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NOCTURNE: 8-Week Study of Tolvaptan Dose Forms in Autosomal Dominant Polycystic Kidney Disease (ADPKD)

Sponsor
Otsuka Pharmaceutical Development & Commercialization, Inc. (Industry)
Overall Status
Completed
CT.gov ID
NCT01451827
Collaborator
(none)
178
Enrollment
35
Locations
4
Arms
21
Duration (Months)
5.1
Patients Per Site
0.2
Patients Per Site Per Month

Study Details

Study Description

Brief Summary

The purpose of this study is to compare the short-term effects of two tolvaptan formulations in patients with ADPKD.

Condition or Disease Intervention/Treatment Phase
  • Drug: Tolvaptan MR
  • Drug: Tolvaptan IR
  • Drug: Placebo
 Phase 2

Study Design

Study Type:
Interventional
Actual Enrollment :
178 participants
Allocation:
Randomized
Intervention Model:
Parallel Assignment
Masking:
Triple (Participant, Care Provider, Investigator)
Primary Purpose:
Treatment
Official Title:
A Phase 2, Multicenter, Randomized, Placebo-controlled, Double-blind, Placebo-masked, Parallel-group Pilot Trial to Compare the Efficacy, Tolerability, and Safety of Tolvaptan Modified-release and Immediate-release Formulations in Subjects With Autosomal Dominant Polycystic Kidney Disease
Study Start Date :
Oct 1, 2011
Actual Primary Completion Date :
Jul 1, 2013
Actual Study Completion Date :
Jul 1, 2013

Arms and Interventions

Arm Intervention/Treatment
Experimental: Tolvaptan MR 50 mg

Tolvaptan MR 50 mg capsule and 2 placebo IR tablets ( 8 AM) and 1 placebo IR tablet (4 PM) daily.

Drug: Tolvaptan MR
50/80 mg capsules
Other Names:
  • OPC-41061

    • Drug: Placebo
    tablet
    Experimental: Tolvaptan MR 80 mg

    Tolvaptan MR 80 mg capsule and 2 placebo IR tablets (8 AM) and 1 placebo IR tablet (4 PM) daily.

    Drug: Tolvaptan MR
    50/80 mg capsules
    Other Names:
  • OPC-41061

    • Drug: Placebo
    tablet
    Experimental: Tolvaptan IR 60/30 mg

    Two tolvaptan IR 30-mg tablets and 1 placebo MR capsule (8 AM) and 1 tolvaptan IR 30-mg tablet (4 PM) daily.

    Drug: Tolvaptan IR
    60/30 mg capsules
    Other Names:
  • OPC-41061

    • Drug: Placebo
    tablet
    Placebo Comparator: Placebo

    Placebo MR capsule and 2 placebo IR tablets (8 AM) and 1 placebo IR tablet (4 PM) daily.

    Drug: Placebo
    tablet

    Outcome Measures

    Primary Outcome Measures

    1. Percent Change From Baseline in Total Kidney Volume (TKV) at Week 3 [Baseline to Week 3]

      The primary endpoint was percent change from baseline in TKV at Week 3. Total kidney volume is an important measure of disease progression. A 3-week time point is adequate to assess acute effects on kidney cyst shrinkage.

    Secondary Outcome Measures

    1. Change From Baseline in Total Score of the Autosomal Dominant Polycystic Kidney Disease Urinary Impact Scale (ADPKD-UIS) [Baseline to Week 8]

      The ADPKD-UIS was a self-administered questionnaire designed to measure ADPKD-related urinary symptoms in participants with ADPKD. This instrument contained 11 items in 3 domains (Urinary Frequency, Urinary Urgency, and Nocturia). Each item was scored using a scale of 1 to 5 (a higher score indicated increased difficulty/extremely bothered). The maximum total score is 55; 1: not difficult/not bothered at all; 55: extremely difficult/extremely bothered.

    2. Percent Change From Baseline in TKV at Week 8. [Baseline to Week 8]

      Total kidney volume is an important measure of disease progression. A 3-week time point is adequate to assess acute effects on kidney cyst shrinkage.

