 Participants Participants had received tolvaptan tablets of 60+30 mg orally twice daily during the fixed-dose period from Month 2 to Month 36 followed by a planned extension period for an additional 12 Months.
Change From Pre-dose Baseline in Renal Function Estimated by GFR- Extension. Month 24 (N= 17, 17)	-0.04 dL/mg Standard Deviation 0.11	-0.02 dL/mg Standard Deviation 0.14
Change From Pre-dose Baseline in Renal Function Estimated by GFR- Extension. Month 28 (N= 17, 18)	-0.06 dL/mg Standard Deviation 0.10	-0.02 dL/mg Standard Deviation 0.14
Change From Pre-dose Baseline in Renal Function Estimated by GFR- Extension. Month 32 (N= 17, 18)	-0.09 dL/mg Standard Deviation 0.14	-0.05 dL/mg Standard Deviation 0.12
Change From Pre-dose Baseline in Renal Function Estimated by GFR- Extension. Month 36 (N= 17, 18)	-0.07 dL/mg Standard Deviation 0.11	-0.05 dL/mg Standard Deviation 0.14
Change From Pre-dose Baseline in Renal Function Estimated by GFR- Extension. Extension Day 1 (N= 17, 18)	-0.04 dL/mg Standard Deviation 0.13	-0.01 dL/mg Standard Deviation 0.17
Change From Pre-dose Baseline in Renal Function Estimated by GFR- Extension. Extension Month 12 (N= 17, 18)	-0.05 dL/mg Standard Deviation 0.17	-0.04 dL/mg Standard Deviation 0.14
Change From Pre-dose Baseline in Renal Function Estimated by GFR- Extension. Month 2 (N= 17, 18)	-0.09 dL/mg Standard Deviation 0.11	-0.04 dL/mg Standard Deviation 0.15
Change From Pre-dose Baseline in Renal Function Estimated by GFR- Extension. Month 6 (N= 17, 16)	-0.03 dL/mg Standard Deviation 0.11	-0.00 dL/mg Standard Deviation 0.13
Change From Pre-dose Baseline in Renal Function Estimated by GFR- Extension. Month 9 (N= 16, 18)	-0.01 dL/mg Standard Deviation 0.11	-0.01 dL/mg Standard Deviation 0.14
Change From Pre-dose Baseline in Renal Function Estimated by GFR- Extension. Month 12 (N= 16, 17)	-0.03 dL/mg Standard Deviation 0.12	-0.00 dL/mg Standard Deviation 0.21
Change From Pre-dose Baseline in Renal Function Estimated by GFR- Extension. Month 16 (N= 17, 16)	-0.06 dL/mg Standard Deviation 0.12	-0.01 dL/mg Standard Deviation 0.13
Change From Pre-dose Baseline in Renal Function Estimated by GFR- Extension. Month 20 (N= 17, 18)	-0.06 dL/mg Standard Deviation 0.10	-0.02 dL/mg Standard Deviation 0.16

SECONDARY outcome

Timeframe: Baseline to Month 36

Population: The ITT dataset was defined as a dataset that included data from all participants who enrolled to the study with observations at Baseline and Post Baseline. OC dataset were used.

The participants were seated and resting systolic and diastolic BP for each scheduled assessment was recorded. At each assessment, participants were categorized (based on repeated blood pressure measurements as being normotensive (MAP \< 100 mm Hg and off therapy), high normal (sBP \> 129 and or dBP \> 84 mm Hg off therapy) or hypertensive (sBP \>140 and/or dBP \> 90 mm Hg). The mean arterial pressure (MAP) was derived from these values and were not recorded (MAP = diastolic pressure + \[1/3 x pulse pressure (ie systolic - diastolic pressure)\] in mm Hg).

Outcome measures

Outcome measures
Measure	Tolvaptan 45+15 mg n=22 Participants Participants had received tolvaptan tablets of 45+15 mg orally twice daily during the fixed-dose period from Month 2 to Month 36 followed by a planned extension period for an additional 12 Months.	Tolvaptan 60+30 mg n=24 Participants Participants had received tolvaptan tablets of 60+30 mg orally twice daily during the fixed-dose period from Month 2 to Month 36 followed by a planned extension period for an additional 12 Months.
Mean Change From Baseline in Systolic Blood Pressure (sBP) for Hypertension Assessment. Month 2 (N= 22, 24)	-3.2 mmHg Standard Deviation 12.6	-3.0 mmHg Standard Deviation 15.4
Mean Change From Baseline in Systolic Blood Pressure (sBP) for Hypertension Assessment. Month 6 (N= 19, 23)	-3.6 mmHg Standard Deviation 10.8	-5.0 mmHg Standard Deviation 12.4
Mean Change From Baseline in Systolic Blood Pressure (sBP) for Hypertension Assessment. Month 9 (N= 18, 23)	-4.6 mmHg Standard Deviation 12.5	-3.5 mmHg Standard Deviation 12.5
Mean Change From Baseline in Systolic Blood Pressure (sBP) for Hypertension Assessment. Month 12 (N= 18, 23)	-8.0 mmHg Standard Deviation 14.6	-3.5 mmHg Standard Deviation 14.2
Mean Change From Baseline in Systolic Blood Pressure (sBP) for Hypertension Assessment. Month 16 (N= 18, 23)	-6.2 mmHg Standard Deviation 14.2	-2.9 mmHg Standard Deviation 12.6
Mean Change From Baseline in Systolic Blood Pressure (sBP) for Hypertension Assessment. Month 20 (N= 18, 21)	-7.9 mmHg Standard Deviation 11.4	-10.0 mmHg Standard Deviation 16.4
Mean Change From Baseline in Systolic Blood Pressure (sBP) for Hypertension Assessment. Month 24 (N= 18, 21)	-2.1 mmHg Standard Deviation 18.4	-0.1 mmHg Standard Deviation 14.7
Mean Change From Baseline in Systolic Blood Pressure (sBP) for Hypertension Assessment. Month 28 (N= 18, 21)	-4.7 mmHg Standard Deviation 14.2	-4.1 mmHg Standard Deviation 17.1
Mean Change From Baseline in Systolic Blood Pressure (sBP) for Hypertension Assessment. Month 32 (N= 18, 21)	-7.3 mmHg Standard Deviation 10.9	-7.2 mmHg Standard Deviation 14.8
Mean Change From Baseline in Systolic Blood Pressure (sBP) for Hypertension Assessment. Month 36 (N= 18, 21)	-0.2 mmHg Standard Deviation 13.2	-5.4 mmHg Standard Deviation 17.6

SECONDARY outcome

Timeframe: Baseline to Month 36

Population: The ITT dataset was defined as a dataset that included data from all participants who enrolled to the study with observations at Baseline and Post Baseline. OC dataset were used.

