Dose-finding Study of New Tolvaptan Formulation in Subjec... | NCT01210560

Status Module

Description Module

Label	Type	Intervention Names
20 mg MR	Experimental	Drug: Tolvaptan MR
40 mg MR	Experimental	Drug: Tolvaptan MR
60 mg MR	Experimental	Drug: Tolvaptan MR
120 mg MR	Experimental	Drug: Tolvaptan MR
120 mg IR	Experimental	Drug: Tolvaptan IR

Name	Type	Description	Arm Group Labels	Other Names
Tolvaptan MR	Drug	20 mg Tolvaptan MR capsule(morning); Placebo capsules/tablets (morning and afternoon) for 7 days	20 mg MR

Outcomes Module

Primary Outcomes

Measure	Description	Time Frame
Maximum (Peak) Plasma Concentration of the Drug [Cmax] and Minimum (Trough) Plasma Concentration of the Drug [Cmin] After Tolvaptan Treatment on 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.	Day 7
Time to Maximum (Peak) Plasma Concentration (Tmax) After Tolvaptan Treatment on 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.	Day 7
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.	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.	Day 7

Secondary Outcomes

Measure	Description	Time Frame
Number of Participants With Urine Osmolality < 300 mOsm/kg at 23.5 Hours Postdose.	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.	23.5 hours post-dose

Eligibility Module

Eligibility Criteria

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

Name	Affiliation	Role
Frank Czerwiec, M.D., Ph.D.	Otsuka Pharmaceutical Development & Commercialization, Inc.	Study Director

Facility	Status	City	State	ZIP	Country	Contacts
Tufts-New England Medical Center		Boston	Massachusetts	02111	United States
Davita Clinical Research

PubMed Identifier	Type	Citation	Retractions
39356039	Derived	St Pierre K, Cashmore BA, Bolignano D, Zoccali C, Ruospo M, Craig JC, Strippoli GF, Mallett AJ, Green SC, Tunnicliffe DJ. Interventions for preventing the progression of autosomal dominant polycystic kidney disease. Cochrane Database Syst Rev. 2024 Oct 2;10(10):CD010294. doi: 10.1002/14651858.CD010294.pub3.
37986188	Derived

Results Section

Participant Flow Module

Arm/Group Information

ID	Title	Description
FG000	Group 1: DAE	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
FG001	Group 1: DBE

Baseline Characteristics Module

Outcome Measures Module

Adverse Events Module

More Info Module

Type

Title

Description

Population Description

Reporting Status

Anticipated Posting Date

Parameter Type

Dispersion Type

Unit of Measure

Calculate Percentage

Time Frame

Units Analyzed

Denominator Units Selected

Arm/Group Information

Denominators

Classes

Analyses

Primary

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

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

Posted

Mean

Standard Deviation

ng/mL

Day 7

ID	Title	Description
OG000	MR 20 mg	Participants received MR tolvaptan 20 mg QD.
OG001	MR 20+20 mg	Participants received MR tolvaptan 20 mg BID.
OG002	MR 60 mg	Participants received MR tolvaptan 60 mg QD.
OG003	MR 120 mg	Participants received MR tolvaptan 120 mg QD.
OG004	IR 90+30 mg	Participants received IR tolvaptan 90+30 mg QD.

Units	Counts
Participants	OG00017 OG00116 OG00217 OG003

Title

Denominators

Categories

Cmax

Title	Measurements
	OG000140± 68.4 OG001175± 60.1 OG002350± 156 OG003

Primary

Time to Maximum (Peak) Plasma Concentration (Tmax) After Tolvaptan Treatment on 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.

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

Posted

Median

Full Range

Hours

Day 7

ID	Title	Description
OG000	MR 20 mg	Participants received MR tolvaptan 20 mg QD.
OG001	MR 20+20 mg	Participants received MR tolvaptan 20 mg BID.
OG002	MR 60 mg	Participants received MR tolvaptan 60 mg QD.
OG003	MR 120 mg	Participants received MR tolvaptan 120 mg QD.

