Dose-finding Study of New Tolvaptan Formulation in Subjects With ADPKD

• Sponsor: Otsuka Pharmaceutical Development & Commercialization, Inc. (Industry)
• Overall Status: Completed
• CT.gov ID: NCT01210560
• Collaborator: (none)
• Enrollment: 25
• Locations: 6
• Arms: 5
• Duration (Months): 8
• Patients Per Site: 4.2
• Patients Per Site Per Month: 0.5

Study Details

Study Description

Brief Summary

To establish pharmacokinetics (PK), pharmacodynamics (PD), and adverse event (AE) profile of tolvaptan administered as the modified-release (MR) formulation in ADPKD subjects. The goals of this trial are two-fold:

1. To directly compare the immediate release (IR) and MR formulations

2. To determine the dose range and dose regimen for MR (dose finding)

Condition or Disease	Intervention/Treatment	Phase
Autosomal Dominant Polycystic Kidney Disease	Drug: Tolvaptan MR; Drug: Tolvaptan MR; Drug: Tolvaptan MR; Drug: Tolvaptan IR; Drug: Tolvaptan MR	Phase 2

Detailed Description

Group 1 will have 12 subjects enrolled in a 3-period, randomized, crossover to compare multiple doses of a 90-30 mg split-dose of the tolvaptan IR formulation, a 120 mg once daily (QD) dose of the tolvaptan MR formulation, and, in an incomplete block randomization, multiple doses of either 20 mg QD, 60 mg QD, or 20 mg twice daily (BID) tolvaptan MR formulation. All dose regimens will be administered for 7 days. Placebo doses will be administered in order to mask QD vs BID treatments.

Group 2 will have 12 subjects enrolled in a 3-period, randomized, crossover to compare multiple oral doses of the tolvaptan MR formulation administered for 7 days as 20 mg QD, 60 mg QD, and 20 mg BID. Placebo capsules will be administered in order to mask QD vs BID treatments.

Subjects will have in-clinic assessments on 12 days to obtain 24-hour PK and PD data. Subjects will visit the clinic from the afternoon of Day -1 through the morning of Day 1. They will return at the end of each dosing period for a similar inpatient period (ie, from the afternoon of Day 6 through the morning of Day 8, from the afternoon of Day 13 through the morning of Day 15, from the afternoon of Day 20 through the morning of Day 22). Except for the first dose of each period and the doses taken in the clinic on the last day of each regimen and the afternoon of Days 6, 13 and 20, all other doses will be taken by the subject as an outpatient.

Study Design

• Study Type: Interventional
• Actual Enrollment: 25 participants
• Allocation: Randomized
• Intervention Model: Crossover Assignment
• Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
• Primary Purpose: Treatment
• Official Title: A Multi-center, Parallel-group, Randomized, Double-blind, Placebo-masked, Multiple Dose Trial of Modified-release (MR) and Immediate-release (IR) Tolvaptan in Subjects With Autosomal Dominant Polycystic Kidney Disease (ADPKD)
• Study Start Date: Oct 1, 2010
• Actual Primary Completion Date: Jun 1, 2011
• Actual Study Completion Date: Jun 1, 2011

Arms and Interventions

Arm	Intervention/Treatment
Experimental: 20 mg MR	Drug: Tolvaptan MR; 20 mg Tolvaptan MR capsule(morning); Placebo capsules/tablets (morning and afternoon) for 7 days; Other Names: OPC-41061
Experimental: 40 mg MR	Drug: Tolvaptan MR; 20 mg Tolvaptan MR capsule(morning and afternoon); Placebo capsules/tablets (morning and afternoon) for 7 days; Other Names: OPC-41061
Experimental: 60 mg MR	Drug: Tolvaptan MR; 60 mg Tolvaptan MR capsule(morning); Placebo capsules/tablets (morning and afternoon) for 7 days; Other Names: OPC-41061
Experimental: 120 mg MR	Drug: Tolvaptan MR; 120 mg Tolvaptan MR capsule(morning); Placebo capsules/tablets (morning and afternoon) for 7 days; Other Names: OPC-41061
Experimental: 120 mg IR	Drug: Tolvaptan IR; 90 mg Tolvaptan IR tablet(morning); 30 mg Tolvaptan IR tablet (afternoon); Placebo capsules (morning and afternoon) for 7 days; Other Names: OPC-41061

Outcome Measures

Primary Outcome Measures

1. Maximum (Peak) Plasma Concentration of the Drug [Cmax] and Minimum (Trough) Plasma Concentration of the Drug [Cmin] After Tolvaptan Treatment on Day 7. [Day 7]

   Blood samples (6 mL) for determination of tolvaptan PK parameters were collected on Day 1 predose, and on Days 7, 14 and 21 at predose, and 1, 2, 4, 6, 8, 9, 10, 12, 16, and 24 hours postdose. If a sample was not drawn at the designated time, a window of ± 3 minutes for each blood draw was acceptable. Maximum and minimum plasma concentration of the drug was calculated.

2. Time to Maximum (Peak) Plasma Concentration (Tmax) After Tolvaptan Treatment on Day 7. [Day 7]

   Blood samples (6 mL) for determination of tolvaptan PK parameters were collected on Day 1 predose, and on Days 7, 14 and 21 at predose, and 1, 2, 4, 6, 8, 9, 10, 12, 16, and 24 hours postdose. If a sample was not drawn at the designated time, a window of ± 3 minutes for each blood draw was acceptable. Time to maximum plasma concentration was calculated.

3. Area Under the Concentration-time Curve During the Dosing Interval at Steady State and Area Under the Concentration-time Curve From Time 0 to 24 Hours Postdose (AUCT & AUC0-24h) After Tolvaptan Treatment on Day 7. [Day 7]

   Blood samples (6 mL) for determination of tolvaptan PK parameters were collected on Day 1 predose, and on Days 7, 14 and 21 at predose, and 1, 2, 4, 6, 8, 9, 10, 12, 16, and 24 hours postdose. If a sample was not drawn at the designated time, a window of ± 3 minutes for each blood draw was acceptable. Hence, both AUCT and AUC0-24h values were calculated.

Secondary Outcome Measures

1. Number of Participants With Urine Osmolality < 300 mOsm/kg at 23.5 Hours Postdose. [23.5 hours post-dose]

   For determination of duration of urine osmolality <300 mOsm/kg, the value was the end time of the last collection interval in which urine osmolality was <300 mOsm/kg. Day 8 in the table below was defined as Day 8 of Period 1, Day 15 of Period 2, and Day 22 of period 3.

