Autosomal Dominant Polycystic Kidney Disease
Conditions
Keywords
Kidney Disease, Polycystic Kidney Disease
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)
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.
Interventions
DRUGTolvaptan MR
20 mg Tolvaptan MR capsule(morning); Placebo capsules/tablets (morning and afternoon) for 7 days
DRUGTolvaptan IR
90 mg Tolvaptan IR tablet(morning); 30 mg Tolvaptan IR tablet (afternoon); Placebo capsules (morning and afternoon) for 7 days
Sponsors
Otsuka Pharmaceutical Development & Commercialization, Inc.
Study design
Allocation
RANDOMIZED
Intervention model
CROSSOVER
Primary purpose
TREATMENT
Masking
QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)
Eligibility
Sex/Gender
ALL
Age
18 Years to 50 Years
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
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| 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. |
| 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. |
| 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
| Measure | Time frame | Description |
|---|---|---|
| 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. |
| 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. |
| 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. |
| 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. |
| 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. |
| 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. |
| 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. |
| 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. |
| 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. |
| 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. |
| 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?. |
| 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. |
| 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. |
| 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) |
Countries
United States
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 details
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.
Participants by arm
| Arm | Count |
|---|---|
| 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. | 12 |
| 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. | 13 |
| Total | 25 |
Baseline characteristics
| Characteristic | Group 1 | Group 2 | Total |
|---|---|---|---|
| Age, Continuous | 39.4 Years STANDARD_DEVIATION 4.3 | 36.8 Years STANDARD_DEVIATION 9 | 38.0 Years STANDARD_DEVIATION 7.1 |
| Sex: Female, Male Female | 7 Participants | 4 Participants | 11 Participants |
| Sex: Female, Male Male | 5 Participants | 9 Participants | 14 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk | EG003 affected / at risk | EG004 affected / at risk |
|---|---|---|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — | — / — | — / — | — / — |
| other Total, other adverse events | 5 / 17 | 10 / 17 | 6 / 17 | 8 / 12 | 7 / 12 |
| serious Total, serious adverse events | 0 / 17 | 0 / 17 | 0 / 17 | 0 / 12 | 0 / 12 |
Outcome results
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.
Time frame: Day 7
Population: Participants having valid measurements (per clinical pharmacology) were included.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| MR 20 mg | 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. | 1260 ng·h/mL | Standard Deviation 654 |
| MR 20+20 mg | 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. | 2310 ng·h/mL | Standard Deviation 704 |
| MR 60 mg | 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. | 3600 ng·h/mL | Standard Deviation 1670 |
| MR 120 mg | 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. | 7740 ng·h/mL | Standard Deviation 3650 |
| IR 90+30 mg | 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. | 6570 ng·h/mL | Standard Deviation 3230 |
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.
Time frame: Day 7
Population: Participants having valid measurements (per clinical pharmacology) were included.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| MR 20 mg | Maximum (Peak) Plasma Concentration of the Drug [Cmax] and Minimum (Trough) Plasma Concentration of the Drug [Cmin] After Tolvaptan Treatment on Day 7. | Cmax | 140 ng/mL | Standard Deviation 68.4 |
| MR 20 mg | Maximum (Peak) Plasma Concentration of the Drug [Cmax] and Minimum (Trough) Plasma Concentration of the Drug [Cmin] After Tolvaptan Treatment on Day 7. | Cmin | 14.7 ng/mL | Standard Deviation 9.95 |
| MR 20+20 mg | Maximum (Peak) Plasma Concentration of the Drug [Cmax] and Minimum (Trough) Plasma Concentration of the Drug [Cmin] After Tolvaptan Treatment on Day 7. | Cmax | 175 ng/mL | Standard Deviation 60.1 |
| MR 20+20 mg | Maximum (Peak) Plasma Concentration of the Drug [Cmax] and Minimum (Trough) Plasma Concentration of the Drug [Cmin] After Tolvaptan Treatment on Day 7. | Cmin | 50.8 ng/mL | Standard Deviation 24 |
| MR 60 mg | Maximum (Peak) Plasma Concentration of the Drug [Cmax] and Minimum (Trough) Plasma Concentration of the Drug [Cmin] After Tolvaptan Treatment on Day 7. | Cmax | 350 ng/mL | Standard Deviation 156 |
| MR 60 mg | Maximum (Peak) Plasma Concentration of the Drug [Cmax] and Minimum (Trough) Plasma Concentration of the Drug [Cmin] After Tolvaptan Treatment on Day 7. | Cmin | 51.1 ng/mL | Standard Deviation 32.3 |
| MR 120 mg | Maximum (Peak) Plasma Concentration of the Drug [Cmax] and Minimum (Trough) Plasma Concentration of the Drug [Cmin] After Tolvaptan Treatment on Day 7. | Cmin | 139 ng/mL | Standard Deviation 75.5 |
| MR 120 mg | Maximum (Peak) Plasma Concentration of the Drug [Cmax] and Minimum (Trough) Plasma Concentration of the Drug [Cmin] After Tolvaptan Treatment on Day 7. | Cmax | 669 ng/mL | Standard Deviation 370 |
| IR 90+30 mg | Maximum (Peak) Plasma Concentration of the Drug [Cmax] and Minimum (Trough) Plasma Concentration of the Drug [Cmin] After Tolvaptan Treatment on Day 7. | Cmax | 716 ng/mL | Standard Deviation 344 |
| IR 90+30 mg | Maximum (Peak) Plasma Concentration of the Drug [Cmax] and Minimum (Trough) Plasma Concentration of the Drug [Cmin] After Tolvaptan Treatment on Day 7. | Cmin | 57.5 ng/mL | Standard Deviation 41.8 |
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.