    Eligibility Criteria

    Criteria

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

    1. Age 18 to 50

    2. Subjects with:

    • BMI between 19 and 35 kg/m2

    • diagnosis of ADPKD by modified Ravine criteria:

    • family history: 3cysts/kidney if by sonography or 5 by CT or MRI

    • Without family history: 10 cysts per kidney

    • an eGFR > 45 mL/min/1.73 m2 by the CKD-EPI equation

    1. Subjects not planning to become pregnant willing to comply with birth control requirements.

    2. Subjects must be in good health as determined by screening tests.

    3. Subjects providing informed consent and able to comply with all trial requirements.

    Exclusion Criteria:

    1. Subjects using diuretics within 14 days prior to randomization, or the requirement for intermittent or constant diuretic use for any reason

    2. Subjects who had an eGFR < 45 mL/min/1.73 m2 calculated based on the most recent historical creatinine during the last 12 months

    3. Subjects with:

    • incontinence, overactive bladder, or urinary retention (eg, BPH), meaning subjects with symptoms of frequent nocturia, as determined by medical history or urinary urgency should be carefully evaluated to exclude non-ADPKD GU issues prior to entry.

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

    • a history of renal surgery or cyst drainage within 6 months of randomization

    • blood pressure 150/95 mmHg or < 90/40 mmHg.

    • heart rate outside the range of 40 to 90 bpm.

    • advanced diabetes with a history of poor control, evidence of significant renal disease renal cancer, single kidney, or recent renal surgery

    • other significant medical history that may interfere with the study objectives

    • significant abnormalities in serum sodium concentration (< 135 or > 145 mEq/L)

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

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

    1. Subjects having taken an investigational drug within 30 days preceding randomization on Day 0

    2. Subjects taking medications or having concomitant illnesses likely to confound endpoint assessments, including taking approved (ie, marketed) therapies for the purpose of affecting PKD cysts such as tolvaptan, somatostatin agonists (ie, octreotide, sandostatin), Rapamune (sirolimus), anti-sense RNA therapies, other vasopressin antagonists (eg, OPC-31260 [mozavaptan] and Vaprisol® [conivaptan]) or agonists (eg, desmopressin), and cyst reduction surgery

    3. Subjects on antihypertensives that have not been on the same antihypertensive regimen for at least 30 days prior to the first dose of IMP

    4. Subjects having contraindications to, or interference with, MRI assessments

    5. Subjects with a history of serious mental disorders that, in the opinion of the investigator, would exclude the subject from participating in this trial

    6. Subjects with previous exposure to tolvaptan

    Contacts and Locations

    Locations

    Site City State Country Postal Code
    1 Otsuka Investigational Site Huntsville Alabama United States 35802
    2 Otsuka Investigational Site Mobile Alabama United States 36617
    3 Otsuka Investigational Site Peoria Arizona United States 85381
    4 Otsuka Investigational Site Tempe Arizona United States 85284
    5 Otsuka Investigational Site Los Angeles California United States 90025
    6 Otsuka Investigational Site San Diego California United States 92108
    7 Otsuka Investigational Site 2 Aurora Colorado United States 80045
    8 Otsuka Investigational Site Aurora Colorado United States 80045
    9 Otsuka Investigational Site Denver Colorado United States 80210
    10 Otsuka Investigational Site New Haven Connecticut United States 06510
    11 Otsuka Investigational Site Jacksonville Florida United States 32216
    12 Otsuka Investigational Site Melbourne Florida United States 32935
    13 Otsuka Investigational Site Atlanta Georgia United States 30322
    14 Otsuka Investigational Site Augusta Georgia United States 30901
    15 Otsuka Investigational Site Peoria Illinois United States 61602
    16 Otsuka Investigational Site Mishawaka Indiana United States 46545
    17 Otsuka Investigational Site Kansas City Kansas United States 66160
    18 Otsuka Investigational Site Paducah Kentucky United States 42003
    19 Otsuka Investigational Site Shreveport Louisiana United States 71101
    20 Otsuka Investigational Site Baltimore Maryland United States 21224
    21 Otsuka Investigational Site Rockville Maryland United States 20850
    22 Otsuka Investigational Site Boston Massachusetts United States 02111
    23 Otsuka Investigational Site Detroit Michigan United States 48236
    24 Otsuka Investigational Site Rochester Minnesota United States 55905
    25 Otsuka Investigational Site Voorhees New Jersey United States 08043
    26 Otsuka Investigational Site Buffalo New York United States 14215
    27 Otsuka Investigational Site Chapel Hill North Carolina United States 27599
    28 Otsuka Investigational Site Cleveland Ohio United States 44106
    29 Otsuka Investigational Site Bethlehem Pennsylvania United States 18017
    30 Otsuka Investigational Site Philadelphia Pennsylvania United States 19104
    31 Otsuka Investigational Site Anderson South Carolina United States 29621
    32 Otsuka Investigational Site Nashville Tennessee United States 37205
    33 Otsuka Investigational Site Arlington Texas United States 76015
    34 Otsuka Investigational Site Mission Texas United States 78572
    35 Otsuka Investigational Site Charlottesville Virginia United States 22908

    Sponsors and Collaborators

    • Otsuka Pharmaceutical Development & Commercialization, Inc.

