Efficacy and Safety of Tolvaptan in Subjects With Chronic Kidney Disease Between Late Stage 2 to Early Stage 4 Due to Autosomal Dominant Polycystic Kidney Disease

• Sponsor: Otsuka Pharmaceutical Development & Commercialization, Inc. (Industry)
• Overall Status: Completed
• CT.gov ID: NCT02160145
• Collaborator: (none)
• Enrollment: 1,370
• Locations: 231
• Arms: 2
• Duration (Months): 35.6
• Patients Per Site: 5.9
• Patients Per Site Per Month: 0.2

Study Details

Study Description

Brief Summary

The purpose of the study is to determine whether tolvaptan is effective and safe for the treatment of late-stage chronic kidney disease due to autosomal dominant polycystic kidney disease (ADPKD)

Condition or Disease	Intervention/Treatment	Phase
Chronic Kidney Disease; Autosomal Dominant Polycystic Kidney Disease	Drug: Tolvaptan (OPC-41061); Drug: Placebo	Phase 3

Detailed Description

The protocol will extend the understanding of the efficacy and safety of tolvaptan treatment in ADPKD patients with late stage 2 to early stage 4 CKD (chronic kidney disease).

This trial will compare the efficacy of tolvaptan treatment in reducing the annualized change in estimated glomerular filtration rate (eGFR) from pre-treatment baseline to post-treatment follow-up, as compared with placebo, in subjects who tolerate tolvaptan during an initial run-in period. The change in eGFR, calculated by the Chronic Kidney Disease-Epidemiology (CKD-EPI) formula, will provide kidney function data that are complementary to the data demonstrating the benefits previously observed primarily in ADPKD subjects with earlier stages of disease.

Also, it will compare the efficacy of tolvaptan treatment in reducing the decline of annualized eGFR slope, as compared with placebo, in this type of subjects. Finally, it will compare the overall and hepatic safety profile of tolvaptan with placebo and to compare incidence of ADPKD complications (outcomes) during the trial

Study Design

• Study Type: Interventional
• Actual Enrollment: 1370 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
• Primary Purpose: Treatment
• Official Title: A Phase 3b, Multi-center, Randomized-withdrawal, Placebo-controlled, Double-blind, Parallel-group Trial to Compare the Efficacy and Safety of Tolvaptan (45 to 120 mg/Day, Split-dose) in Subjects With Chronic Kidney Disease Between Late Stage 2 to Early Stage 4 Due to Autosomal Dominant Polycystic Kidney Disease
• Study Start Date: May 1, 2014
• Actual Primary Completion Date: Apr 18, 2017
• Actual Study Completion Date: Apr 18, 2017

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Tolvaptan Tolvaptan (OPC-41061)	Drug: Tolvaptan (OPC-41061); Tolvaptan tablets (15 or 30 mg) will be self-administered orally as split-dose regimens, once upon awakening and another approximately 8 to 9 hours later.
Placebo Comparator: Placebo Placebo	Drug: Placebo; Matching placebo tablets will be self-administered orally as split-dose regimens, once upon awakening and another approximately 8 to 9 hours later

Outcome Measures

Primary Outcome Measures

1. The Mean Annualized Change in eGFR From Pretreatment Baseline to Post-treatment Follow-up. [Pretreatment baseline to post-treatment follow-up (up to 61 weeks).]

   The mean annualized change in eGFR was calculated using the Chronic Kidney Disease-Epidemiology (CKD-EPI) formula from pretreatment baseline to post-treatment follow-up, annualized (divided) by each subject's trial duration. The baseline for the primary endpoint was defined as the average of up to 3 eGFR values observed during the screening and placebo run-in periods.

Secondary Outcome Measures

1. Mean Annualized Slope of eGFR Change [Pretreatment baseline to post-treatment follow-up (up to 61 weeks).]

   To compare the efficacy of tolvaptan treatment in reducing the decline of annualized eGFR slope, as compared with placebo, in subjects with late-stage CKD due to ADPKD who tolerated tolvaptan during an initial run-in period, the annualized rate of eGFR change was derived from each individual subject's eGFR slope using the CKD-EPI formula. The annualized eGFR change slope was derived from all eGFR observations from placebo-run-in, tolvaptan run-in, double-blind treatment and post-treatment follow-up periods using the linear mixed model of analysis. The mean annualized slope of eGFR change is presented.

Other Outcome Measures

1. Mean Change From Baseline in Urine Osmolality During the Double-blind Treatment Period and Post-treatment Follow-up [Baseline and Months 3, 6, 9 and 12 (End of treatment visit) of the double-blind treatment period, and post-treatment follow-up.]

   The mean change from baseline in urine osmolality for the double-blind treatment period collection timepoints and post-treatment follow-up are presented. Baseline was defined as the last evaluation prior to post-randomization dosing.

2. Mean Change From Baseline in Urine Specific Gravity During the Double-blind Treatment Period and Post-treatment Follow-up [Baseline and Months 3, 6, 9 and 12 (End of treatment visit) of the double-blind treatment period, and post-treatment follow-up.]

   The mean change from baseline in urine specific gravity for the double-blind treatment period collection timepoints and post-treatment follow up are presented. Baseline was defined as the last evaluation prior to post-randomization dosing.

Eligibility Criteria

Criteria

• Ages Eligible for Study: 18 Years to 65 Years
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Inclusion Criteria:

• Male and female subjects with eGFR between 25-65 mL/min/1.73m2 (if aged 18 to55) or eGFR between 25-44 mL/min/1.73m2 (if aged 56 to <66)

• Tolvaptan naïve

• Diagnosis of ADPKD by modified pei-Ravine criteria 1) 3 cysts per kidney by sonography or 5 cysts by CT or MRI with family history of ADPKD or 2) 10 cysts per kidney by any radiologic method and exclusion of other cystic kidney diseases if without family history

Exclusion Criteria:

• Women of childbearing potential who do not agree to practice 2 different methods of birth control or remain abstinent during the trial and for 30 days after the last dose of Investigational medicinal product (IMP)

• Women who are breast-feeding and/or who have a positive pregnancy test prior to receiving IMP

• Need for chronic diuretic use

• Hepatic impairment or liver function abnormalities other than that expected for ADPKD with typical cystic liver disease

• Advanced diabetes, evidence of additional significant renal disease, renal cancer, single kidney, recent renal surgery or acute kidney injury

• Contraindications to required trial assessments

• Medical history or medical findings inconsistent with safety or compliance with trial assessments