Time frame: Day 7
Population: Participants having valid measurements (per clinical pharmacology) were included.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| MR 20 mg | Time to Maximum (Peak) Plasma Concentration (Tmax) After Tolvaptan Treatment on Day 7. | 6.00 Hours |
| MR 20+20 mg | Time to Maximum (Peak) Plasma Concentration (Tmax) After Tolvaptan Treatment on Day 7. | 6.00 Hours |
| MR 60 mg | Time to Maximum (Peak) Plasma Concentration (Tmax) After Tolvaptan Treatment on Day 7. | 6.00 Hours |
| MR 120 mg | Time to Maximum (Peak) Plasma Concentration (Tmax) After Tolvaptan Treatment on Day 7. | 5.98 Hours |
| IR 90+30 mg | Time to Maximum (Peak) Plasma Concentration (Tmax) After Tolvaptan Treatment on Day 7. | 2.00 Hours |
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.
Time frame: Days 1, 2, 3, 4, 5, 6 and 7
Population: All participants who had taken study drug and had measurements of the pharmacodynamic endpoint were included.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| MR 20 mg | Change From Baseline in Number of Urine Voids During Awake Periods. | Day 1 | 1.7 Number of urine voids | Standard Deviation 4.1 |
| MR 20 mg | Change From Baseline in Number of Urine Voids During Awake Periods. | Day 7 | 2.0 Number of urine voids | Standard Deviation 3 |
| MR 20 mg | Change From Baseline in Number of Urine Voids During Awake Periods. | Day 6 | 0.0 Number of urine voids | Standard Deviation 3.3 |
| MR 20 mg | Change From Baseline in Number of Urine Voids During Awake Periods. | Day 3 | -0.8 Number of urine voids | Standard Deviation 2.4 |
| MR 20 mg | Change From Baseline in Number of Urine Voids During Awake Periods. | Day 2 | -0.4 Number of urine voids | Standard Deviation 2.9 |
| MR 20 mg | Change From Baseline in Number of Urine Voids During Awake Periods. | Day 4 | -1.4 Number of urine voids | Standard Deviation 2.3 |
| MR 20 mg | Change From Baseline in Number of Urine Voids During Awake Periods. | Day 5 | -0.5 Number of urine voids | Standard Deviation 2.9 |
| MR 20+20 mg | Change From Baseline in Number of Urine Voids During Awake Periods. | Day 5 | 0.6 Number of urine voids | Standard Deviation 3.5 |
| MR 20+20 mg | Change From Baseline in Number of Urine Voids During Awake Periods. | Day 4 | 1.5 Number of urine voids | Standard Deviation 3.8 |
| MR 20+20 mg | Change From Baseline in Number of Urine Voids During Awake Periods. | Day 2 | 1.2 Number of urine voids | Standard Deviation 4 |
| MR 20+20 mg | Change From Baseline in Number of Urine Voids During Awake Periods. | Day 1 | 1.5 Number of urine voids | Standard Deviation 3.1 |
| MR 20+20 mg | Change From Baseline in Number of Urine Voids During Awake Periods. | Day 6 | 2.9 Number of urine voids | Standard Deviation 4.1 |
| MR 20+20 mg | Change From Baseline in Number of Urine Voids During Awake Periods. | Day 3 | 0.9 Number of urine voids | Standard Deviation 2.4 |
| MR 20+20 mg | Change From Baseline in Number of Urine Voids During Awake Periods. | Day 7 | 3.5 Number of urine voids | Standard Deviation 2.4 |
| MR 60 mg | Change From Baseline in Number of Urine Voids During Awake Periods. | Day 4 | 0.4 Number of urine voids | Standard Deviation 5 |
| MR 60 mg | Change From Baseline in Number of Urine Voids During Awake Periods. | Day 1 | 3.5 Number of urine voids | Standard Deviation 4.3 |
| MR 60 mg | Change From Baseline in Number of Urine Voids During Awake Periods. | Day 2 | 1.8 Number of urine voids | Standard Deviation 4.1 |
| MR 60 mg | Change From Baseline in Number of Urine Voids During Awake Periods. | Day 3 | 2.4 Number of urine voids | Standard Deviation 3.9 |
| MR 60 mg | Change From Baseline in Number of Urine Voids During Awake Periods. | Day 5 | -0.4 Number of urine voids | Standard Deviation 4.2 |
| MR 60 mg | Change From Baseline in Number of Urine Voids During Awake Periods. | Day 6 | 5.8 Number of urine voids | Standard Deviation 10.6 |
| MR 60 mg | Change From Baseline in Number of Urine Voids During Awake Periods. | Day 7 | 3.5 Number of urine voids | Standard Deviation 3.8 |
| MR 120 mg | Change From Baseline in Number of Urine Voids During Awake Periods. | Day 3 | 3.1 Number of urine voids | Standard Deviation 4.6 |
| MR 120 mg | Change From Baseline in Number of Urine Voids During Awake Periods. | Day 5 | 3.3 Number of urine voids | Standard Deviation 5.6 |
| MR 120 mg | Change From Baseline in Number of Urine Voids During Awake Periods. | Day 2 | 4.8 Number of urine voids | Standard Deviation 7.8 |
| MR 120 mg | Change From Baseline in Number of Urine Voids During Awake Periods. | Day 7 | 2.8 Number of urine voids | Standard Deviation 6.4 |
| MR 120 mg | Change From Baseline in Number of Urine Voids During Awake Periods. | Day 6 | 2.3 Number of urine voids | Standard Deviation 6.8 |
| MR 120 mg | Change From Baseline in Number of Urine Voids During Awake Periods. | Day 1 | 5.6 Number of urine voids | Standard Deviation 5.6 |
| MR 120 mg | Change From Baseline in Number of Urine Voids During Awake Periods. | Day 4 | 2.8 Number of urine voids | Standard Deviation 5 |
| IR 90+30 mg | Change From Baseline in Number of Urine Voids During Awake Periods. | Day 3 | 3.3 Number of urine voids | Standard Deviation 5.2 |
| IR 90+30 mg | Change From Baseline in Number of Urine Voids During Awake Periods. | Day 7 | 4.3 Number of urine voids | Standard Deviation 4.5 |
| IR 90+30 mg | Change From Baseline in Number of Urine Voids During Awake Periods. | Day 6 | 4.8 Number of urine voids | Standard Deviation 5.2 |
| IR 90+30 mg | Change From Baseline in Number of Urine Voids During Awake Periods. | Day 5 | 4.0 Number of urine voids | Standard Deviation 4.9 |
| IR 90+30 mg | Change From Baseline in Number of Urine Voids During Awake Periods. | Day 2 | 3.8 Number of urine voids | Standard Deviation 4.2 |
| IR 90+30 mg | Change From Baseline in Number of Urine Voids During Awake Periods. | Day 1 | 4.8 Number of urine voids | Standard Deviation 4.1 |
| IR 90+30 mg | Change From Baseline in Number of Urine Voids During Awake Periods. | Day 4 | 3.7 Number of urine voids | Standard Deviation 5.9 |
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.
