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Clinical Trial Results:
A Phase 3b, Two-part, Multicenter, One Year Randomized, Double-blind, Placebo-controlled Trial of the Safety, Pharmacokinetics, Tolerability, and Efficacy of Tolvaptan followed by a Two Year Open-label Extension in Children and Adolescent Subjects with Autosomal Dominant Polycystic Kidney Disease (ADPKD)

Summary
EudraCT number	2016-000187-42
Trial protocol	GB DE IT BE
Global end of trial date	17 Nov 2021

Results information
Results version number	v1(current)
This version publication date	29 May 2022
First version publication date	29 May 2022
Other versions

Trial Information
Subject Disposition
Baseline Characteristics
End Points
Adverse Events
More Information

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Trial information

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Sponsor protocol code

156-12-298

ISRCTN number

US NCT number

NCT02964273

WHO universal trial number (UTN)

Sponsor organisation name

Otsuka Pharmaceutical Development & Commercialization, Inc.

Sponsor organisation address

2440 Research Boulevard, Rockville, United States, 20850

Public contact

Global Clinical Development, Otsuka Pharmaceutical Development & Commercialization, Inc., clinicaltransparency@otsuka-us.com

Scientific contact

Global Clinical Development, Otsuka Pharmaceutical Development & Commercialization, Inc., clinicaltransparency@otsuka-us.com

Is trial part of an agreed paediatric investigation plan (PIP)

Yes

EMA paediatric investigation plan number(s)

EMEA-001231-PIP02-13

Does article 45 of REGULATION (EC) No 1901/2006 apply to this trial?

Does article 46 of REGULATION (EC) No 1901/2006 apply to this trial?

Yes

Analysis stage

Final

Date of interim/final analysis

17 Nov 2021

Is this the analysis of the primary completion data?

Global end of trial reached?

Yes

Global end of trial date

17 Nov 2021

Was the trial ended prematurely?

Main objective of the trial

To assess the long term safety of treatment with tolvaptan in a pediatric and adolescent ADPKD population.

Protection of trial subjects

All study subjects were required to read and sign an Assent Form and subject legal guardians read and signed Informed Consent Form. Written informed consent was freely obtained from all subject’s guardian(s) or legally acceptable representative(s), as applicable for local laws.

Background therapy

Evidence for comparator

Actual start date of recruitment

23 Sep 2016

Long term follow-up planned

Independent data monitoring committee (IDMC) involvement?

Yes

Number of subjects enrolled per country

Country: Number of subjects enrolled

United Kingdom: 32

Country: Number of subjects enrolled

Belgium: 20

Country: Number of subjects enrolled

Germany: 10

Country: Number of subjects enrolled

Italy: 29

Worldwide total number of subjects

EEA total number of subjects

Number of subjects enrolled per age group

In utero

Preterm newborn - gestational age < 37 wk

Newborns (0-27 days)

Infants and toddlers (28 days-23 months)

Children (2-11 years)

Adolescents (12-17 years)

Adults (18-64 years)

From 65 to 84 years

85 years and over

Subject disposition

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Recruitment details

Subjects took part in the study at 18 sites in Belgium, Germany, Italy, and the United Kingdom from 23 September 2016 to 17 November 2021.

Screening details

A total of 91 subjects with autosomal dominant polycystic kidney disease (ADPKD) were randomised into 2 groups in a 1:1 ratio to receive tolvaptan or a matching placebo.

Period 1 title

Phase A: Double-blind Period (12 Months)

Is this the baseline period?

Yes

Allocation method

Randomised - controlled

Blinding used

Double blind

Roles blinded

Subject, Investigator, Monitor, Data analyst, Carer, Assessor

Are arms mutually exclusive

Yes

Phase A: Tolvaptan

Arm description

Subjects received tolvaptan tablets, orally as a split dose (with the first dose taken upon awakening and the second dose taken approximately 8 hours later), and starting doses based on their weight as per the following specifications: ≥20 to 45 kg: 15/7.5 mg; ≥45 to ≤75 kg: 30/15 mg; >75 kg: 45/15 mg, for 1 week. The starting dose was up-titrated (≥20 to <45 kg: 30/15 mg; ≥45 to ≤75 kg: 45/15 mg; >75 kg: 60/30 mg) after 1 week based upon tolerability and thereafter subjects continued the same dose for 12 months. Doses may be titrated down dependent upon subject tolerability.

Arm type

Experimental

Investigational medicinal product name

Tolvaptan

Investigational medicinal product code

OPC-41061

Other name

JINARC®

Pharmaceutical forms

Tablet

Routes of administration

Oral use

Dosage and administration details

Tolvaptan spray-dried, immediate release tablets

Phase A: Placebo

Arm description

Subjects received matching-placebo tablets, orally as a split-dose (with the first dose taken upon awakening and second dose taken approximately 8 hours later), and starting dose based on their weight as per the following specifications: ≥20 to <45 kg: 15/7.5 mg; ≥45 to ≤75 kg: 30/15 mg; >75 kg: 45/15 mg, for 1 week. The starting dose was up-titrated (≥20 to <45 kg: 30/15 mg; ≥45 to ≤75 kg: 45/15 mg; >75 kg: 60/30 mg) after 1 week based upon tolerability and thereafter subjects continued the same dose for 12 months. Doses may be titrated down dependent upon subject tolerability.

Arm type

Placebo

Investigational medicinal product name

Tolvaptan Matching-placebo

Investigational medicinal product code

Other name

Pharmaceutical forms

Tablet

Routes of administration

Oral use

Dosage and administration details

Tolvaptan matching-placebo tablets

Number of subjects in period 1	Phase A: Tolvaptan	Phase A: Placebo
Started	48	43
Dense Pharmacokinetic/dynamic(PK/PD) Set	12 ^[1]	8 ^[2]
Completed	44	40
Not completed	4	3
Consent withdrawn by subject	3	1
Physician decision	-	2
Adverse event	1	-

Notes
[1] - The number of subjects at this milestone seems inconsistent with the number of subjects in the arm. It is expected that the number of subjects will be greater than, or equal to the number that completed, minus those who left.
Justification: The Dense PK/PD Population included a subset of subjects half on tolvaptan and half on placebo, in the 12 to 17 year old age group who had dense PK sampling after at least 1 month on IMP.
[2] - The number of subjects at this milestone seems inconsistent with the number of subjects in the arm. It is expected that the number of subjects will be greater than, or equal to the number that completed, minus those who left.
Justification: The Dense PK/PD Population included a subset of subjects half on tolvaptan and half on placebo, in the 12 to 17 year old age group who had dense PK sampling after at least 1 month on IMP.

Period 2 title

Phase B: Open-label Period (24 Months)

Is this the baseline period?

Allocation method

Not applicable

Blinding used

Not blinded

Are arms mutually exclusive

Yes

Phase B: Prior Tolvaptan

Arm description

Qualified subjects (defined as those who were willing to continue in the trial and who did not have any adverse events [AEs] that would require investigational medicinal product [IMP] discontinuation) who received tolvaptan and completed Phase A were enrolled in Phase B and received tolvaptan tablets, orally as a split dose (with the first dose taken upon awakening and the second dose taken approximately 8 hours later), and starting dose based on their body weight as per following specifications: ≥20 to <45 kg: 15/7.5 mg; ≥45 to ≤75 kg: 30/15 mg; >75 kg: 45/15 mg, for 1 week. The starting dose was up-titrated (≥20 to <45 kg: 30/15 mg; ≥45 to ≤75 kg: 45/15 mg; >75 kg: 60/30 mg) after 1 week based upon tolerability and thereafter subjects continued the same dose for 24 months. Doses may be titrated down dependent upon subject tolerability.

Arm type

Experimental

Investigational medicinal product name

Tolvaptan

Investigational medicinal product code

OPC-41061

Other name

JINARC®

Pharmaceutical forms

Tablet

Routes of administration

Oral use

Dosage and administration details

Tolvaptan spray-dried, immediate release tablets

Phase B: Prior Placebo

Arm description

Qualified subjects (defined as those who were willing to continue in the trial and who did not have any AEs that would require IMP discontinuation) who received matching-placebo and completed Phase A, were enrolled in Phase B and received tolvaptan tablets, orally as a split dose (with the first dose taken upon awakening and the second dose taken approximately 8 hours later), based on their current body weight as per following specifications: ≥20 to <45 kg: 15/7.5 mg; ≥45 to ≤75 kg: 30/15 mg; >75 kg: 45/15 mg, for 1 week. The starting dose was up-titrated (≥20 to <45 kg: 30/15 mg; ≥45 to ≤75 kg: 45/15 mg; >75 kg: 60/30 mg) after 1 week based upon tolerability and thereafter subjects continued the same dose for 24 months. Doses may be titrated down dependent upon subject tolerability.

Arm type

Experimental

Investigational medicinal product name

Tolvaptan

Investigational medicinal product code

OPC-41061

Other name

JINARC®

Pharmaceutical forms

Tablet

Routes of administration

Oral use

Dosage and administration details

Tolvaptan spray-dried, immediate release tablets

Number of subjects in period 2 ^[3]	Phase B: Prior Tolvaptan	Phase B: Prior Placebo
Started	42	39
Completed	36	33
Not completed	6	6
Consent withdrawn by subject	4	3
Reason Not Specified	2	1
Adverse event	-	2

Notes
[3] - The number of subjects starting the period is not consistent with the number completing the preceding period. It is expected the number of subjects starting the subsequent period will be the same as the number completing the preceding period.
Justification: 2 Phase A: Tolvaptan completers did not enter Phase B. 1 Phase A: Placebo completer did not enter Phase B.

Baseline characteristics

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Reporting group title

Phase A: Tolvaptan

Reporting group description

Reporting group title

Phase A: Placebo

Reporting group description

Reporting group values	Phase A: Tolvaptan	Phase A: Placebo	Total
Number of subjects	48	43	91
Age categorical
Units: Subjects
In utero			0
Preterm newborn infants (gestational age < 37 wks)			0
Newborns (0-27 days)			0
Infants and toddlers (28 days-23 months)			0
Children (2-11 years)			0
Adolescents (12-17 years)			0
Adults (18-64 years)			0
From 65-84 years			0
85 years and over			0
Age continuous
Units: years
arithmetic mean (standard deviation)	12.9 ( 3.2 )	12.8 ( 2.8 )	-
Gender categorical
Units: Subjects
Female	21	23	44
Male	27	20	47
Race
Units: Subjects
White	46	42	88
Black or African American	0	1	1
Asian	2	0	2
EthnicityHispanic or Latino
Units: Subjects
Hispanic or Latino	1	1	2
Not Hispanic or Latino	47	42	89

End points

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Reporting group title

Phase A: Tolvaptan

Reporting group description

Reporting group title

Phase A: Placebo

Reporting group description

Reporting group title

Phase B: Prior Tolvaptan

Reporting group description

Reporting group title

Phase B: Prior Placebo

Reporting group description

Primary: Phase A: Change From Baseline in Spot Urine Osmolality (Pre-morning Dose)

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End point title

Phase A: Change From Baseline in Spot Urine Osmolality (Pre-morning Dose) ^[1]

End point description

Urine osmolality is a measure of urine concentration, measured by osmometer, which evaluates the freezing point depression of a solution and supplies results as milliosmoles per kilogram of water. Spot urine osmolality was determined for urine samples collected immediately prior to morning dosing for Day 1 (Baseline), and Week 1 for all subjects. Sample was taken after the first morning’s void and was provided as a mid-stream, clean catch sample. All subjects were fasting. The Full Analysis Set (FAS) included all subjects who were randomised to a treatment group, received at least 1 dose of the investigational medicinal product (IMP), and had both a Phase A baseline and at least 1 postbaseline efficacy evaluation. n = Number analysed is the number of subjects with data available for analysis at the given time point.