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1		Birmingham	Alabama	United States	35294
2		Huntsville	Alabama	United States	35805
3		Mobile	Alabama	United States	36617
4		Phoenix	Arizona	United States	85381
5		Tempe	Arizona	United States	85284
6		Tucson	Arizona	United States	85745
7		La Jolla	California	United States	92037
8		Los Angeles	California	United States	90022
9		Los Angeles	California	United States	90025
10		San Francisco	California	United States	94143
11		Aurora	Colorado	United States	80045
12		Denver	Colorado	United States	80210
13		New Haven	Connecticut	United States	06520
14		Hudson	Florida	United States	34667
15		Jacksonville	Florida	United States	32216
16		Miami	Florida	United States	33150
17		Ocala	Florida	United States	34471
18		Port Charlotte	Florida	United States	33952
19		Tampa	Florida	United States	33614
20		Atlanta	Georgia	United States	30322
21		Augusta	Georgia	United States	30909
22		Meridian	Idaho	United States	83642
23		Chicago	Illinois	United States	60637
24		Kansas City	Kansas	United States	66160
25		Wichita	Kansas	United States	67214
26		Baton Rouge	Louisiana	United States	70808
27		Lafayette	Louisiana	United States	70503
28		Baltimore	Maryland	United States	21201
29		Greenbelt	Maryland	United States	20770
30		Rockville	Maryland	United States	20850
31		Wheaton	Maryland	United States	20906
32		Boston	Massachusetts	United States	02215
33		Springfield	Massachusetts	United States	01107
34		Detroit	Michigan	United States	48202
35		Kalamazoo	Michigan	United States	49007
36		Pontiac	Michigan	United States	48341
37		Roseville	Michigan	United States	48066
38		Minneapolis	Minnesota	United States	55404
39		Rochester	Minnesota	United States	55905
40		Saint Louis	Missouri	United States	63110
41		Las Vegas	Nevada	United States	89128
42		Reno	Nevada	United States	89511
43		Eatontown	New Jersey	United States	07724
44		Voorhees	New Jersey	United States	08043
45		Buffalo	New York	United States	14215
46		Mineola	New York	United States	11501
47		New York	New York	United States	10016
48		New York	New York	United States	10021
49		New York	New York	United States	10032
50		Rosedale	New York	United States	11422
51		Asheville	North Carolina	United States	28801
52		Chapel Hill	North Carolina	United States	27599-7155
53		Charlotte	North Carolina	United States	28207
54		Winston-Salem	North Carolina	United States	27103
55		Fargo	North Dakota	United States	58122
56		Grand Forks	North Dakota	United States	58201
57		Akron	Ohio	United States	44302
58		Cincinnati	Ohio	United States	45206
59		Cleveland	Ohio	United States	44106
60		Cleveland	Ohio	United States	44195
61		Columbus	Ohio	United States	43210
62		Portland	Oregon	United States	98686
63		Bethlehem	Pennsylvania	United States	18017
64		Doylestown	Pennsylvania	United States	18901
65		Philadelphia	Pennsylvania	United States	19104
66		Charleston	South Carolina	United States	29425
67		Columbia	South Carolina	United States	29203
68		Orangeburg	South Carolina	United States	29118
69		Knoxville	Tennessee	United States	39723
70		Nashville	Tennessee	United States	37205
71		Nashville	Tennessee	United States	37232
72		Arlington	Texas	United States	76015
73		Houston	Texas	United States	77030-3411
74		Houston	Texas	United States	77030
75		McAllen	Texas	United States	78503
76		Burlington	Vermont	United States	05401
77		Arlington	Virginia	United States	22205
78		Charlottesville	Virginia	United States	22908
79		Norfolk	Virginia	United States	23507
80		Wenatchee	Washington	United States	98801
81		Morgantown	West Virginia	United States	26506
82		La Crosse	Wisconsin	United States	54601
83		Bahia Blanca	Buenos Aires	Argentina	B8000FTD
84		Ciudad Autonoma	Buenos Aires	Argentina	C1093AAS
85		Ciudad Autonoma	Buenos Aires	Argentina	C1119ACN
86		Ciudad Autonoma	Buenos Aires	Argentina	C1425APQ
87		Ciudad Autonoma	Buenos Aires	Argentina	C1429BWN
88		Ciudad Autonoma	Buenos Aires	Argentina	C1431FWO
89		Junin	Buenos Aires	Argentina	6000
90		Pergamino	Buenos Aires	Argentina	B2700CPM
91		Pilar	Buenos Aires	Argentina	B1629ODT
92		Sarandi	Buenos Aires	Argentina	B1872EEA
93		Cordoba		Argentina	X5000JHQ
94		Cordoba		Argentina	X5003DCE
95		Cordoba		Argentina	X5016KEH
96		Camperdown	New South Wales	Australia	2050
97		Concord	New South Wales	Australia	2139
98		New Lambton Heights	New South Wales	Australia	2305
99		St. Leonards	New South Wales	Australia	2065
100		Westmead	New South Wales	Australia	2145
101		Woolloongabba	Queensland	Australia	4102
102		Adelaide	South Australia	Australia	5000
103		Launceston	Tasmania	Australia	7250
104		Parkville	Victoria	Australia	3050
105		Reservoir	Victoria	Australia	3073
106		Richmond	Victoria	Australia	3121
107		Perth	Western Australia	Australia	6000
108		Aalst		Belgium	9300
109		Antwerpen		Belgium	2650
110		Bruxelles		Belgium	1090
111		Bruxelles		Belgium	1200
112		Gent		Belgium	9000
113		Kortrijk		Belgium	8500
114		Leuven		Belgium	3000
115		Liège		Belgium	400
116		Edmonton	Alberta	Canada	T6G 2B7
117		St. John's	Newfoundland and Labrador	Canada	A1B 3V6
118		Scarborough	Ontario	Canada	M1H 3G4
119		Toronto	Ontario	Canada	M4C 5T2
120		Toronto	Ontario	Canada	M5C 2T2
121		Toronto	Ontario	Canada	M5G 2N2
122		Greenfield Park	Quebec	Canada	J4V 2H1
123		Montreal	Quebec	Canada	H3A 1A1
124		Montréal	Quebec	Canada	H4J 1C5
125		Brno		Czechia	625 00
126		Ceske Budejovice		Czechia	370 01
127		Hradec Kralove		Czechia	500 05
128		Jihlava		Czechia	586 33
129		Jilemnice		Czechia	51401
130		Liberec		Czechia	460 63
131		Ostrava		Czechia	708 52
132		Praha 2		Czechia	128 08
133		Praha 4		Czechia	140 21
134		Tabor		Czechia	390 03
135		Aalborg		Denmark	9100
136		Aarhus C		Denmark	8000
137		Holstebro		Denmark	7500
138		Odense C		Denmark	5000
139		Viborg		Denmark	8800
140		Brest cedex 2	Finistere	France	29609
141		Bordeaux Cedex	Gironde	France	33000
142		Toulouse Cedex 9	Haute Garonne	France	31059
143		Montpellier cedex 5	Herault	France	34295
144		Grenoble cedex 9	Isere	France	38043
145		Saint-Priest-En-Jarez	Loire	France	42055
146		Reims Cedex	Marne	France	51090
147		Vandoeuvre les Nancy	Meurthe Et Moselle	France	54511
148		Lyon Cedex 03	Rhone	France	69437
149		Pierre-Bénite cedex	Rhone	France	69495
150		Heidelberg	Baden Wuerttemberg	Germany	69120
151		Muenchen	Bayern	Germany	81675
152		Nuernberg	Bayern	Germany	90471
153		Hannover	Niedersachsen	Germany	30625
154		Duesseldorf	Nordrhein Westfalen	Germany	40210
155		Essen	Nordrhein Westfalen	Germany	45147
156		Wiesbaden	Nordrhein Westfalen	Germany	65191
157		Dresden	Sachsen	Germany	01307
158		Budapest		Hungary	1032
159		Pecs		Hungary	7623
160		Szeged		Hungary	6720
161		Ashkelon		Israel	7830604
162		Jerusalem		Israel	9112001
163		Nahariya		Israel	22100
164		Petach Tikva		Israel	4941492
165		Petaẖ Tiqwa		Israel	4941492
166		Ramat-Gan		Israel	52621
167		Tel Aviv		Israel	34239
168		Torrette Di Ancona	Ancona	Italy	60126
169		Montichiari	Brescia	Italy	25018
170		Bari		Italy	70124
171		Bologna		Italy	40138
172		Lecco		Italy	23900
173		Milano		Italy	20122
174		Milano		Italy	20132
175		Modena		Italy	41124
176		Napoli		Italy	80131
177		Pavia		Italy	27100
178		Groningen		Netherlands	9713 GZ
179		Nijmegen		Netherlands	6525 GA
180		Bergen		Norway	5021
181		Oslo		Norway	0424
182		Stavanger		Norway	4068
183		Ciechanow		Poland	06-400
184		Golub Dobrzyn		Poland	87-400
185		Kraków		Poland	31-559
186		Lodz		Poland	92-213
187		Lublin		Poland	20-954
188		Warszawa		Poland	04-749
189		Wroclaw		Poland	50-556
190		Łódź		Poland	92-313
191		San Juan		Puerto Rico	00918
192		Bucuresti		Romania	011794
193		Bucuresti		Romania	022328
194		Oradea		Romania	410649
195		Krasnoyarsk		Russian Federation	660062
196		St. Petersburg		Russian Federation	194044
197		St. Petersburg		Russian Federation	197110
198		Yaroslavl		Russian Federation	150062
199		Pretoria	Gauteng	South Africa	0002
200		Durban	KwaZulu-Natal	South Africa	4001
201		Cape Town	Western Cape	South Africa	7925
202		L'Hospitalet de Llobregat	Barcelona	Spain	08907
203		Ciudad Real		Spain	13005
204		Madrid		Spain	28041
205		Madrid		Spain	28046
206		Sevilla		Spain	41009
207		Sevilla		Spain	41071
208		Valencia		Spain	46017
209		Göteborg		Sweden	41345
210		Linköping		Sweden	58185
211		Stockholm		Sweden	141 86
212		Stockholm		Sweden	14186
213		Uppsala		Sweden	75185
214		Örebro		Sweden	70185
215		Exeter	Devon	United Kingdom	EX2 5DW
216		Hull	East Riding Of Yorkshire	United Kingdom	HU3 2JZ
217		Brighton	East Sussex	United Kingdom	BN2 5BE
218		London	Greater London	United Kingdom	NW3 2QG
219		Manchester	Greater Manchester	United Kingdom	M13 9WL
220		Salford	Greater Manchester	United Kingdom	M6 8HD
221		Stevenage	Hertfordshire	United Kingdom	SG1 4AB
222		Inverness	Highland Region	United Kingdom	IV2 3UJ
223		Leicester	Leicestershire	United Kingdom	LE5 4PW
224		Edinburgh	Lothian Region	United Kingdom	EH16 4SA
225		Liverpool	Merseyside	United Kingdom	L7 8XP
226		Middlesbrough	North Yorkshire	United Kingdom	TS4 3BW
227		Sheffield	South Yorkshire	United Kingdom	S5 7AU
228		Stoke-on-Trent	Staffordshire	United Kingdom	ST4 6QG
229		Newcastle upon Tyne	Tyne & Wear	United Kingdom	NE7 7DN
230		Coventry	Warwickshire	United Kingdom	CV2 2DX
231		Swansea		United Kingdom	SA6 6NL