    Investigators

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

    Study Documents (Full-Text)

    None provided.

    More Information

    Publications

    None provided.
    Responsible Party:
    Otsuka Pharmaceutical Development & Commercialization, Inc.
    ClinicalTrials.gov Identifier:
    NCT01451827
    Other Study ID Numbers:
    • 156-09-290
    First Posted:
    Oct 14, 2011
    Last Update Posted:
    Sep 27, 2018
    Last Verified:
    Aug 1, 2018
    Keywords provided by Otsuka Pharmaceutical Development & Commercialization, Inc.
    Kidney Disease
    Polycystic Kidney Disease
    Autosomal Dominant Polycystic Kidney Disease
    PKD
    ADPKD
    Additional relevant MeSH terms:
    Arthrogryposis
    Kidney Diseases
    Polycystic Kidney Diseases
    Polycystic Kidney, Autosomal Dominant
    Tolvaptan

    Study Results

    Participant Flow

    Recruitment Details The trial was conducted in 177 participants at 41 trial states in the United States.
    Pre-assignment Detail Participants entered a screening period within 4 weeks of being randomized (1:1:1:1) to one of four treatment groups. 178 is the number of subjects who enrolled due to informed consent, 177 is the number of subjects who were assigned to each treatment group.
    Arm/Group Title Tolvaptan Modifed Release (MR) 50 mg Tolvaptan MR 80 mg Tolvaptan Immediate Release (IR) 60/30 mg Placebo
    Arm/Group Description Tolvaptan MR 50 mg capsule and 2 placebo immediate release (IR) tablets (morning) and 1 placebo IR tablet (evening) Tolvaptan MR: 50/80 mg capsules Placebo: tablet Tolvaptan MR 80 mg capsule and 2 placebo immediate release (IR) tablets (morning) and 1 placebo IR tablet (evening) Tolvaptan MR: 50/80 mg capsules Placebo: tablet Two tolvaptan IR 30-mg tablets and 1 placebo MR capsule (morning) and 1 tolvaptan IR 30-mg tablet (evening) Tolvaptan IR: 60/30 mg capsules Placebo: tablet Placebo MR capsule and 2 placebo IR tablets (morning) and 1 placebo IR tablet (evening) Placebo: tablet
    Period Title: Overall Study
    STARTED 45 45 44 43
    COMPLETED 42 40 42 39
    NOT COMPLETED 3 5 2 4

    Baseline Characteristics

    Arm/Group Title Tolvaptan MR 50 mg Tolvaptan MR 80 mg Tolvaptan IR 60/30 mg Placebo Total
    Arm/Group Description Tolvaptan MR 50 mg capsule and 2 placebo IR tablets (morning) and 1 placebo IR tablet (evening) Tolvaptan MR: 50/80 mg capsules Placebo: tablet Tolvaptan MR 80 mg capsule and 2 placebo IR tablets (morning) and 1 placebo IR tablet (evening) Tolvaptan MR: 50/80 mg capsules Placebo: tablet Two tolvaptan IR 30-mg tablets and 1 placebo MR capsule (morning) and 1 tolvaptan IR 30-mg tablet (PM) Tolvaptan IR: 60/30 mg capsules Placebo: tablet Placebo MR capsule and 2 placebo IR tablets (evening) and 1 placebo IR tablet (morning) Placebo: tablet Total of all reporting groups
    Overall Participants 45 45 44 43 177
    Age (years) [Mean (Standard Deviation) ]
    Mean (Standard Deviation) [years]
    34.1
    (10.1)
    35.8
    (7.9)
    32.2
    (7.6)
    33.9
    (8.1)
    34.0
    (8.5)
    Sex: Female, Male (Count of Participants)
    Female
    18
    40%
    23
    51.1%
    20
    45.5%
    23
    53.5%
    84
    47.5%
    Male
    27
    60%
    22
    48.9%
    24
    54.5%
    20
    46.5%
    93
    52.5%

    Outcome Measures

    1. Primary Outcome
    Title Percent Change From Baseline in Total Kidney Volume (TKV) at Week 3
    Description The primary endpoint was percent change from baseline in TKV at Week 3. Total kidney volume is an important measure of disease progression. A 3-week time point is adequate to assess acute effects on kidney cyst shrinkage.
    Time Frame Baseline to Week 3