2. Change From Baseline in Urine Osmolality Area Under the Concentration-time Curve From Time 0 to 24 Hours Postdose (AUC0-24h) at Day 7. [Day 7]

   The AUC0-24h for urine osmolality was determined by multiplying the concentration by the collection interval duration for each collection interval and summing all the intervals in the 24-hour period. If the urine volume for an interval is zero, the duration of that interval will be added to the next collection interval. Day 7 was defined as Day 7 of Period 1, Day 14 of Period 2 and Day 21 of Period 3.

3. Change From Baseline in Urine Osmolality at Day 7. [0-4, 4-8, 8-12, 12-16, 16-24 Hours at Day 7]

   To determine the tolerability and nighttime urinary suppression of osmolality. The urine osmolality was summarized by collection interval (0 to 4, 4 to 8, 8 to 12, 12 to 16, and 16 to 24 hours)

4. Change From Baseline in Urine Volume at 24 Hours at Day 7. [Day 7]

   Urine volume was collected by 0 to 24-hour interval at Day 7. Day 7 was defined as Day 7 of Period 1, Day 14 of Period 2 and Day 21 of Period 3.

5. Change From Baseline in Urine Volume by Interval at Day 7. [0-4, 4-8, 8-12, 12-16, 16-24 Hours at Day 7]

   Urine volume collected was by interval (0-4, 4-8, 8-12, 12-16, 16-24 hours). Day 7 was defined as Day 7 of Period 1, Day 14 of Period 2 and Day 21 of Period 3.

6. Duration of Urine Osmolality Less Than 300 mOsm/kg at Baseline and Day 7. [Baseline and Day 7]

   Duration of urine osmolality remains below 300 mOsm/kg was the sum of the durations (nominal times) of all intervals where the urine concentration was < 300 mOsm/kg. Day 7 was defined as Day 7 of Period 1, Day 14 of Period 2, and Day 21 of Period 3.

7. Change From Baseline in Number of Urine Voids During Awake Periods. [Days 1, 2, 3, 4, 5, 6 and 7]

   Average number of daily urine voids during awake periods for each dose group. Day 1 was defined as Day1 of Period 1, Day 8 of Period 2 adn Day 15 of Period 3; Day 7 was defined as Day 7 of Period 1, Day 14 of Period 2 and Day 21 of Period 3; Same rule applied to Day 2 and Day 6.

8. Change From Baseline in Number of Urine Voids During Sleep Periods. [Days 1, 2, 3, 4, 5, 6 and 7]

   Average number of daily urine voids during sleep periods for each dose group. Day 1 was defined as Day 1 of Period 1, Day 8 of Period 2, Day 15 of Period 3; Day 7 was defined as Day 7 of Period 1, Day 14 of Period 2 and Day 21 of Period 3; Same rule applied to Day 2 to 6.

9. Change From Baseline in Symptom Burden by Autosomal Dominant Polycystic Kidney Disease (ADPKD) Nocturia Quality of Life Questionnaire at Day 6. [Day 6]

   In ADPKD Nocturia Quality of Life Questionnaire, questions 1 to 11 (with possible scores ranging from 0 to 4 and higher scores indicating better quality of life) were pooled to provide a total score (maximum of 44 points). Response scores of Question 12 (with possible scores ranging from 1 to 10, with higher scores indicating more interference (worse quality of life) with everyday life due to urination at night) were pooled separately. Day 6 was defined as Day 6 of Period 1, Day 13 of Period 2 and Day 20 of Period 3.

10. Number of Participants Experiencing Urinary Urgency Based on Urinary Urgency Questionnaire (Question 1) at Baseline and Day 6. [Baseline and Day 6]

    For the ADPKD Urinary Urgency Questionnaire, Question 1 (currently experiencing urgency?) was assigned 'Yes' or 'No' to measure current urine urgency status. Baseline was defined as last pre-dose evaluation; Day 6 was defined as Day 6 of Period 1, Day 13 of Period 2 and Day 20 of Period 3.

11. Change From Baseline in Urinary Urgency Questionnaire (Questions 2 to 5 and Questions 7 to 14) at Day 6. [Day 6]

    Question 2 to Question 6 were assigned scores of 0 to 4 with higher scores indicating worse cases in experience of urinary urgency. Scores for Question 2 to Question 5 were pooled, with a maximum possible score of 16. Question 6 was excluded from the analysis since it was only asked at screening. Question 7 to Question 14 were also assigned scores of 0 to 4 with higher scores indicating worse cases in impact of urinary urgency on life; scores for these questions were pooled, with a maximum possible score of 32. Baseline was defined as last pre-dose evaluation; Day 6 was defined as Day 6 of Period 1, Day 13 of Period 2 and Day 20 of Period 3.

12. Number of Participants Experiencing Urinary Frequency Based on Urinary Frequency Questionnaire (Question 1) at Baseline and Day 6. [Baseline and Day 6]

    The ADPKD Urinary Frequency Questionnaire: Question 1 (currently experiencing frequency) was assigned 'Yes' or 'No' to measure current urine frequency status. Baseline was defined as last pre-dose evaluation; Day 6 was defined as Day 6 of Period 1, Day 13 of Period 2 and Day 20 of Period 3.

13. Change From Baseline in Urinary Frequency Questionnaire (Question 2 and Questions 3 to 10) at Day 6. [Day 6]

    Question 2 asked, "During the last 5 days, how much has urinary frequency bothered you?" In order to score the response, the written answers were assigned values from 0 to 4 as follows: 0) Not at all, 1) Somewhat, 2) Moderately, 3) Quite a bit, and 4) Constantly. Question 3 to Question 10 were assigned scores of 0 to 4 with higher scores indicating worse cases in impact of urinary frequency on life; scores for these questions were pooled, with a maximum possible score of 32. Baseline was defined as last pre-dose evaluation; Day 6 was defined as Day 6 of Period 1, Day 13 of Period 2 and Day 20 of Period 3.

14. Ranking of Treatment Tolerability. [Day 22/Early Termination]

    Ranking of treatment tolerability was evaluated based on a questionnaire. At Day 22, participants were asked the following questions and their responses recorded on the eCRF: "Which treatment period did you find most tolerable?" and "Which treatment period did you find the least tolerable?".