Sponsors and Collaborators

• Otsuka Pharmaceutical Development & Commercialization, Inc.

Investigators

None specified.

Study Documents (Full-Text)

• Statistical Analysis Plan - Mar 31, 2017
• Study Protocol - Mar 26, 2015

More Information

Publications

None provided.

• Responsible Party: Otsuka Pharmaceutical Development & Commercialization, Inc.
• ClinicalTrials.gov Identifier: NCT02160145
• Other Study ID Numbers: 156-13-210
• First Posted: Jun 10, 2014
• Last Update Posted: Aug 8, 2018
• Last Verified: Jul 1, 2018

• Keywords provided by Otsuka Pharmaceutical Development & Commercialization, Inc.: Chronic Kidney Disease; Autosomal Dominant Polycystic Kidney Disease
• Additional relevant MeSH terms: Arthrogryposis; Kidney Diseases; Renal Insufficiency, Chronic; Polycystic Kidney Diseases; Polycystic Kidney, Autosomal Dominant; Tolvaptan

Study Results

Participant Flow

Recruitment Details	First subject first visit: 21 May 2014; Last subject last visit: 18 April 2017. Subjects were recruited from 213 sites in 21 countries. Of 2292 subjects screened, 1519 entered the 6-week run-in period; 23 were placebo run-in failures and 126 were tolvaptan titration/run-in failures.
Pre-assignment Detail	Subjects with Stage 2 - 4 chronic kidney disease (CKD) due to Autosomal Dominant Polycystic Kidney Disease (ADPKD) were stratified by baseline estimated glomerular filtration rate (eGFR) (≤ 45 or > 45 milliliters/minute/ 1.73 square metres [mL/min/1.73 m^2]), by age (≤ 55 or > 55 years), and total kidney volume (≤ 2000 mL, > 2000 mL, or unknown).