End point type

Primary

End point timeframe

Baseline, and Week 1 of Phase A

Notes
[1] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
Justification: Only descriptive statistics was planned to be reported for this endpoint.

End point values	Phase A: Tolvaptan	Phase A: Placebo
Number of subjects analysed	48	43
Units: milliosmoles per kilogram (mOsm/kg)
arithmetic mean (standard deviation)
Baseline (n=48, 43)	635 ( 252 )	646 ( 250 )
Change From Baseline at Week 1, Phase A (n =48,42)	-386 ( 284 )	-93 ( 332 )

No statistical analyses for this end point

Primary: Phase A: Change From Baseline in Specific Gravity (Pre-morning Dose)

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End point title

Phase A: Change From Baseline in Specific Gravity (Pre-morning Dose) ^[2]

End point description

Urine specific gravity is a measure of the concentration of solutes in the urine and provides information on the kidney’s ability to concentrate urine. Spot urine sample for determination of specific gravity was collected immediately prior to morning dosing for Day 1 (Baseline), and Week 1 for all subjects. Sample was taken after the first morning’s void and was provided as a mid-stream, clean catch sample. All subjects were fasting. The FAS included all subjects who were randomised to a treatment group, received at least 1 dose of the IMP, and had both a Phase A baseline and at least 1 postbaseline efficacy evaluation. n=Number analysed is the number of subjects with data available for analysis at the given time point.

End point type

Primary

End point timeframe

Baseline, and Week 1 of Phase A

Notes
[2] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
Justification: Only descriptive statistics was planned to be reported for this endpoint.

End point values	Phase A: Tolvaptan	Phase A: Placebo
Number of subjects analysed	48	43
Units: ratio
arithmetic mean (standard deviation)
Baseline (n=48, 43)	1.017 ( 0.006 )	1.017 ( 0.006 )
Change From Baseline at Week 1, Phase A (n =48,41)	-0.009 ( 0.007 )	-0.002 ( 0.008 )

No statistical analyses for this end point

Secondary: Phase A: Percent Change From Phase A Baseline in Height-Adjusted Total Kidney Volume (htTKV) as Measured by Magnetic Resonance Imaging (MRI)

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End point title

Phase A: Percent Change From Phase A Baseline in Height-Adjusted Total Kidney Volume (htTKV) as Measured by Magnetic Resonance Imaging (MRI)

End point description

htTKV is used in subjects with autosomal dominant polycystic kidney disease to predict the onset of renal insufficiency. The FAS included all subjects who were randomised to a treatment group, received at least 1 dose of the IMP, and had both a Phase A baseline and at least 1 postbaseline efficacy evaluation. Overall number analysed are the number of subjects with data available for analyses.

End point type

Secondary

End point timeframe

Baseline, and Month 12 of Phase A

End point values	Phase A: Tolvaptan	Phase A: Placebo
Number of subjects analysed	30	27
Units: percent change
arithmetic mean (standard deviation)	2.28 ( 8.75 )	6.11 ( 7.48 )

No statistical analyses for this end point

Secondary: Phase A and B: Mean 24-hour Fluid Balance Prior to Week 1

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End point title

Phase A and B: Mean 24-hour Fluid Balance Prior to Week 1

End point description

Subjects were instructed to record all fluid taken and all urine output for the 24-hour period. The FAS for Phase A included all subjects who were randomised to a treatment group, received at least 1 dose of the IMP, and had both a Phase A Baseline and at least 1 postbaseline efficacy evaluation. The FAS for Phase B included all subjects who enrolled to Phase B, received at least 1 dose of the IMP, and had both a baseline and at least 1 postbaseline efficacy evaluation in Phase B. Overall number analysed are the number of subjects with data available for analyses.

End point type

Secondary

End point timeframe

Prior to Week 1 in Phase A and B

End point values	Phase A: Tolvaptan	Phase A: Placebo	Phase B: Prior Tolvaptan	Phase B: Prior Placebo
Number of subjects analysed	43	41	37	37
Units: milliliter (mL)
arithmetic mean (standard deviation)	31 ( 1978 )	241 ( 867 )	138 ( 1382 )	207 ( 1355 )

No statistical analyses for this end point

Secondary: Phase A: Change From Baseline in Renal Function (Estimated Glomerular Filtration Rate [eGFR] by Schwartz Formula) at Each Clinic Visit in Phase A

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End point title

Phase A: Change From Baseline in Renal Function (Estimated Glomerular Filtration Rate [eGFR] by Schwartz Formula) at Each Clinic Visit in Phase A

End point description

Renal function was assessed by estimated eGFR calculated by the Schwartz formula (eGFR = 0.413 × height [cm] /serum creatinine mg/dL), expressed as mean change in eGFR at the specified time points. The units for the data reported are milliliter per minute per 1.73 meter square (mL/min/1.73 m^2). The FAS included all subjects who were randomised to a treatment group, received at least 1 dose of the IMP, and had both a Phase A baseline and at least 1 postbaseline efficacy evaluation. n=Number analysed is the number of subjects with data available for analysis at the given time point.

End point type

Secondary

End point timeframe

Phase A Baseline, Week 1, Months 1, 6, and 12

End point values	Phase A: Tolvaptan	Phase A: Placebo
Number of subjects analysed	48	43
Units: mL/min/1.73 m^2
arithmetic mean (standard deviation)
Baseline (n=48,43)	98.8 ( 19.4 )	99.9 ( 15.0 )
Change From Baseline at Week 1, Phase A (n=44,42)	-4.9 ( 10.3 )	1.5 ( 9.2 )
Change From Baseline at Month 1, Phase A (n=45,43)	-2.3 ( 12.2 )	-0.3 ( 9.2 )
Change From Baseline at Month 6, Phase A (n=44,41)	-0.2 ( 13.6 )	-0.9 ( 9.2 )
Change From Baseline at Month 12, Phase A(n=43,40)	-1.4 ( 14.9 )	-0.9 ( 8.5 )

No statistical analyses for this end point

Secondary: Phase B: Change From Phase B Baseline in Renal Function (eGFR by Schwartz Formula) at Each Clinic Visit in Phase B

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End point title

Phase B: Change From Phase B Baseline in Renal Function (eGFR by Schwartz Formula) at Each Clinic Visit in Phase B

End point description

Renal function was assessed by estimated eGFR calculated by the Schwartz formula (eGFR = 0.413 × height [cm] /serum creatinine mg/dL), expressed as mean change in eGFR at the specified time points. The FAS for Phase B included all subjects who enrolled to Phase B, received at least 1 dose of the IMP, and had both a baseline and at least 1 postbaseline efficacy evaluation in Phase B. n=Number analysed is the number of subjects with data available for analysis at the given time point.

End point type

Secondary

End point timeframe

Phase B Baseline, Week 1, Months 1, 6, 12, 18, and 24

End point values	Phase B: Prior Tolvaptan	Phase B: Prior Placebo
Number of subjects analysed	42	39
Units: mL/min/1.73 m^2
arithmetic mean (standard deviation)
Phase B Baseline (n=42,39)	97.0 ( 17.1 )	98.5 ( 14.1 )
Change From Baseline (CFB) at Week 1 (n=40,37)	-1.7 ( 10.4 )	-6.7 ( 8.0 )
CFB at Month 1, Phase B (n=41,38)	-0.9 ( 10.2 )	-4.8 ( 9.0 )
CFB at Month 6, Phase B (n=38,33)	-4.2 ( 9.6 )	-6.4 ( 7.9 )
CFB at Month 12, Phase B (n=36,36)	-5.6 ( 11.1 )	-7.2 ( 9.3 )
CFB at Month 18, Phase B (n=29,27)	-3.5 ( 9.8 )	-9.0 ( 10.9 )
CFB at Month 24, Phase B (n=34,31)	-5.2 ( 9.4 )	-10.3 ( 11.0 )

No statistical analyses for this end point

Secondary: Phase B: Percent Change From Phase B Baseline in htTKV as Measured by MRI at Month 12 and Month 24

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End point title

Phase B: Percent Change From Phase B Baseline in htTKV as Measured by MRI at Month 12 and Month 24

End point description

htTKV is used in subjects with autosomal dominant polycystic kidney disease to predict the onset of renal insufficiency. The FAS for Phase B included all subjects who enrolled to Phase B, received at least 1 dose of the IMP, and had both a baseline and at least 1 postbaseline efficacy evaluation in Phase B. n = Number analysed is the number of subjects with data available for analysis at the given time point.

End point type

Secondary

End point timeframe

Phase B Baseline, Months 12, and 24

End point values	Phase B: Prior Tolvaptan	Phase B: Prior Placebo
Number of subjects analysed	26	23
Units: percent change
arithmetic mean (standard deviation)
Percent Change From Baseline at Month 12 (n=26,23)	7.68 ( 9.67 )	3.09 ( 8.97 )
Percent Change From Baseline at Month 24 (n=24,21)	13.55 ( 12.88 )	7.35 ( 9.57 )

No statistical analyses for this end point

Secondary: Phase A: 24-hour Urine Volume

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End point title

Phase A: 24-hour Urine Volume

End point description

Urine volume refers to the quantity of urine produced per unit of time. The Dense PK/PD Population included a subset of subjects half on tolvaptan and half on placebo, in the 12 to 17 year old age group who had dense PK sampling after at least 1 month on IMP. Overall number analysed are the number of subjects with data available for analyses.

End point type

Secondary

End point timeframe

24 hours post dose after Month 1 on study medication in Phase A

End point values	Phase A: Tolvaptan	Phase A: Placebo
Number of subjects analysed	12	8
Units: milliliter
arithmetic mean (standard deviation)	7171 ( 2810 )	2529 ( 2164 )

No statistical analyses for this end point

Secondary: Phase A: 24-hour Fluid Intake

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End point title

Phase A: 24-hour Fluid Intake

End point description

Daily fluid intake (total water) is defined as the amount of water consumed from foods, plain drinking water, and other beverages. The Dense PK/PD Population included a subset of subjects half on tolvaptan and half on placebo, in the 12 to 17 year old age group who had dense PK sampling after at least 1 month on IMP. Overall number analysed are the number of subjects with data available for analyses.