Eligibility Criteria

Criteria

• Ages Eligible for Study: 18 Years to 50 Years
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Inclusion Criteria:

• Subjects (male or female) who are surgically sterile (ie, have undergone hysterectomy) or using contraception or agree to remain abstinent

• Subjects between the ages of 18 and 50, inclusive

• Subjects with a body mass index between 19 to 35 kg/m2 (inclusive)

• Subjects with a diagnosis of ADPKD by modified Ravine criteria

• Subjects must be in good health as determined by medical history, physical examination, ECG, serum/urine biochemistry, hematology, and serology tests

• Subjects with the ability to provide written, informed consent prior to initiation of any trial-related procedures, and ability, in the opinion of the principle investigator, to comply with all requirements of the trial

• Subjects who expect to be able to complete all dosing periods and assessments within 42 (+2) days after dosing on Day 1

Exclusion Criteria:

• Subjects using diuretics within 14 days prior to check in on Day -1

• Subjects with incontinence, overactive bladder, or urinary retention (eg, benign prostatic hyperplasia)

• Subjects (male or female) with nocturia/urgency (outside of the 2 to 4 times awakening per night expected for ADPKD patients) at screening

• Subjects with liver disease, liver function abnormalities or serology other than that expected for ADPKD with cystic liver disease at baseline

• Subjects with clinically significant abnormality in past medical history, or at the Screening physical examination, that in the investigator's or sponsor's opinion may place the volunteer at risk or interfere with outcome variables including absorption, distribution, metabolism, and excretion of drug. This includes, but is not limited to, history of or concurrent cardiac, hepatic, renal, neurologic, endocrine, gastrointestinal, respiratory, hematologic, and immunologic disease

• Subjects with a history of drug and/or alcohol abuse within 2 years prior to screening

• Subjects who have a history of or test positive at screening for hepatitis B surface antigen (HBsAg), hepatitis C antibodies (anti-HCV), and/or human immunodeficiency virus (HIV)

• Subjects who have clinically significant allergic reactions to tolvaptan or chemically related structures such as benzazepines (eg, benzazepril, conivaptan, fenoldopam mesylate or mirtazapine)

• Subjects who have taken an investigational drug within 30 days preceding trial entry

• Subjects with any history of significant bleeding or hemorrhagic tendencies

• Subjects with a history of difficulty in donating blood

• Subjects who have donated blood or plasma within 30 days prior to dosing

• Subjects who have consumed alcohol and/or food or beverages containing methylxanthines, grapefruit, grapefruit juice, Seville oranges, or Seville orange juice within 72 hours prior to Day 1 dosing

• Subjects taking CYP3A4 inhibitors, with the exception of amiodarone, taken within 30 days of dosing (eg, amprenavir, atorvastatin, aprepitant, chloramphenicol [not eye drops], cimetidine, clarithromycin, clotrimazole [if used orally], danazol, delavirdine, diltiazem, erythromycin, fluconazole, fluvoxamine, indinavir, isoniazid, itraconazole, josamycin, ketoconazole, nelfinavir, nefazadone, quinupristin/dalfopristin, ritonavir, saquinavir, troleandomycin, verapamil)

• Subjects taking CYP3A4 inducers taken within 7 days of dosing (eg, rifampin, St. Johns Wort)

• Subjects with a history of serious mental disorders

• Subjects with previous exposure to tolvaptan

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Tufts-New England Medical Center	Boston	Massachusetts	United States	02111
2	Davita Clinical Research	Minneapolis	Minnesota	United States	55404
3	Mayo Medical Center	Rochester	Minnesota	United States	55905
4	University Hospitals of Cleveland/Case	Cleveland	Ohio	United States	44106
5	Northwest Renal Clinic Inc.	Portland	Oregon	United States	97210
6	University of Pennsylvania Medical Center	Philadelphia	Pennsylvania	United States	19104

Sponsors and Collaborators

• Otsuka Pharmaceutical Development & Commercialization, Inc.

Investigators

• Study Director: Frank Czerwiec, M.D., Ph.D., Otsuka Pharmaceutical Development & Commercialization, Inc.

Study Documents (Full-Text)

None provided.

More Information

Publications

None provided.

• Responsible Party: Otsuka Pharmaceutical Development & Commercialization, Inc.
• ClinicalTrials.gov Identifier: NCT01210560
• Other Study ID Numbers: 156-09-285
• First Posted: Sep 28, 2010
• Last Update Posted: Jun 14, 2018
• Last Verified: May 1, 2018

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

Study Results

Participant Flow

Recruitment Details	Study was conducted at 6 centers in the United States. 25 participants were randomized (12+13) to Group 1 & 2 with 5 & 3 treatment sequences, respectively; received tolvaptan Modified-release [MR] capsules & Immediate-release [IR] tablets in Group 1 & MR in Group 2 over 3 therapy periods (each 7 days) in parallel-group, crossover design
Pre-assignment Detail	Screening visit, baseline visit, 3 periods - each with 3 treatments in Group 1 & 2 in one of the sequences DAE, DBE, DCE, EAD, EBD / ECD & FGH, HFG / GHF (2 & 4 participants per sequence) respectively; (MR: A&F= 20mg, B&G = 20+20mg, C&H = 60mg, D = 120mg; IR: E = 90+30mg) and 7 Day follow-up. All doses were taken orally once/twice(B&G) daily.

Arm/Group Title	Group 1: DAE	Group 1: DBE	Group 1: DCE	Group 1: EAD	Group 1: EBD	Group 1: ECD	Group 2: FGH	Group 2: HFG	Group 2: GHF
Arm/Group Description	D = participants received MR tolvaptan 120 mg QD A = participants received MR tolvaptan 20 mg QD E = participants received IR tolvaptan 90 + 30 mg QD	D = participants received MR tolvaptan 120 mg QD B = participants received MR tolvaptan 20 mg BID E = participants received IR tolvaptan 90 + 30 mg QD	D = participants received MR tolvaptan 120 mg QD C = participants received MR tolvaptan 60 mg QD E = participants received IR tolvaptan 90 + 30 mg QD	E = participants received IR tolvaptan 90 + 30 mg QD A = participants received MR tolvaptan 20 mg QD D = participants received MR tolvaptan 120 mg QD	E = participants received IR tolvaptan 90 + 30 mg QD B = participants received MR tolvaptan 20 mg BID D = participants received MR tolvaptan 120 mg QD	E = participants received IR tolvaptan 90 + 30 mg QD C = participants received MR tolvaptan 60 mg QD D = participants received MR tolvaptan 120 mg QD	F = participants received MR tolvaptan 20 mg QD G = participants received MR tolvaptan 20 + 20 mg BID H = participants received MR tolvaptan 60 mg QD	H = participants received MR tolvaptan 60 mg QD F = participants received MR tolvaptan 20 mg QD G = participants received MR tolvaptan 20 + 20 mg BID	G = participants received MR tolvaptan 20 + 20 mg BID H = participants received MR tolvaptan 60 mg QD F = participants received MR tolvaptan 20 mg QD
Period Title: Intervention 1 (7 Days)
STARTED	2	2	2	2	2	2	4	4	5
COMPLETED	2	2	2	2	2	2	4	4	5
NOT COMPLETED	0	0	0	0	0	0	0	0	0
Period Title: Intervention 1 (7 Days)
STARTED	2	2	2	2	2	2	4	4	5
COMPLETED	2	2	2	2	2	2	4	4	5
NOT COMPLETED	0	0	0	0	0	0	0	0	0
Period Title: Intervention 1 (7 Days)
STARTED	2	2	2	2	2	2	4	4	5
COMPLETED	2	2	2	2	2	2	4	4	5
NOT COMPLETED	0	0	0	0	0	0	0	0	0