    Outcome Measure Data

    Analysis Population Description
    Participants who were randomized and had baseline and post-baseline observations in the total renal volume.
    Arm/Group Title Tolvaptan MR 50 mg Tolvaptan MR 80 mg Tolvaptan IR 60/30 mg Placebo
    Arm/Group Description Tolvaptan MR 50 mg capsule and 2 placebo IR tablets (AM) and 1 placebo IR tablet (PM) Tolvaptan MR: 50/80 mg capsules Placebo: tablet Tolvaptan MR 80 mg capsule and 2 placebo IR tablets (AM) and 1 placebo IR tablet (PM) Tolvaptan MR: 50/80 mg capsules Placebo: tablet Two tolvaptan IR 30-mg tablets and 1 placebo MR capsule (AM) and 1 tolvaptan IR 30-mg tablet (PM) Tolvaptan IR: 60/30 mg capsules Placebo: tablet Placebo MR capsule and 2 placebo IR tablets (AM) and 1 placebo IR tablet (PM) Placebo: tablet
    Measure Participants 41 43 41 39
    Mean (Standard Deviation) [Percentage change]
    -2.46
    (4.40)
    -2.55
    (3.85)
    -1.17
    (4.52)
    0.09
    (5.31)
    Statistical Analysis 1
    Statistical Analysis Overview Comparison Group Selection Tolvaptan MR 50 mg, Tolvaptan MR 80 mg, Tolvaptan IR 60/30 mg, Placebo
    Comments Hierarchical tests were used to control the type I error in the primary analysis. They are given in the following order: 1. Pooled tolvaptan treatment groups (IR and MR) versus placebo; 2. Tolvaptan MR 80 mg versus placebo; 3. Tolvaptan MR 50 mg versus placebo; 4. Tolvaptan IR 60/30 mg versus placebo.
    Type of Statistical Test Superiority or Other
    Comments
    Statistical Test of Hypothesis p-Value 0.0127
    Comments
    Method ANCOVA
    Comments
    Method of Estimation Estimation Parameter Ratio of geometric means
    Estimated Value 0.98
    Confidence Interval (2-Sided) 95%
    0.96 to 1.00
    Parameter Dispersion Type:
    Value:
    Estimation Comments
    Statistical Analysis 2
    Statistical Analysis Overview Comparison Group Selection Tolvaptan MR 80 mg, Placebo
    Comments Hierarchical tests were used to control the type I error in the primary analysis. They are given in the following order: 1. Pooled tolvaptan treatment groups (IR and MR) versus placebo; 2. Tolvaptan MR 80 mg versus placebo; 3. Tolvaptan MR 50 mg versus placebo; 4. Tolvaptan IR 60/30 mg versus placebo.
    Type of Statistical Test Superiority or Other
    Comments
    Statistical Test of Hypothesis p-Value 0.0108
    Comments
    Method ANCOVA
    Comments
    Method of Estimation Estimation Parameter Ratio of geometric means
    Estimated Value 0.97
    Confidence Interval (2-Sided) 95%
    0.95 to 0.99
    Parameter Dispersion Type:
    Value:
    Estimation Comments
    Statistical Analysis 3
    Statistical Analysis Overview Comparison Group Selection Tolvaptan MR 50 mg, Placebo
    Comments Hierarchical tests were used to control the type I error in the primary analysis. They are given in the following order: 1. Pooled tolvaptan treatment groups (IR and MR) versus placebo; 2. Tolvaptan MR 80 mg versus placebo; 3. Tolvaptan MR 50 mg versus placebo; 4. Tolvaptan IR 60/30 mg versus placebo.
    Type of Statistical Test Superiority or Other
    Comments
    Statistical Test of Hypothesis p-Value 0.0155
    Comments
    Method ANCOVA
    Comments
    Method of Estimation Estimation Parameter Ratio of geometric means
    Estimated Value 0.98
    Confidence Interval (2-Sided) 95%
    0.96 to 1.00
    Parameter Dispersion Type:
    Value:
    Estimation Comments
    Statistical Analysis 4
    Statistical Analysis Overview Comparison Group Selection Tolvaptan IR 60/30 mg, Placebo
    Comments Hierarchical tests were used to control the type I error in the primary analysis. They are given in the following order: 1. Pooled tolvaptan treatment groups (IR and MR) versus placebo; 2. Tolvaptan MR 80 mg versus placebo; 3. Tolvaptan MR 50 mg versus placebo; 4. Tolvaptan IR 60/30 mg versus placebo.
    Type of Statistical Test Superiority or Other
    Comments
    Statistical Test of Hypothesis p-Value 0.2417
    Comments
    Method ANCOVA
    Comments
    Method of Estimation Estimation Parameter Ratio of geometric means
    Estimated Value 0.99
    Confidence Interval (2-Sided) 95%
    0.97 to 1.01
    Parameter Dispersion Type:
    Value:
    Estimation Comments
    2. Secondary Outcome
    Title Change From Baseline in Total Score of the Autosomal Dominant Polycystic Kidney Disease Urinary Impact Scale (ADPKD-UIS)
    Description The ADPKD-UIS was a self-administered questionnaire designed to measure ADPKD-related urinary symptoms in participants with ADPKD. This instrument contained 11 items in 3 domains (Urinary Frequency, Urinary Urgency, and Nocturia). Each item was scored using a scale of 1 to 5 (a higher score indicated increased difficulty/extremely bothered). The maximum total score is 55; 1: not difficult/not bothered at all; 55: extremely difficult/extremely bothered.
    Time Frame Baseline to Week 8