Arm/Group Title	All Subjects Prerandomization	Tolvaptan	Placebo
Arm/Group Description	Following screening, the single-blind prerandomization period (Day -42 to Day -1) consisted of: Placebo Run-in: All subjects received a daily split-dose of placebo (0/0 milligrams [mg]) in a form identical to 15/15 mg tolvaptan split-dose for 1 week. Tolvaptan Titration: Over 2 weeks all subjects received a split-dose of 30/15 mg (2 x 15mg tablets upon waking, then 1 x 15 mg tablet 8-9 hours later) which was titrated up every 3-4 days to 45/15 mg, then 60/30 mg, and up to a maximum dose of 90/30 mg. Tolvaptan Run-in: Eligible subjects who tolerated at least 60/30 mg tolvaptan during titration entered the 3-week run-in period and continued on a stable dose of 60/30 mg or 90/30 mg tolvaptan to confirm eligibility and establish prerandomization baseline.	Double-blind Randomized Treatment Period (Day 0 to Month 12): Following randomization subjects continued on the same dose of tolvaptan they received during the tolvaptan run-in period (60/30 mg or 90/30 mg) for a duration of 12 months. Follow-up Period: A 3-week final follow-up for efficacy analysis.	Double-blind Randomized Treatment Period (Day 0 to Month 12): Following randomization subjects received placebo tablets matching their tolerated tolvaptan dose during the tolvaptan run-in period (60/30 mg or 90/30 mg) for a duration of 12 months. Follow-up Period: A 3-week final follow-up for efficacy analysis.
Period Title: Prerandomization Single-blind Period
STARTED	1519	0	0
Treated in Placebo Run-in	1514	0	0
Treated in Tolvaptan Titration/Run-in	1491	0	0
Randomized	1370	0	0
COMPLETED	1370	0	0
NOT COMPLETED	149	0	0
Period Title: Prerandomization Single-blind Period
STARTED	0	683	687
On-treatment Completers	0	578	637
Off-treatment Completers	0	76	22
COMPLETED	0	654	659
NOT COMPLETED	0	29	28

Baseline Characteristics

Arm/Group Title	Tolvaptan	Placebo	Total Title
Arm/Group Description	Double-blind Randomized Treatment Period (Day 0 to Month 12): Following randomization subjects continued on the same dose of tolvaptan they received during the tolvaptan run-in period (60/30 mg or 90/30 mg) for a duration of 12 months. Follow-up Period: A 3-week final follow-up for efficacy analysis.	Double-blind Randomized Treatment Period (Day 0 to Month 12): Following randomization subjects received placebo tablets matching their tolerated tolvaptan dose during the tolvaptan run-in period (60/30 mg or 90/30 mg) for a duration of 12 months. Follow-up Period: A 3-week final follow-up for efficacy analysis.
Overall Participants	683	687	1370
Age (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	47.3 (8.2)	47.2 (8.2)	47.3 (8.2)
Sex: Female, Male (Count of Participants)
Female	336 49.2%	354 51.5%	690 50.4%
Male	347 50.8%	333 48.5%	680 49.6%
Ethnicity (NIH/OMB) (Count of Participants)
Hispanic or Latino	44 6.4%	35 5.1%	79 5.8%
Not Hispanic or Latino	632 92.5%	647 94.2%	1279 93.4%
Unknown or Not Reported	7 1%	5 0.7%	12 0.9%
Race (NIH/OMB) (Count of Participants)
American Indian or Alaska Native	3 0.4%	1 0.1%	4 0.3%
Asian	22 3.2%	19 2.8%	41 3%
Native Hawaiian or Other Pacific Islander	0 0%	0 0%	0 0%
Black or African American	25 3.7%	23 3.3%	48 3.5%
White	626 91.7%	632 92%	1258 91.8%
More than one race	0 0%	0 0%	0 0%
Unknown or Not Reported	7 1%	12 1.7%	19 1.4%

Outcome Measures

1. Primary Outcome

Title	The Mean Annualized Change in eGFR From Pretreatment Baseline to Post-treatment Follow-up.
Description	The mean annualized change in eGFR was calculated using the Chronic Kidney Disease-Epidemiology (CKD-EPI) formula from pretreatment baseline to post-treatment follow-up, annualized (divided) by each subject's trial duration. The baseline for the primary endpoint was defined as the average of up to 3 eGFR values observed during the screening and placebo run-in periods.
Time Frame	Pretreatment baseline to post-treatment follow-up (up to 61 weeks).

Outcome Measure Data

Analysis Population Description

The primary endpoint efficacy population consisted of all subjects who were in the randomized sample, took at least 1 dose of investigational medicinal product (IMP) after randomization, and had a baseline and at least 1 valid post-treatment evaluation in eGFR (i.e at least 1 week off-treatment).

Arm/Group Title	Tolvaptan	Placebo
Arm/Group Description	Double-blind Randomized Treatment Period (Day 0 to Month 12): Following randomization subjects continued on the same dose of tolvaptan they received during the tolvaptan run-in period (60/30 mg or 90/30 mg) for a duration of 12 months. Follow-up Period: A 3-week final follow-up for efficacy analysis.	Double-blind Randomized Treatment Period (Day 0 to Month 12): Following randomization subjects received placebo tablets matching their tolerated tolvaptan dose during the tolvaptan run-in period (60/30 mg or 90/30 mg) for a duration of 12 months. Follow-up Period: A 3-week final follow-up for efficacy analysis.
Measure Participants	668	663
Least Squares Mean (Standard Error) [mL/min/1.73 m^2/year]	-2.339 (0.240)	-3.610 (0.240)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Tolvaptan, Placebo
	Comments	Tolvaptan versus placebo. Treatment difference in the change of eGFR assessed the efficacy of tolvaptan treatment as compared with placebo in subjects with late-stage CKD due to ADPKD who tolerated tolvaptan during an initial run-in period.
	Type of Statistical Test	Other
	Comments
Statistical Test of Hypothesis	p-Value	<0.0001
	Comments	A 2-sided alpha of 0.05 was applied to the primary analysis of the primary endpoint.
	Method	ANCOVA
	Comments	Weighted Analysis of Covariance (ANCOVA) with effects of treatment and randomization stratification factors and covariate baseline.
Method of Estimation	Estimation Parameter	Treatment difference
	Estimated Value	1.271
	Confidence Interval	(2-Sided) 95%; 0.859 to 1.684
	Parameter Dispersion	Type: Value:
	Estimation Comments