Baseline Characteristics

Arm/Group Title	Group 1	Group 2	Total
Arm/Group Description	Group 1 participants enrolled in a 3-period, randomized, crossover design to compare multiple doses of a 90+30 mg split-dose of the tolvaptan IR formulation, a 120 mg QD dose of the tolvaptan MR formulation, and, in an incomplete block randomization, multiple doses of either 20 mg QD, 60 mg QD, or 20 mg BID tolvaptan MR formulation. All dose regimens were administered for 7 days. Placebo doses were administered in order to mask formulation and dosing regimen.	Group 2 participants enrolled in a 3-period, randomized, crossover design to compare multiple oral doses of the tolvaptan MR formulation administered for 7 days as 20 mg QD, 60 mg QD, and 20 mg BID. Placebo capsules were administered in order to mask dosing regimen.	Total of all reporting groups
Overall Participants	12	13	25
Age (Years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [Years]	39.4 (4.3)	36.8 (9.0)	38.0 (7.1)
Sex: Female, Male (Count of Participants)
Female	7 58.3%	4 30.8%	11 44%
Male	5 41.7%	9 69.2%	14 56%

Outcome Measures

1. Primary Outcome

Title	Maximum (Peak) Plasma Concentration of the Drug [Cmax] and Minimum (Trough) Plasma Concentration of the Drug [Cmin] After Tolvaptan Treatment on Day 7.
Description	Blood samples (6 mL) for determination of tolvaptan PK parameters were collected on Day 1 predose, and on Days 7, 14 and 21 at predose, and 1, 2, 4, 6, 8, 9, 10, 12, 16, and 24 hours postdose. If a sample was not drawn at the designated time, a window of ± 3 minutes for each blood draw was acceptable. Maximum and minimum plasma concentration of the drug was calculated.
Time Frame	Day 7

Outcome Measure Data

Analysis Population Description

Participants having valid measurements (per clinical pharmacology) were included.

Arm/Group Title	MR 20 mg	MR 20+20 mg	MR 60 mg	MR 120 mg	IR 90+30 mg
Arm/Group Description	Participants received MR tolvaptan 20 mg QD.	Participants received MR tolvaptan 20 mg BID.	Participants received MR tolvaptan 60 mg QD.	Participants received MR tolvaptan 120 mg QD.	Participants received IR tolvaptan 90+30 mg QD.
Measure Participants	17	16	17	12	12
Cmax	140 (68.4)	175 (60.1)	350 (156)	669 (370)	716 (344)
Cmin	14.7 (9.95)	50.8 (24.0)	51.1 (32.3)	139 (75.5)	57.5 (41.8)

2. Primary Outcome

Title	Time to Maximum (Peak) Plasma Concentration (Tmax) After Tolvaptan Treatment on Day 7.
Description	Blood samples (6 mL) for determination of tolvaptan PK parameters were collected on Day 1 predose, and on Days 7, 14 and 21 at predose, and 1, 2, 4, 6, 8, 9, 10, 12, 16, and 24 hours postdose. If a sample was not drawn at the designated time, a window of ± 3 minutes for each blood draw was acceptable. Time to maximum plasma concentration was calculated.
Time Frame	Day 7

Outcome Measure Data

Analysis Population Description

Participants having valid measurements (per clinical pharmacology) were included.

Arm/Group Title	MR 20 mg	MR 20+20 mg	MR 60 mg	MR 120 mg	IR 90+30 mg
Arm/Group Description	Participants received MR tolvaptan 20 mg QD.	Participants received MR tolvaptan 20 mg BID.	Participants received MR tolvaptan 60 mg QD.	Participants received MR tolvaptan 120 mg QD.	Participants received IR tolvaptan 90+30 mg QD.
Measure Participants	17	16	17	12	12
Median (Full Range) [Hours]	6.00	6.00	6.00	5.98	2.00

3. Primary Outcome

Title	Area Under the Concentration-time Curve During the Dosing Interval at Steady State and Area Under the Concentration-time Curve From Time 0 to 24 Hours Postdose (AUCT & AUC0-24h) After Tolvaptan Treatment on Day 7.
Description	Blood samples (6 mL) for determination of tolvaptan PK parameters were collected on Day 1 predose, and on Days 7, 14 and 21 at predose, and 1, 2, 4, 6, 8, 9, 10, 12, 16, and 24 hours postdose. If a sample was not drawn at the designated time, a window of ± 3 minutes for each blood draw was acceptable. Hence, both AUCT and AUC0-24h values were calculated.
Time Frame	Day 7

Outcome Measure Data

Analysis Population Description

Participants having valid measurements (per clinical pharmacology) were included.

Arm/Group Title	MR 20 mg	MR 20+20 mg	MR 60 mg	MR 120 mg	IR 90+30 mg
Arm/Group Description	Participants received MR tolvaptan 20 mg QD.	Participants received MR tolvaptan 20 mg BID.	Participants received MR tolvaptan 60 mg QD.	Participants received MR tolvaptan 120 mg QD.	Participants received IR tolvaptan 90+30 mg QD.
Measure Participants	17	16	17	12	12
Mean (Standard Deviation) [ng·h/mL]	1260 (654)	2310 (704)	3600 (1670)	7740 (3650)	6570 (3230)

4. Secondary Outcome

Title	Number of Participants With Urine Osmolality < 300 mOsm/kg at 23.5 Hours Postdose.
Description	For determination of duration of urine osmolality <300 mOsm/kg, the value was the end time of the last collection interval in which urine osmolality was <300 mOsm/kg. Day 8 in the table below was defined as Day 8 of Period 1, Day 15 of Period 2, and Day 22 of period 3.
Time Frame	23.5 hours post-dose

Outcome Measure Data

Analysis Population Description

All participants who had taken study drug and had measurements of the pharmacodynamic endpoint were included.