Outcome measures

Outcome measures
Measure	Tolvaptan 45+15 mg n=22 Participants Participants had received tolvaptan tablets of 45+15 mg orally twice daily during the fixed-dose period from Month 2 to Month 36 followed by a planned extension period for an additional 12 Months.	Tolvaptan 60+30 mg n=24 Participants Participants had received tolvaptan tablets of 60+30 mg orally twice daily during the fixed-dose period from Month 2 to Month 36 followed by a planned extension period for an additional 12 Months.
Mean Change From Baseline in Diastolic Blood Pressure (dBP) for Hypertension Assessment. Month 2 (N= 22, 24)	-4.0 mmHg Standard Deviation 11.4	-0.2 mmHg Standard Deviation 9.8
Mean Change From Baseline in Diastolic Blood Pressure (dBP) for Hypertension Assessment. Month 6 (N= 19, 23)	-3.6 mmHg Standard Deviation 8.2	-2.5 mmHg Standard Deviation 11.2
Mean Change From Baseline in Diastolic Blood Pressure (dBP) for Hypertension Assessment. Month 9 (N= 18, 23)	-4.8 mmHg Standard Deviation 8.9	-2.8 mmHg Standard Deviation 11.4
Mean Change From Baseline in Diastolic Blood Pressure (dBP) for Hypertension Assessment. Month 12 (N= 17, 23)	-9.2 mmHg Standard Deviation 12.6	-1.1 mmHg Standard Deviation 12.6
Mean Change From Baseline in Diastolic Blood Pressure (dBP) for Hypertension Assessment. Month 16 (N= 18, 23)	-5.6 mmHg Standard Deviation 11.4	-2.3 mmHg Standard Deviation 10.7
Mean Change From Baseline in Diastolic Blood Pressure (dBP) for Hypertension Assessment. Month 20 (N= 18, 21)	-7.4 mmHg Standard Deviation 9.8	-5.6 mmHg Standard Deviation 12.1
Mean Change From Baseline in Diastolic Blood Pressure (dBP) for Hypertension Assessment. Month 24 (N= 18, 21)	-3.1 mmHg Standard Deviation 11.6	-0.1 mmHg Standard Deviation 12.4
Mean Change From Baseline in Diastolic Blood Pressure (dBP) for Hypertension Assessment. Month 28 (N= 18, 21)	-5.3 mmHg Standard Deviation 10.6	-2.2 mmHg Standard Deviation 8.8
Mean Change From Baseline in Diastolic Blood Pressure (dBP) for Hypertension Assessment. Month 32 (N= 18, 21)	-4.6 mmHg Standard Deviation 11.2	-3.0 mmHg Standard Deviation 10.9
Mean Change From Baseline in Diastolic Blood Pressure (dBP) for Hypertension Assessment. Month 36 (N= 18, 21)	-5.4 mmHg Standard Deviation 10.0	-4.0 mmHg Standard Deviation 13.2

SECONDARY outcome

Timeframe: Baseline to Month 36

Population: The ITT dataset was defined as a dataset that included data from all participants who enrolled to the study with observations at Baseline and Post Baseline. OC dataset were used.

Outcome measures

Outcome measures
Measure	Tolvaptan 45+15 mg n=22 Participants Participants had received tolvaptan tablets of 45+15 mg orally twice daily during the fixed-dose period from Month 2 to Month 36 followed by a planned extension period for an additional 12 Months.	Tolvaptan 60+30 mg n=24 Participants Participants had received tolvaptan tablets of 60+30 mg orally twice daily during the fixed-dose period from Month 2 to Month 36 followed by a planned extension period for an additional 12 Months.
Mean Change From Baseline in Mean Arterial Pressure (MAP) for Hypertension Assessment. Month 2 (N= 22, 24)	-3.7 mmHg Standard Deviation 10.5	-1.0 mmHg Standard Deviation 10.5
Mean Change From Baseline in Mean Arterial Pressure (MAP) for Hypertension Assessment. Month 6 (N= 19, 23)	-3.6 mmHg Standard Deviation 7.4	-3.3 mmHg Standard Deviation 11.1
Mean Change From Baseline in Mean Arterial Pressure (MAP) for Hypertension Assessment. Month 9 (N= 18, 23)	-4.7 mmHg Standard Deviation 9.2	-3.0 mmHg Standard Deviation 10.8
Mean Change From Baseline in Mean Arterial Pressure (MAP) for Hypertension Assessment. Month 12 (N= 18, 23)	-12.0 mmHg Standard Deviation 18.9	-1.8 mmHg Standard Deviation 12.1
Mean Change From Baseline in Mean Arterial Pressure (MAP) for Hypertension Assessment. Month 16 (N= 18, 23)	-5.8 mmHg Standard Deviation 11.0	-2.5 mmHg Standard Deviation 10.6
Mean Change From Baseline in Mean Arterial Pressure (MAP) for Hypertension Assessment. Month 20 (N= 18, 21)	-7.6 mmHg Standard Deviation 9.7	-7.0 mmHg Standard Deviation 12.3
Mean Change From Baseline in Mean Arterial Pressure (MAP) for Hypertension Assessment. Month 24 (N= 18, 21)	-2.7 mmHg Standard Deviation 13.0	-0.1 mmHg Standard Deviation 12.0
Mean Change From Baseline in Mean Arterial Pressure (MAP) for Hypertension Assessment. Month 28 (N= 18, 21)	-5.2 mmHg Standard Deviation 11.2	-2.7 mmHg Standard Deviation 10.1
Mean Change From Baseline in Mean Arterial Pressure (MAP) for Hypertension Assessment. Month 32 (N= 18, 21)	-5.6 mmHg Standard Deviation 10.0	-4.3 mmHg Standard Deviation 11.2
Mean Change From Baseline in Mean Arterial Pressure (MAP) for Hypertension Assessment. Month 36 (N= 18, 21)	-3.8 mmHg Standard Deviation 9.6	-4.4 mmHg Standard Deviation 13.8