2. Secondary Outcome

Title	Mean Annualized Slope of eGFR Change
Description	To compare the efficacy of tolvaptan treatment in reducing the decline of annualized eGFR slope, as compared with placebo, in subjects with late-stage CKD due to ADPKD who tolerated tolvaptan during an initial run-in period, the annualized rate of eGFR change was derived from each individual subject's eGFR slope using the CKD-EPI formula. The annualized eGFR change slope was derived from all eGFR observations from placebo-run-in, tolvaptan run-in, double-blind treatment and post-treatment follow-up periods using the linear mixed model of analysis. The mean annualized slope of eGFR change is presented.
Time Frame	Pretreatment baseline to post-treatment follow-up (up to 61 weeks).

Outcome Measure Data

Analysis Population Description

The key secondary endpoint efficacy population consisted of all randomized subjects who took at least 1 dose of IMP after randomization, and have a baseline (average of up to 3 eGFR values observed during screening and placebo run-in periods) and at least 1 post-randomization evaluation in eGFR during the double-blind treatment period.

Arm/Group Title	Tolvaptan	Placebo
Arm/Group Description	Double-blind Randomized Treatment Period (Day 0 to Month 12): Following randomization subjects continued on the same dose of tolvaptan they received during the tolvaptan run-in period (60/30 mg or 90/30 mg) for a duration of 12 months. Follow-up Period: A 3-week final follow-up for efficacy analysis.	Double-blind Randomized Treatment Period (Day 0 to Month 12): Following randomization subjects received placebo tablets matching their tolerated tolvaptan dose during the tolvaptan run-in period (60/30 mg or 90/30 mg) for a duration of 12 months. Follow-up Period: A 3-week final follow-up for efficacy analysis.
Measure Participants	680	682
Least Squares Mean (Standard Error) [mL/min/1.73m^2/year]	-3.160 (0.140)	-4.170 (0.142)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Tolvaptan, Placebo
	Comments	Difference in treatment effect was derived from a linear mixed model with effects of treatment, time, treatment ime interaction, acute haemodynamic effect, pretreatment baseline, and randomization stratification factors. An unstructured variance matrix was assumed for the random intercept and time.
	Type of Statistical Test	Other
	Comments
Statistical Test of Hypothesis	p-Value	<0.0001
	Comments	A two-sided alpha of 0.05 was applied when the primary endpoint reached a two-sided alpha of 0.05.
	Method	Mixed Models Analysis
	Comments
Method of Estimation	Estimation Parameter	Treatment difference
	Estimated Value	1.011
	Confidence Interval	(2-Sided) 95%; 0.618 to 1.403
	Parameter Dispersion	Type: Value:
	Estimation Comments

3. Other Pre-specified Outcome

Title	Mean Change From Baseline in Urine Osmolality During the Double-blind Treatment Period and Post-treatment Follow-up
Description	The mean change from baseline in urine osmolality for the double-blind treatment period collection timepoints and post-treatment follow-up are presented. Baseline was defined as the last evaluation prior to post-randomization dosing.
Time Frame	Baseline and Months 3, 6, 9 and 12 (End of treatment visit) of the double-blind treatment period, and post-treatment follow-up.

Outcome Measure Data

Analysis Population Description

The primary safety population consisted of all subjects who were randomized and took at least 1 dose of IMP after randomization. Only subjects with data available for analysis at the timepoints of testing are presented.

Arm/Group Title	Tolvaptan	Placebo
Arm/Group Description	Double-blind Randomized Treatment Period (Day 0 to Month 12): Following randomization subjects continued on the same dose of tolvaptan they received during the tolvaptan run-in period (60/30 mg or 90/30 mg) for a duration of 12 months. Follow-up Period: A 3-week final follow-up for efficacy analysis.	Double-blind Randomized Treatment Period (Day 0 to Month 12): Following randomization subjects received placebo tablets matching their tolerated tolvaptan dose during the tolvaptan run-in period (60/30 mg or 90/30 mg) for a duration of 12 months. Follow-up Period: A 3-week final follow-up for efficacy analysis.
Measure Participants	681	685
Month 3	10.2 (80.3)	177.7 (124.5)
Month 6	22.9 (84.3)	179.1 (126.2)
Month 9	30.4 (92.1)	179.9 (125.1)
Month12	36.9 (96.0)	180.3 (121.1)
Follow-up	162.4 (114.0)	179.5 (128.9)

4. Other Pre-specified Outcome

Title	Mean Change From Baseline in Urine Specific Gravity During the Double-blind Treatment Period and Post-treatment Follow-up
Description	The mean change from baseline in urine specific gravity for the double-blind treatment period collection timepoints and post-treatment follow up are presented. Baseline was defined as the last evaluation prior to post-randomization dosing.
Time Frame	Baseline and Months 3, 6, 9 and 12 (End of treatment visit) of the double-blind treatment period, and post-treatment follow-up.

Outcome Measure Data

Analysis Population Description

The primary safety population consisted of all subjects who were randomized and took at least 1 dose of IMP after randomization. Only subjects with data available for analysis at the timepoints of testing are presented.

Arm/Group Title	Tolvaptan	Placebo
Arm/Group Description	Double-blind Randomized Treatment Period (Day 0 to Month 12): Following randomization subjects continued on the same dose of tolvaptan they received during the tolvaptan run-in period (60/30 mg or 90/30 mg) for a duration of 12 months. Follow-up Period: A 3-week final follow-up for efficacy analysis.	Double-blind Randomized Treatment Period (Day 0 to Month 12): Following randomization subjects received placebo tablets matching their tolerated tolvaptan dose during the tolvaptan run-in period (60/30 mg or 90/30 mg) for a duration of 12 months. Follow-up Period: A 3-week final follow-up for efficacy analysis.
Measure Participants	681	685
Month 3	0.0001 (0.0022)	0.0041 (0.0033)
Month 6	0.0003 (0.0024)	0.0042 (0.0033)
Month 9	0.004 (0.0025)	0.0040 (0.0032)
Month 12	0.0006 (0.0027)	0.0040 (0.0033)
Follow-up	0.0037 (0.0031)	0.0040 (0.0034)