End point type

Secondary

End point timeframe

24 hours post dose after Month 1 on study medication in Phase A

End point values	Phase A: Tolvaptan	Phase A: Placebo
Number of subjects analysed	11	5
Units: milliliter
arithmetic mean (standard deviation)	7486 ( 2350 )	3156 ( 1775 )

No statistical analyses for this end point

Secondary: Phase A: 24-hour Fluid Balance

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End point title

Phase A: 24-hour Fluid Balance

End point description

Fluid balance is a term used to describe the balance of the input and output of fluids in the body to allow metabolic processes to function correctly. The Dense PK/PD Population included a subset of subjects half on tolvaptan and half on placebo, in the 12 to 17 year old age group who had dense PK sampling after at least 1 month on IMP. Overall number analysed are the number of subjects with data available for analyses.

End point type

Secondary

End point timeframe

24 hours post dose after Month 1 on study medication in Phase A

End point values	Phase A: Tolvaptan	Phase A: Placebo
Number of subjects analysed	11	5
Units: milliliter
arithmetic mean (standard deviation)	53 ( 1894 )	230 ( 1254 )

No statistical analyses for this end point

Secondary: Phase A: 24-hour Sodium Clearance

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End point title

Phase A: 24-hour Sodium Clearance

End point description

Data was categorised and reported based on the total daily dose for the given time point of 0-24 hours. The Dense PK/PD Population included a subset of subjects half on tolvaptan and half on placebo, in the 12 to 17 year old age group who had dense PK sampling after at least 1 month on IMP. Overall number analysed are the number of subjects with data available for analyses. n = Number analysed is the number of subjects with data available for analysis at the given time point. 9999 = The mean or standard deviation was not estimable due to lower number of subjects with event.

End point type

Secondary

End point timeframe

24 hours post dose after Month 1 on study medication in Phase A

End point values	Phase A: Tolvaptan	Phase A: Placebo
Number of subjects analysed	10	7
Units: milliliter per minute (mL/min)
arithmetic mean (standard deviation)
Total Daily Dose: 37.5 mg (n=3,0)	0.8 ( 0.3 )	9999 ( 9999 )
Total Daily Dose: 45 mg (n=3,0)	0.7 ( 0.3 )	9999 ( 9999 )
Total Daily Dose: 60 mg (n=4,0)	0.9 ( 0.3 )	9999 ( 9999 )
Total Daily Dose: Placebo (n=0,7)	9999 ( 9999 )	0.7 ( 0.5 )

No statistical analyses for this end point

Secondary: Phase A: 24-hour Creatinine Clearance

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End point title

Phase A: 24-hour Creatinine Clearance

End point description

Creatinine is produced from the metabolism of protein, when muscles burn energy. Most creatinine is filtered out of the blood by the kidneys and excreted in urine. The creatinine clearance value is determined by measuring the concentration of endogenous creatinine (that which is produced by the body) in both plasma and urine. Data was categorised and reported based on the total daily dose for the given time point of 0-24 hours. The Dense PK/PD Population included a subset of subjects half on tolvaptan and half on placebo, in the 12 to 17 year old age group who had dense PK sampling after at least 1 month on IMP. Overall number analysed are the number of subjects with data available for analyses. n = Number analysed is the number of subjects with data available for analysis for the specified category. 9999 = The mean or standard deviation was not estimable due to lower number of subjects with event.

End point type

Secondary

End point timeframe

24 hours post dose after Month 1 on study medication in Phase A

End point values	Phase A: Tolvaptan	Phase A: Placebo
Number of subjects analysed	11	8
Units: mL/min
arithmetic mean (standard deviation)
Total Daily Dose: 22.5 mg (n=1,0)	124.6 ( 9999 )	9999 ( 9999 )
Total Daily Dose: 37.5 mg (n=3,0)	148.5 ( 23.4 )	9999 ( 9999 )
Total Daily Dose: 45 mg (n=3,0)	95.0 ( 10.1 )	9999 ( 9999 )
Total Daily Dose: 60 mg (n=4,0)	123.7 ( 23.2 )	9999 ( 9999 )
Total Daily Dose: Placebo (n=0,8)	9999 ( 9999 )	105.1 ( 51.7 )

No statistical analyses for this end point

Secondary: Phase A: 24-hour Free Water Clearance

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End point title

Phase A: 24-hour Free Water Clearance

End point description

Data was categorised and reported based on the total daily dose for the given time point of 0-24 hours. The Dense PK/PD Population included a subset of subjects half on tolvaptan and half on placebo, in the 12 to 17 year old age group who had dense PK sampling after at least 1 month on IMP. Overall number analysed are the number of subjects with data available for analyses. n = Number analysed is the number of subjects with data available for analysis for the specified category. 9999 = The mean or standard deviation was not estimable due to lower number of subjects with event.

End point type

Secondary

End point timeframe

24 hours post dose after Month 1 on study medication in Phase A

End point values	Phase A: Tolvaptan	Phase A: Placebo
Number of subjects analysed	11	8
Units: mL/min
arithmetic mean (standard deviation)
Total Daily Dose: 37.5 mg (n=3,0)	2.3 ( 0.9 )	9999 ( 9999 )
Total Daily Dose: 45 mg (n=3,0)	2.6 ( 0.9 )	9999 ( 9999 )
Total Daily Dose: 60 mg (n=5,0)	3.0 ( 1.2 )	9999 ( 9999 )
Total Daily Dose: Placebo (n=0,8)	9999 ( 9999 )	0.1 ( 1.2 )

No statistical analyses for this end point

Secondary: Phase A: Percentage of Each Tanner Stage by Gender and Age Compared to Normative Populations

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End point title

Phase A: Percentage of Each Tanner Stage by Gender and Age Compared to Normative Populations

End point description

Tanner stages is a scale that defines physical measurements of development based on external primary and secondary sex characteristics. It was used in this study to assess pubertal development with values ranging from Stage 1 (pre-pubertal characteristics) to Stage 5 (adult or mature characteristics). Only those categories with at least one subject with event are reported. The Phase A Safety Set included all subjects who were randomised and received at least 1 dose of IMP in Phase A.

End point type

Secondary

End point timeframe

At Baseline, Months 6 and 12 of Phase A

End point values	Phase A: Tolvaptan	Phase A: Placebo
Number of subjects analysed	48	43
Units: percentage of subjects
number (not applicable)
Female (>=4 to <12 Years): Baseline- Stage 1	6.3	11.6
Female (>=4 to <12 Years): Baseline- Stage 3	0.0	2.3
Female (>=4 to <12 Years): Month 6, Phase A-Stage1	6.3	9.3
Female (>=4 to <12 Years): Month 6, Phase A-Stage2	0.0	2.3
Female (>=4 to <12 Years): Month 6, Phase A-Stage4	0.0	2.3
Female (>=4 to <12 Years): Month 12,Phase A-Stage1	4.2	7.0
Female (>=4 to <12 Years): Month 12,Phase A-Stage2	0.0	2.3
Female (>=4 to <12 Years): Month 12,Phase A-Stage4	0.0	2.3
Male (>=4 to <12 Years): Baseline- Stage 1	16.7	4.7
Male (>=4 to <12 Years): Baseline- Stage 2	0.0	4.7
Male (>=4 to <12 Years): Baseline- Stage 3	2.1	0.0
Male (>=4 to <12 Years): Month 6, Phase A- Stage 1	16.7	7.0
Male (>=4 to <12 Years): Month 6, Phase A- Stage 2	2.1	0.0
Male (>=4 to <12 Years): Month 6, Phase A- Stage 3	2.1	4.7
Male (>=4 to <12 Years): Month 12, Phase A- Stage1	14.6	4.7
Male (>=4 to <12 Years): Month 12, Phase A- Stage2	4.2	2.3
Male (>=4 to <12 Years): Month 12, Phase A- Stage3	0.0	4.7
Male (>=4 to <12 Years): Month 12, Phase A- Stage4	2.1	0.0
Female (>=12 to <15 Years): Baseline- Stage 1	2.1	0.0
Female (>=12 to <15 Years): Baseline- Stage 2	0.0	4.7
Female (>=12 to <15 Years): Baseline- Stage 3	2.1	2.3
Female (>=12 to <15 Years): Baseline- Stage 4	4.2	0.0
Female (>=12 to <15 Years): Baseline- Stage 5	10.4	7.0
Female (>=12 to <15 Years): Month 6,Phase A-Stage2	0.0	2.3
Female (>=12 to <15 Years): Month 6,Phase A-Stage3	0.0	2.3
Female (>=12 to <15 Years): Month 6,Phase A-Stage4	2.1	0.0
Female (>=12 to <15 Years): Month 6,Phase A-Stage5	12.5	7.0
Female (>=12 to <15 Years):Month 12,Phase A-Stage2	0.0	2.3
Female (>=12 to <15 Years):Month 12,Phase A-Stage3	0.0	2.3
Female (>=12 to <15 Years):Month 12,Phase A-Stage4	0.0	4.7
Female (>=12 to <15 Years):Month 12,Phase A-Stage5	14.6	9.3
Male (>=12 to <15 Years): Baseline- Stage 2	6.3	4.7
Male (>=12 to <15 Years): Baseline- Stage 3	4.2	4.7
Male (>=12 to <15 Years): Baseline- Stage 4	2.1	4.7
Male (>=12 to <15 Years): Baseline- Stage 5	2.1	2.3
Male (>=12 to <15 Years): Month 6, Phase A-Stage2	4.2	2.3
Male (>=12 to <15 Years): Month 6, Phase A- Stage3	4.2	2.3
Male (>=12 to <15 Years): Month 6, Phase A- Stage4	4.2	4.7
Male (>=12 to <15 Years): Month 6, Phase A- Stage5	2.1	2.3
Male (>=12 to <15 Years): Month 12,Phase A- Stage2	0.0	2.3
Male (>=12 to <15 Years): Month 12,Phase A- Stage3	2.1	0.0
Male (>=12 to <15 Years): Month 12,Phase A- Stage4	8.3	7.0
Male (>=12 to <15 Years): Month 12,Phase A- Stage5	4.2	2.3
Male (>=12 to <15 Years): End of Treatment- Stage5	2.1	2.3
Female (>=15 to <18 Years): Baseline- Stage 4	2.1	0.0
Female (>=15 to <18 Years): Baseline- Stage 5	12.5	18.6
Female (>=15 to <18 Years): Month 6,Phase A-Stage4	2.1	0.0
Female (>=15 to <18 Years): Month 6,Phase A-Stage5	12.5	16.3
Female (>=15 to <18 Years):Month 12,Phase A-Stage4	2.1	0.0
Female (>=15 to <18 Years):Month 12,Phase A-Stage5	14.6	16.3
Female (>=15 to <18 Years):End of Treatment-Stage5	0.0	2.3
Male (>=15 to <18 Years): Baseline- Stage 4	2.1	4.7
Male (>=15 to <18 Years): Baseline- Stage 5	16.7	14.0
Male (>=15 to <18 Years): Month 6, Phase A- Stage4	2.1	2.3
Male (>=15 to <18 Years): Month 6, Phase A- Stage5	14.6	16.3
Male (>=15 to <18 Years): Month 12, Phase A-Stage4	2.1	0.0
Male (>=15 to <18 Years): Month 12, Phase A-Stage5	14.6	18.6
Male (>=15 to <18 Years): End of Treatment- Stage5	2.1	0.0

No statistical analyses for this end point

Secondary: Phase B: Percentage of Each Tanner Stage by Gender and Age Compared to Normative Populations

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End point title

Phase B: Percentage of Each Tanner Stage by Gender and Age Compared to Normative Populations

End point description

Tanner stages is a scale that defines physical measurements of development based on external primary and secondary sex characteristics. It was used in this study to assess pubertal development with values ranging from Stage 1 (pre-pubertal characteristics) to Stage 5 (adult or mature characteristics). Only those categories with at least one subject with event are reported. The Phase B Safety Set included all subjects who were enrolled in Phase B and received at least 1 dose of IMP in Phase B. End of Treatment = EOT.