Primary

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.

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.

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

Posted

Mean

Standard Deviation

ng·h/mL

Day 7

ID	Title	Description
OG000	MR 20 mg	Participants received MR tolvaptan 20 mg QD.
OG001	MR 20+20 mg	Participants received MR tolvaptan 20 mg BID.
OG002	MR 60 mg	Participants received MR tolvaptan 60 mg QD.
OG003	MR 120 mg	Participants received MR tolvaptan 120 mg QD.

Secondary

Number of Participants With Urine Osmolality < 300 mOsm/kg at 23.5 Hours Postdose.

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.

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

Posted

Count of Participants

Participants

23.5 hours post-dose

ID	Title	Description
OG000	MR 20 mg	Participants received MR tolvaptan 20 mg QD.
OG001	MR 20+20 mg	Participants received MR tolvaptan 20 mg BID.
OG002	MR 60 mg	Participants received MR tolvaptan 60 mg QD.
OG003	MR 120 mg	Participants received MR tolvaptan 120 mg QD.
OG004

Secondary

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

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

Posted

Mean

Standard Deviation

mOsm/kg*Hour

Day 7

ID	Title	Description
OG000	MR 20 mg	Participants received MR tolvaptan 20 mg QD.
OG001	MR 20+20 mg	Participants received MR tolvaptan 20 mg BID.
OG002	MR 60 mg	Participants received MR tolvaptan 60 mg QD.
OG003	MR 120 mg	Participants received MR tolvaptan 120 mg QD.

Secondary

Change From Baseline in Urine Osmolality 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)

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

Posted

Mean

Standard Deviation

mOsm/kg

0-4, 4-8, 8-12, 12-16, 16-24 Hours at Day 7

ID	Title	Description
OG000	MR 20 mg	Participants received MR tolvaptan 20 mg QD.
OG001	MR 20+20 mg	Participants received MR tolvaptan 20 mg BID.
OG002	MR 60 mg	Participants received MR tolvaptan 60 mg QD.
OG003	MR 120 mg	Participants received MR tolvaptan 120 mg QD.
OG004	IR 90+30 mg

Secondary

Change From Baseline in Urine Volume at 24 Hours at 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.

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

Posted

Mean

Standard Deviation

Day 7

ID	Title	Description
OG000	MR 20 mg	Participants received MR tolvaptan 20 mg QD.
OG001	MR 20+20 mg	Participants received MR tolvaptan 20 mg BID.
OG002	MR 60 mg	Participants received MR tolvaptan 60 mg QD.
OG003	MR 120 mg	Participants received MR tolvaptan 120 mg QD.
OG004	IR 90+30 mg	Participants received IR tolvaptan 90+30 mg QD.

Secondary

Change From Baseline in Urine Volume by Interval 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.

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

Posted

Mean

Standard Deviation

0-4, 4-8, 8-12, 12-16, 16-24 Hours at Day 7

ID	Title	Description
OG000	MR 20 mg	Participants received MR tolvaptan 20 mg QD.
OG001	MR 20+20 mg	Participants received MR tolvaptan 20 mg BID.
OG002	MR 60 mg	Participants received MR tolvaptan 60 mg QD.
OG003	MR 120 mg	Participants received MR tolvaptan 120 mg QD.
OG004	IR 90+30 mg

Secondary

Duration of Urine Osmolality Less Than 300 mOsm/kg at 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.

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.

Posted

Median

Full Range

Hours

Baseline and Day 7

ID	Title	Description
OG000	MR 20 mg	Participants received MR tolvaptan 20 mg QD.
OG001	MR 20+20 mg	Participants received MR tolvaptan 20 mg BID.
OG002	MR 60 mg	Participants received MR tolvaptan 60 mg QD.
OG003	MR 120 mg

Secondary

Change From Baseline in Number of Urine Voids During Awake Periods.