Adverse Events

Time Frame	For the tolvaptan single-blind period: 35 days (Day -35 to Day -1). For the double-blind treatment period: 12 months (Day 0 to 12 months).
Adverse Event Reporting Description	Treatment emergent adverse events (AEs) were collected, defined as an AE that started after IMP treatment or an AE that was continuous from baseline and was serious, IMP related or resulted in death, discontinuation, interruption or reduction of IMP treatment.
Arm/Group Title	Tolvaptan (Single-blind Treatment Period)		Tolvaptan (Double-blind Treatment Period)		Placebo (Double-blind Treatment Period)
Arm/Group Description	The secondary safety population consisted of all subjects who took at least one dose of tolvaptan during the tolvaptan titration/run-in periods.		The tolvaptan primary safety population consisted of all subjects who were randomized in the double-blind treatment period and who took at least one dose of tolvaptan after randomization.		The placebo primary safety population consisted of all subjects who were randomized in the double-blind treatment period and who took at least one dose of placebo after randomization.
All Cause Mortality
	Tolvaptan (Single-blind Treatment Period)		Tolvaptan (Double-blind Treatment Period)		Placebo (Double-blind Treatment Period)
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	1/1491 (0.1%)		0/681 (0%)		1/685 (0.1%)
Serious Adverse Events
	Tolvaptan (Single-blind Treatment Period)		Tolvaptan (Double-blind Treatment Period)		Placebo (Double-blind Treatment Period)
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	43/1491 (2.9%)		85/681 (12.5%)		60/685 (8.8%)
Blood and lymphatic system disorders
Anaemia	0/1491 (0%)	0	1/681 (0.1%)	1	0/685 (0%)	0
Neutropenia	0/1491 (0%)	0	1/681 (0.1%)	1	0/685 (0%)	0
Cardiac disorders
Angina Pectoris	1/1491 (0.1%)	1	0/681 (0%)	0	0/685 (0%)	0
Atrial fibrillation	1/1491 (0.1%)	1	1/681 (0.1%)	1	1/685 (0.1%)	1
Acute myocardial infarction	0/1491 (0%)	0	0/681 (0%)	0	2/685 (0.3%)	2
Aortic valve incompetence	0/1491 (0%)	0	1/681 (0.1%)	1	0/685 (0%)	0
Arteriosclerosis coronary artery	0/1491 (0%)	0	1/681 (0.1%)	1	0/685 (0%)	0
Mitral valve incompetence	0/1491 (0%)	0	1/681 (0.1%)	1	0/685 (0%)	0
Mitral valve prolapse	0/1491 (0%)	0	1/681 (0.1%)	1	0/685 (0%)	0
Pericardial effusion	0/1491 (0%)	0	1/681 (0.1%)	1	0/685 (0%)	0
Congenital, familial and genetic disorders
Congenital Hepatic Fibrosis	0/1491 (0%)	0	0/681 (0%)	0	1/685 (0.1%)	1
Ear and labyrinth disorders
Vertigo	1/1491 (0.1%)	1	0/681 (0%)	0	0/685 (0%)	0
Gastrointestinal disorders
Abdominal pain	1/1491 (0.1%)	1	1/681 (0.1%)	1	0/685 (0%)	0
Gastritis	1/1491 (0.1%)	1	0/681 (0%)	0	0/685 (0%)	0
Intestinal obstruction	1/1491 (0.1%)	1	0/681 (0%)	0	0/685 (0%)	0
Abdominal Hernia	0/1491 (0%)	0	0/681 (0%)	0	1/685 (0.1%)	1
Abdominal Incarcerated Hernia	0/1491 (0%)	0	0/681 (0%)	0	1/685 (0.1%)	1
Abdominal pain lower	0/1491 (0%)	0	0/681 (0%)	0	1/685 (0.1%)	1
Gastrointestinal haemorrhage	0/1491 (0%)	0	1/681 (0.1%)	1	1/685 (0.1%)	1
Gastrooesophageal reflux disease	0/1491 (0%)	0	1/681 (0.1%)	1	0/685 (0%)	0
Ileus	0/1491 (0%)	0	0/681 (0%)	0	1/685 (0.1%)	1
Nausea	0/1491 (0%)	0	1/681 (0.1%)	1	0/685 (0%)	0
Pancreatitis acute	0/1491 (0%)	0	0/681 (0%)	0	1/685 (0.1%)	1
Swollen tongue	0/1491 (0%)	0	0/681 (0%)	0	1/685 (0.1%)	1
Umbilical hernia	0/1491 (0%)	0	1/681 (0.1%)	1	0/685 (0%)	0
General disorders
Fatigue	1/1491 (0.1%)	1	1/681 (0.1%)	1	1/685 (0.1%)	1
Pyrexia	1/1491 (0.1%)	1	0/681 (0%)	0	1/685 (0.1%)	1
Thirst	2/1491 (0.1%)	2	0/681 (0%)	0	0/685 (0%)	0
Cyst rupture	0/1491 (0%)	0	1/681 (0.1%)	1	0/685 (0%)	0
Non-cardiac chest pain	0/1491 (0%)	0	1/681 (0.1%)	1	1/685 (0.1%)	1
Hepatobiliary disorders
Drug-induced liver injury	1/1491 (0.1%)	1	0/681 (0%)	0	0/685 (0%)	0
Hepatic function abnormal	1/1491 (0.1%)	1	0/681 (0%)	0	0/685 (0%)	0
Cholangitis	0/1491 (0%)	0	0/681 (0%)	0	1/685 (0.1%)	2
Cholelithiasis	0/1491 (0%)	0	1/681 (0.1%)	1	0/685 (0%)	0
Haemorrhagic hepatic cyst	0/1491 (0%)	0	0/681 (0%)	0	1/685 (0.1%)	1
Hepatic cyst	0/1491 (0%)	0	1/681 (0.1%)	1	0/685 (0%)	0