End point type

Secondary

End point timeframe

At Baseline, Months 6, 12, 18, and 24 of Phase B

End point values	Phase B: Prior Tolvaptan	Phase B: Prior Placebo
Number of subjects analysed	42	39
Units: percentage of subjects
number (not applicable)
Female (>=4 to <12 Years): Phase B Baseline-Stage1	7.1	10.3
Female (>=4 to <12 Years): Phase B Baseline-Stage2	0.0	2.6
Female (>=4 to <12 Years): Phase B Baseline-Stage4	0.0	2.6
Female (>=4 to <12 Years): Month 6, Phase B-Stage1	4.8	7.7
Female (>=4 to <12 Years): Month 6, Phase B-Stage2	0.0	2.6
Female (>=4 to <12 Years): Month 6, Phase B-Stage4	0.0	2.6
Female (>=4 to <12 Years): Month 12,Phase B-Stage1	4.8	7.7
Female (>=4 to <12 Years): Month 12,Phase B-Stage2	0.0	2.6
Female (>=4 to <12 Years): Month 12,Phase B-Stage3	0.0	2.6
Female (>=4 to <12 Years): Month 12,Phase B-Stage4	0.0	2.6
Female (>=4 to <12 Years): Month 18,Phase B-Stage1	4.8	2.6
Female (>=4 to <12 Years): Month 18,Phase B-Stage2	0.0	7.7
Female (>=4 to <12 Years): Month 18,Phase B-Stage4	0.0	2.6
Female (>=4 to <12 Years): Month 24,Phase B-Stage1	2.4	2.6
Female (>=4 to <12 Years): Month 24,Phase B-Stage2	2.4	5.1
Female (>=4 to <12 Years): Month 24,Phase B-Stage3	0.0	2.6
Female (>=4 to <12 Years): Month 24,Phase B-Stage4	0.0	2.6
Male (>=4 to <12 Years): Phase B Baseline- Stage 1	11.9	5.1
Male (>=4 to <12 Years): Phase B Baseline- Stage 2	4.8	2.6
Male (>=4 to <12 Years): Phase B Baseline- Stage 3	0.0	5.1
Male (>=4 to <12 Years): Phase B Baseline- Stage 4	2.4	0.0
Male (>=4 to <12 Years): Month 6, Phase B- Stage 1	9.5	2.6
Male (>=4 to <12 Years): Month 6, Phase B- Stage 2	2.4	2.6
Male (>=4 to <12 Years): Month 6, Phase B- Stage 3	2.4	2.6
Male (>=4 to <12 Years): Month 6, Phase B- Stage 4	2.4	2.6
Male (>=4 to <12 Years): Month 12, Phase B- Stage1	9.5	2.6
Male (>=4 to <12 Years): Month 12, Phase B- Stage2	2.4	0.0
Male (>=4 to <12 Years): Month 12, Phase B- Stage3	2.4	5.1
Male (>=4 to <12 Years): Month 12, Phase B- Stage4	2.4	2.6
Male (>=4 to <12 Years): Month 18, Phase B- Stage1	4.8	2.6
Male (>=4 to <12 Years): Month 18, Phase B- Stage2	2.4	0.0
Male (>=4 to <12 Years): Month 18, Phase B- Stage3	0.0	5.1
Male (>=4 to <12 Years): Month 18, Phase B- Stage4	4.8	0.0
Male (>=4 to <12 Years): Month 18, Phase B- Stage5	0.0	2.6
Male (>=4 to <12 Years): Month 24, Phase B- Stage1	4.8	0.0
Male (>=4 to <12 Years): Month 24, Phase B- Stage2	4.8	0.0
Male (>=4 to <12 Years): Month 24, Phase B- Stage3	2.4	5.1
Male (>=4 to <12 Years): Month 24, Phase B- Stage4	2.4	0.0
Male (>=4 to <12 Years): Month 24, Phase B- Stage5	2.4	2.6
Female (>=12 to <15 Years):Phase B Baseline-Stage2	0.0	2.6
Female (>=12 to <15 Years):Phase B Baseline-Stage3	0.0	2.6
Female (>=12 to <15 Years):Phase B Baseline-Stage4	0.0	5.1
Female (>=12 to <15 Years):Phase B Baseline-Stage5	16.7	10.3
Female (>=12 to <15 Years): Month 6,Phase B-Stage3	0.0	5.1
Female (>=12 to <15 Years): Month 6,Phase B-Stage4	0.0	5.1
Female (>=12 to <15 Years): Month 6,Phase B-Stage5	16.7	10.3
Female (>=12 to <15 Years):Month 12,Phase B-Stage4	0.0	5.1
Female (>=12 to <15 Years):Month 12,Phase B-Stage5	14.3	10.3
Female (>=12 to <15 Years):Month 18,Phase B-Stage4	0.0	2.6
Female (>=12 to <15 Years):Month 18,Phase B-Stage5	11.9	10.3
Female (>=12 to <15 Years):Month 24,Phase B-Stage4	0.0	5.1
Female (>=12 to <15 Years):Month 24,Phase B-Stage5	9.5	10.3
Female (>=12 to <15 Years): EOT, Phase B, Stage 4	0.0	2.6
Female (>=12 to <15 Years): EOT, Phase B, Stage 5	7.1	2.6
Male (>=12 to <15 Years): Phase B Baseline- Stage2	0.0	2.6
Male (>=12 to <15 Years): Phase B Baseline- Stage3	2.4	0.0
Male (>=12 to <15 Years): Phase B Baseline- Stage4	9.5	7.7
Male (>=12 to <15 Years): Phase B Baseline- Stage5	4.8	2.6
Male (>=12 to <15 Years): Month 6, Phase B- Stage2	0.0	2.6
Male (>=12 to <15 Years): Month 6, Phase B- Stage3	2.4	0.0
Male (>=12 to <15 Years): Month 6, Phase B- Stage4	4.8	5.1
Male (>=12 to <15 Years): Month 6, Phase B- Stage5	4.8	2.6
Male (>=12 to <15 Years): Month 12, Phase B-Stage2	0.0	2.6
Male (>=12 to <15 Years): Month 12, Phase B-Stage4	7.1	5.1
Male (>=12 to <15 Years): Month 12, Phase B-Stage5	7.1	5.1
Male (>=12 to <15 Years): Month 18, Phase B-Stage2	0.0	2.6
Male (>=12 to <15 Years): Month 18, Phase B-Stage4	4.8	0.0
Male (>=12 to <15 Years): Month 18, Phase B-Stage5	9.5	7.7
Male (>=12 to <15 Years): Month 24, Phase B-Stage2	0.0	2.6
Male (>=12 to <15 Years): Month 24, Phase B-Stage4	4.8	0.0
Male (>=12 to <15 Years): Month 24, Phase B-Stage5	9.5	10.3
Male (>=12 to <15 Years): EOT, Phase B- Stage 5	0.0	2.6
Female (>=15 to <18 Years):Phase B Baseline-Stage4	2.4	0.0
Female (>=15 to <18 Years):Phase B Baseline-Stage5	16.7	15.4
Female (>=15 to <18 Years): Month 6,Phase B-Stage4	2.4	0.0
Female (>=15 to <18 Years): Month 6,Phase B-Stage5	16.7	12.8
Female(>=15 to <18 Years):Month 12,Phase B-Stage4	2.4	0.0
Female(>=15 to <18 Years):Month 12,Phase B-Stage5	16.7	12.8
Female(>=15 to <18 Years):Month 18,Phase B-Stage4	2.4	0.0
Female(>=15 to <18 Years):Month 18,Phase B-Stage5	16.7	12.8
Female(>=15 to <18 Years):Month 24,Phase B-Stage4	2.4	0.0
Female(>=15 to <18 Years):Month 24,Phase B-Stage5	16.7	12.8
Female (>=15 to <18 Years): EOT, Phase B- Stage 5	0.0	5.1
Male (>=15 to <18 Years): Phase B Baseline- Stage4	2.4	0.0
Male (>=15 to <18 Years): Phase B Baseline- Stage5	16.7	20.5
Male (>=15 to <18 Years): Month 6, Phase B- Stage5	19.0	17.9
Male (>=15 to <18 Years): Month 12, Phase B-Stage5	16.7	17.9
Male (>=15 to <18 Years): Month 18, Phase B-Stage5	16.7	15.4
Male (>=15 to <18 Years): Month 24, Phase B-Stage5	16.7	12.8
Male (>=15 to <18 Years): EOT, Phase B- Stage 5	4.8	7.7

No statistical analyses for this end point

Secondary: Phase A: Change From Baseline in Growth Percentile by Gender and Age

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End point title

Phase A: Change From Baseline in Growth Percentile by Gender and Age

End point description

The growth percentile was based on the assessment of height and weight. The Phase A Safety Set included all subjects who were randomised and received at least 1 dose of IMP in Phase A. Number analysed is the number of subjects with data available for analysis at the given time point. Change From Baseline = CFB, End of Treatment = EOT. 9999 = The mean or standard deviation was not estimable due to lower number of subjects with event. n = Number analysed is the number of subjects with data available for analysis at the given time point.