SECONDARY outcome

Timeframe: Baseline to Months 2, 6, 9, 12, 16, 20, 24, 28, 32, 36, Extension Day 1, Extension Month 4, Extension Month 8, Extension Month 12

Population: The ITT dataset was defined as a dataset that included data from all participants who enrolled to the study with observations at Baseline and Post Baseline. OC dataset were used.

Outcome measures

Outcome measures
Measure	Tolvaptan 45+15 mg n=17 Participants Participants had received tolvaptan tablets of 45+15 mg orally twice daily during the fixed-dose period from Month 2 to Month 36 followed by a planned extension period for an additional 12 Months.	Tolvaptan 60+30 mg n=18 Participants Participants had received tolvaptan tablets of 60+30 mg orally twice daily during the fixed-dose period from Month 2 to Month 36 followed by a planned extension period for an additional 12 Months.
Mean Change From Baseline in sBP for Hypertension Assessment- Extension. Month 2 (N= 17, 18)	-1.6 mmHg Standard Deviation 13.0	-2.7 mmHg Standard Deviation 15.0
Mean Change From Baseline in sBP for Hypertension Assessment- Extension. Month 6 (N= 17, 18)	-3.4 mmHg Standard Deviation 11.4	-5.6 mmHg Standard Deviation 13.7
Mean Change From Baseline in sBP for Hypertension Assessment- Extension. Month 9 (N= 16, 18)	-4.1 mmHg Standard Deviation 13.2	-4.3 mmHg Standard Deviation 13.7
Mean Change From Baseline in sBP for Hypertension Assessment- Extension. Month 12 (N= 17, 18)	-8.9 mmHg Standard Deviation 14.5	-3.3 mmHg Standard Deviation 15.5
Mean Change From Baseline in sBP for Hypertension Assessment- Extension. Month 16 (N= 17, 18)	-6.5 mmHg Standard Deviation 14.5	-1.7 mmHg Standard Deviation 13.9
Mean Change From Baseline in sBP for Hypertension Assessment- Extension. Month 20 (N= 17, 18)	-7.7 mmHg Standard Deviation 11.7	-9.3 mmHg Standard Deviation 17.1
Mean Change From Baseline in sBP for Hypertension Assessment- Extension. Month 24 (N= 17, 18)	-1.8 mmHg Standard Deviation 18.9	1.4 mmHg Standard Deviation 15.2
Mean Change From Baseline in sBP for Hypertension Assessment- Extension. Month 28 (N= 17, 18)	-4.9 mmHg Standard Deviation 14.6	-3.4 mmHg Standard Deviation 17.7
Mean Change From Baseline in sBP for Hypertension Assessment- Extension. Month 32 (N= 17, 18)	-7.6 mmHg Standard Deviation 11.1	-6.8 mmHg Standard Deviation 16.0
Mean Change From Baseline in sBP for Hypertension Assessment- Extension. Month 36 (N= 17, 18)	-0.6 mmHg Standard Deviation 13.5	-5.4 mmHg Standard Deviation 18.8
Mean Change From Baseline in sBP for Hypertension Assessment- Extension. Extension Day 1 (N= 17, 18)	-4.4 mmHg Standard Deviation 11.8	-5.1 mmHg Standard Deviation 14.9
Mean Change From Baseline in sBP for Hypertension Assessment- Extension. Extension Month 4 (N= 17, 18)	-1.1 mmHg Standard Deviation 16.1	-8.7 mmHg Standard Deviation 11.8
Mean Change From Baseline in sBP for Hypertension Assessment- Extension. Extension Month 8 (N= 17, 18)	1.8 mmHg Standard Deviation 13.1	-7.3 mmHg Standard Deviation 14.8
Mean Change From Baseline in sBP for Hypertension Assessment- Extension. Extension Month 12 (N= 17, 18)	-0.5 mmHg Standard Deviation 13.5	-7.1 mmHg Standard Deviation 12.2

SECONDARY outcome

Timeframe: Baseline to Months 2, 6, 9, 12, 16, 20, 24, 28, 32, 36, Extension Day 1, Extension Month 4, Extension Month 8, Extension Month 12

Population: The ITT dataset was defined as a dataset that included data from all participants who enrolled to the study with observations at Baseline and Post Baseline. OC dataset were used.