Hepatitis toxic	0/1491 (0%)	0	1/681 (0.1%)	1	0/685 (0%)	0
Hypertransaminasaemia	0/1491 (0%)	0	1/681 (0.1%)	1	1/685 (0.1%)	1
Liver injury	0/1491 (0%)	0	1/681 (0.1%)	1	0/685 (0%)	0
Immune system disorders
Drug hypersensitivity	0/1491 (0%)	0	0/681 (0%)	0	1/685 (0.1%)	1
Hypersensitivity	0/1491 (0%)	0	0/681 (0%)	0	1/685 (0.1%)	1
Infections and infestations
HIV infection	1/1491 (0.1%)	1	0/681 (0%)	0	0/685 (0%)	0
Pneumonia	1/1491 (0.1%)	1	1/681 (0.1%)	1	0/685 (0%)	0
Pyelonephritis	1/1491 (0.1%)	1	1/681 (0.1%)	1	3/685 (0.4%)	3
Pyelonephritis acute	1/1491 (0.1%)	1	0/681 (0%)	0	0/685 (0%)	0
Renal cyst infection	2/1491 (0.1%)	2	2/681 (0.3%)	2	1/685 (0.1%)	1
Sinusitis	1/1491 (0.1%)	1	0/681 (0%)	0	0/685 (0%)	0
Urinary tract infection	1/1491 (0.1%)	1	3/681 (0.4%)	4	0/685 (0%)	0
Appendicitis	0/1491 (0%)	0	0/681 (0%)	0	1/685 (0.1%)	1
Bacteraemia	0/1491 (0%)	0	1/681 (0.1%)	1	0/685 (0%)	0
Cellulitis	0/1491 (0%)	0	0/681 (0%)	0	1/685 (0.1%)	1
Diverticulitis	0/1491 (0%)	0	1/681 (0.1%)	1	0/685 (0%)	0
Enterobacter bacteraemia	0/1491 (0%)	0	0/681 (0%)	0	1/685 (0.1%)	1
Erysipelas	0/1491 (0%)	0	1/681 (0.1%)	1	0/685 (0%)	0
Gastroenteritis	0/1491 (0%)	0	1/681 (0.1%)	1	1/685 (0.1%)	1
Hepatic cyst infection	0/1491 (0%)	0	0/681 (0%)	0	1/685 (0.1%)	1
Influenza	0/1491 (0%)	0	1/681 (0.1%)	1	0/685 (0%)	0
Klebsiella infection	0/1491 (0%)	0	1/681 (0.1%)	1	0/685 (0%)	0
Otitis media	0/1491 (0%)	0	1/681 (0.1%)	1	0/685 (0%)	0
Respiratory tract infection	0/1491 (0%)	0	1/681 (0.1%)	1	0/685 (0%)	0
Rhinovirus infection	0/1491 (0%)	0	0/681 (0%)	0	1/685 (0.1%)	1
Sepsis	0/1491 (0%)	0	1/681 (0.1%)	1	1/685 (0.1%)	1
Tonsillitis	0/1491 (0%)	0	0/681 (0%)	0	1/685 (0.1%)	1
Upper respiratory tract infection	0/1491 (0%)	0	1/681 (0.1%)	1	0/685 (0%)	0
Urosepsis	0/1491 (0%)	0	0/681 (0%)	0	1/685 (0.1%)	1
Injury, poisoning and procedural complications
Accidental overdose	1/1491 (0.1%)	1	0/681 (0%)	0	0/685 (0%)	0
Fall	0/1491 (0%)	0	0/681 (0%)	0	1/685 (0.1%)	1
Incisional hernia	0/1491 (0%)	0	1/681 (0.1%)	3	0/685 (0%)	0
Ligament rupture	0/1491 (0%)	0	1/681 (0.1%)	1	0/685 (0%)	0
Meniscus injury	0/1491 (0%)	0	0/681 (0%)	0	1/685 (0.1%)	1
Procedural intestinal perforation	0/1491 (0%)	0	1/681 (0.1%)	1	0/685 (0%)	0
Road traffic accident	0/1491 (0%)	0	0/681 (0%)	0	1/685 (0.1%)	1
Subarachnoid haemorrhage	0/1491 (0%)	0	1/681 (0.1%)	1	3/685 (0.4%)	3
Subdural haematoma	0/1491 (0%)	0	2/681 (0.3%)	2	0/685 (0%)	0
Tibia fracture	0/1491 (0%)	0	0/681 (0%)	0	1/685 (0.1%)	1
Investigations
Alanine aminotransferase increased	4/1491 (0.3%)	4	8/681 (1.2%)	8	0/685 (0%)	0
Blood creatinine increased	1/1491 (0.1%)	1	0/681 (0%)	0	2/685 (0.3%)	2
Liver function test abnormal	1/1491 (0.1%)	1	3/681 (0.4%)	3	0/685 (0%)	0
Transaminases increased	1/1491 (0.1%)	1	2/681 (0.3%)	3	0/685 (0%)	0
Aspartate aminotransferase increased	0/1491 (0%)	0	3/681 (0.4%)	3	0/685 (0%)	0
Blood alkaline phosphatase increased	0/1491 (0%)	0	1/681 (0.1%)	1	0/685 (0%)	0
Blood bicarbonate decreased	0/1491 (0%)	0	0/681 (0%)	0	1/685 (0.1%)	1
Gamma-glutamyltransferase increased	0/1491 (0%)	0	1/681 (0.1%)	1	0/685 (0%)	0
Hepatic enzyme increased	0/1491 (0%)	0	11/681 (1.6%)	12	1/685 (0.1%)	1
Liver function test increased	0/1491 (0%)	0	4/681 (0.6%)	7	2/685 (0.3%)	2
Prostatic specific antigen increased	0/1491 (0%)	0	0/681 (0%)	0	1/685 (0.1%)	1
Weight decreased	0/1491 (0%)	0	1/681 (0.1%)	1	0/685 (0%)	0
Metabolism and nutrition disorders
Polydipsia	1/1491 (0.1%)	1	0/681 (0%)	0	0/685 (0%)	0
Hyperglycaemia	0/1491 (0%)	0	0/681 (0%)	0	1/685 (0.1%)	1
Hypokalaemia	0/1491 (0%)	0	0/681 (0%)	0	1/685 (0.1%)	1
Hyponatraemia	0/1491 (0%)	0	0/681 (0%)	0	2/685 (0.3%)	2
Vitamin B complex deficiency	0/1491 (0%)	0	1/681 (0.1%)	1	0/685 (0%)	0
Musculoskeletal and connective tissue disorders
Back pain	1/1491 (0.1%)	1	2/681 (0.3%)	2	1/685 (0.1%)	1
Arthritis	0/1491 (0%)	0	0/681 (0%)	0	1/685 (0.1%)	1
Cervical spinal stenosis	0/1491 (0%)	0	0/681 (0%)	0	1/685 (0.1%)	1
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Basal cell carcinoma	0/1491 (0%)	0	0/681 (0%)	0	2/685 (0.3%)	2
Brain neoplasm benign	0/1491 (0%)	0	0/681 (0%)	0	1/685 (0.1%)	1