End point type

Secondary

End point timeframe

At Baseline, Months 6 and 12 of Phase A

End point values	Phase A: Tolvaptan	Phase A: Placebo
Number of subjects analysed	48	43
Units: growth percentile
arithmetic mean (standard deviation)
Females: Age 15-18 Years - Baseline (n=9,8)	62 ( 28 )	60 ( 34 )
CFB in Females: Age 15-18 Years - Month 6 (n=9,6)	2 ( 18 )	-2 ( 12 )
CFB in Females: Age 15-18 Years - Month 12 (n=9,7)	7 ( 10 )	-5 ( 11 )
Males: Age 15-18 Years - Baseline(n=9,8)	56 ( 29 )	73 ( 18 )
CFB in Males: Age 15-18 Years - Month 6(n=8,8)	12 ( 16 )	-1 ( 30 )
CFB in Males: Age 15-18 Years - Month 12(n=8,8)	2 ( 37 )	-3 ( 25 )
Females: Age 12-15 Years - Baseline (n=9,8)	71 ( 20 )	72 ( 29 )
CFB in Females: Age 12-15 Years - Month 6(n=7,8)	-2 ( 12 )	-20 ( 21 )
CFB in Females: Age 12-15 Years - Month 12 (n=7,8)	-11 ( 9 )	-18 ( 27 )
Males: Age 12-15 Years - Baseline(n=8,7)	70 ( 21 )	76 ( 24 )
CFB in Males: Age 12-15 Years - Month 6(n=7,7)	-7 ( 13 )	-13 ( 38 )
CFB in Males: Age 12-15 Years - Month 12(n=7,5)	0 ( 20 )	8 ( 17 )
Females: Age 4-11 Years - Baseline(n=3,7)	71 ( 25 )	57 ( 14 )
CFB in Females: Age 4-11 Years - Month 6(n=3,7)	-1 ( 3 )	4 ( 16 )
CFB in Females: Age 4-11 Years - Month 12(n=3,7)	7 ( 15 )	2 ( 18 )
Males: Age 4-11 Years - Baseline(n=10,5)	57 ( 31 )	63 ( 19 )
CFB in Males: Age 4-11 Years - Month 6 (n=10,5)	4 ( 16 )	0 ( 0 )
CFB in Males: Age 4-11 Years - Month 12 (n=10,5)	1 ( 3 )	1 ( 4 )

No statistical analyses for this end point

Secondary: Phase B: Change From Baseline in Growth Percentile by Gender and Age

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End point title

Phase B: Change From Baseline in Growth Percentile by Gender and Age

End point description

The growth percentile was based on the assessment of height and weight. The Phase B Safety Set included all subjects who were enrolled in Phase B and received at least 1 dose of IMP in Phase B. n = Number analysed is the number of subjects with data available for analysis at the given time point. Change from Baseline = CFB, End of Treatment = EOT. 9999 = The mean or standard deviation was not estimable due to lower number of subjects with event.

End point type

Secondary

End point timeframe

At Baseline, Months 6, 12, 18, 24 of Phase B

End point values	Phase B: Prior Tolvaptan	Phase B: Prior Placebo
Number of subjects analysed	42	39
Units: growth percentile
arithmetic mean (standard deviation)
Females: Age 15-18 Years - Baseline(n=9,6)	69 ( 32 )	46 ( 28 )
CFB in Females: Age 15-18 Years - Month 6(n=7,5)	-7 ( 17 )	12 ( 21 )
CFB in Females: Age 15-18 Years - Month 12(n=8,5)	0 ( 7 )	20 ( 18 )
CFB in Females: Age 15-18 Years - Month 18(n=6,3)	-2 ( 2 )	10 ( 9 )
CFB in Females: Age 15-18 Years - Month 24(n=8,5)	6 ( 16 )	16 ( 20 )
Males: Age 15-18 Years - Baseline(n=8,8)	60 ( 34 )	69 ( 18 )
CFB in Males: Age 15-18 Years - Month 6(n=8,7)	-13 ( 53 )	1 ( 2 )
CFB in Males: Age 15-18 Years - Month 12(n=6,6)	-8 ( 47 )	8 ( 11 )
CFB in Males: Age 15-18 Years - Month 18(n=5,6)	16 ( 65 )	-4 ( 25 )
CFB in Males: Age 15-18 Years - Month 24(n=6,5)	-2 ( 50 )	-11 ( 25 )
Females: Age 12-15 Years - Baseline(n=7,8)	62 ( 24 )	54 ( 34 )
CFB in Females: Age 12-15 Years - Month 6(n=7,8)	3 ( 6 )	13 ( 18 )
CFB in Females: Age 12-15 Years - Month 12(n=6,8)	12 ( 20 )	12 ( 23 )
CFB in Females: Age 12-15 Years - Month 18(n=5,5)	5 ( 9 )	10 ( 22 )
CFB in Females: Age 12-15 Years - Month 24(n=4,7)	1 ( 3 )	13 ( 18 )
Males: Age 12-15 Years - Baseline(n=7,5)	67 ( 26 )	77 ( 23 )
CFB in Males: Age 12-15 Years - Month 6(n=5,5)	1 ( 10 )	-15 ( 38 )
CFB in Males: Age 12-15 Years - Month 12(n=7,5)	4 ( 16 )	-23 ( 37 )
CFB in Males: Age 12-15 Years - Month 18 (n=5,4)	-4 ( 14 )	-22 ( 40 )
CFB in Males: Age 12-15 Years - Month 24(n=6,5)	-8 ( 15 )	-18 ( 36 )
Females: Age 4-11 Years - Baseline(n=3,7)	78 ( 19 )	59 ( 22 )
CFB in Females: Age 4-11 Years - Month 6(n=3,6)	-2 ( 2 )	2 ( 12 )
CFB in Females: Age 4-11 Years - Month 12(n=3,7)	5 ( 8 )	1 ( 12 )
CFB in Females: Age 4-11 Years - Month 18(n=3,7)	-5 ( 6 )	2 ( 23 )
CFB in Females: Age 4-11 Years - Month 24(n=3,7)	-4 ( 5 )	10 ( 21 )
Males: Age 4-11 Years -Baseline (n=8,5)	65 ( 30 )	64 ( 21 )
CFB in Males: Age 4-11 Years - Month 6(n=8,4)	0 ( 13 )	1 ( 2 )
CFB in Males: Age 4-11 Years - Month 12(n=8,5)	3 ( 20 )	4 ( 8 )
CFB in Males: Age 4-11 Years - Month 18(n=5,4)	-4 ( 12 )	2 ( 9 )
CFB in Males: Age 4-11 Years - Month 24(n=7,4)	0 ( 18 )	21 ( 23 )

No statistical analyses for this end point

Secondary: Phase A: Change From Baseline in Creatinine Value

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End point title

Phase A: Change From Baseline in Creatinine Value

End point description

Phase A Baseline is the last pre-dose evaluation. The Last Visit is the last available post-baseline evaluation including early term. The Phase A Safety Set included all subjects who were randomised and received at least 1 dose of IMP in Phase A. n = Number analysed is the number of subjects with data available for analysis at the given time point. 9999 = The mean or standard deviation was not estimable due to lower number of subjects with event. As prespecified in the protocol, data for safety is reported by the treatment group (Phase A: Tolvaptan and Phase A: Placebo)

End point type

Secondary

End point timeframe

Baseline, Week 1, Months 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, Follow Up Day 7, End of Treatment, and Last Visit

End point values	Phase A: Tolvaptan	Phase A: Placebo
Number of subjects analysed	48	43
Units: milligrams per deciliter (mg/dL)
arithmetic mean (standard deviation)
Baseline (n=48,43)	0.70 ( 0.16 )	0.67 ( 0.12 )
Change From Baseline at Week 1(n=47,42)	0.04 ( 0.09 )	-0.01 ( 0.06 )
Change From Baseline at Month 1(n=48,43)	0.01 ( 0.08 )	0.01 ( 0.06 )
Change From Baseline at Month 2(n=44,42)	0.01 ( 0.09 )	0.00 ( 0.07 )
Change From Baseline at Month 3(n=45,43)	0.00 ( 0.11 )	0.01 ( 0.06 )
Change From Baseline at Month 4(n=45,40)	0.00 ( 0.09 )	-0.01 ( 0.07 )
Change From Baseline at Month 5(n=45,39)	0.01 ( 0.09 )	0.01 ( 0.06 )
Change From Baseline at Month 6(n=44,41)	0.01 ( 0.10 )	0.02 ( 0.07 )
Change From Baseline at Month 7(n=44,39)	0.01 ( 0.10 )	0.02 ( 0.06 )
Change From Baseline at Month 8(n=43,39)	0.01 ( 0.11 )	0.02 ( 0.07 )
Change From Baseline at Month 9(n=44,39)	0.04 ( 0.11 )	0.01 ( 0.07 )
Change From Baseline at Month 10(n=40,34)	0.01 ( 0.10 )	0.03 ( 0.07 )
Change From Baseline at Month 11(n=41,38)	0.02 ( 0.11 )	0.04 ( 0.08 )
Change From Baseline at Month 12(n=43,40)	0.02 ( 0.09 )	0.02 ( 0.06 )
Change From Baseline at Follow Up Day 7(n=1,1)	0.09 ( 9999 )	-0.02 ( 9999 )
Change From Baseline at End of Treatment(n=2,3)	0.03 ( 0.10 )	0.03 ( 0.04 )
Change From Baseline at Last Visit(n=48,43)	0.03 ( 0.09 )	0.02 ( 0.06 )

No statistical analyses for this end point

Secondary: Phase B: Change From Baseline in Creatinine Value

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End point title

Phase B: Change From Baseline in Creatinine Value

End point description

Phase B Baseline is the last evaluation prior to the first dose in Phase B. The Last Visit is the last available post-baseline evaluation including early term. The Phase B Safety Set included all subjects who were enrolled in Phase B and received at least 1 dose of IMP in Phase B. n = Number analysed is the number of subjects with data available for analysis at the given time point. 9999 = The mean or standard deviation was not estimable due to lower number of subjects with event. As prespecified in the protocol, data for safety is reported by the treatment group (Phase A: Tolvaptan and Phase A: Placebo)

End point type

Secondary

End point timeframe

Baseline, Week 1, Months 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, Follow Up Day 7, End of Treatment, and Last Visit