    Outcome Measure Data

    Analysis Population Description
    Participants who were randomized and had baseline and post-baseline observations in the total renal volume.
    Arm/Group Title Tolvaptan MR 50 mg Tolvaptan MR 80 mg Tolvaptan IR 60/30 mg Placebo
    Arm/Group Description Tolvaptan MR 50 mg capsule and 2 placebo IR tablets (AM) and 1 placebo IR tablet (PM) Tolvaptan MR: 50/80 mg capsules Placebo: tablet Tolvaptan MR 80 mg capsule and 2 placebo IR tablets (AM) and 1 placebo IR tablet (PM) Tolvaptan MR: 50/80 mg capsules Placebo: tablet Two tolvaptan IR 30-mg tablets and 1 placebo MR capsule (AM) and 1 tolvaptan IR 30-mg tablet (PM) Tolvaptan IR: 60/30 mg capsules Placebo: tablet Placebo MR capsule and 2 placebo IR tablets (AM) and 1 placebo IR tablet (PM) Placebo: tablet
    Measure Participants 39 40 42 38
    Urinary Frequency
    0.74
    (0.94)
    0.82
    (0.83)
    0.99
    (0.78)
    0.10
    (0.35)
    Urinary Urgency
    0.69
    (0.96)
    0.66
    (0.77)
    1.01
    (0.95)
    0.05
    (0.30)
    Nocturia
    0.97
    (1.28)
    1.15
    (0.89)
    1.36
    (1.12)
    0.11
    (0.59)
    Statistical Analysis 1
    Statistical Analysis Overview Comparison Group Selection Tolvaptan MR 50 mg, Placebo
    Comments Urinary Frequency
    Type of Statistical Test Superiority or Other
    Comments
    Statistical Test of Hypothesis p-Value 0.0002
    Comments
    Method ANCOVA
    Comments
    Method of Estimation Estimation Parameter Mean Difference (Final Values)
    Estimated Value 0.65
    Confidence Interval (2-Sided) 95%
    0.31 to 0.99
    Parameter Dispersion Type:
    Value:
    Estimation Comments
    Statistical Analysis 2
    Statistical Analysis Overview Comparison Group Selection Tolvaptan MR 80 mg, Placebo
    Comments Urinary Frequency
    Type of Statistical Test Superiority or Other
    Comments
    Statistical Test of Hypothesis p-Value < 0.0001
    Comments
    Method ANCOVA
    Comments
    Method of Estimation Estimation Parameter Mean Difference (Final Values)
    Estimated Value 0.74
    Confidence Interval (2-Sided) 95%
    0.40 to 1.08
    Parameter Dispersion Type:
    Value:
    Estimation Comments
    Statistical Analysis 3
    Statistical Analysis Overview Comparison Group Selection Tolvaptan IR 60/30 mg
    Comments Urinary Frequency
    Type of Statistical Test Superiority or Other
    Comments
    Statistical Test of Hypothesis p-Value < 0.0001
    Comments
    Method ANCOVA
    Comments
    Method of Estimation Estimation Parameter Mean Difference (Final Values)
    Estimated Value 0.92
    Confidence Interval (2-Sided) 95%
    0.58 to 1.25
    Parameter Dispersion Type:
    Value:
    Estimation Comments
    Statistical Analysis 4
    Statistical Analysis Overview Comparison Group Selection Tolvaptan MR 50 mg, Placebo
    Comments Urinary Urgency
    Type of Statistical Test Superiority or Other
    Comments
    Statistical Test of Hypothesis p-Value 0.0004
    Comments
    Method ANCOVA
    Comments
    Method of Estimation Estimation Parameter Mean Difference (Final Values)