Invasive ductal breast carcinoma	0/1491 (0%)	0	0/681 (0%)	0	1/685 (0.1%)	1
Meningioma	0/1491 (0%)	0	0/681 (0%)	0	1/685 (0.1%)	1
Phaeochromocytoma	0/1491 (0%)	0	0/681 (0%)	0	1/685 (0.1%)	1
Nervous system disorders
Carotid artery aneurysm	0/1491 (0%)	0	0/681 (0%)	0	1/685 (0.1%)	1
Cerebral artery thrombosis	0/1491 (0%)	0	0/681 (0%)	0	1/685 (0.1%)	1
Cerebrovascular accident	0/1491 (0%)	0	1/681 (0.1%)	1	1/685 (0.1%)	1
Intracranial aneurysm	0/1491 (0%)	0	1/681 (0.1%)	1	1/685 (0.1%)	1
Intracranial pressure increased	0/1491 (0%)	0	0/681 (0%)	0	1/685 (0.1%)	1
Transient ischaemic attack	0/1491 (0%)	0	2/681 (0.3%)	2	1/685 (0.1%)	1
Psychiatric disorders
Insomnia	1/1491 (0.1%)	1	0/681 (0%)	0	0/685 (0%)	0
Confusional state	0/1491 (0%)	0	0/681 (0%)	0	1/685 (0.1%)	1
Renal and urinary disorders
Acute kidney injury	2/1491 (0.1%)	2	2/681 (0.3%)	2	1/685 (0.1%)	1
Chronic kidney disease	1/1491 (0.1%)	1	1/681 (0.1%)	1	0/685 (0%)	0
Nephrolithiasis	1/1491 (0.1%)	1	0/681 (0%)	0	1/685 (0.1%)	1
Haematuria	0/1491 (0%)	0	1/681 (0.1%)	1	2/685 (0.3%)	2
Nocturia	3/1491 (0.2%)	3	0/681 (0%)	0	0/685 (0%)	0
Pollakiuria	2/1491 (0.1%)	2	0/681 (0%)	0	0/685 (0%)	0
Polyuria	4/1491 (0.3%)	4	0/681 (0%)	0	0/685 (0%)	0
Renal colic	1/1491 (0.1%)	1	0/681 (0%)	0	0/685 (0%)	0
Renal cyst haemorrhage	2/1491 (0.1%)	2	3/681 (0.4%)	3	2/685 (0.3%)	2
Renal impairment	1/1491 (0.1%)	1	2/681 (0.3%)	2	3/685 (0.4%)	3
Renal pain	1/1491 (0.1%)	1	1/681 (0.1%)	1	3/685 (0.4%)	3
Ureteric obstruction	1/1491 (0.1%)	1	0/681 (0%)	0	0/685 (0%)	0
Renal haemorrhage	0/1491 (0%)	0	0/681 (0%)	0	1/685 (0.1%)	1
Reproductive system and breast disorders
Vaginal haemorrhage	0/1491 (0%)	0	1/681 (0.1%)	1	0/685 (0%)	0
Respiratory, thoracic and mediastinal disorders
Pulmonary embolism	1/1491 (0.1%)	1	2/681 (0.3%)	2	0/685 (0%)	0
Cough	0/1491 (0%)	0	1/681 (0.1%)	1	0/685 (0%)	0
Epistaxis	0/1491 (0%)	0	1/681 (0.1%)	1	0/685 (0%)	0
Skin and subcutaneous tissue disorders
Rash	1/1491 (0.1%)	1	0/681 (0%)	0	0/685 (0%)	0
Rash pruritic	0/1491 (0%)	0	1/681 (0.1%)	1	0/685 (0%)	0
Rash Maculo-papular	1/1491 (0.1%)	1	0/681 (0%)	0	0/685 (0%)	0
Vascular disorders
Hypertension	1/1491 (0.1%)	1	0/681 (0%)	0	1/685 (0.1%)	1
Aortic dissection	0/1491 (0%)	0	1/681 (0.1%)	1	0/685 (0%)	0
Other (Not Including Serious) Adverse Events
	Tolvaptan (Single-blind Treatment Period)		Tolvaptan (Double-blind Treatment Period)		Placebo (Double-blind Treatment Period)
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	1051/1491 (70.5%)		581/681 (85.3%)		564/685 (82.3%)
Gastrointestinal disorders
Dry mouth	132/1491 (8.9%)	134	0/681 (0%)	0	0/685 (0%)	0
Diarrhoea	0/1491 (0%)	0	47/681 (6.9%)	54	23/685 (3.4%)	25
General disorders
Thirst	430/1491 (28.8%)	453	0/681 (0%)	0	0/685 (0%)	0
Fatigue	0/1491 (0%)	0	46/681 (6.8%)	49	24/685 (3.5%)	27
Oedema peripheral	0/1491 (0%)	0	30/681 (4.4%)	37	45/685 (6.6%)	50
Infections and infestations
Upper respiratory tract infection	0/1491 (0%)	0	59/681 (8.7%)	70	58/685 (8.5%)	71
Urinary tract infection	0/1491 (0%)	0	39/681 (5.7%)	48	55/685 (8%)	65
Viral upper respiratory tract infection	0/1491 (0%)	0	72/681 (10.6%)	98	84/685 (12.3%)	111
Investigations
Blood creatinine increased	0/1491 (0%)	0	46/681 (6.8%)	58	46/685 (6.7%)	56
Metabolism and nutrition disorders
Polydipsia	146/1491 (9.8%)	147	0/681 (0%)	0	0/685 (0%)	0
Musculoskeletal and connective tissue disorders
Back pain	0/1491 (0%)	0	34/681 (5%)	37	41/685 (6%)	46
Nervous system disorders
Headache	0/1491 (0%)	0	55/681 (8.1%)	66	59/685 (8.6%)	65
Renal and urinary disorders
Nocturia	308/1491 (20.7%)	319	0/681 (0%)	0	0/685 (0%)	0
Polyuria	475/1491 (31.9%)	488	36/681 (5.3%)	38	11/685 (1.6%)	11
Haematuria	0/1491 (0%)	0	37/681 (5.4%)	52	35/685 (5.1%)	42
Renal pain	0/1491 (0%)	0	113/681 (16.6%)	158	130/685 (19%)	174
Vascular disorders
Hypertension	0/1491 (0%)	0	73/681 (10.7%)	88	79/685 (11.5%)	96

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

Principal Investigators are NOT employed by the organization sponsoring the study.

There IS an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.