Outcome measures

Outcome measures
Measure	Tolvaptan 45+15 mg n=17 Participants Participants had received tolvaptan tablets of 45+15 mg orally twice daily during the fixed-dose period from Month 2 to Month 36 followed by a planned extension period for an additional 12 Months.	Tolvaptan 60+30 mg n=18 Participants Participants had received tolvaptan tablets of 60+30 mg orally twice daily during the fixed-dose period from Month 2 to Month 36 followed by a planned extension period for an additional 12 Months.
Mean Change From Baseline in dBP for Hypertension Assessment- Extension. Month 2 (N= 17, 18)	-5.5 mmHg Standard Deviation 12.4	0.3 mmHg Standard Deviation 9.7
Mean Change From Baseline in dBP for Hypertension Assessment- Extension. Month 6 (N= 17, 18)	-4.5 mmHg Standard Deviation 8.2	-2.4 mmHg Standard Deviation 12.6
Mean Change From Baseline in dBP for Hypertension Assessment- Extension. Month 9 (N= 16, 18)	-5.3 mmHg Standard Deviation 9.4	-2.9 mmHg Standard Deviation 11.8
Mean Change From Baseline in dBP for Hypertension Assessment- Extension. Month 12 (N= 16, 18)	-10.1 mmHg Standard Deviation 12.4	-1.9 mmHg Standard Deviation 13.0
Mean Change From Baseline in dBP for Hypertension Assessment- Extension. Month 16 (N= 17, 18)	-6.9 mmHg Standard Deviation 10.1	-2.1 mmHg Standard Deviation 12.0
Mean Change From Baseline in dBP for Hypertension Assessment- Extension. Month 20 (N= 17, 18)	-7.5 mmHg Standard Deviation 10.0	-6.1 mmHg Standard Deviation 12.1
Mean Change From Baseline in dBP for Hypertension Assessment- Extension. Month 24 (N= 17, 18)	-3.9 mmHg Standard Deviation 11.4	-0.6 mmHg Standard Deviation 12.7
Mean Change From Baseline in dBP for Hypertension Assessment- Extension. Month 28 (N= 17, 18)	-5.6 mmHg Standard Deviation 10.8	-2.9 mmHg Standard Deviation 8.4
Mean Change From Baseline in dBP for Hypertension Assessment- Extension. Month 32 (N= 17, 18)	-5.4 mmHg Standard Deviation 11.0	-3.6 mmHg Standard Deviation 11.4
Mean Change From Baseline in dBP for Hypertension Assessment- Extension. Month 36 (N= 17, 18)	-5.7 mmHg Standard Deviation 10.2	-4.8 mmHg Standard Deviation 14.0
Mean Change From Baseline in dBP for Hypertension Assessment- Extension. Extension Day 1 (N= 17, 18)	-7.9 mmHg Standard Deviation 7.3	-4.0 mmHg Standard Deviation 10.8
Mean Change From Baseline in dBP for Hypertension Assessment- Extension. Extension Month 4 (N= 17, 18)	-6.8 mmHg Standard Deviation 10.6	-6.1 mmHg Standard Deviation 10.8
Mean Change From Baseline in dBP for Hypertension Assessment- Extension. Extension Month 8 (N= 17, 18)	-5.0 mmHg Standard Deviation 7.9	-6.7 mmHg Standard Deviation 12.7
Mean Change From Baseline in dBP for Hypertension Assessment- Extension. Extension Month 12 (N= 17, 18)	-6.0 mmHg Standard Deviation 8.9	-5.6 mmHg Standard Deviation 11.7

SECONDARY outcome

Timeframe: Baseline to Months 2, 6, 9, 12, 16, 20, 24, 28, 32, 36, Extension Day 1, Extension Month 4, Extension Month 8, Extension Month 12

Population: The ITT dataset was defined as a dataset that included data from all participants who enrolled to the study with observations at Baseline and Post Baseline. OC dataset were used.

Outcome measures

Outcome measures
Measure	Tolvaptan 45+15 mg n=17 Participants Participants had received tolvaptan tablets of 45+15 mg orally twice daily during the fixed-dose period from Month 2 to Month 36 followed by a planned extension period for an additional 12 Months.	Tolvaptan 60+30 mg n=18 Participants Participants had received tolvaptan tablets of 60+30 mg orally twice daily during the fixed-dose period from Month 2 to Month 36 followed by a planned extension period for an additional 12 Months.
Mean Change From Baseline in MAP for Hypertension Assessment- Extension. Month 2 (N= 17, 18)	-4.1 mmHg Standard Deviation 11.6	-0.6 mmHg Standard Deviation 10.0
Mean Change From Baseline in MAP for Hypertension Assessment- Extension. Month 6 (N= 17, 18)	-4.2 mmHg Standard Deviation 7.7	-3.4 mmHg Standard Deviation 12.5
Mean Change From Baseline in MAP for Hypertension Assessment- Extension. Month 9 (N= 16, 18)	-4.8 mmHg Standard Deviation 9.8	-3.4 mmHg Standard Deviation 11.5
Mean Change From Baseline in MAP for Hypertension Assessment- Extension. Month 12 (N= 17, 18)	-13.1 mmHg Standard Deviation 18.9	-2.3 mmHg Standard Deviation 12.9
Mean Change From Baseline in MAP for Hypertension Assessment- Extension. Month 16 (N= 17, 18)	-6.8 mmHg Standard Deviation 10.4	-1.9 mmHg Standard Deviation 11.8
Mean Change From Baseline in MAP for Hypertension Assessment- Extension. Month 20 (N= 17, 18)	-7.5 mmHg Standard Deviation 10.0	-7.2 mmHg Standard Deviation 12.8
Mean Change From Baseline in MAP for Hypertension Assessment- Extension. Month 24 (N= 17, 18)	-3.1 mmHg Standard Deviation 13.2	0.1 mmHg Standard Deviation 12.6
Mean Change From Baseline in MAP for Hypertension Assessment- Extension. Month 28 (N= 17, 18)	-5.5 mmHg Standard Deviation 11.4	-2.9 mmHg Standard Deviation 10.2
Mean Change From Baseline in MAP for Hypertension Assessment- Extension. Month 32 (N= 17, 18)	-6.2 mmHg Standard Deviation 10.0	-4.6 mmHg Standard Deviation 12.0
Mean Change From Baseline in MAP for Hypertension Assessment- Extension. Month 36 (N= 17, 18)	-4.1 mmHg Standard Deviation 9.8	-5.1 mmHg Standard Deviation 14.8
Mean Change From Baseline in MAP for Hypertension Assessment- Extension. Extension Day 1 (N= 17, 18)	-6.8 mmHg Standard Deviation 7.8	-4.4 mmHg Standard Deviation 11.0
Mean Change From Baseline in MAP for Hypertension Assessment- Extension. Extension Month 4 (N= 17, 18)	-5.1 mmHg Standard Deviation 10.7	-6.9 mmHg Standard Deviation 10.1
Mean Change From Baseline in MAP for Hypertension Assessment- Extension. Extension Month 8 (N= 17, 18)	-2.8 mmHg Standard Deviation 8.6	-6.8 mmHg Standard Deviation 12.1
Mean Change From Baseline in MAP for Hypertension Assessment- Extension. Extension Month 12 (N= 17, 18)	-4.2 mmHg Standard Deviation 9.3	-6.0 mmHg Standard Deviation 10.9

SECONDARY outcome

Timeframe: Baseline to Month 36

Population: The ITT dataset was defined as a dataset that included data from all participants who enrolled to the study with observations at Baseline and Post Baseline. OC dataset were used.