End point values	Phase B: Prior Tolvaptan	Phase B: Prior Placebo
Number of subjects analysed	42	39
Units: mg/dL
arithmetic mean (standard deviation)
Baseline (n=42,39)	0.73 ( 0.17 )	0.69 ( 0.13 )
Change From Baseline at Week 1(n=42,38)	0.01 ( 0.06 )	0.04 ( 0.06 )
Change From Baseline at Month 1(n=41,38)	0.01 ( 0.07 )	0.04 ( 0.06 )
Change From Baseline at Month 2(n=41,37)	0.02 ( 0.07 )	0.04 ( 0.07 )
Change From Baseline at Month 3(n=41,37)	0.02 ( 0.07 )	0.04 ( 0.07 )
Change From Baseline at Month 4(n=40,36)	0.04 ( 0.06 )	0.05 ( 0.07 )
Change From Baseline at Month 5(n=38,30)	0.03 ( 0.06 )	0.07 ( 0.07 )
Change From Baseline at Month 6(n=38,33)	0.03 ( 0.07 )	0.06 ( 0.07 )
Change From Baseline at Month 7(n=38,32)	0.04 ( 0.07 )	0.06 ( 0.07 )
Change From Baseline at Month 8(n=38,34)	0.05 ( 0.08 )	0.07 ( 0.07 )
Change From Baseline at Month 9(n=38,35)	0.07 ( 0.11 )	0.09 ( 0.13 )
Change From Baseline at Month 10(n=37,34)	0.06 ( 0.07 )	0.06 ( 0.07 )
Change From Baseline at Month 11(n=38,32)	0.05 ( 0.07 )	0.08 ( 0.08 )
Change From Baseline at Month 12(n=36,36)	0.06 ( 0.12 )	0.07 ( 0.08 )
Change From Baseline at Month 13(n=34,34)	0.04 ( 0.08 )	0.08 ( 0.08 )
Change From Baseline at Month 14(n=33,31)	0.08 ( 0.07 )	0.08 ( 0.08 )
Change From Baseline at Month 15(n=37,30)	0.06 ( 0.07 )	0.06 ( 0.08 )
Change From Baseline at Month 16(n=36,29)	0.05 ( 0.08 )	0.08 ( 0.09 )
Change From Baseline at Month 17(n=33,27)	0.07 ( 0.08 )	0.08 ( 0.09 )
Change From Baseline at Month 18(n=30,27)	0.05 ( 0.09 )	0.09 ( 0.07 )
Change From Baseline at Month 19(n=29,25)	0.06 ( 0.10 )	0.09 ( 0.10 )
Change From Baseline at Month 20(n=27,20)	0.04 ( 0.08 )	0.11 ( 0.08 )
Change From Baseline at Month 21(n=27,23)	0.09 ( 0.12 )	0.09 ( 0.10 )
Change From Baseline at Month 22(n=29,23)	0.06 ( 0.08 )	0.09 ( 0.10 )
Change From Baseline at Month 23(n=25,24)	0.07 ( 0.06 )	0.12 ( 0.08 )
Change From Baseline at Month 24(n=34,31)	0.07 ( 0.08 )	0.12 ( 0.10 )
Change From Baseline at Follow Up Day 7(n=2,7)	-0.01 ( 0.02 )	0.14 ( 0.08 )
Change From Baseline at End of Treatment(n=5,7)	-0.01 ( 0.11 )	0.02 ( 0.08 )
Change From Baseline at Last Visit(n=42,39)	0.05 ( 0.09 )	0.10 ( 0.08 )

No statistical analyses for this end point

Secondary: Phase A and B: Percentage of Subjects With Potentially Clinically Significant Abnormalities in Vital Signs

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End point title

Phase A and B: Percentage of Subjects With Potentially Clinically Significant Abnormalities in Vital Signs

End point description

Vital signs=measurements of respiratory rate, blood pressure, body temperature and pulse. Any value outside the normal range was flagged for the attention of the investigator who assessed whether or not a flagged value is of clinical significance. Only those categories with at least one subject with event are reported. The Phase A Safety Set included all subjects who were randomized and received at least 1 dose of IMP in Phase A. The Phase B Safety Set included all subjects who were enrolled in Phase B and received at least 1 dose of IMP in Phase B. n=Number analysed is the number of subjects with at least one post-baseline numeric result for the given vital sign parameter. Pulse rate(PR) is measured in beats per minute(BPM), Systolic and Diastolic Blood Pressure (BP) is measured in millimetre of mercury (mmHg). As prespecified in the protocol, data for safety is reported by the treatment group (Phase A: Tolvaptan, Phase A: Placebo, Phase B: Prior Tolvaptan).

End point type

Secondary

End point timeframe

From first dose of study drug up to 14 days post last dose (up to approximately 37 months)

End point values	Phase A: Tolvaptan	Phase A: Placebo	Phase B: Prior Tolvaptan	Phase B: Prior Placebo
Number of subjects analysed	48	43	42	39
Units: percentage of subjects
number (not applicable)
PR <=50 and Baseline Decrease >=15(n=48,43,42,38)	0.0	2.3	0.0	5.3
SystolicBP>=130&BaselineIncrease>=20;n=48,43,42,39	2.1	0.0	0.0	0.0
SystolicBP<=120&BaselineDecrease>=20;n=48,43,42,39	4.2	7.0	9.5	10.3
SystolicBP>=144&BaselineIncrease>=20;n=48,43,42,39	2.1	2.3	0.0	2.6
DiastolicBP<=50&BaselineDecrease>=15;n=48,43,42,39	4.2	7.0	9.5	0.0
DiastolicBP>=86&BaselineIncrease>=15;n=48,43,42,39	0.0	0.0	7.1	0.0
DiastolicBP<=80&BaselineDecrease>=15;n=48,43,42,39	12.5	18.6	16.7	12.8
DiastolicBP>=92&BaselineIncrease>=15;n=48,43,42,39	0.0	4.7	4.8	2.6

No statistical analyses for this end point

Secondary: Phase A and B: Percentage of Subjects With Potentially Clinically Significant Abnormalities in Laboratory Test Results Including Liver Function Tests (LFTs)

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End point title

Phase A and B: Percentage of Subjects With Potentially Clinically Significant Abnormalities in Laboratory Test Results Including Liver Function Tests (LFTs)

End point description

Parameters=haematology,chemistry,urinalysis,&LFTs.Criteria=Increased(INC)creatinine level: Baseline(BSL):Grade 0,>BSL-1.5xBSL:1,>1.5-3xBSL:2,>3-6xBSL:3,>6xBSL:4.Decreased(DEC) glucose level: <30:-4,30-<40:-3, 40-<55:-2, 55-<65:-1,>=65:0; INC:<=115:0,>115-160:1,>160-250:2,>250-500:3,>500:4.DEC potassium: <2.5:-4,2.5-<3:-3,3-<lower limit of normal(LLN):-1,LLN:0; INC: upper limit of normal(ULN):0,>ULN-5.5:1,>5.5-6:2,>6-7:3,>7:4.DEC sodium: <120:-4,120-124:-3,125-129:-2,130-135:-1,>=136:0; INC:<=145:0,146-150:1,151-155:2,156-160:3,>160:4. INC triglyceride:ULN:0,>ULN-2.5xULN:1,>2.5-5xULN:2,>5-6xULN:3,>6xULN:4. DEC Neutrophils:<0.5:-4,0.5-<1:-3,1-<1.5:-2,1.5-<LLN:-1,LLN:0. Potentially clinically significant INC/DEC=BSL grade 0,1,-1 and post-BSL grade >1,<-1 or BSL grade >1,<-1 and post-BSL grade >or<BSL grade. Only those categories with atleast 1 subject with event are reported. Phase A and B Safety Set; n=number of subjects with≥1 post-baseline result. milliequivalents per deciliter=mEq/dL

End point type

Secondary

End point timeframe

From first dose of study drug up to 14 days post last dose (up to approximately 37 months)

End point values	Phase A: Tolvaptan	Phase A: Placebo	Phase B: Prior Tolvaptan	Phase B: Prior Placebo
Number of subjects analysed	48	43	42	39
Units: percentage of subjects
number (not applicable)
Increase in Creatinine Level(mg/dL)(n=48,43,42,39)	8.3	0.0	7.1	7.7
Decrease in Glucose Level(mg/dL)(n=36,39,32,34)	0.0	2.6	0.0	2.9
Increase in Potassium Level(mEq/dL)(n=47,43,40,38)	2.1	0.0	0.0	2.6
Increase in Sodium Level (mEq/dL)(n=48,43,42,39)	0.0	0.0	0.0	2.6
Increased TriglycerideLevel(mg/dL)(n=36,39,32,34)	0.0	0.0	3.1	0.0
Decrease in Neutrophils (10^9/L)(n=46,41,40,38)	0.0	4.9	5.0	2.6

No statistical analyses for this end point

Secondary: Phase A and B: Percentage of Subjects With Aquaretic Adverse Events (AEs)

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End point title

Phase A and B: Percentage of Subjects With Aquaretic Adverse Events (AEs)

End point description

An AE was defined as any untoward medical occurrence in a subject administered a medicinal product and which does not necessarily have a causal relationship with this treatment. Aquaretic AEs included Medical Dictionary for Regulatory Activities [MedDRA] preferred terms of thirst, polyuria (production of large volumes of dilute urine), nocturia (need to wake up to urinate at night), pollakiuria (abnormally frequent urination), and polydipsia (excessive thirst). The Phase A Safety Set included all subjects who were randomised and received at least 1 dose of IMP in Phase A. The Phase B Safety Set included all subjects who were enrolled in Phase B and received at least 1 dose of IMP in Phase B. As prespecified in the protocol, data for safety is reported by the treatment group (Phase A: Tolvaptan, Phase A: Placebo, Phase B: Prior Tolvaptan and Phase B: Prior Placebo).

End point type

Secondary

End point timeframe

From first dose of study drug up to 14 days post last dose (up to approximately 37 months)

End point values	Phase A: Tolvaptan	Phase A: Placebo	Phase B: Prior Tolvaptan	Phase B: Prior Placebo
Number of subjects analysed	48	43	42	39
Units: percentage of subjects
number (not applicable)	64.6	16.3	14.3	48.7

No statistical analyses for this end point

Adverse events

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Timeframe for reporting adverse events

From the first dose of the study drug up to 14 days post last dose (up to approximately 37 months)

Adverse event reporting additional description

Phase A Safety Set=all subjects randomised and received atleast 1 dose of IMP in Phase A.Phase B Safety Set=all subjects enrolled in Phase B and received atleast 1 dose of IMP in Phase B. As prespecified in protocol, data for safety is reported by treatment group(PhaseA:Tolvaptan, PhaseA:Placebo, PhaseB:Prior Tolvaptan and PhaseB:Prior Placebo).