Time frame: Days 1, 2, 3, 4, 5, 6 and 7
Population: All participants who had taken study drug and have measurements of the pharmacodynamic endpoint were included.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| MR 20 mg | Change From Baseline in Number of Urine Voids During Sleep Periods. | Day 1 | 0.6 Number of urine voids | Standard Deviation 1.6 |
| MR 20 mg | Change From Baseline in Number of Urine Voids During Sleep Periods. | Day 4 | 0.6 Number of urine voids | Standard Deviation 2.3 |
| MR 20 mg | Change From Baseline in Number of Urine Voids During Sleep Periods. | Day 5 | 0.3 Number of urine voids | Standard Deviation 1.3 |
| MR 20 mg | Change From Baseline in Number of Urine Voids During Sleep Periods. | Day 2 | -0.2 Number of urine voids | Standard Deviation 1.7 |
| MR 20 mg | Change From Baseline in Number of Urine Voids During Sleep Periods. | Day 7 | 0.1 Number of urine voids | Standard Deviation 1.3 |
| MR 20 mg | Change From Baseline in Number of Urine Voids During Sleep Periods. | Day 3 | 0.1 Number of urine voids | Standard Deviation 1 |
| MR 20 mg | Change From Baseline in Number of Urine Voids During Sleep Periods. | Day 6 | 1.2 Number of urine voids | Standard Deviation 3.3 |
| MR 20+20 mg | Change From Baseline in Number of Urine Voids During Sleep Periods. | Day 4 | 0.7 Number of urine voids | Standard Deviation 1.6 |
| MR 20+20 mg | Change From Baseline in Number of Urine Voids During Sleep Periods. | Day 2 | 0.8 Number of urine voids | Standard Deviation 1.6 |
| MR 20+20 mg | Change From Baseline in Number of Urine Voids During Sleep Periods. | Day 3 | 1.4 Number of urine voids | Standard Deviation 2.4 |
| MR 20+20 mg | Change From Baseline in Number of Urine Voids During Sleep Periods. | Day 6 | 1.3 Number of urine voids | Standard Deviation 2 |
| MR 20+20 mg | Change From Baseline in Number of Urine Voids During Sleep Periods. | Day 5 | 0.9 Number of urine voids | Standard Deviation 2 |
| MR 20+20 mg | Change From Baseline in Number of Urine Voids During Sleep Periods. | Day 7 | 1.0 Number of urine voids | Standard Deviation 1.7 |
| MR 20+20 mg | Change From Baseline in Number of Urine Voids During Sleep Periods. | Day 1 | 1.1 Number of urine voids | Standard Deviation 2 |
| MR 60 mg | Change From Baseline in Number of Urine Voids During Sleep Periods. | Day 5 | 0.2 Number of urine voids | Standard Deviation 1.4 |
| MR 60 mg | Change From Baseline in Number of Urine Voids During Sleep Periods. | Day 6 | 0.4 Number of urine voids | Standard Deviation 1.6 |
| MR 60 mg | Change From Baseline in Number of Urine Voids During Sleep Periods. | Day 4 | 0.5 Number of urine voids | Standard Deviation 1.7 |
| MR 60 mg | Change From Baseline in Number of Urine Voids During Sleep Periods. | Day 3 | 0.8 Number of urine voids | Standard Deviation 1.7 |
| MR 60 mg | Change From Baseline in Number of Urine Voids During Sleep Periods. | Day 1 | 0.4 Number of urine voids | Standard Deviation 2.2 |
| MR 60 mg | Change From Baseline in Number of Urine Voids During Sleep Periods. | Day 2 | 0.8 Number of urine voids | Standard Deviation 1.9 |
| MR 60 mg | Change From Baseline in Number of Urine Voids During Sleep Periods. | Day 7 | 0.9 Number of urine voids | Standard Deviation 1.8 |
| MR 120 mg | Change From Baseline in Number of Urine Voids During Sleep Periods. | Day 4 | 1.7 Number of urine voids | Standard Deviation 1.3 |
| MR 120 mg | Change From Baseline in Number of Urine Voids During Sleep Periods. | Day 5 | 1.0 Number of urine voids | Standard Deviation 2 |
| MR 120 mg | Change From Baseline in Number of Urine Voids During Sleep Periods. | Day 6 | 1.1 Number of urine voids | Standard Deviation 2.1 |
| MR 120 mg | Change From Baseline in Number of Urine Voids During Sleep Periods. | Day 7 | 1.8 Number of urine voids | Standard Deviation 2.4 |
| MR 120 mg | Change From Baseline in Number of Urine Voids During Sleep Periods. | Day 1 | 2.5 Number of urine voids | Standard Deviation 1.7 |
| MR 120 mg | Change From Baseline in Number of Urine Voids During Sleep Periods. | Day 2 | 1.8 Number of urine voids | Standard Deviation 1.4 |
| MR 120 mg | Change From Baseline in Number of Urine Voids During Sleep Periods. | Day 3 | 1.9 Number of urine voids | Standard Deviation 1.5 |
| IR 90+30 mg | Change From Baseline in Number of Urine Voids During Sleep Periods. | Day 1 | 1.5 Number of urine voids | Standard Deviation 1.6 |
| IR 90+30 mg | Change From Baseline in Number of Urine Voids During Sleep Periods. | Day 4 | 1.8 Number of urine voids | Standard Deviation 1.9 |
| IR 90+30 mg | Change From Baseline in Number of Urine Voids During Sleep Periods. | Day 3 | 1.9 Number of urine voids | Standard Deviation 1.7 |
| IR 90+30 mg | Change From Baseline in Number of Urine Voids During Sleep Periods. | Day 7 | 2.1 Number of urine voids | Standard Deviation 1.9 |
| IR 90+30 mg | Change From Baseline in Number of Urine Voids During Sleep Periods. | Day 6 | 1.7 Number of urine voids | Standard Deviation 1.7 |
| IR 90+30 mg | Change From Baseline in Number of Urine Voids During Sleep Periods. | Day 5 | 0.9 Number of urine voids | Standard Deviation 1.7 |
| IR 90+30 mg | Change From Baseline in Number of Urine Voids During Sleep Periods. | Day 2 | 1.7 Number of urine voids | Standard Deviation 1.2 |
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.