Participants were asked the question to assess the relative level of pain attributed to their kidneys. This question was, "On a scale of 0 to 10, with zero represented no pain at all and 10 represented the worst pain ever experienced, what was the worst kidney pain experienced in the last 4 months?" If the latest assessment was less than 4 months prior, the question was substituted "since your last visit" for "in the last 4 months". The same interrogator designated to this task was used throughout the study for each participant.

Outcome measures

Outcome measures
Measure	Tolvaptan 45+15 mg n=22 Participants Participants had received tolvaptan tablets of 45+15 mg orally twice daily during the fixed-dose period from Month 2 to Month 36 followed by a planned extension period for an additional 12 Months.	Tolvaptan 60+30 mg n=24 Participants Participants had received tolvaptan tablets of 60+30 mg orally twice daily during the fixed-dose period from Month 2 to Month 36 followed by a planned extension period for an additional 12 Months.
Mean Change From Baseline in Patient-assessed Renal Pain Scale. Month 2 (N= 22, 24)	0.6 Units on a scale Standard Deviation 3.1	0.0 Units on a scale Standard Deviation 1.6
Mean Change From Baseline in Patient-assessed Renal Pain Scale. Month 6 (N= 19, 23)	0.4 Units on a scale Standard Deviation 2.8	-0.1 Units on a scale Standard Deviation 1.7
Mean Change From Baseline in Patient-assessed Renal Pain Scale. Month 12 (N= 18, 23)	1.2 Units on a scale Standard Deviation 3.3	-0.1 Units on a scale Standard Deviation 2.1
Mean Change From Baseline in Patient-assessed Renal Pain Scale. Month 24 (N= 18, 21)	0.2 Units on a scale Standard Deviation 1.6	1.0 Units on a scale Standard Deviation 3.3
Mean Change From Baseline in Patient-assessed Renal Pain Scale. Month 36 (N= 18, 21)	0.6 Units on a scale Standard Deviation 2.3	0.5 Units on a scale Standard Deviation 2.2

SECONDARY outcome

Timeframe: Baseline to Months 2, 6, 12, 24, 36, Extension Day 1, Extension Month 12

Population: The ITT dataset was defined as a dataset that included data from all participants who enrolled to the study with observations at Baseline and Post Baseline. OC dataset were used.

Outcome measures

Outcome measures
Measure	Tolvaptan 45+15 mg n=17 Participants Participants had received tolvaptan tablets of 45+15 mg orally twice daily during the fixed-dose period from Month 2 to Month 36 followed by a planned extension period for an additional 12 Months.	Tolvaptan 60+30 mg n=18 Participants Participants had received tolvaptan tablets of 60+30 mg orally twice daily during the fixed-dose period from Month 2 to Month 36 followed by a planned extension period for an additional 12 Months.
Mean Change From Baseline in Patient-assessed Renal Pain Scale- Extension. Month 2 (N= 17, 18)	0.9 Units on a scale Standard Deviation 2.7	0.3 Units on a scale Standard Deviation 1.3
Mean Change From Baseline in Patient-assessed Renal Pain Scale- Extension. Month 6 (N=17, 18)	0.8 Units on a scale Standard Deviation 2.5	-0.2 Units on a scale Standard Deviation 1.9
Mean Change From Baseline in Patient-assessed Renal Pain Scale- Extension. Month 12 (N= 17, 18)	1.2 Units on a scale Standard Deviation 3.4	-0.3 Units on a scale Standard Deviation 2.0
Mean Change From Baseline in Patient-assessed Renal Pain Scale- Extension. Month 24 (N= 17, 18)	0.2 Units on a scale Standard Deviation 1.6	0.8 Units on a scale Standard Deviation 3.3
Mean Change From Baseline in Patient-assessed Renal Pain Scale- Extension. Month 36 (N= 17, 18)	0.6 Units on a scale Standard Deviation 2.3	0.5 Units on a scale Standard Deviation 2.4
Mean Change From Baseline in Patient-assessed Renal Pain Scale- Extension. Extension Day 1 (N= 17, 18)	-0.3 Units on a scale Standard Deviation 0.6	0.8 Units on a scale Standard Deviation 2.1
Mean Change From Baseline in Patient-assessed Renal Pain Scale- Extension. Extension Month 12 (N= 17, 18)	-0.4 Units on a scale Standard Deviation 1.3	-0.6 Units on a scale Standard Deviation 2.2

SECONDARY outcome

Timeframe: Baseline to Month 36

Population: The ITT dataset was defined as a dataset that included data from all participants who enrolled to the study with observations at Baseline and Post Baseline. OC dataset were used.

The participant had a measurement of their abdominal girth recorded. The measurement will be taken with a tape measure extending around the abdomen at the level of the iliac crests laterally and the umbilicus anteriorly. The examiner should also palpate for each kidney and liver edge, noting presence or enlargement. (By definition if the kidneys are palpable they are enlarged, the liver edge may be palpable but not enlarged).