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.

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

Posted

Mean

Standard Deviation

Number of urine voids

Days 1, 2, 3, 4, 5, 6 and 7

ID	Title	Description
OG000	MR 20 mg	Participants received MR tolvaptan 20 mg QD.
OG001	MR 20+20 mg	Participants received MR tolvaptan 20 mg BID.
OG002	MR 60 mg	Participants received MR tolvaptan 60 mg QD.
OG003	MR 120 mg	Participants received MR tolvaptan 120 mg QD.
OG004

Secondary

Change From Baseline in Number of Urine Voids During Sleep Periods.

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.

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

Posted

Mean

Standard Deviation

Number of urine voids

Days 1, 2, 3, 4, 5, 6 and 7

ID	Title	Description
OG000	MR 20 mg	Participants received MR tolvaptan 20 mg QD.
OG001	MR 20+20 mg	Participants received MR tolvaptan 20 mg BID.
OG002	MR 60 mg	Participants received MR tolvaptan 60 mg Q
OG003	MR 120 mg	Participants received MR tolvaptan 120 mg QD.
OG004

Secondary

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

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

Posted

Mean

Standard Deviation

Units on a scale

Day 6

ID	Title	Description
OG000	MR 20 mg	Participants received MR tolvaptan 20 mg QD.
OG001	MR 20+20 mg	Participants received MR tolvaptan 20 mg BID.
OG002	MR 60 mg	Participants received MR tolvaptan 60 mg QD.
OG003

Secondary

Number of Participants Experiencing Urinary Urgency Based on Urinary Urgency Questionnaire (Question 1) at 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.

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

Posted

Number

Participants

Baseline and Day 6

ID	Title	Description
OG000	MR 20 mg	Participants received MR tolvaptan 20 mg QD.
OG001	MR 20+20 mg	Participants received MR tolvaptan 20 mg BID.
OG002	MR 60 mg	Participants received MR tolvaptan 60 mg QD.
OG003	MR 120 mg	Participants received MR tolvaptan 120 mg QD.

Secondary

Change From Baseline in Urinary Urgency Questionnaire (Questions 2 to 5 and Questions 7 to 14) at 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.

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

Posted

Mean

Standard Deviation

Units on a scale

Day 6

ID	Title	Description
OG000	MR 20 mg	Participants received MR tolvaptan 20 mg QD.
OG001	MR 20+20 mg	Participants received MR tolvaptan 20 mg BID.
OG002	MR 60 mg	Participants received MR tolvaptan 60 mg QD.

Secondary

Number of Participants Experiencing Urinary Frequency Based on Urinary Frequency Questionnaire (Question 1) at 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.

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

Posted

Number

Participants

Baseline and Day 6

ID	Title	Description
OG000	MR 20 mg	Participants received MR tolvaptan 20 mg QD.
OG001	MR 20+20 mg	Participants received MR tolvaptan 20 mg BID.
OG002	MR 60 mg	Participants received MR tolvaptan 60 mg QD.
OG003	MR 120 mg	Participants received MR tolvaptan 120 mg QD.

Secondary

Change From Baseline in Urinary Frequency Questionnaire (Question 2 and Questions 3 to 10) at 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.

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

Posted

Mean

Standard Deviation

Units on a scale

Day 6

ID	Title	Description
OG000	MR 20 mg	Participants received MR tolvaptan 20 mg QD.
OG001	MR 20+20 mg	Participants received MR tolvaptan 20 mg BID.
OG002	MR 60 mg	Participants received MR tolvaptan 60 mg QD.

Secondary

Ranking of Treatment Tolerability.

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?".