Arm/Group Title	MR 20 mg	MR 20+20 mg	MR 60 mg	MR 120 mg	IR 90+30 mg
Arm/Group Description	Participants received MR tolvaptan 20 mg QD.	Participants received MR tolvaptan 20 mg BID.	Participants received MR tolvaptan 60 mg QD.	Participants received MR tolvaptan 120 mg QD.	Participants received IR tolvaptan 90+30 mg QD.
Measure Participants	17	17	17	12	12
Baseline	1 8.3%	1 7.7%	1 4%	0 NaN	0 NaN
Day 8	5 41.7%	11 84.6%	9 36%	11 NaN	11 NaN

5. Secondary Outcome

Title	Change From Baseline in Urine Osmolality Area Under the Concentration-time Curve From Time 0 to 24 Hours Postdose (AUC0-24h) at Day 7.
Description	The AUC0-24h for urine osmolality was determined by multiplying the concentration by the collection interval duration for each collection interval and summing all the intervals in the 24-hour period. If the urine volume for an interval is zero, the duration of that interval will be added to the next collection interval. Day 7 was defined as Day 7 of Period 1, Day 14 of Period 2 and Day 21 of Period 3.
Time Frame	Day 7

Outcome Measure Data

Analysis Population Description

All participants who had taken study drug and had measurements of the pharmacodynamic endpoint were included.

Arm/Group Title	MR 20 mg	MR 20+20 mg	MR 60 mg	MR 120 mg	IR 90+30 mg
Arm/Group Description	Participants received MR tolvaptan 20 mg QD.	Participants received MR tolvaptan 20 mg BID.	Participants received MR tolvaptan 60 mg QD.	Participants received MR tolvaptan 120 mg QD.	Participants received IR tolvaptan 90+30 mg QD.
Measure Participants	17	16	17	12	11
Mean (Standard Deviation) [mOsm/kg*Hour]	-2546 (1743)	-3438 (2277)	-4209 (2569)	-4325 (2237)	-4620 (2419)

6. Secondary Outcome

Title	Change From Baseline in Urine Osmolality at Day 7.
Description	To determine the tolerability and nighttime urinary suppression of osmolality. The urine osmolality was summarized by collection interval (0 to 4, 4 to 8, 8 to 12, 12 to 16, and 16 to 24 hours)
Time Frame	0-4, 4-8, 8-12, 12-16, 16-24 Hours at Day 7

Outcome Measure Data

Analysis Population Description

All participants who had taken study drug and have measurements of the pharmacodynamic endpoint were included.

Arm/Group Title	MR 20 mg	MR 20+20 mg	MR 60 mg	MR 120 mg	IR 90+30 mg
Arm/Group Description	Participants received MR tolvaptan 20 mg QD.	Participants received MR tolvaptan 20 mg BID.	Participants received MR tolvaptan 60 mg QD.	Participants received MR tolvaptan 120 mg QD.	Participants received IR tolvaptan 90+30 mg QD.
Measure Participants	17	17	17	12	12
0-4 Hour	2.6 (132.1)	-0.7 (111.9)	-88.9 (130.9)	-59.5 (169.2)	-123.3 (139.5)
4-8 Hour	-140.9 (127.1)	-128.3 (127.2)	-188.2 (140.5)	-186.1 (161.1)	-191.8 (155.1)
8-12 Hour	-123.1 (115.9)	-172.1 (129.8)	-201.8 (158.8)	-167.1 (148.7)	-166.9 (131.7)
12-16 Hour	-128.3 (142.9)	-193.6 (152.5)	-195.8 (151.6)	-176.3 (121.8)	-178.3 (128.9)
16-24 Hour	-123.4 (102.6)	-182.4 (145.6)	-188.8 (160.0)	-246.1 (108.9)	-239.8 (117.8)

7. Secondary Outcome

Title	Change From Baseline in Urine Volume at 24 Hours at Day 7.
Description	Urine volume was collected by 0 to 24-hour interval at Day 7. Day 7 was defined as Day 7 of Period 1, Day 14 of Period 2 and Day 21 of Period 3.
Time Frame	Day 7

Outcome Measure Data

Analysis Population Description

All participants who had taken study drug and have measurements of the pharmacodynamic endpoint were included.

Arm/Group Title	MR 20 mg	MR 20+20 mg	MR 60 mg	MR 120 mg	IR 90+30 mg
Arm/Group Description	Participants received MR tolvaptan 20 mg QD.	Participants received MR tolvaptan 20 mg BID.	Participants received MR tolvaptan 60 mg QD.	Participants received MR tolvaptan 120 mg QD.	Participants received IR tolvaptan 90+30 mg QD.
Measure Participants	17	16	16	12	12
Mean (Standard Deviation) [mL]	1111 (919)	2066 (1237)	2396 (1022)	3722 (1776)	3820 (1759)

8. Secondary Outcome

Title	Change From Baseline in Urine Volume by Interval at Day 7.
Description	Urine volume collected was by interval (0-4, 4-8, 8-12, 12-16, 16-24 hours). Day 7 was defined as Day 7 of Period 1, Day 14 of Period 2 and Day 21 of Period 3.
Time Frame	0-4, 4-8, 8-12, 12-16, 16-24 Hours at Day 7

Outcome Measure Data

Analysis Population Description

All participants who had taken study drug and have measurements of the pharmacodynamic endpoint were included.

Arm/Group Title	MR 20 mg	MR 20+20 mg	MR 60 mg	MR 120 mg	IR 90+30 mg
Arm/Group Description	Participants received MR tolvaptan 20 mg QD.	Participants received MR tolvaptan 20 mg BID.	Participants received MR tolvaptan 60 mg QD.	Participants received MR tolvaptan 120 mg QD.	Participants received IR tolvaptan 90+30 mg QD.
Measure Participants	17	17	17	12	12
0-4 Hour	-87 (348)	-118 (391)	56 (345)	87 (449)	241 (412)
4-8 Hour	326 (531)	423 (439)	636 (382)	785 (605)	825 (472)
8-12 Hour	301 (317)	529 (349)	689 (603)	887 (558)	801 (494)
12-16 Hour	314 (328)	635 (473)	667 (337)	926 (459)	910 (738)
16-24 Hour	257 (407)	598 (482)	286 (421)	1038 (642)	1044 (421)

9. Secondary Outcome

Title	Duration of Urine Osmolality Less Than 300 mOsm/kg at Baseline and Day 7.
Description	Duration of urine osmolality remains below 300 mOsm/kg was the sum of the durations (nominal times) of all intervals where the urine concentration was < 300 mOsm/kg. Day 7 was defined as Day 7 of Period 1, Day 14 of Period 2, and Day 21 of Period 3.
Time Frame	Baseline and Day 7

Outcome Measure Data

Analysis Population Description

The duration that urine osmolality remained < 300 mOsm/kg was not calculated. Instead was calculated as the sum where urine osmolality was < 300 mOsm/kg in the 24-hour postdose period. The change was made because low doses of the MR formulation frequently do not produce suppression of urine osmolality in the 0- to 4-hour period.