Outcome measures

Outcome measures
Measure	Tolvaptan 45+15 mg n=22 Participants Participants had received tolvaptan tablets of 45+15 mg orally twice daily during the fixed-dose period from Month 2 to Month 36 followed by a planned extension period for an additional 12 Months.	Tolvaptan 60+30 mg n=24 Participants Participants had received tolvaptan tablets of 60+30 mg orally twice daily during the fixed-dose period from Month 2 to Month 36 followed by a planned extension period for an additional 12 Months.
Mean Change From Baseline in Abdominal Girth Measurement. Month 2 (N= 22, 24)	0.6 cm Standard Deviation 5.0	-2.3 cm Standard Deviation 6.1
Mean Change From Baseline in Abdominal Girth Measurement. Month 6 (N= 18, 23)	1.4 cm Standard Deviation 6.5	0.5 cm Standard Deviation 4.6
Mean Change From Baseline in Abdominal Girth Measurement. Month 12 (N= 18, 23)	1.3 cm Standard Deviation 4.7	-2.8 cm Standard Deviation 11.5
Mean Change From Baseline in Abdominal Girth Measurement. Month 24 (N= 17, 21)	2.0 cm Standard Deviation 7.4	-0.6 cm Standard Deviation 6.7
Mean Change From Baseline in Abdominal Girth Measurement. Month 36 (N= 18, 21)	3.1 cm Standard Deviation 7.2	0.3 cm Standard Deviation 7.3

SECONDARY outcome

Timeframe: Baseline to Extension Day 1, Extension Month 12

Population: The ITT dataset was defined as a dataset that included data from all participants who enrolled to the study with observations at Baseline and Post Baseline. OC dataset were used.

Outcome measures

Outcome measures
Measure	Tolvaptan 45+15 mg n=17 Participants Participants had received tolvaptan tablets of 45+15 mg orally twice daily during the fixed-dose period from Month 2 to Month 36 followed by a planned extension period for an additional 12 Months.	Tolvaptan 60+30 mg n=18 Participants Participants had received tolvaptan tablets of 60+30 mg orally twice daily during the fixed-dose period from Month 2 to Month 36 followed by a planned extension period for an additional 12 Months.
Mean Change From Baseline in Abdominal Girth Measurement- Extension. Month 36 (N= 17, 18)	2.5 cm Standard Deviation 6.9	0.1 cm Standard Deviation 7.7
Mean Change From Baseline in Abdominal Girth Measurement- Extension. Extension Day 1 (N= 17, 18)	4.2 cm Standard Deviation 7.2	2.9 cm Standard Deviation 7.9
Mean Change From Baseline in Abdominal Girth Measurement- Extension. Extension Month 12 (N= 17, 18)	4.6 cm Standard Deviation 9.5	1.6 cm Standard Deviation 6.1
Mean Change From Baseline in Abdominal Girth Measurement- Extension. Month 2 (N= 17, 18)	-0.8 cm Standard Deviation 3.9	-2.8 cm Standard Deviation 7.0
Mean Change From Baseline in Abdominal Girth Measurement- Extension. Month 6 (N= 16, 18)	0.3 cm Standard Deviation 5.6	0.3 cm Standard Deviation 5.1
Mean Change From Baseline in Abdominal Girth Measurement- Extension. Month 12 (N= 17, 18)	1.1 cm Standard Deviation 4.8	-3.5 cm Standard Deviation 12.9
Mean Change From Baseline in Abdominal Girth Measurement- Extension. Month 24 (N= 17, 21)	2.0 cm Standard Deviation 7.4	-1.1 cm Standard Deviation 7.1

Adverse Events

Tolvaptan 45+15 mg

Serious events: 3 serious events

Other events: 20 other events

Deaths: 0 deaths

Tolvaptan 60+30 mg

Serious events: 8 serious events

Other events: 23 other events

Deaths: 0 deaths

Serious adverse events

Other adverse events

Additional Information

Global Medical Affairs

Otsuka Pharmaceutical Development and Commercialization, Inc.

Phone: 800 562-3974

Results disclosure agreements

Principal investigator is a sponsor employee
Publication restrictions are in place