Assessment type

Systematic

Dictionary name

MedDRA

Dictionary version

25.0

Reporting group title

Phase A: Tolvaptan

Reporting group description

Reporting group title

Phase A: Placebo

Reporting group description

Reporting group title

Phase B: Prior Tolvaptan

Reporting group description

Reporting group title

Phase B: Prior Placebo

Reporting group description

Serious adverse events	Phase A: Tolvaptan	Phase A: Placebo	Phase B: Prior Tolvaptan	Phase B: Prior Placebo
Total subjects affected by serious adverse events
subjects affected / exposed	1 / 48 (2.08%)	6 / 43 (13.95%)	7 / 42 (16.67%)	8 / 39 (20.51%)
number of deaths (all causes)	0	0	0	0
number of deaths resulting from adverse events	0	0	0	0
Investigations
Alanine aminotransferase increased
subjects affected / exposed	0 / 48 (0.00%)	0 / 43 (0.00%)	1 / 42 (2.38%)	1 / 39 (2.56%)
occurrences causally related to treatment / all	0 / 0	0 / 0	1 / 1	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Aspartate aminotransferase increased
subjects affected / exposed	0 / 48 (0.00%)	0 / 43 (0.00%)	0 / 42 (0.00%)	2 / 39 (5.13%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	1 / 2
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Heart rate increased
subjects affected / exposed	0 / 48 (0.00%)	0 / 43 (0.00%)	0 / 42 (0.00%)	1 / 39 (2.56%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
SARS-CoV-2 test positive
subjects affected / exposed	0 / 48 (0.00%)	0 / 43 (0.00%)	1 / 42 (2.38%)	1 / 39 (2.56%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Injury, poisoning and procedural complications
Hand fracture
subjects affected / exposed	0 / 48 (0.00%)	1 / 43 (2.33%)	0 / 42 (0.00%)	0 / 39 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Intentional overdose
subjects affected / exposed	0 / 48 (0.00%)	1 / 43 (2.33%)	0 / 42 (0.00%)	0 / 39 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Ulna fracture
subjects affected / exposed	0 / 48 (0.00%)	1 / 43 (2.33%)	0 / 42 (0.00%)	0 / 39 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Expired product administered
subjects affected / exposed	0 / 48 (0.00%)	0 / 43 (0.00%)	0 / 42 (0.00%)	1 / 39 (2.56%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Vascular disorders
Hypertensive crisis
subjects affected / exposed	0 / 48 (0.00%)	1 / 43 (2.33%)	0 / 42 (0.00%)	0 / 39 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Nervous system disorders
Petit mal epilepsy
subjects affected / exposed	0 / 48 (0.00%)	1 / 43 (2.33%)	0 / 42 (0.00%)	0 / 39 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Immune system disorders
Anaphylactic reaction
subjects affected / exposed	0 / 48 (0.00%)	0 / 43 (0.00%)	1 / 42 (2.38%)	0 / 39 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Reproductive system and breast disorders
Pelvic pain
subjects affected / exposed	0 / 48 (0.00%)	1 / 43 (2.33%)	0 / 42 (0.00%)	0 / 39 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Gastrointestinal disorders
Abdominal Pain
subjects affected / exposed	0 / 48 (0.00%)	0 / 43 (0.00%)	1 / 42 (2.38%)	1 / 39 (2.56%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Colitis ulcerative
subjects affected / exposed	0 / 48 (0.00%)	0 / 43 (0.00%)	1 / 42 (2.38%)	0 / 39 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Pancreatitis acute
subjects affected / exposed	0 / 48 (0.00%)	0 / 43 (0.00%)	1 / 42 (2.38%)	0 / 39 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Psychiatric disorders
Intentional self-injury
subjects affected / exposed	0 / 48 (0.00%)	1 / 43 (2.33%)	0 / 42 (0.00%)	0 / 39 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Eating disorder
subjects affected / exposed	0 / 48 (0.00%)	0 / 43 (0.00%)	0 / 42 (0.00%)	1 / 39 (2.56%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Renal and urinary disorders
Haematuria
subjects affected / exposed	0 / 48 (0.00%)	1 / 43 (2.33%)	0 / 42 (0.00%)	0 / 39 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Renal pain
subjects affected / exposed	0 / 48 (0.00%)	1 / 43 (2.33%)	0 / 42 (0.00%)	0 / 39 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Renal impairment
subjects affected / exposed	0 / 48 (0.00%)	0 / 43 (0.00%)	1 / 42 (2.38%)	1 / 39 (2.56%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Infections and infestations
Viral pericarditis
subjects affected / exposed	1 / 48 (2.08%)	0 / 43 (0.00%)	0 / 42 (0.00%)	0 / 39 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Arthritis bacterial
subjects affected / exposed	0 / 48 (0.00%)	0 / 43 (0.00%)	0 / 42 (0.00%)	1 / 39 (2.56%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
COVID-19
subjects affected / exposed	0 / 48 (0.00%)	0 / 43 (0.00%)	2 / 42 (4.76%)	0 / 39 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 2	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0

Frequency threshold for reporting non-serious adverse events: 5%

Non-serious adverse events	Phase A: Tolvaptan	Phase A: Placebo	Phase B: Prior Tolvaptan	Phase B: Prior Placebo
Total subjects affected by non serious adverse events
subjects affected / exposed	45 / 48 (93.75%)	42 / 43 (97.67%)	38 / 42 (90.48%)	39 / 39 (100.00%)
Vascular disorders
Hypertension
subjects affected / exposed	4 / 48 (8.33%)	1 / 43 (2.33%)	4 / 42 (9.52%)	2 / 39 (5.13%)
occurrences all number	4	1	5	2
Hypotension
subjects affected / exposed	0 / 48 (0.00%)	0 / 43 (0.00%)	2 / 42 (4.76%)	3 / 39 (7.69%)
occurrences all number	0	0	2	3
Orthostatic hypotension
subjects affected / exposed	5 / 48 (10.42%)	0 / 43 (0.00%)	3 / 42 (7.14%)	3 / 39 (7.69%)
occurrences all number	5	0	3	4
General disorders and administration site conditions
Asthenia
subjects affected / exposed	0 / 48 (0.00%)	3 / 43 (6.98%)	3 / 42 (7.14%)	2 / 39 (5.13%)
occurrences all number	0	3	3	2
Fatigue
subjects affected / exposed	4 / 48 (8.33%)	3 / 43 (6.98%)	3 / 42 (7.14%)	3 / 39 (7.69%)
occurrences all number	5	4	3	4
Non-cardiac chest pain
subjects affected / exposed	0 / 48 (0.00%)	0 / 43 (0.00%)	3 / 42 (7.14%)	0 / 39 (0.00%)
occurrences all number	0	0	3	0
Pyrexia
subjects affected / exposed	4 / 48 (8.33%)	3 / 43 (6.98%)	8 / 42 (19.05%)	7 / 39 (17.95%)
occurrences all number	5	6	10	11
Thirst
subjects affected / exposed	7 / 48 (14.58%)	2 / 43 (4.65%)	1 / 42 (2.38%)	3 / 39 (7.69%)
occurrences all number	8	2	1	3
Immune system disorders
Seasonal allergy
subjects affected / exposed	4 / 48 (8.33%)	1 / 43 (2.33%)	0 / 42 (0.00%)	3 / 39 (7.69%)
occurrences all number	4	1	0	3
Reproductive system and breast disorders
Dysmenorrhoea
subjects affected / exposed	0 / 48 (0.00%)	0 / 43 (0.00%)	0 / 42 (0.00%)	3 / 39 (7.69%)
occurrences all number	0	0	0	8
Respiratory, thoracic and mediastinal disorders
Cough
subjects affected / exposed	7 / 48 (14.58%)	5 / 43 (11.63%)	7 / 42 (16.67%)	8 / 39 (20.51%)
occurrences all number	10	8	9	10
Epistaxis
subjects affected / exposed	3 / 48 (6.25%)	0 / 43 (0.00%)	1 / 42 (2.38%)	7 / 39 (17.95%)
occurrences all number	3	0	3	7
Oropharyngeal pain
subjects affected / exposed	4 / 48 (8.33%)	6 / 43 (13.95%)	9 / 42 (21.43%)	7 / 39 (17.95%)
occurrences all number	5	6	11	8
Psychiatric disorders
Enuresis
subjects affected / exposed	0 / 48 (0.00%)	0 / 43 (0.00%)	2 / 42 (4.76%)	2 / 39 (5.13%)
occurrences all number	0	0	4	3
Investigations
Aspartate aminotransferase increased
subjects affected / exposed	0 / 48 (0.00%)	0 / 43 (0.00%)	1 / 42 (2.38%)	2 / 39 (5.13%)
occurrences all number	0	0	1	2
Blood creatinine increased
subjects affected / exposed	9 / 48 (18.75%)	2 / 43 (4.65%)	7 / 42 (16.67%)	5 / 39 (12.82%)
occurrences all number	12	2	9	11
Liver function test increased
subjects affected / exposed	0 / 48 (0.00%)	0 / 43 (0.00%)	0 / 42 (0.00%)	2 / 39 (5.13%)
occurrences all number	0	0	0	2
Vitamin D decreased
subjects affected / exposed	0 / 48 (0.00%)	0 / 43 (0.00%)	4 / 42 (9.52%)	1 / 39 (2.56%)
occurrences all number	0	0	5	1
Weight decreased
subjects affected / exposed	0 / 48 (0.00%)	0 / 43 (0.00%)	1 / 42 (2.38%)	5 / 39 (12.82%)
occurrences all number	0	0	1	5
Injury, poisoning and procedural complications
Contusion
subjects affected / exposed	0 / 48 (0.00%)	0 / 43 (0.00%)	2 / 42 (4.76%)	3 / 39 (7.69%)
occurrences all number	0	0	2	5
Hand fracture
subjects affected / exposed	0 / 48 (0.00%)	0 / 43 (0.00%)	0 / 42 (0.00%)	2 / 39 (5.13%)
occurrences all number	0	0	0	2
Head injury
subjects affected / exposed	0 / 48 (0.00%)	0 / 43 (0.00%)	0 / 42 (0.00%)	3 / 39 (7.69%)
occurrences all number	0	0	0	3
Nervous system disorders
Dizziness
subjects affected / exposed	3 / 48 (6.25%)	5 / 43 (11.63%)	4 / 42 (9.52%)	4 / 39 (10.26%)
occurrences all number	3	6	5	6
Headache
subjects affected / exposed	16 / 48 (33.33%)	21 / 43 (48.84%)	15 / 42 (35.71%)	17 / 39 (43.59%)
occurrences all number	23	37	22	66
Migraine
subjects affected / exposed	2 / 48 (4.17%)	3 / 43 (6.98%)	1 / 42 (2.38%)	2 / 39 (5.13%)
occurrences all number	2	3	1	2
Ear and labyrinth disorders
Ear pain
subjects affected / exposed	3 / 48 (6.25%)	2 / 43 (4.65%)	2 / 42 (4.76%)	2 / 39 (5.13%)
occurrences all number	6	4	6	4
Gastrointestinal disorders
Abdominal pain
subjects affected / exposed	6 / 48 (12.50%)	3 / 43 (6.98%)	4 / 42 (9.52%)	12 / 39 (30.77%)
occurrences all number	7	3	4	16
Abdominal pain upper
subjects affected / exposed	5 / 48 (10.42%)	4 / 43 (9.30%)	5 / 42 (11.90%)	4 / 39 (10.26%)
occurrences all number	8	6	6	8
Constipation
subjects affected / exposed	5 / 48 (10.42%)	1 / 43 (2.33%)	4 / 42 (9.52%)	2 / 39 (5.13%)
occurrences all number	5	1	4	2
Diarrhoea
subjects affected / exposed	3 / 48 (6.25%)	7 / 43 (16.28%)	3 / 42 (7.14%)	5 / 39 (12.82%)
occurrences all number	3	8	3	6
Enteritis
subjects affected / exposed	0 / 48 (0.00%)	0 / 43 (0.00%)	0 / 42 (0.00%)	2 / 39 (5.13%)
occurrences all number	0	0	0	2
Nausea
subjects affected / exposed	3 / 48 (6.25%)	7 / 43 (16.28%)	7 / 42 (16.67%)	5 / 39 (12.82%)
occurrences all number	4	7	16	9
Toothache
subjects affected / exposed	0 / 48 (0.00%)	0 / 43 (0.00%)	1 / 42 (2.38%)	2 / 39 (5.13%)
occurrences all number	0	0	1	2
Vomiting
subjects affected / exposed	7 / 48 (14.58%)	10 / 43 (23.26%)	5 / 42 (11.90%)	7 / 39 (17.95%)
occurrences all number	9	17	9	17
Renal and urinary disorders
Nocturia
subjects affected / exposed	7 / 48 (14.58%)	3 / 43 (6.98%)	1 / 42 (2.38%)	6 / 39 (15.38%)
occurrences all number	8	3	1	9
Pollakiuria
subjects affected / exposed	9 / 48 (18.75%)	0 / 43 (0.00%)	1 / 42 (2.38%)	2 / 39 (5.13%)
occurrences all number	9	0	2	2
Polyuria
subjects affected / exposed	13 / 48 (27.08%)	2 / 43 (4.65%)	2 / 42 (4.76%)	13 / 39 (33.33%)
occurrences all number	13	2	2	13
Renal impairment
subjects affected / exposed	0 / 48 (0.00%)	0 / 43 (0.00%)	1 / 42 (2.38%)	3 / 39 (7.69%)
occurrences all number	0	0	1	9
Renal pain
subjects affected / exposed	0 / 48 (0.00%)	0 / 43 (0.00%)	4 / 42 (9.52%)	3 / 39 (7.69%)
occurrences all number	0	0	5	5
Musculoskeletal and connective tissue disorders
Arthralgia
subjects affected / exposed	0 / 48 (0.00%)	0 / 43 (0.00%)	0 / 42 (0.00%)	5 / 39 (12.82%)
occurrences all number	0	0	0	5
Back pain
subjects affected / exposed	4 / 48 (8.33%)	5 / 43 (11.63%)	5 / 42 (11.90%)	2 / 39 (5.13%)
occurrences all number	5	5	7	2
Flank pain
subjects affected / exposed	0 / 48 (0.00%)	0 / 43 (0.00%)	3 / 42 (7.14%)	2 / 39 (5.13%)
occurrences all number	0	0	3	3
Pain in extremity
subjects affected / exposed	0 / 48 (0.00%)	6 / 43 (13.95%)	1 / 42 (2.38%)	3 / 39 (7.69%)
occurrences all number	0	6	2	4
Infections and infestations
Bronchitis
subjects affected / exposed	3 / 48 (6.25%)	1 / 43 (2.33%)	2 / 42 (4.76%)	2 / 39 (5.13%)
occurrences all number	4	1	2	2
Cystitis
subjects affected / exposed	0 / 48 (0.00%)	0 / 43 (0.00%)	3 / 42 (7.14%)	0 / 39 (0.00%)
occurrences all number	0	0	6	0
Ear infection
subjects affected / exposed	1 / 48 (2.08%)	4 / 43 (9.30%)	3 / 42 (7.14%)	2 / 39 (5.13%)
occurrences all number	1	4	3	2
Gastoenteritis
subjects affected / exposed	0 / 48 (0.00%)	0 / 43 (0.00%)	3 / 42 (7.14%)	5 / 39 (12.82%)
occurrences all number	0	0	5	6
Nasopharyngitis
subjects affected / exposed	10 / 48 (20.83%)	14 / 43 (32.56%)	11 / 42 (26.19%)	13 / 39 (33.33%)
occurrences all number	14	24	18	19
Pharyngitis
subjects affected / exposed	4 / 48 (8.33%)	0 / 43 (0.00%)	3 / 42 (7.14%)	2 / 39 (5.13%)
occurrences all number	4	0	3	2
Rhinitis
subjects affected / exposed	3 / 48 (6.25%)	3 / 43 (6.98%)	11 / 42 (26.19%)	4 / 39 (10.26%)
occurrences all number	3	3	14	5
Sinusitis
subjects affected / exposed	0 / 48 (0.00%)	0 / 43 (0.00%)	3 / 42 (7.14%)	2 / 39 (5.13%)
occurrences all number	0	0	3	2
Tonsillitis
subjects affected / exposed	0 / 48 (0.00%)	0 / 43 (0.00%)	4 / 42 (9.52%)	3 / 39 (7.69%)
occurrences all number	0	0	4	3
Upper respiratory tract infection
subjects affected / exposed	4 / 48 (8.33%)	2 / 43 (4.65%)	2 / 42 (4.76%)	5 / 39 (12.82%)
occurrences all number	6	2	3	6
Urinary tract infection
subjects affected / exposed	0 / 48 (0.00%)	0 / 43 (0.00%)	1 / 42 (2.38%)	2 / 39 (5.13%)
occurrences all number	0	0	1	4
Viral infection
subjects affected / exposed	3 / 48 (6.25%)	1 / 43 (2.33%)	5 / 42 (11.90%)	3 / 39 (7.69%)
occurrences all number	5	1	5	5
Viral upper respiratory tract infection
subjects affected / exposed	0 / 48 (0.00%)	0 / 43 (0.00%)	0 / 42 (0.00%)	2 / 39 (5.13%)
occurrences all number	0	0	0	2
Metabolism and nutrition disorders
Decreased appetite
subjects affected / exposed	4 / 48 (8.33%)	2 / 43 (4.65%)	1 / 42 (2.38%)	5 / 39 (12.82%)
occurrences all number	4	2	2	5
Polydipsia
subjects affected / exposed	5 / 48 (10.42%)	1 / 43 (2.33%)	1 / 42 (2.38%)	2 / 39 (5.13%)
occurrences all number	5	1	1	2