Arm/Group Title	MR 20 mg	MR 20+20 mg	MR 60 mg	MR 120 mg	IR 90+30 mg
Arm/Group Description	Participants received MR tolvaptan 20 mg QD.	Participants received MR tolvaptan 20 mg BID.	Participants received MR tolvaptan 60 mg QD.	Participants received MR tolvaptan 120 mg QD.	Participants received IR tolvaptan 90+30 mg QD.
Measure Participants	17	17	17	12	12
Baseline	8.0	8.0	8.0	14.0	14.0
Day 7	16.0	24.0	24.0	24.0	24.0

10. Secondary Outcome

Title	Change From Baseline in Number of Urine Voids During Awake Periods.
Description	Average number of daily urine voids during awake periods for each dose group. Day 1 was defined as Day1 of Period 1, Day 8 of Period 2 adn Day 15 of Period 3; Day 7 was defined as Day 7 of Period 1, Day 14 of Period 2 and Day 21 of Period 3; Same rule applied to Day 2 and Day 6.
Time Frame	Days 1, 2, 3, 4, 5, 6 and 7

Outcome Measure Data

Analysis Population Description

All participants who had taken study drug and had measurements of the pharmacodynamic endpoint were included.

Arm/Group Title	MR 20 mg	MR 20+20 mg	MR 60 mg	MR 120 mg	IR 90+30 mg
Arm/Group Description	Participants received MR tolvaptan 20 mg QD.	Participants received MR tolvaptan 20 mg BID.	Participants received MR tolvaptan 60 mg QD.	Participants received MR tolvaptan 120 mg QD.	Participants received IR tolvaptan 90+30 mg QD.
Measure Participants	17	17	17	12	12
Day 1	1.7 (4.1)	1.5 (3.1)	3.5 (4.3)	5.6 (5.6)	4.8 (4.1)
Day 2	-0.4 (2.9)	1.2 (4.0)	1.8 (4.1)	4.8 (7.8)	3.8 (4.2)
Day 3	-0.8 (2.4)	0.9 (2.4)	2.4 (3.9)	3.1 (4.6)	3.3 (5.2)
Day 4	-1.4 (2.3)	1.5 (3.8)	0.4 (5.0)	2.8 (5.0)	3.7 (5.9)
Day 5	-0.5 (2.9)	0.6 (3.5)	-0.4 (4.2)	3.3 (5.6)	4.0 (4.9)
Day 6	0.0 (3.3)	2.9 (4.1)	5.8 (10.6)	2.3 (6.8)	4.8 (5.2)
Day 7	2.0 (3.0)	3.5 (2.4)	3.5 (3.8)	2.8 (6.4)	4.3 (4.5)

11. Secondary Outcome

Title	Change From Baseline in Number of Urine Voids During Sleep Periods.
Description	Average number of daily urine voids during sleep periods for each dose group. Day 1 was defined as Day 1 of Period 1, Day 8 of Period 2, Day 15 of Period 3; Day 7 was defined as Day 7 of Period 1, Day 14 of Period 2 and Day 21 of Period 3; Same rule applied to Day 2 to 6.
Time Frame	Days 1, 2, 3, 4, 5, 6 and 7

Outcome Measure Data

Analysis Population Description

All participants who had taken study drug and have measurements of the pharmacodynamic endpoint were included.

Arm/Group Title	MR 20 mg	MR 20+20 mg	MR 60 mg	MR 120 mg	IR 90+30 mg
Arm/Group Description	Participants received MR tolvaptan 20 mg QD.	Participants received MR tolvaptan 20 mg BID.	Participants received MR tolvaptan 60 mg Q	Participants received MR tolvaptan 120 mg QD.	Participants received IR tolvaptan 90+30 mg QD.
Measure Participants	17	17	17	12	12
Day 1	0.6 (1.6)	1.1 (2.0)	0.4 (2.2)	2.5 (1.7)	1.5 (1.6)
Day 2	-0.2 (1.7)	0.8 (1.6)	0.8 (1.9)	1.8 (1.4)	1.7 (1.2)
Day 3	0.1 (1.0)	1.4 (2.4)	0.8 (1.7)	1.9 (1.5)	1.9 (1.7)
Day 4	0.6 (2.3)	0.7 (1.6)	0.5 (1.7)	1.7 (1.3)	1.8 (1.9)
Day 5	0.3 (1.3)	0.9 (2.0)	0.2 (1.4)	1.0 (2.0)	0.9 (1.7)
Day 6	1.2 (3.3)	1.3 (2.0)	0.4 (1.6)	1.1 (2.1)	1.7 (1.7)
Day 7	0.1 (1.3)	1.0 (1.7)	0.9 (1.8)	1.8 (2.4)	2.1 (1.9)

12. Secondary Outcome

Title	Change From Baseline in Symptom Burden by Autosomal Dominant Polycystic Kidney Disease (ADPKD) Nocturia Quality of Life Questionnaire at Day 6.
Description	In ADPKD Nocturia Quality of Life Questionnaire, questions 1 to 11 (with possible scores ranging from 0 to 4 and higher scores indicating better quality of life) were pooled to provide a total score (maximum of 44 points). Response scores of Question 12 (with possible scores ranging from 1 to 10, with higher scores indicating more interference (worse quality of life) with everyday life due to urination at night) were pooled separately. Day 6 was defined as Day 6 of Period 1, Day 13 of Period 2 and Day 20 of Period 3.
Time Frame	Day 6

Outcome Measure Data

Analysis Population Description

All participants who had taken study drug and have measurements of the pharmacodynamic endpoint were included.

Arm/Group Title	MR 20 mg	MR 20+20 mg	MR 60 mg	MR 120 mg	IR 90+30 mg
Arm/Group Description	Participants received MR tolvaptan 20 mg QD.	Participants received MR tolvaptan 20 mg BID.	Participants received MR tolvaptan 60 mg QD.	Participants received MR tolvaptan 120 mg QD.	Participants received IR tolvaptan 90+30 mg QD.
Measure Participants	17	17	17	12	12
Nocturia Quality of life Question (Q) 1 To Q 11	-1.5 (4.3)	-6.9 (9.9)	-5.1 (7.6)	-15.0 (13.3)	-13.1 (12.3)
Nocturia Quality of life Q 12	0.6 (1.3)	1.9 (2.7)	1.4 (2.5)	4.2 (3.6)	3.7 (3.5)

13. Secondary Outcome

Title	Number of Participants Experiencing Urinary Urgency Based on Urinary Urgency Questionnaire (Question 1) at Baseline and Day 6.
Description	For the ADPKD Urinary Urgency Questionnaire, Question 1 (currently experiencing urgency?) was assigned 'Yes' or 'No' to measure current urine urgency status. Baseline was defined as last pre-dose evaluation; Day 6 was defined as Day 6 of Period 1, Day 13 of Period 2 and Day 20 of Period 3.
Time Frame	Baseline and Day 6

Outcome Measure Data

Analysis Population Description

All participants who had taken study drug and have measurements of the pharmacodynamic endpoint were included.