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

Posted

Number

Participants

Day 22/Early Termination

ID	Title	Description
OG000	MR 20 mg	Participants received MR tolvaptan 20 mg QD.
OG001	MR 20+20 mg	Participants received MR tolvaptan 20 mg BID.
OG002	MR 60 mg	Participants received MR tolvaptan 60 mg QD.
OG003	MR 120 mg	Participants received MR tolvaptan 120 mg QD.
OG004	IR 90+30 mg

Other Adverse Events

Term	Organ System	Source Vocabulary	Assessment Type	Statistical Information
Abdominal distension	Gastrointestinal disorders	MedDRA 11.0	Non-systematic Assessment	EG0000 affected17 at risk EG0010 affected17 at risk EG0020 affected17 at risk EG0030 affected12 at risk EG0041 affected12 at risk
Abdominal pain lower	Gastrointestinal disorders	MedDRA 11.0	Non-systematic Assessment	EG0001 affected17 at risk EG0010 affected17 at risk EG0020 affected17 at risk EG003
Diarrhoea	Gastrointestinal disorders	MedDRA 11.0	Non-systematic Assessment	EG0000 affected17 at risk EG0010 affected17 at risk EG0020 affected17 at risk EG003
Dry mouth	Gastrointestinal disorders	MedDRA 11.0	Non-systematic Assessment	EG0001 affected17 at risk EG0011 affected17 at risk EG0020 affected17 at risk EG003
Lip dry	Gastrointestinal disorders	MedDRA 11.0	Non-systematic Assessment	EG0001 affected17 at risk EG0011 affected17 at risk EG0020 affected17 at risk EG003
Nausea	Gastrointestinal disorders	MedDRA 11.0	Non-systematic Assessment	EG0000 affected17 at risk EG0010 affected17 at risk EG0021 affected17 at risk EG003
Vomiting	Gastrointestinal disorders	MedDRA 11.0	Non-systematic Assessment	EG0000 affected17 at risk EG0010 affected17 at risk EG0021 affected17 at risk EG003
Chest discomfort	General disorders	MedDRA 11.0	Non-systematic Assessment	EG0000 affected17 at risk EG0011 affected17 at risk EG0020 affected17 at risk EG003
Feeling cold	General disorders	MedDRA 11.0	Non-systematic Assessment	EG0001 affected17 at risk EG0010 affected17 at risk EG0020 affected17 at risk EG003
Feeling hot	General disorders	MedDRA 11.0	Non-systematic Assessment	EG0001 affected17 at risk EG0010 affected17 at risk EG0021 affected17 at risk EG003
Mucosal dryness	General disorders	MedDRA 11.0	Non-systematic Assessment	EG0000 affected17 at risk EG0010 affected17 at risk EG0020 affected17 at risk EG003
Thirst	General disorders	MedDRA 11.0	Non-systematic Assessment	EG0001 affected17 at risk EG0013 affected17 at risk EG0022 affected17 at risk EG003
Upper respiratory tract infection	Infections and infestations	MedDRA 11.0	Non-systematic Assessment	EG0000 affected17 at risk EG0010 affected17 at risk EG0020 affected17 at risk EG003
Blood creatinine increased	Investigations	MedDRA 11.0	Non-systematic Assessment	EG0000 affected17 at risk EG0010 affected17 at risk EG0021 affected17 at risk EG003
Dehydration	Metabolism and nutrition disorders	MedDRA 11.0	Non-systematic Assessment	EG0000 affected17 at risk EG0010 affected17 at risk EG0020 affected17 at risk EG003
Polydipsia	Metabolism and nutrition disorders	MedDRA 11.0	Non-systematic Assessment	EG0001 affected17 at risk EG0012 affected17 at risk EG0020 affected17 at risk EG003
Dizziness	Nervous system disorders	MedDRA 11.0	Non-systematic Assessment	EG0000 affected17 at risk EG0011 affected17 at risk EG0020 affected17 at risk EG003
Headache	Nervous system disorders	MedDRA 11.0	Non-systematic Assessment	EG0000 affected17 at risk EG0012 affected17 at risk EG0021 affected17 at risk EG003
Somnolence	Nervous system disorders	MedDRA 11.0	Non-systematic Assessment	EG0000 affected17 at risk EG0010 affected17 at risk EG0021 affected17 at risk EG003
Nervousness	Psychiatric disorders	MedDRA 11.0	Non-systematic Assessment	EG0000 affected17 at risk EG0010 affected17 at risk EG0020 affected17 at risk EG003
Haematuria	Renal and urinary disorders	MedDRA 11.0	Non-systematic Assessment	EG0000 affected17 at risk EG0010 affected17 at risk EG0020 affected17 at risk EG003
Micturition urgency	Renal and urinary disorders	MedDRA 11.0	Non-systematic Assessment	EG0002 affected17 at risk EG0012 affected17 at risk EG0020 affected17 at risk EG003
Nocturia	Renal and urinary disorders	MedDRA 11.0	Non-systematic Assessment	EG0001 affected17 at risk EG0012 affected17 at risk EG0021 affected17 at risk EG003
Pollakiuria	Renal and urinary disorders	MedDRA 11.0	Non-systematic Assessment	EG0002 affected17 at risk EG0012 affected17 at risk EG0021 affected17 at risk EG003
Polyuria	Renal and urinary disorders	MedDRA 11.0	Non-systematic Assessment	EG0002 affected17 at risk EG0015 affected17 at risk EG0021 affected17 at risk EG003
Renal pain	Renal and urinary disorders	MedDRA 11.0	Non-systematic Assessment	EG0000 affected17 at risk EG0010 affected17 at risk EG0020 affected17 at risk EG003
Acne	Skin and subcutaneous tissue disorders	MedDRA 11.0	Non-systematic Assessment	EG0001 affected17 at risk EG0010 affected17 at risk EG0020 affected17 at risk EG003
Alopecia	Skin and subcutaneous tissue disorders	MedDRA 11.0	Non-systematic Assessment	EG0001 affected17 at risk EG0011 affected17 at risk EG0020 affected17 at risk EG003
Dry skin	Skin and subcutaneous tissue disorders	MedDRA 11.0	Non-systematic Assessment	EG0000 affected17 at risk EG0011 affected17 at risk EG0020 affected17 at risk EG003
Hypertension	Vascular disorders	MedDRA 11.0	Non-systematic Assessment	EG0000 affected17 at risk EG0011 affected17 at risk EG0020 affected17 at risk EG003