Time frame: Day 6
Population: All participants who had taken study drug and have measurements of the pharmacodynamic endpoint were included.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| MR 20 mg | Change From Baseline in Symptom Burden by Autosomal Dominant Polycystic Kidney Disease (ADPKD) Nocturia Quality of Life Questionnaire at Day 6. | Nocturia Quality of life Question (Q) 1 To Q 11 | -1.5 Units on a scale | Standard Deviation 4.3 |
| MR 20 mg | Change From Baseline in Symptom Burden by Autosomal Dominant Polycystic Kidney Disease (ADPKD) Nocturia Quality of Life Questionnaire at Day 6. | Nocturia Quality of life Q 12 | 0.6 Units on a scale | Standard Deviation 1.3 |
| MR 20+20 mg | Change From Baseline in Symptom Burden by Autosomal Dominant Polycystic Kidney Disease (ADPKD) Nocturia Quality of Life Questionnaire at Day 6. | Nocturia Quality of life Question (Q) 1 To Q 11 | -6.9 Units on a scale | Standard Deviation 9.9 |
| MR 20+20 mg | Change From Baseline in Symptom Burden by Autosomal Dominant Polycystic Kidney Disease (ADPKD) Nocturia Quality of Life Questionnaire at Day 6. | Nocturia Quality of life Q 12 | 1.9 Units on a scale | Standard Deviation 2.7 |
| MR 60 mg | Change From Baseline in Symptom Burden by Autosomal Dominant Polycystic Kidney Disease (ADPKD) Nocturia Quality of Life Questionnaire at Day 6. | Nocturia Quality of life Question (Q) 1 To Q 11 | -5.1 Units on a scale | Standard Deviation 7.6 |
| MR 60 mg | Change From Baseline in Symptom Burden by Autosomal Dominant Polycystic Kidney Disease (ADPKD) Nocturia Quality of Life Questionnaire at Day 6. | Nocturia Quality of life Q 12 | 1.4 Units on a scale | Standard Deviation 2.5 |
| MR 120 mg | Change From Baseline in Symptom Burden by Autosomal Dominant Polycystic Kidney Disease (ADPKD) Nocturia Quality of Life Questionnaire at Day 6. | Nocturia Quality of life Q 12 | 4.2 Units on a scale | Standard Deviation 3.6 |
| MR 120 mg | Change From Baseline in Symptom Burden by Autosomal Dominant Polycystic Kidney Disease (ADPKD) Nocturia Quality of Life Questionnaire at Day 6. | Nocturia Quality of life Question (Q) 1 To Q 11 | -15.0 Units on a scale | Standard Deviation 13.3 |
| IR 90+30 mg | Change From Baseline in Symptom Burden by Autosomal Dominant Polycystic Kidney Disease (ADPKD) Nocturia Quality of Life Questionnaire at Day 6. | Nocturia Quality of life Question (Q) 1 To Q 11 | -13.1 Units on a scale | Standard Deviation 12.3 |
| IR 90+30 mg | Change From Baseline in Symptom Burden by Autosomal Dominant Polycystic Kidney Disease (ADPKD) Nocturia Quality of Life Questionnaire at Day 6. | Nocturia Quality of life Q 12 | 3.7 Units on a scale | Standard Deviation 3.5 |
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.
Time frame: Day 6
Population: All participants who had taken study drug and have measurements of the pharmacodynamic endpoint were included.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| MR 20 mg | Change From Baseline in Urinary Frequency Questionnaire (Question 2 and Questions 3 to 10) at Day 6. | Urinary frequency questionnaire-Q 3 to Q 10 | 1.4 Units on a scale | Standard Deviation 2.1 |
| MR 20 mg | Change From Baseline in Urinary Frequency Questionnaire (Question 2 and Questions 3 to 10) at Day 6. | Urinary frequency questionnaire-Question (Q) 2 | 0.4 Units on a scale | Standard Deviation 0.6 |
| MR 20+20 mg | Change From Baseline in Urinary Frequency Questionnaire (Question 2 and Questions 3 to 10) at Day 6. | Urinary frequency questionnaire-Question (Q) 2 | 1.1 Units on a scale | Standard Deviation 1.1 |
| MR 20+20 mg | Change From Baseline in Urinary Frequency Questionnaire (Question 2 and Questions 3 to 10) at Day 6. | Urinary frequency questionnaire-Q 3 to Q 10 | 4.6 Units on a scale | Standard Deviation 6.9 |
| MR 60 mg | Change From Baseline in Urinary Frequency Questionnaire (Question 2 and Questions 3 to 10) at Day 6. | Urinary frequency questionnaire-Q 3 to Q 10 | 4.1 Units on a scale | Standard Deviation 5.7 |
| MR 60 mg | Change From Baseline in Urinary Frequency Questionnaire (Question 2 and Questions 3 to 10) at Day 6. | Urinary frequency questionnaire-Question (Q) 2 | 0.9 Units on a scale | Standard Deviation 0.9 |
| MR 120 mg | Change From Baseline in Urinary Frequency Questionnaire (Question 2 and Questions 3 to 10) at Day 6. | Urinary frequency questionnaire-Question (Q) 2 | 1.7 Units on a scale | Standard Deviation 1.4 |
| MR 120 mg | Change From Baseline in Urinary Frequency Questionnaire (Question 2 and Questions 3 to 10) at Day 6. | Urinary frequency questionnaire-Q 3 to Q 10 | 12.2 Units on a scale | Standard Deviation 11 |
| IR 90+30 mg | Change From Baseline in Urinary Frequency Questionnaire (Question 2 and Questions 3 to 10) at Day 6. | Urinary frequency questionnaire-Q 3 to Q 10 | 9.1 Units on a scale | Standard Deviation 10.5 |
| IR 90+30 mg | Change From Baseline in Urinary Frequency Questionnaire (Question 2 and Questions 3 to 10) at Day 6. | Urinary frequency questionnaire-Question (Q) 2 | 1.5 Units on a scale | Standard Deviation 1.1 |
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.