Arm/Group Title	MR 20 mg	MR 20+20 mg	MR 60 mg	MR 120 mg	IR 90+30 mg
Arm/Group Description	Participants received MR tolvaptan 20 mg QD.	Participants received MR tolvaptan 20 mg BID.	Participants received MR tolvaptan 60 mg QD.	Participants received MR tolvaptan 120 mg QD.	Participants received IR tolvaptan 90+30 mg QD.
Measure Participants	17	17	17	12	12
Baseline	5 41.7%	3 23.1%	3 12%	2 NaN	2 NaN
Day 6	8 66.7%	13 100%	12 48%	10 NaN	11 NaN

14. Secondary Outcome

Title	Change From Baseline in Urinary Urgency Questionnaire (Questions 2 to 5 and Questions 7 to 14) at Day 6.
Description	Question 2 to Question 6 were assigned scores of 0 to 4 with higher scores indicating worse cases in experience of urinary urgency. Scores for Question 2 to Question 5 were pooled, with a maximum possible score of 16. Question 6 was excluded from the analysis since it was only asked at screening. Question 7 to Question 14 were also assigned scores of 0 to 4 with higher scores indicating worse cases in impact of urinary urgency on life; scores for these questions were pooled, with a maximum possible score of 32. Baseline was defined as last pre-dose evaluation; Day 6 was defined as Day 6 of Period 1, Day 13 of Period 2 and Day 20 of Period 3.
Time Frame	Day 6

Outcome Measure Data

Analysis Population Description

All participants who had taken study drug and have measurements of the pharmacodynamic endpoint were included.

Arm/Group Title	MR 20 mg	MR 20+20 mg	MR 60 mg	MR 120 mg	IR 90+30 mg
Arm/Group Description	Participants received MR tolvaptan 20 mg QD.	Participants received MR tolvaptan 20 mg BID.	Participants received MR tolvaptan 60 mg QD.	Participants received MR tolvaptan 120 mg QD.	Participants received IR tolvaptan 90+30 mg QD.
Measure Participants	17	17	17	12	12
Urinary urgency questionnaire-Question (Q) 2 to Q5	1.4 (2.1)	3.2 (2.4)	3.2 (3.1)	4.6 (3.9)	4.7 (3.0)
Urinary urgency questionnaire-Q 7 to Q 14	0.9 (1.2)	4.2 (5.5)	3.5 (5.0)	10.9 (10.9)	8.8 (9.8)

15. Secondary Outcome

Title	Number of Participants Experiencing Urinary Frequency Based on Urinary Frequency Questionnaire (Question 1) at Baseline and Day 6.
Description	The ADPKD Urinary Frequency Questionnaire: Question 1 (currently experiencing frequency) was assigned 'Yes' or 'No' to measure current urine frequency status. Baseline was defined as last pre-dose evaluation; Day 6 was defined as Day 6 of Period 1, Day 13 of Period 2 and Day 20 of Period 3.
Time Frame	Baseline and Day 6

Outcome Measure Data

Analysis Population Description

All participants who had taken study drug and have measurements of the pharmacodynamic endpoint were included.

Arm/Group Title	MR 20 mg	MR 20+20 mg	MR 60 mg	MR 120 mg	IR 90+30 mg
Arm/Group Description	Participants received MR tolvaptan 20 mg QD.	Participants received MR tolvaptan 20 mg BID.	Participants received MR tolvaptan 60 mg QD.	Participants received MR tolvaptan 120 mg QD.	Participants received IR tolvaptan 90+30 mg QD.
Measure Participants	17	17	17	12	12
Baseline	5 41.7%	4 30.8%	4 16%	4 NaN	4 NaN
Day 6	10 83.3%	15 115.4%	16 64%	12 NaN	12 NaN

16. Secondary Outcome

Title	Change From Baseline in Urinary Frequency Questionnaire (Question 2 and Questions 3 to 10) at Day 6.
Description	Question 2 asked, "During the last 5 days, how much has urinary frequency bothered you?" In order to score the response, the written answers were assigned values from 0 to 4 as follows: 0) Not at all, 1) Somewhat, 2) Moderately, 3) Quite a bit, and 4) Constantly. Question 3 to Question 10 were assigned scores of 0 to 4 with higher scores indicating worse cases in impact of urinary frequency on life; scores for these questions were pooled, with a maximum possible score of 32. Baseline was defined as last pre-dose evaluation; Day 6 was defined as Day 6 of Period 1, Day 13 of Period 2 and Day 20 of Period 3.
Time Frame	Day 6

Outcome Measure Data

Analysis Population Description

All participants who had taken study drug and have measurements of the pharmacodynamic endpoint were included.

Arm/Group Title	MR 20 mg	MR 20+20 mg	MR 60 mg	MR 120 mg	IR 90+30 mg
Arm/Group Description	Participants received MR tolvaptan 20 mg QD.	Participants received MR tolvaptan 20 mg BID.	Participants received MR tolvaptan 60 mg QD.	Participants received MR tolvaptan 120 mg QD.	Participants received IR tolvaptan 90+30 mg QD.
Measure Participants	17	17	17	12	12
Urinary frequency questionnaire-Question (Q) 2	0.4 (0.6)	1.1 (1.1)	0.9 (0.9)	1.7 (1.4)	1.5 (1.1)
Urinary frequency questionnaire-Q 3 to Q 10	1.4 (2.1)	4.6 (6.9)	4.1 (5.7)	12.2 (11.0)	9.1 (10.5)

17. Secondary Outcome

Title	Ranking of Treatment Tolerability.
Description	Ranking of treatment tolerability was evaluated based on a questionnaire. At Day 22, participants were asked the following questions and their responses recorded on the eCRF: "Which treatment period did you find most tolerable?" and "Which treatment period did you find the least tolerable?".
Time Frame	Day 22/Early Termination

Outcome Measure Data

Analysis Population Description

All participants who had taken study drug and have measurements of the pharmacodynamic endpoint were included.