Measure	Tolvaptan 45+15 mg n=22 participants at risk Participants had received tolvaptan tablets of 45+15 mg orally twice daily during the fixed-dose period from Month 2 to Month 36 followed by a planned extension period for an additional 12 Months.	Tolvaptan 60+30 mg n=24 participants at risk Participants had received tolvaptan tablets of 60+30 mg orally twice daily during the fixed-dose period from Month 2 to Month 36 followed by a planned extension period for an additional 12 Months.
Cardiac disorders Atrial fibrillation	0.00% 0/22 • AEs were recorded from screening (ICF was signed) until 7-days of safety follow-up. Participants with AEs in multiple system organ classes were counted only once towards the total. A SAE was any untoward medical occurrence resulted in death or was life-threatening or required inpatient hospitalization or prolonged hospitalization. An AE was an exacerbation of an existing problem or any new problem, experienced by a participant when enrolled in a trial, whether or not it was considered drug related by the study physician.	8.3% 2/24 • AEs were recorded from screening (ICF was signed) until 7-days of safety follow-up. Participants with AEs in multiple system organ classes were counted only once towards the total. A SAE was any untoward medical occurrence resulted in death or was life-threatening or required inpatient hospitalization or prolonged hospitalization. An AE was an exacerbation of an existing problem or any new problem, experienced by a participant when enrolled in a trial, whether or not it was considered drug related by the study physician.
Cardiac disorders Tachycardia	0.00% 0/22 • AEs were recorded from screening (ICF was signed) until 7-days of safety follow-up. Participants with AEs in multiple system organ classes were counted only once towards the total. A SAE was any untoward medical occurrence resulted in death or was life-threatening or required inpatient hospitalization or prolonged hospitalization. An AE was an exacerbation of an existing problem or any new problem, experienced by a participant when enrolled in a trial, whether or not it was considered drug related by the study physician.	4.2% 1/24 • AEs were recorded from screening (ICF was signed) until 7-days of safety follow-up. Participants with AEs in multiple system organ classes were counted only once towards the total. A SAE was any untoward medical occurrence resulted in death or was life-threatening or required inpatient hospitalization or prolonged hospitalization. An AE was an exacerbation of an existing problem or any new problem, experienced by a participant when enrolled in a trial, whether or not it was considered drug related by the study physician.
Congenital, familial and genetic disorders Polycystic liver disease	0.00% 0/22 • AEs were recorded from screening (ICF was signed) until 7-days of safety follow-up. Participants with AEs in multiple system organ classes were counted only once towards the total. A SAE was any untoward medical occurrence resulted in death or was life-threatening or required inpatient hospitalization or prolonged hospitalization. An AE was an exacerbation of an existing problem or any new problem, experienced by a participant when enrolled in a trial, whether or not it was considered drug related by the study physician.	4.2% 1/24 • AEs were recorded from screening (ICF was signed) until 7-days of safety follow-up. Participants with AEs in multiple system organ classes were counted only once towards the total. A SAE was any untoward medical occurrence resulted in death or was life-threatening or required inpatient hospitalization or prolonged hospitalization. An AE was an exacerbation of an existing problem or any new problem, experienced by a participant when enrolled in a trial, whether or not it was considered drug related by the study physician.
Gastrointestinal disorders Abdominal pain	0.00% 0/22 • AEs were recorded from screening (ICF was signed) until 7-days of safety follow-up. Participants with AEs in multiple system organ classes were counted only once towards the total. A SAE was any untoward medical occurrence resulted in death or was life-threatening or required inpatient hospitalization or prolonged hospitalization. An AE was an exacerbation of an existing problem or any new problem, experienced by a participant when enrolled in a trial, whether or not it was considered drug related by the study physician.	4.2% 1/24 • AEs were recorded from screening (ICF was signed) until 7-days of safety follow-up. Participants with AEs in multiple system organ classes were counted only once towards the total. A SAE was any untoward medical occurrence resulted in death or was life-threatening or required inpatient hospitalization or prolonged hospitalization. An AE was an exacerbation of an existing problem or any new problem, experienced by a participant when enrolled in a trial, whether or not it was considered drug related by the study physician.
Gastrointestinal disorders Epiploic appendagitis	0.00% 0/22 • AEs were recorded from screening (ICF was signed) until 7-days of safety follow-up. Participants with AEs in multiple system organ classes were counted only once towards the total. A SAE was any untoward medical occurrence resulted in death or was life-threatening or required inpatient hospitalization or prolonged hospitalization. An AE was an exacerbation of an existing problem or any new problem, experienced by a participant when enrolled in a trial, whether or not it was considered drug related by the study physician.	4.2% 1/24 • AEs were recorded from screening (ICF was signed) until 7-days of safety follow-up. Participants with AEs in multiple system organ classes were counted only once towards the total. A SAE was any untoward medical occurrence resulted in death or was life-threatening or required inpatient hospitalization or prolonged hospitalization. An AE was an exacerbation of an existing problem or any new problem, experienced by a participant when enrolled in a trial, whether or not it was considered drug related by the study physician.
General disorders Chest pain	0.00% 0/22 • AEs were recorded from screening (ICF was signed) until 7-days of safety follow-up. Participants with AEs in multiple system organ classes were counted only once towards the total. A SAE was any untoward medical occurrence resulted in death or was life-threatening or required inpatient hospitalization or prolonged hospitalization. An AE was an exacerbation of an existing problem or any new problem, experienced by a participant when enrolled in a trial, whether or not it was considered drug related by the study physician.	4.2% 1/24 • AEs were recorded from screening (ICF was signed) until 7-days of safety follow-up. Participants with AEs in multiple system organ classes were counted only once towards the total. A SAE was any untoward medical occurrence resulted in death or was life-threatening or required inpatient hospitalization or prolonged hospitalization. An AE was an exacerbation of an existing problem or any new problem, experienced by a participant when enrolled in a trial, whether or not it was considered drug related by the study physician.
Hepatobiliary disorders Cholelithiasis	4.5% 1/22 • AEs were recorded from screening (ICF was signed) until 7-days of safety follow-up. Participants with AEs in multiple system organ classes were counted only once towards the total. A SAE was any untoward medical occurrence resulted in death or was life-threatening or required inpatient hospitalization or prolonged hospitalization. An AE was an exacerbation of an existing problem or any new problem, experienced by a participant when enrolled in a trial, whether or not it was considered drug related by the study physician.	0.00% 0/24 • AEs were recorded from screening (ICF was signed) until 7-days of safety follow-up. Participants with AEs in multiple system organ classes were counted only once towards the total. A SAE was any untoward medical occurrence resulted in death or was life-threatening or required inpatient hospitalization or prolonged hospitalization. An AE was an exacerbation of an existing problem or any new problem, experienced by a participant when enrolled in a trial, whether or not it was considered drug related by the study physician.