Time frame: Day 6
Population: All participants who had taken study drug and have measurements of the pharmacodynamic endpoint were included.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| MR 20 mg | Change From Baseline in Urinary Urgency Questionnaire (Questions 2 to 5 and Questions 7 to 14) at Day 6. | Urinary urgency questionnaire-Q 7 to Q 14 | 0.9 Units on a scale | Standard Deviation 1.2 |
| MR 20 mg | Change From Baseline in Urinary Urgency Questionnaire (Questions 2 to 5 and Questions 7 to 14) at Day 6. | Urinary urgency questionnaire-Question (Q) 2 to Q5 | 1.4 Units on a scale | Standard Deviation 2.1 |
| MR 20+20 mg | Change From Baseline in Urinary Urgency Questionnaire (Questions 2 to 5 and Questions 7 to 14) at Day 6. | Urinary urgency questionnaire-Question (Q) 2 to Q5 | 3.2 Units on a scale | Standard Deviation 2.4 |
| MR 20+20 mg | Change From Baseline in Urinary Urgency Questionnaire (Questions 2 to 5 and Questions 7 to 14) at Day 6. | Urinary urgency questionnaire-Q 7 to Q 14 | 4.2 Units on a scale | Standard Deviation 5.5 |
| MR 60 mg | Change From Baseline in Urinary Urgency Questionnaire (Questions 2 to 5 and Questions 7 to 14) at Day 6. | Urinary urgency questionnaire-Question (Q) 2 to Q5 | 3.2 Units on a scale | Standard Deviation 3.1 |
| MR 60 mg | Change From Baseline in Urinary Urgency Questionnaire (Questions 2 to 5 and Questions 7 to 14) at Day 6. | Urinary urgency questionnaire-Q 7 to Q 14 | 3.5 Units on a scale | Standard Deviation 5 |
| MR 120 mg | Change From Baseline in Urinary Urgency Questionnaire (Questions 2 to 5 and Questions 7 to 14) at Day 6. | Urinary urgency questionnaire-Q 7 to Q 14 | 10.9 Units on a scale | Standard Deviation 10.9 |
| MR 120 mg | Change From Baseline in Urinary Urgency Questionnaire (Questions 2 to 5 and Questions 7 to 14) at Day 6. | Urinary urgency questionnaire-Question (Q) 2 to Q5 | 4.6 Units on a scale | Standard Deviation 3.9 |
| IR 90+30 mg | Change From Baseline in Urinary Urgency Questionnaire (Questions 2 to 5 and Questions 7 to 14) at Day 6. | Urinary urgency questionnaire-Question (Q) 2 to Q5 | 4.7 Units on a scale | Standard Deviation 3 |
| IR 90+30 mg | Change From Baseline in Urinary Urgency Questionnaire (Questions 2 to 5 and Questions 7 to 14) at Day 6. | Urinary urgency questionnaire-Q 7 to Q 14 | 8.8 Units on a scale | Standard Deviation 9.8 |
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.
Time frame: Day 7
Population: All participants who had taken study drug and had measurements of the pharmacodynamic endpoint were included.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| MR 20 mg | Change From Baseline in Urine Osmolality Area Under the Concentration-time Curve From Time 0 to 24 Hours Postdose (AUC0-24h) at Day 7. | -2546 mOsm/kg*Hour | Standard Deviation 1743 |
| MR 20+20 mg | Change From Baseline in Urine Osmolality Area Under the Concentration-time Curve From Time 0 to 24 Hours Postdose (AUC0-24h) at Day 7. | -3438 mOsm/kg*Hour | Standard Deviation 2277 |
| MR 60 mg | Change From Baseline in Urine Osmolality Area Under the Concentration-time Curve From Time 0 to 24 Hours Postdose (AUC0-24h) at Day 7. | -4209 mOsm/kg*Hour | Standard Deviation 2569 |
| MR 120 mg | Change From Baseline in Urine Osmolality Area Under the Concentration-time Curve From Time 0 to 24 Hours Postdose (AUC0-24h) at Day 7. | -4325 mOsm/kg*Hour | Standard Deviation 2237 |
| IR 90+30 mg | Change From Baseline in Urine Osmolality Area Under the Concentration-time Curve From Time 0 to 24 Hours Postdose (AUC0-24h) at Day 7. | -4620 mOsm/kg*Hour | Standard Deviation 2419 |
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)
Time frame: 0-4, 4-8, 8-12, 12-16, 16-24 Hours at Day 7
Population: All participants who had taken study drug and have measurements of the pharmacodynamic endpoint were included.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| MR 20 mg | Change From Baseline in Urine Osmolality at Day 7. | 4-8 Hour | -140.9 mOsm/kg | Standard Deviation 127.1 |