    Estimated Value 0.66
    Confidence Interval (2-Sided) 95%
    0.30 to 1.01
    Parameter Dispersion Type:
    Value:
    Estimation Comments
    Statistical Analysis 5
    Statistical Analysis Overview Comparison Group Selection Tolvaptan MR 80 mg, Placebo
    Comments Urinary Urgency
    Type of Statistical Test Superiority or Other
    Comments
    Statistical Test of Hypothesis p-Value 0.0004
    Comments
    Method ANCOVA
    Comments
    Method of Estimation Estimation Parameter Mean Difference (Final Values)
    Estimated Value 0.65
    Confidence Interval (2-Sided) 95%
    0.29 to 1.01
    Parameter Dispersion Type:
    Value:
    Estimation Comments
    Statistical Analysis 6
    Statistical Analysis Overview Comparison Group Selection Tolvaptan IR 60/30 mg, Placebo
    Comments Urinary Urgency
    Type of Statistical Test Superiority or Other
    Comments
    Statistical Test of Hypothesis p-Value < 0.0001
    Comments
    Method ANCOVA
    Comments
    Method of Estimation Estimation Parameter Mean Difference (Final Values)
    Estimated Value 0.99
    Confidence Interval (2-Sided) 95%
    0.63 to 1.34
    Parameter Dispersion Type:
    Value:
    Estimation Comments
    Statistical Analysis 7
    Statistical Analysis Overview Comparison Group Selection Tolvaptan MR 50 mg, Placebo
    Comments Nocturia
    Type of Statistical Test Superiority or Other
    Comments
    Statistical Test of Hypothesis p-Value 0.0002
    Comments
    Method ANCOVA
    Comments
    Method of Estimation Estimation Parameter Mean Difference (Final Values)
    Estimated Value 0.86
    Confidence Interval (2-Sided) 95%
    0.42 to 1.30
    Parameter Dispersion Type:
    Value:
    Estimation Comments
    Statistical Analysis 8
    Statistical Analysis Overview Comparison Group Selection Tolvaptan MR 80 mg, Placebo
    Comments Nocturia
    Type of Statistical Test Superiority or Other
    Comments
    Statistical Test of Hypothesis p-Value < 0.0001
    Comments
    Method ANCOVA
    Comments
    Method of Estimation Estimation Parameter Median Difference (Final Values)
    Estimated Value 1.07
    Confidence Interval (2-Sided) 95%
    0.63 to 1.51
    Parameter Dispersion Type:
    Value:
    Estimation Comments
    Statistical Analysis 9
    Statistical Analysis Overview Comparison Group Selection Tolvaptan IR 60/30 mg, Placebo
    Comments Nocturia
    Type of Statistical Test Superiority or Other
    Comments
    Statistical Test of Hypothesis p-Value < 0.0001
    Comments
    Method ANCOVA
    Comments
    Method of Estimation Estimation Parameter Mean Difference (Final Values)
    Estimated Value 1.23
    Confidence Interval (2-Sided) 95%
    0.80 to 1.66
    Parameter Dispersion Type:
    Value:
    Estimation Comments
    3. Secondary Outcome
    Title Percent Change From Baseline in TKV at Week 8.
    Description Total kidney volume is an important measure of disease progression. A 3-week time point is adequate to assess acute effects on kidney cyst shrinkage.
    Time Frame Baseline to Week 8