ID	Title	Description
BG000	Group 1	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.
BG001	Group 2	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.
BG002	Total	Total of all reporting groups

ID	Term
D016891	Polycystic Kidney, Autosomal Dominant
D007674	Kidney Diseases
D007690	Polycystic Kidney Diseases

ID	Term
D052177	Kidney Diseases, Cystic
D014570	Urologic Diseases
D052776	Female Urogenital Diseases
D005261	Female Urogenital Diseases and Pregnancy Complications
D000091642	Urogenital Diseases
D052801	Male Urogenital Diseases
D000015	Abnormalities, Multiple
D000013	Congenital Abnormalities
D009358	Congenital, Hereditary, and Neonatal Diseases and Abnormalities
D000072661	Ciliopathies
D030342	Genetic Diseases, Inborn

ID	Term
D001552	Benzazepines
D006574	Heterocyclic Compounds, 2-Ring
D000072471	Heterocyclic Compounds, Fused-Ring
D006571	Heterocyclic Compounds

ID	Title	Description	Serious Events (At Risk)	Other Events (Affected)	Other Events (At Risk)
EG000	MR 20 mg	Participants received MR tolvaptan 20 mg QD.	17	5	17
EG001	MR 20+20 mg	Participants received MR tolvaptan 20 mg BID.	17	10	17
EG002	MR 60 mg	Participants received MR tolvaptan 60 mg QD.	17	6	17
EG003	MR 120 mg	Participants received MR tolvaptan 120 mg QD.	12	8	12
EG004	IR 90+30 mg	Participants received IR tolvaptan 90+30 mg QD.	12	7	12