| MR 20 mg | Change From Baseline in Urine Osmolality at Day 7. | 8-12 Hour | -123.1 mOsm/kg | Standard Deviation 115.9 |
| MR 20 mg | Change From Baseline in Urine Osmolality at Day 7. | 16-24 Hour | -123.4 mOsm/kg | Standard Deviation 102.6 |
| MR 20 mg | Change From Baseline in Urine Osmolality at Day 7. | 0-4 Hour | 2.6 mOsm/kg | Standard Deviation 132.1 |
| MR 20 mg | Change From Baseline in Urine Osmolality at Day 7. | 12-16 Hour | -128.3 mOsm/kg | Standard Deviation 142.9 |
| MR 20+20 mg | Change From Baseline in Urine Osmolality at Day 7. | 4-8 Hour | -128.3 mOsm/kg | Standard Deviation 127.2 |
| MR 20+20 mg | Change From Baseline in Urine Osmolality at Day 7. | 8-12 Hour | -172.1 mOsm/kg | Standard Deviation 129.8 |
| MR 20+20 mg | Change From Baseline in Urine Osmolality at Day 7. | 12-16 Hour | -193.6 mOsm/kg | Standard Deviation 152.5 |
| MR 20+20 mg | Change From Baseline in Urine Osmolality at Day 7. | 0-4 Hour | -0.7 mOsm/kg | Standard Deviation 111.9 |
| MR 20+20 mg | Change From Baseline in Urine Osmolality at Day 7. | 16-24 Hour | -182.4 mOsm/kg | Standard Deviation 145.6 |
| MR 60 mg | Change From Baseline in Urine Osmolality at Day 7. | 4-8 Hour | -188.2 mOsm/kg | Standard Deviation 140.5 |
| MR 60 mg | Change From Baseline in Urine Osmolality at Day 7. | 0-4 Hour | -88.9 mOsm/kg | Standard Deviation 130.9 |
| MR 60 mg | Change From Baseline in Urine Osmolality at Day 7. | 12-16 Hour | -195.8 mOsm/kg | Standard Deviation 151.6 |
| MR 60 mg | Change From Baseline in Urine Osmolality at Day 7. | 8-12 Hour | -201.8 mOsm/kg | Standard Deviation 158.8 |
| MR 60 mg | Change From Baseline in Urine Osmolality at Day 7. | 16-24 Hour | -188.8 mOsm/kg | Standard Deviation 160 |
| MR 120 mg | Change From Baseline in Urine Osmolality at Day 7. | 0-4 Hour | -59.5 mOsm/kg | Standard Deviation 169.2 |
| MR 120 mg | Change From Baseline in Urine Osmolality at Day 7. | 8-12 Hour | -167.1 mOsm/kg | Standard Deviation 148.7 |
| MR 120 mg | Change From Baseline in Urine Osmolality at Day 7. | 12-16 Hour | -176.3 mOsm/kg | Standard Deviation 121.8 |
| MR 120 mg | Change From Baseline in Urine Osmolality at Day 7. | 16-24 Hour | -246.1 mOsm/kg | Standard Deviation 108.9 |
| MR 120 mg | Change From Baseline in Urine Osmolality at Day 7. | 4-8 Hour | -186.1 mOsm/kg | Standard Deviation 161.1 |
| IR 90+30 mg | Change From Baseline in Urine Osmolality at Day 7. | 16-24 Hour | -239.8 mOsm/kg | Standard Deviation 117.8 |
| IR 90+30 mg | Change From Baseline in Urine Osmolality at Day 7. | 0-4 Hour | -123.3 mOsm/kg | Standard Deviation 139.5 |
| IR 90+30 mg | Change From Baseline in Urine Osmolality at Day 7. | 4-8 Hour | -191.8 mOsm/kg | Standard Deviation 155.1 |
| IR 90+30 mg | Change From Baseline in Urine Osmolality at Day 7. | 8-12 Hour | -166.9 mOsm/kg | Standard Deviation 131.7 |
| IR 90+30 mg | Change From Baseline in Urine Osmolality at Day 7. | 12-16 Hour | -178.3 mOsm/kg | Standard Deviation 128.9 |
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.
Time frame: Day 7
Population: All participants who had taken study drug and have measurements of the pharmacodynamic endpoint were included.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| MR 20 mg | Change From Baseline in Urine Volume at 24 Hours at Day 7. | 1111 mL | Standard Deviation 919 |
| MR 20+20 mg | Change From Baseline in Urine Volume at 24 Hours at Day 7. | 2066 mL | Standard Deviation 1237 |
| MR 60 mg | Change From Baseline in Urine Volume at 24 Hours at Day 7. | 2396 mL | Standard Deviation 1022 |
| MR 120 mg | Change From Baseline in Urine Volume at 24 Hours at Day 7. | 3722 mL | Standard Deviation 1776 |
| IR 90+30 mg | Change From Baseline in Urine Volume at 24 Hours at Day 7. | 3820 mL | Standard Deviation 1759 |
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.