Infections and infestations Pyelonephritis	0.00% 0/22 • AEs were recorded from screening (ICF was signed) until 7-days of safety follow-up. Participants with AEs in multiple system organ classes were counted only once towards the total. A SAE was any untoward medical occurrence resulted in death or was life-threatening or required inpatient hospitalization or prolonged hospitalization. An AE was an exacerbation of an existing problem or any new problem, experienced by a participant when enrolled in a trial, whether or not it was considered drug related by the study physician.	4.2% 1/24 • AEs were recorded from screening (ICF was signed) until 7-days of safety follow-up. Participants with AEs in multiple system organ classes were counted only once towards the total. A SAE was any untoward medical occurrence resulted in death or was life-threatening or required inpatient hospitalization or prolonged hospitalization. An AE was an exacerbation of an existing problem or any new problem, experienced by a participant when enrolled in a trial, whether or not it was considered drug related by the study physician.
Neoplasms benign, malignant and unspecified (incl cysts and polyps) Malignant melanoma in situ	0.00% 0/22 • AEs were recorded from screening (ICF was signed) until 7-days of safety follow-up. Participants with AEs in multiple system organ classes were counted only once towards the total. A SAE was any untoward medical occurrence resulted in death or was life-threatening or required inpatient hospitalization or prolonged hospitalization. An AE was an exacerbation of an existing problem or any new problem, experienced by a participant when enrolled in a trial, whether or not it was considered drug related by the study physician.	4.2% 1/24 • AEs were recorded from screening (ICF was signed) until 7-days of safety follow-up. Participants with AEs in multiple system organ classes were counted only once towards the total. A SAE was any untoward medical occurrence resulted in death or was life-threatening or required inpatient hospitalization or prolonged hospitalization. An AE was an exacerbation of an existing problem or any new problem, experienced by a participant when enrolled in a trial, whether or not it was considered drug related by the study physician.
Neoplasms benign, malignant and unspecified (incl cysts and polyps) Pituitary tumor benign	4.5% 1/22 • AEs were recorded from screening (ICF was signed) until 7-days of safety follow-up. Participants with AEs in multiple system organ classes were counted only once towards the total. A SAE was any untoward medical occurrence resulted in death or was life-threatening or required inpatient hospitalization or prolonged hospitalization. An AE was an exacerbation of an existing problem or any new problem, experienced by a participant when enrolled in a trial, whether or not it was considered drug related by the study physician.	0.00% 0/24 • AEs were recorded from screening (ICF was signed) until 7-days of safety follow-up. Participants with AEs in multiple system organ classes were counted only once towards the total. A SAE was any untoward medical occurrence resulted in death or was life-threatening or required inpatient hospitalization or prolonged hospitalization. An AE was an exacerbation of an existing problem or any new problem, experienced by a participant when enrolled in a trial, whether or not it was considered drug related by the study physician.
Neoplasms benign, malignant and unspecified (incl cysts and polyps) Uterine leiomyoma	0.00% 0/22 • AEs were recorded from screening (ICF was signed) until 7-days of safety follow-up. Participants with AEs in multiple system organ classes were counted only once towards the total. A SAE was any untoward medical occurrence resulted in death or was life-threatening or required inpatient hospitalization or prolonged hospitalization. An AE was an exacerbation of an existing problem or any new problem, experienced by a participant when enrolled in a trial, whether or not it was considered drug related by the study physician.	4.2% 1/24 • AEs were recorded from screening (ICF was signed) until 7-days of safety follow-up. Participants with AEs in multiple system organ classes were counted only once towards the total. A SAE was any untoward medical occurrence resulted in death or was life-threatening or required inpatient hospitalization or prolonged hospitalization. An AE was an exacerbation of an existing problem or any new problem, experienced by a participant when enrolled in a trial, whether or not it was considered drug related by the study physician.
Nervous system disorders Transient ischaemic attack	0.00% 0/22 • AEs were recorded from screening (ICF was signed) until 7-days of safety follow-up. Participants with AEs in multiple system organ classes were counted only once towards the total. A SAE was any untoward medical occurrence resulted in death or was life-threatening or required inpatient hospitalization or prolonged hospitalization. An AE was an exacerbation of an existing problem or any new problem, experienced by a participant when enrolled in a trial, whether or not it was considered drug related by the study physician.	4.2% 1/24 • AEs were recorded from screening (ICF was signed) until 7-days of safety follow-up. Participants with AEs in multiple system organ classes were counted only once towards the total. A SAE was any untoward medical occurrence resulted in death or was life-threatening or required inpatient hospitalization or prolonged hospitalization. An AE was an exacerbation of an existing problem or any new problem, experienced by a participant when enrolled in a trial, whether or not it was considered drug related by the study physician.
Renal and urinary disorders Renal pain	4.5% 1/22 • AEs were recorded from screening (ICF was signed) until 7-days of safety follow-up. Participants with AEs in multiple system organ classes were counted only once towards the total. A SAE was any untoward medical occurrence resulted in death or was life-threatening or required inpatient hospitalization or prolonged hospitalization. An AE was an exacerbation of an existing problem or any new problem, experienced by a participant when enrolled in a trial, whether or not it was considered drug related by the study physician.	4.2% 1/24 • AEs were recorded from screening (ICF was signed) until 7-days of safety follow-up. Participants with AEs in multiple system organ classes were counted only once towards the total. A SAE was any untoward medical occurrence resulted in death or was life-threatening or required inpatient hospitalization or prolonged hospitalization. An AE was an exacerbation of an existing problem or any new problem, experienced by a participant when enrolled in a trial, whether or not it was considered drug related by the study physician.
Respiratory, thoracic and mediastinal disorders Dyspnoea	0.00% 0/22 • AEs were recorded from screening (ICF was signed) until 7-days of safety follow-up. Participants with AEs in multiple system organ classes were counted only once towards the total. A SAE was any untoward medical occurrence resulted in death or was life-threatening or required inpatient hospitalization or prolonged hospitalization. An AE was an exacerbation of an existing problem or any new problem, experienced by a participant when enrolled in a trial, whether or not it was considered drug related by the study physician.	4.2% 1/24 • AEs were recorded from screening (ICF was signed) until 7-days of safety follow-up. Participants with AEs in multiple system organ classes were counted only once towards the total. A SAE was any untoward medical occurrence resulted in death or was life-threatening or required inpatient hospitalization or prolonged hospitalization. An AE was an exacerbation of an existing problem or any new problem, experienced by a participant when enrolled in a trial, whether or not it was considered drug related by the study physician.
Skin and subcutaneous tissue disorders Rash	0.00% 0/22 • AEs were recorded from screening (ICF was signed) until 7-days of safety follow-up. Participants with AEs in multiple system organ classes were counted only once towards the total. A SAE was any untoward medical occurrence resulted in death or was life-threatening or required inpatient hospitalization or prolonged hospitalization. An AE was an exacerbation of an existing problem or any new problem, experienced by a participant when enrolled in a trial, whether or not it was considered drug related by the study physician.	4.2% 1/24 • AEs were recorded from screening (ICF was signed) until 7-days of safety follow-up. Participants with AEs in multiple system organ classes were counted only once towards the total. A SAE was any untoward medical occurrence resulted in death or was life-threatening or required inpatient hospitalization or prolonged hospitalization. An AE was an exacerbation of an existing problem or any new problem, experienced by a participant when enrolled in a trial, whether or not it was considered drug related by the study physician.