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Were there any global substantial amendments to the protocol? Yes

08 Aug 2016

The following changes were implemented with Amendment 1: -Exclusion of subjects who had a known lactose intolerance. -Removed ADPKD Teen Scale.

29 Jul 2020

The following changes were implemented with Amendment 2: Added trial conduct information to introduce the Coronavirus 2019 (COVID-19) Addendum. Updated text for secondary endpoints.

Were there any global interruptions to the trial? No

Limitations of the trial such as small numbers of subjects analysed or technical problems leading to unreliable data.

None reported

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Clinical trials

Trial information

Trial information

Subject disposition

Subject disposition

Baseline characteristics

Baseline characteristics

End points

End points

Primary: Phase A: Change From Baseline in Spot Urine Osmolality (Pre-morning Dose)

Primary: Phase A: Change From Baseline in Spot Urine Osmolality (Pre-morning Dose)

Primary: Phase A: Change From Baseline in Specific Gravity (Pre-morning Dose)

Primary: Phase A: Change From Baseline in Specific Gravity (Pre-morning Dose)

Secondary: Phase A: Percent Change From Phase A Baseline in Height-Adjusted Total Kidney Volume (htTKV) as Measured by Magnetic Resonance Imaging (MRI)

Secondary: Phase A: Percent Change From Phase A Baseline in Height-Adjusted Total Kidney Volume (htTKV) as Measured by Magnetic Resonance Imaging (MRI)

Secondary: Phase A and B: Mean 24-hour Fluid Balance Prior to Week 1

Secondary: Phase A and B: Mean 24-hour Fluid Balance Prior to Week 1

Secondary: Phase A: Change From Baseline in Renal Function (Estimated Glomerular Filtration Rate [eGFR] by Schwartz Formula) at Each Clinic Visit in Phase A

Secondary: Phase A: Change From Baseline in Renal Function (Estimated Glomerular Filtration Rate [eGFR] by Schwartz Formula) at Each Clinic Visit in Phase A

Secondary: Phase B: Change From Phase B Baseline in Renal Function (eGFR by Schwartz Formula) at Each Clinic Visit in Phase B

Secondary: Phase B: Change From Phase B Baseline in Renal Function (eGFR by Schwartz Formula) at Each Clinic Visit in Phase B

Secondary: Phase B: Percent Change From Phase B Baseline in htTKV as Measured by MRI at Month 12 and Month 24

Secondary: Phase B: Percent Change From Phase B Baseline in htTKV as Measured by MRI at Month 12 and Month 24

Secondary: Phase A: 24-hour Urine Volume

Secondary: Phase A: 24-hour Urine Volume

Secondary: Phase A: 24-hour Fluid Intake

Secondary: Phase A: 24-hour Fluid Intake

Secondary: Phase A: 24-hour Fluid Balance

Secondary: Phase A: 24-hour Fluid Balance

Secondary: Phase A: 24-hour Sodium Clearance

Secondary: Phase A: 24-hour Sodium Clearance

Secondary: Phase A: 24-hour Creatinine Clearance

Secondary: Phase A: 24-hour Creatinine Clearance

Secondary: Phase A: 24-hour Free Water Clearance

Secondary: Phase A: 24-hour Free Water Clearance

Secondary: Phase A: Percentage of Each Tanner Stage by Gender and Age Compared to Normative Populations

Secondary: Phase A: Percentage of Each Tanner Stage by Gender and Age Compared to Normative Populations

Secondary: Phase B: Percentage of Each Tanner Stage by Gender and Age Compared to Normative Populations

Secondary: Phase B: Percentage of Each Tanner Stage by Gender and Age Compared to Normative Populations

Secondary: Phase A: Change From Baseline in Growth Percentile by Gender and Age

Secondary: Phase A: Change From Baseline in Growth Percentile by Gender and Age

Secondary: Phase B: Change From Baseline in Growth Percentile by Gender and Age

Secondary: Phase B: Change From Baseline in Growth Percentile by Gender and Age

Secondary: Phase A: Change From Baseline in Creatinine Value

Secondary: Phase A: Change From Baseline in Creatinine Value

Secondary: Phase B: Change From Baseline in Creatinine Value

Secondary: Phase B: Change From Baseline in Creatinine Value

Secondary: Phase A and B: Percentage of Subjects With Potentially Clinically Significant Abnormalities in Vital Signs

Secondary: Phase A and B: Percentage of Subjects With Potentially Clinically Significant Abnormalities in Vital Signs

Secondary: Phase A and B: Percentage of Subjects With Potentially Clinically Significant Abnormalities in Laboratory Test Results Including Liver Function Tests (LFTs)

Secondary: Phase A and B: Percentage of Subjects With Potentially Clinically Significant Abnormalities in Laboratory Test Results Including Liver Function Tests (LFTs)

Secondary: Phase A and B: Percentage of Subjects With Aquaretic Adverse Events (AEs)

Secondary: Phase A and B: Percentage of Subjects With Aquaretic Adverse Events (AEs)

Adverse events

Adverse events

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Substantial protocol amendments (globally)

Interruptions (globally)

Limitations and caveats

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