Time frame: 0-4, 4-8, 8-12, 12-16, 16-24 Hours at Day 7
Population: All participants who had taken study drug and have measurements of the pharmacodynamic endpoint were included.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| MR 20 mg | Change From Baseline in Urine Volume by Interval at Day 7. | 16-24 Hour | 257 mL | Standard Deviation 407 |
| MR 20 mg | Change From Baseline in Urine Volume by Interval at Day 7. | 4-8 Hour | 326 mL | Standard Deviation 531 |
| MR 20 mg | Change From Baseline in Urine Volume by Interval at Day 7. | 12-16 Hour | 314 mL | Standard Deviation 328 |
| MR 20 mg | Change From Baseline in Urine Volume by Interval at Day 7. | 8-12 Hour | 301 mL | Standard Deviation 317 |
| MR 20 mg | Change From Baseline in Urine Volume by Interval at Day 7. | 0-4 Hour | -87 mL | Standard Deviation 348 |
| MR 20+20 mg | Change From Baseline in Urine Volume by Interval at Day 7. | 4-8 Hour | 423 mL | Standard Deviation 439 |
| MR 20+20 mg | Change From Baseline in Urine Volume by Interval at Day 7. | 12-16 Hour | 635 mL | Standard Deviation 473 |
| MR 20+20 mg | Change From Baseline in Urine Volume by Interval at Day 7. | 0-4 Hour | -118 mL | Standard Deviation 391 |
| MR 20+20 mg | Change From Baseline in Urine Volume by Interval at Day 7. | 16-24 Hour | 598 mL | Standard Deviation 482 |
| MR 20+20 mg | Change From Baseline in Urine Volume by Interval at Day 7. | 8-12 Hour | 529 mL | Standard Deviation 349 |
| MR 60 mg | Change From Baseline in Urine Volume by Interval at Day 7. | 8-12 Hour | 689 mL | Standard Deviation 603 |
| MR 60 mg | Change From Baseline in Urine Volume by Interval at Day 7. | 12-16 Hour | 667 mL | Standard Deviation 337 |
| MR 60 mg | Change From Baseline in Urine Volume by Interval at Day 7. | 16-24 Hour | 286 mL | Standard Deviation 421 |
| MR 60 mg | Change From Baseline in Urine Volume by Interval at Day 7. | 4-8 Hour | 636 mL | Standard Deviation 382 |
| MR 60 mg | Change From Baseline in Urine Volume by Interval at Day 7. | 0-4 Hour | 56 mL | Standard Deviation 345 |
| MR 120 mg | Change From Baseline in Urine Volume by Interval at Day 7. | 16-24 Hour | 1038 mL | Standard Deviation 642 |
| MR 120 mg | Change From Baseline in Urine Volume by Interval at Day 7. | 0-4 Hour | 87 mL | Standard Deviation 449 |
| MR 120 mg | Change From Baseline in Urine Volume by Interval at Day 7. | 4-8 Hour | 785 mL | Standard Deviation 605 |
| MR 120 mg | Change From Baseline in Urine Volume by Interval at Day 7. | 8-12 Hour | 887 mL | Standard Deviation 558 |
| MR 120 mg | Change From Baseline in Urine Volume by Interval at Day 7. | 12-16 Hour | 926 mL | Standard Deviation 459 |
| IR 90+30 mg | Change From Baseline in Urine Volume by Interval at Day 7. | 12-16 Hour | 910 mL | Standard Deviation 738 |
| IR 90+30 mg | Change From Baseline in Urine Volume by Interval at Day 7. | 8-12 Hour | 801 mL | Standard Deviation 494 |
| IR 90+30 mg | Change From Baseline in Urine Volume by Interval at Day 7. | 4-8 Hour | 825 mL | Standard Deviation 472 |
| IR 90+30 mg | Change From Baseline in Urine Volume by Interval at Day 7. | 0-4 Hour | 241 mL | Standard Deviation 412 |
| IR 90+30 mg | Change From Baseline in Urine Volume by Interval at Day 7. | 16-24 Hour | 1044 mL | Standard Deviation 421 |
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.
Time frame: Baseline and Day 7
Population: 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 | Measure | Group | Value (MEDIAN) |
|---|---|---|---|
| MR 20 mg | Duration of Urine Osmolality Less Than 300 mOsm/kg at Baseline and Day 7. | Baseline | 8.0 Hours |
| MR 20 mg | Duration of Urine Osmolality Less Than 300 mOsm/kg at Baseline and Day 7. | Day 7 | 16.0 Hours |
| MR 20+20 mg | Duration of Urine Osmolality Less Than 300 mOsm/kg at Baseline and Day 7. | Baseline | 8.0 Hours |
| MR 20+20 mg | Duration of Urine Osmolality Less Than 300 mOsm/kg at Baseline and Day 7. | Day 7 | 24.0 Hours |
| MR 60 mg | Duration of Urine Osmolality Less Than 300 mOsm/kg at Baseline and Day 7. | Baseline | 8.0 Hours |
| MR 60 mg | Duration of Urine Osmolality Less Than 300 mOsm/kg at Baseline and Day 7. | Day 7 | 24.0 Hours |
| MR 120 mg | Duration of Urine Osmolality Less Than 300 mOsm/kg at Baseline and Day 7. | Day 7 | 24.0 Hours |
| MR 120 mg | Duration of Urine Osmolality Less Than 300 mOsm/kg at Baseline and Day 7. | Baseline | 14.0 Hours |
| IR 90+30 mg | Duration of Urine Osmolality Less Than 300 mOsm/kg at Baseline and Day 7. | Baseline | 14.0 Hours |
| IR 90+30 mg | Duration of Urine Osmolality Less Than 300 mOsm/kg at Baseline and Day 7. | Day 7 | 24.0 Hours |
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.
Time frame: Baseline and Day 6
Population: All participants who had taken study drug and have measurements of the pharmacodynamic endpoint were included.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| MR 20 mg | Number of Participants Experiencing Urinary Frequency Based on Urinary Frequency Questionnaire (Question 1) at Baseline and Day 6. | Day 6 | 10 Participants |
| MR 20 mg | Number of Participants Experiencing Urinary Frequency Based on Urinary Frequency Questionnaire (Question 1) at Baseline and Day 6. | Baseline | 5 Participants |
| MR 20+20 mg | Number of Participants Experiencing Urinary Frequency Based on Urinary Frequency Questionnaire (Question 1) at Baseline and Day 6. | Baseline | 4 Participants |
| MR 20+20 mg | Number of Participants Experiencing Urinary Frequency Based on Urinary Frequency Questionnaire (Question 1) at Baseline and Day 6. | Day 6 | 15 Participants |
| MR 60 mg | Number of Participants Experiencing Urinary Frequency Based on Urinary Frequency Questionnaire (Question 1) at Baseline and Day 6. | Day 6 | 16 Participants |
| MR 60 mg | Number of Participants Experiencing Urinary Frequency Based on Urinary Frequency Questionnaire (Question 1) at Baseline and Day 6. | Baseline | 4 Participants |
| MR 120 mg | Number of Participants Experiencing Urinary Frequency Based on Urinary Frequency Questionnaire (Question 1) at Baseline and Day 6. | Baseline | 4 Participants |
| MR 120 mg | Number of Participants Experiencing Urinary Frequency Based on Urinary Frequency Questionnaire (Question 1) at Baseline and Day 6. | Day 6 | 12 Participants |
| IR 90+30 mg | Number of Participants Experiencing Urinary Frequency Based on Urinary Frequency Questionnaire (Question 1) at Baseline and Day 6. | Baseline | 4 Participants |
| IR 90+30 mg | Number of Participants Experiencing Urinary Frequency Based on Urinary Frequency Questionnaire (Question 1) at Baseline and Day 6. | Day 6 | 12 Participants |
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.