    Outcome Measure Data

    Analysis Population Description
    The core patient population for all efficacy analyses was based on the intent-to-treat (ITT) population which consisted of all randomized participants who take at least one dose of study drug. Observed Cases (OC) dataset within treatment period was defined as the data observed at study specified visits while subjects are taking study drug.
    Arm/Group Title Tolvaptan MR 50 mg Tolvaptan MR 80 mg Tolvaptan IR 60/30 mg Placebo
    Arm/Group Description Tolvaptan MR 50 mg capsule and 2 placebo IR tablets (AM) and 1 placebo IR tablet (PM) Tolvaptan MR: 50/80 mg capsules Placebo: tablet Tolvaptan MR 80 mg capsule and 2 placebo IR tablets (AM) and 1 placebo IR tablet (PM) Tolvaptan MR: 50/80 mg capsules Placebo: tablet Two tolvaptan IR 30-mg tablets and 1 placebo MR capsule (AM) and 1 tolvaptan IR 30-mg tablet (PM) Tolvaptan IR: 60/30 mg capsules Placebo: tablet Placebo MR capsule and 2 placebo IR tablets (AM) and 1 placebo IR tablet (PM) Placebo: tablet
    Measure Participants 20 22 21 24
    Mean (Standard Deviation) [Percentage change]
    -2.04
    (3.87)
    -2.02
    (3.54)
    -0.08
    (7.31)
    2.13
    (7.99)
    Statistical Analysis 1
    Statistical Analysis Overview Comparison Group Selection Tolvaptan MR 50 mg, Tolvaptan MR 80 mg, Tolvaptan IR 60/30 mg, Placebo
    Comments Hierarchical tests were used to control the type I error in the primary analysis. They are given in the following order: 1. Pooled tolvaptan treatment groups (IR and MR) versus placebo; 2. Tolvaptan MR 80 mg versus placebo; 3. Tolvaptan MR 50 mg versus placebo; 4. Tolvaptan IR 60/30 mg versus placebo.
    Type of Statistical Test Superiority or Other
    Comments
    Statistical Test of Hypothesis p-Value 0.0209
    Comments
    Method ANCOVA
    Comments
    Method of Estimation Estimation Parameter Ratio of geometric means
    Estimated Value 0.97
    Confidence Interval (2-Sided) 95%
    0.94 to 0.99
    Parameter Dispersion Type:
    Value:
    Estimation Comments
    Statistical Analysis 2
    Statistical Analysis Overview Comparison Group Selection Tolvaptan MR 80 mg, Placebo
    Comments Hierarchical tests were used to control the type I error in the primary analysis. They are given in the following order: 1. Pooled tolvaptan treatment groups (IR and MR) versus placebo; 2. Tolvaptan MR 80 mg versus placebo; 3. Tolvaptan MR 50 mg versus placebo; 4. Tolvaptan IR 60/30 mg versus placebo
    Type of Statistical Test Superiority or Other
    Comments
    Statistical Test of Hypothesis p-Value 0.0287
    Comments
    Method ANCOVA
    Comments
    Method of Estimation Estimation Parameter Ratio of geometric means
    Estimated Value 0.96
    Confidence Interval (2-Sided) 95%
    0.93 to 1.00
    Parameter Dispersion Type:
    Value:
    Estimation Comments
    Statistical Analysis 3
    Statistical Analysis Overview Comparison Group Selection Tolvaptan MR 50 mg, Placebo
    Comments Hierarchical tests were used to control the type I error in the primary analysis. They are given in the following order: 1. Pooled tolvaptan treatment groups (IR and MR) versus placebo; 2. Tolvaptan MR 80 mg versus placebo; 3. Tolvaptan MR 50 mg versus placebo; 4. Tolvaptan IR 60/30 mg versus placebo
    Type of Statistical Test Superiority or Other
    Comments
    Statistical Test of Hypothesis p-Value 0.0298
    Comments
    Method ANCOVA
    Comments
    Method of Estimation Estimation Parameter Ratio of geometric means
    Estimated Value 0.96
    Confidence Interval (2-Sided) 95%
    0.93 to 1.00
    Parameter Dispersion Type:
    Value:
    Estimation Comments
    Statistical Analysis 4
    Statistical Analysis Overview Comparison Group Selection Tolvaptan IR 60/30 mg, Placebo
    Comments Hierarchical tests were used to control the type I error in the primary analysis. They are given in the following order: 1. Pooled tolvaptan treatment groups (IR and MR) versus placebo; 2. Tolvaptan MR 80 mg versus placebo; 3. Tolvaptan MR 50 mg versus placebo; 4. Tolvaptan IR 60/30 mg versus placebo
    Type of Statistical Test Superiority or Other
    Comments
    Statistical Test of Hypothesis p-Value 0.2306
    Comments
    Method ANCOVA
    Comments
    Method of Estimation Estimation Parameter Ratio of geometric means
    Estimated Value 0.98
    Confidence Interval (2-Sided) 95%
    0.94 to 1.01
    Parameter Dispersion Type:
    Value:
    Estimation Comments