Arm/Group Title	MR 20 mg	MR 20+20 mg	MR 60 mg	MR 120 mg	IR 90+30 mg
Arm/Group Description	Participants received MR tolvaptan 20 mg QD.	Participants received MR tolvaptan 20 mg BID.	Participants received MR tolvaptan 60 mg QD.	Participants received MR tolvaptan 120 mg QD.	Participants received IR tolvaptan 90+30 mg QD.
Measure Participants	17	17	17	12	12
Most tolerable Group 1	3 25%	2 15.4%	3 12%	1 NaN	1 NaN
Most tolerable Group 2	10 83.3%	3 23.1%
Least tolerable Group 1	0 0%	4 30.8%	6 24%
Least tolerable Group 2	0 0%	7 53.8%	6 24%

Adverse Events

Time Frame	Screening to seven days (+ 1 day) after the last dose of study medication.
Adverse Event Reporting Description	In safety analysis, all participants who had taken at least one dose of study medication were included.
Arm/Group Title	MR 20 mg		MR 20+20 mg		MR 60 mg		MR 120 mg		IR 90+30 mg
Arm/Group Description	Participants received MR tolvaptan 20 mg QD.		Participants received MR tolvaptan 20 mg BID.		Participants received MR tolvaptan 60 mg QD.		Participants received MR tolvaptan 120 mg QD.		Participants received IR tolvaptan 90+30 mg QD.
All Cause Mortality
	MR 20 mg		MR 20+20 mg		MR 60 mg		MR 120 mg		IR 90+30 mg
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	/ (NaN)		/ (NaN)		/ (NaN)		/ (NaN)		/ (NaN)
Serious Adverse Events
	MR 20 mg		MR 20+20 mg		MR 60 mg		MR 120 mg		IR 90+30 mg
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/17 (0%)		0/17 (0%)		0/17 (0%)		0/12 (0%)		0/12 (0%)
Other (Not Including Serious) Adverse Events
	MR 20 mg		MR 20+20 mg		MR 60 mg		MR 120 mg		IR 90+30 mg
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	5/17 (29.4%)		10/17 (58.8%)		6/17 (35.3%)		8/12 (66.7%)		7/12 (58.3%)
Gastrointestinal disorders
Abdominal distension	0/17 (0%)		0/17 (0%)		0/17 (0%)		0/12 (0%)		1/12 (8.3%)
Abdominal pain lower	1/17 (5.9%)		0/17 (0%)		0/17 (0%)		0/12 (0%)		0/12 (0%)
Diarrhoea	0/17 (0%)		0/17 (0%)		0/17 (0%)		1/12 (8.3%)		0/12 (0%)
Dry mouth	1/17 (5.9%)		1/17 (5.9%)		0/17 (0%)		0/12 (0%)		0/12 (0%)
Lip dry	1/17 (5.9%)		1/17 (5.9%)		0/17 (0%)		0/12 (0%)		0/12 (0%)
Nausea	0/17 (0%)		0/17 (0%)		1/17 (5.9%)		2/12 (16.7%)		1/12 (8.3%)
Vomiting	0/17 (0%)		0/17 (0%)		1/17 (5.9%)		1/12 (8.3%)		0/12 (0%)
General disorders
Chest discomfort	0/17 (0%)		1/17 (5.9%)		0/17 (0%)		0/12 (0%)		0/12 (0%)
Feeling cold	1/17 (5.9%)		0/17 (0%)		0/17 (0%)		1/12 (8.3%)		0/12 (0%)
Feeling hot	1/17 (5.9%)		0/17 (0%)		1/17 (5.9%)		0/12 (0%)		0/12 (0%)
Mucosal dryness	0/17 (0%)		0/17 (0%)		0/17 (0%)		1/12 (8.3%)		0/12 (0%)
Thirst	1/17 (5.9%)		3/17 (17.6%)		2/17 (11.8%)		2/12 (16.7%)		1/12 (8.3%)
Infections and infestations
Upper respiratory tract infection	0/17 (0%)		0/17 (0%)		0/17 (0%)		1/12 (8.3%)		0/12 (0%)
Investigations
Blood creatinine increased	0/17 (0%)		0/17 (0%)		1/17 (5.9%)		0/12 (0%)		0/12 (0%)
Metabolism and nutrition disorders
Dehydration	0/17 (0%)		0/17 (0%)		0/17 (0%)		1/12 (8.3%)		1/12 (8.3%)
Polydipsia	1/17 (5.9%)		2/17 (11.8%)		0/17 (0%)		2/12 (16.7%)		3/12 (25%)
Nervous system disorders
Dizziness	0/17 (0%)		1/17 (5.9%)		0/17 (0%)		0/12 (0%)		1/12 (8.3%)
Headache	0/17 (0%)		2/17 (11.8%)		1/17 (5.9%)		1/12 (8.3%)		0/12 (0%)
Somnolence	0/17 (0%)		0/17 (0%)		1/17 (5.9%)		0/12 (0%)		0/12 (0%)
Psychiatric disorders
Nervousness	0/17 (0%)		0/17 (0%)		0/17 (0%)		1/12 (8.3%)		0/12 (0%)
Renal and urinary disorders
Haematuria	0/17 (0%)		0/17 (0%)		0/17 (0%)		0/12 (0%)		1/12 (8.3%)
Micturition urgency	2/17 (11.8%)		2/17 (11.8%)		0/17 (0%)		1/12 (8.3%)		0/12 (0%)
Nocturia	1/17 (5.9%)		2/17 (11.8%)		1/17 (5.9%)		1/12 (8.3%)		3/12 (25%)
Pollakiuria	2/17 (11.8%)		2/17 (11.8%)		1/17 (5.9%)		2/12 (16.7%)		0/12 (0%)
Polyuria	2/17 (11.8%)		5/17 (29.4%)		1/17 (5.9%)		4/12 (33.3%)		5/12 (41.7%)
Renal pain	0/17 (0%)		0/17 (0%)		0/17 (0%)		0/12 (0%)		1/12 (8.3%)
Skin and subcutaneous tissue disorders
Acne	1/17 (5.9%)		0/17 (0%)		0/17 (0%)		0/12 (0%)		0/12 (0%)
Alopecia	1/17 (5.9%)		1/17 (5.9%)		0/17 (0%)		0/12 (0%)		0/12 (0%)
Dry skin	0/17 (0%)		1/17 (5.9%)		0/17 (0%)		1/12 (8.3%)		0/12 (0%)
Vascular disorders
Hypertension	0/17 (0%)		1/17 (5.9%)		0/17 (0%)		0/12 (0%)		0/12 (0%)

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

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

There is NOT 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.