Time frame: Baseline and Day 6
Population: All participants who had taken study drug and have measurements of the pharmacodynamic endpoint were included.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| MR 20 mg | Number of Participants Experiencing Urinary Urgency Based on Urinary Urgency Questionnaire (Question 1) at Baseline and Day 6. | Baseline | 5 Participants |
| MR 20 mg | Number of Participants Experiencing Urinary Urgency Based on Urinary Urgency Questionnaire (Question 1) at Baseline and Day 6. | Day 6 | 8 Participants |
| MR 20+20 mg | Number of Participants Experiencing Urinary Urgency Based on Urinary Urgency Questionnaire (Question 1) at Baseline and Day 6. | Baseline | 3 Participants |
| MR 20+20 mg | Number of Participants Experiencing Urinary Urgency Based on Urinary Urgency Questionnaire (Question 1) at Baseline and Day 6. | Day 6 | 13 Participants |
| MR 60 mg | Number of Participants Experiencing Urinary Urgency Based on Urinary Urgency Questionnaire (Question 1) at Baseline and Day 6. | Baseline | 3 Participants |
| MR 60 mg | Number of Participants Experiencing Urinary Urgency Based on Urinary Urgency Questionnaire (Question 1) at Baseline and Day 6. | Day 6 | 12 Participants |
| MR 120 mg | Number of Participants Experiencing Urinary Urgency Based on Urinary Urgency Questionnaire (Question 1) at Baseline and Day 6. | Baseline | 2 Participants |
| MR 120 mg | Number of Participants Experiencing Urinary Urgency Based on Urinary Urgency Questionnaire (Question 1) at Baseline and Day 6. | Day 6 | 10 Participants |
| IR 90+30 mg | Number of Participants Experiencing Urinary Urgency Based on Urinary Urgency Questionnaire (Question 1) at Baseline and Day 6. | Baseline | 2 Participants |
| IR 90+30 mg | Number of Participants Experiencing Urinary Urgency Based on Urinary Urgency Questionnaire (Question 1) at Baseline and Day 6. | Day 6 | 11 Participants |
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.
Time frame: 23.5 hours post-dose
Population: All participants who had taken study drug and had measurements of the pharmacodynamic endpoint were included.
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| MR 20 mg | Number of Participants With Urine Osmolality < 300 mOsm/kg at 23.5 Hours Postdose. | Baseline | 1 Participants |
| MR 20 mg | Number of Participants With Urine Osmolality < 300 mOsm/kg at 23.5 Hours Postdose. | Day 8 | 5 Participants |
| MR 20+20 mg | Number of Participants With Urine Osmolality < 300 mOsm/kg at 23.5 Hours Postdose. | Baseline | 1 Participants |
| MR 20+20 mg | Number of Participants With Urine Osmolality < 300 mOsm/kg at 23.5 Hours Postdose. | Day 8 | 11 Participants |
| MR 60 mg | Number of Participants With Urine Osmolality < 300 mOsm/kg at 23.5 Hours Postdose. | Baseline | 1 Participants |
| MR 60 mg | Number of Participants With Urine Osmolality < 300 mOsm/kg at 23.5 Hours Postdose. | Day 8 | 9 Participants |
| MR 120 mg | Number of Participants With Urine Osmolality < 300 mOsm/kg at 23.5 Hours Postdose. | Day 8 | 11 Participants |
| MR 120 mg | Number of Participants With Urine Osmolality < 300 mOsm/kg at 23.5 Hours Postdose. | Baseline | 0 Participants |
| IR 90+30 mg | Number of Participants With Urine Osmolality < 300 mOsm/kg at 23.5 Hours Postdose. | Baseline | 0 Participants |
| IR 90+30 mg | Number of Participants With Urine Osmolality < 300 mOsm/kg at 23.5 Hours Postdose. | Day 8 | 11 Participants |
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?.
Time frame: Day 22/Early Termination
Population: All participants who had taken study drug and have measurements of the pharmacodynamic endpoint were included.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| MR 20 mg | Ranking of Treatment Tolerability. | Most tolerable Group 2 | 10 Participants |
| MR 20 mg | Ranking of Treatment Tolerability. | Least tolerable Group 2 | 0 Participants |
| MR 20 mg | Ranking of Treatment Tolerability. | Least tolerable Group 1 | 0 Participants |
| MR 20 mg | Ranking of Treatment Tolerability. | Most tolerable Group 1 | 3 Participants |
| MR 20+20 mg | Ranking of Treatment Tolerability. | Most tolerable Group 1 | 2 Participants |
| MR 20+20 mg | Ranking of Treatment Tolerability. | Least tolerable Group 2 | 7 Participants |
| MR 60 mg | Ranking of Treatment Tolerability. | Least tolerable Group 2 | 6 Participants |
| MR 60 mg | Ranking of Treatment Tolerability. | Most tolerable Group 2 | 3 Participants |
| MR 60 mg | Ranking of Treatment Tolerability. | Most tolerable Group 1 | 3 Participants |
| MR 120 mg | Ranking of Treatment Tolerability. | Most tolerable Group 1 | 1 Participants |
| MR 120 mg | Ranking of Treatment Tolerability. | Least tolerable Group 1 | 4 Participants |
| IR 90+30 mg | Ranking of Treatment Tolerability. | Most tolerable Group 1 | 1 Participants |
| IR 90+30 mg | Ranking of Treatment Tolerability. | Least tolerable Group 1 | 6 Participants |