    Adverse Events

    Time Frame Adverse events were collected from the time of signing the informed consent, throughout the 8 week treatment period and for 7 days after the last dose of study medication.
    Adverse Event Reporting Description Safety analysis set consisted of all participants who took at least one dose of study medication. Serious adverse events, non-serious adverse events, and deaths were analyzed using safety analysis population.
    Arm/Group Title Tolvaptan MR 50 mg Tolvaptan MR 80 mg Tolvaptan IR 60/30 mg Placebo
    Arm/Group Description Tolvaptan MR 50 mg capsule and 2 placebo IR tablets (AM) and 1 placebo IR tablet (PM) Tolvaptan MR: 50/80 mg capsules Placebo: tablet Tolvaptan MR 80 mg capsule and 2 placebo IR tablets (AM) and 1 placebo IR tablet (PM) Tolvaptan MR: 50/80 mg capsules Placebo: tablet Two tolvaptan IR 30-mg tablets and 1 placebo MR capsule (AM) and 1 tolvaptan IR 30-mg tablet (PM) Tolvaptan IR: 60/30 mg capsules Placebo: tablet Placebo MR capsule and 2 placebo IR tablets (AM) and 1 placebo IR tablet (PM) Placebo: tablet
    All Cause Mortality
    Tolvaptan MR 50 mg Tolvaptan MR 80 mg Tolvaptan IR 60/30 mg Placebo
    Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events
    Total 0/45 (0%) 0/44 (0%) 0/44 (0%) 0/42 (0%)
    Serious Adverse Events
    Tolvaptan MR 50 mg Tolvaptan MR 80 mg Tolvaptan IR 60/30 mg Placebo
    Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events
    Total 3/45 (6.7%) 1/44 (2.3%) 1/44 (2.3%) 1/42 (2.4%)
    Cardiac disorders
    Sinus tachycardia 1/45 (2.2%) 0/44 (0%) 0/44 (0%) 0/42 (0%)
    Investigations
    Alanine aminotransferase increased 0/45 (0%) 1/44 (2.3%) 0/44 (0%) 0/42 (0%)
    Blood creatinine increased 1/45 (2.2%) 0/44 (0%) 0/44 (0%) 0/42 (0%)
    Hepatic enzyme increased 0/45 (0%) 0/44 (0%) 0/44 (0%) 1/42 (2.4%)
    Liver function test abnormal 0/45 (0%) 0/44 (0%) 1/44 (2.3%) 0/42 (0%)
    Metabolism and nutrition disorders
    Dehydration 1/45 (2.2%) 0/44 (0%) 0/44 (0%) 0/42 (0%)
    Renal and urinary disorders
    Renal pain 1/45 (2.2%) 0/44 (0%) 0/44 (0%) 0/42 (0%)
    Other (Not Including Serious) Adverse Events
    Tolvaptan MR 50 mg Tolvaptan MR 80 mg Tolvaptan IR 60/30 mg Placebo
    Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events
    Total 27/45 (60%) 25/44 (56.8%) 32/44 (72.7%) 18/42 (42.9%)
    Gastrointestinal disorders
    Dry mouth 7/45 (15.6%) 7/44 (15.9%) 2/44 (4.5%) 1/42 (2.4%)
    Nausea 2/45 (4.4%) 1/44 (2.3%) 2/44 (4.5%) 4/42 (9.5%)
    General disorders
    Fatigue 3/45 (6.7%) 2/44 (4.5%) 6/44 (13.6%) 1/42 (2.4%)
    Thirst 15/45 (33.3%) 15/44 (34.1%) 19/44 (43.2%) 6/42 (14.3%)
    Infections and infestations
    Nasopharyngitis 3/45 (6.7%) 1/44 (2.3%) 0/44 (0%) 1/42 (2.4%)
    Metabolism and nutrition disorders
    Polydipsia 7/45 (15.6%) 6/44 (13.6%) 5/44 (11.4%) 2/42 (4.8%)
    Nervous system disorders
    Headache 1/45 (2.2%) 1/44 (2.3%) 7/44 (15.9%) 1/42 (2.4%)
    Renal and urinary disorders
    Nocturia 14/45 (31.1%) 14/44 (31.8%) 18/44 (40.9%) 3/42 (7.1%)
    Pollakuria 8/45 (17.8%) 9/44 (20.5%) 12/44 (27.3%) 3/42 (7.1%)
    Polyuria 11/45 (24.4%) 11/44 (25%) 13/44 (29.5%) 3/42 (7.1%)
    Renal pain 1/45 (2.2%) 1/44 (2.3%) 2/44 (4.5%) 3/42 (7.1%)
    Vascular disorders
    Hypertension 2/45 (4.4%) 2/44 (4.5%) 3/44 (6.8%) 2/42 (4.8%)

    Limitations/Caveats

    [Not Specified]

    More Information

    Certain Agreements

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

    Center may publish study results but ≥ 60 days prior to any public presentation, a copy is sent to Sponsor for review and Center can delay publication for 60 days to permit Sponsor to protect its intellectual property rights or confidential information contained within the publication. The first publication is a joint publication, if Center is part of a multi-center study. Center is free to publish, if there is no multi-center publication within 18 months of completion/ termination of study.

    Results Point of Contact

    Name/Title Global Medical Affairs
    Organization Otsuka Pharmaceutical Development and Commercialization, Inc.
    Phone 800 562-3974
    Email
    Responsible Party:
    Otsuka Pharmaceutical Development & Commercialization, Inc.
    ClinicalTrials.gov Identifier:
    NCT01451827
    Other Study ID Numbers:
    • 156-09-290
    First Posted:
    Oct 14, 2011
    Last Update Posted:
    Sep 27, 2018
    Last Verified:
    Aug 1, 2018