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The purpose of this study is to compare the short-term effects of two tolvaptan formulations in patients with ADPKD.
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| Label | Type | Description | Intervention Names |
|---|---|---|---|
| Tolvaptan MR 50 mg | Experimental | Tolvaptan MR 50 mg capsule and 2 placebo IR tablets ( 8 AM) and 1 placebo IR tablet (4 PM) daily. |
|
| Tolvaptan MR 80 mg | Experimental | Tolvaptan MR 80 mg capsule and 2 placebo IR tablets (8 AM) and 1 placebo IR tablet (4 PM) daily. |
|
| Tolvaptan IR 60/30 mg | Experimental | Two tolvaptan IR 30-mg tablets and 1 placebo MR capsule (8 AM) and 1 tolvaptan IR 30-mg tablet (4 PM) daily. |
|
| Placebo | Placebo Comparator | Placebo MR capsule and 2 placebo IR tablets (8 AM) and 1 placebo IR tablet (4 PM) daily. |
|
| Name | Type | Description | Arm Group Labels | Other Names |
|---|---|---|---|---|
| Tolvaptan MR | Drug | 50/80 mg capsules |
|
| Measure | Description | Time Frame |
|---|---|---|
| Percent Change From Baseline in Total Kidney Volume (TKV) at 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. | Baseline to Week 3 |
| Measure | Description | Time Frame |
|---|---|---|
| Change From Baseline in Total Score of the Autosomal Dominant Polycystic Kidney Disease Urinary Impact Scale (ADPKD-UIS) | 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. |
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Inclusion Criteria:
Age 18 to 50
Subjects with:
BMI between 19 and 35 kg/m2
diagnosis of ADPKD by modified Ravine criteria:
an eGFR > 45 mL/min/1.73 m2 by the CKD-EPI equation
Subjects not planning to become pregnant willing to comply with birth control requirements.
Subjects must be in good health as determined by screening tests.
Subjects providing informed consent and able to comply with all trial requirements.
Exclusion Criteria:
Subjects using diuretics within 14 days prior to randomization, or the requirement for intermittent or constant diuretic use for any reason
Subjects who had an eGFR < 45 mL/min/1.73 m2 calculated based on the most recent historical creatinine during the last 12 months
Subjects with:
Subjects having taken an investigational drug within 30 days preceding randomization on Day 0
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
Subjects on antihypertensives that have not been on the same antihypertensive regimen for at least 30 days prior to the first dose of IMP
Subjects having contraindications to, or interference with, MRI assessments
Subjects with a history of serious mental disorders that, in the opinion of the investigator, would exclude the subject from participating in this trial
Subjects with previous exposure to tolvaptan
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| Name | Affiliation | Role |
|---|---|---|
| Frank Czerwiec, M.D., Ph.D. | Otsuka Pharmaceutical Development & Commercialization, Inc. | Study Director |
| Facility | Status | City | State | ZIP | Country | Contacts |
|---|---|---|---|---|---|---|
| Otsuka Investigational Site | Huntsville | Alabama | 35802 | United States | ||
| Otsuka Investigational Site |
| PubMed Identifier | Type | Citation | Retractions |
|---|---|---|---|
| 39356039 | Derived | St Pierre K, Cashmore BA, Bolignano D, Zoccali C, Ruospo M, Craig JC, Strippoli GF, Mallett AJ, Green SC, Tunnicliffe DJ. Interventions for preventing the progression of autosomal dominant polycystic kidney disease. Cochrane Database Syst Rev. 2024 Oct 2;10(10):CD010294. doi: 10.1002/14651858.CD010294.pub3. |
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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.
The trial was conducted in 177 participants at 41 trial states in the United States.
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| ID | Title | Description |
|---|---|---|
| FG000 | Tolvaptan Modifed Release (MR) 50 mg | 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 |
| FG001 | Tolvaptan MR 80 mg |
| Title | Milestones | Reasons Not Completed | |||||
|---|---|---|---|---|---|---|---|
| Overall Study |
|
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| Tolvaptan IR | Drug | 60/30 mg capsules |
|
|
| Placebo | Drug | tablet |
|
| Baseline to Week 8 |
| Percent Change From Baseline in TKV at 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. | Baseline to Week 8 |
| Mobile |
| Alabama |
| 36617 |
| United States |
| Otsuka Investigational Site | Peoria | Arizona | 85381 | United States |
| Otsuka Investigational Site | Tempe | Arizona | 85284 | United States |
| Otsuka Investigational Site | Los Angeles | California | 90025 | United States |
| Otsuka Investigational Site | San Diego | California | 92108 | United States |
| Otsuka Investigational Site 2 | Aurora | Colorado | 80045 | United States |
| Otsuka Investigational Site | Aurora | Colorado | 80045 | United States |
| Otsuka Investigational Site | Denver | Colorado | 80210 | United States |
| Otsuka Investigational Site | New Haven | Connecticut | 06510 | United States |
| Otsuka Investigational Site | Jacksonville | Florida | 32216 | United States |
| Otsuka Investigational Site | Melbourne | Florida | 32935 | United States |
| Otsuka Investigational Site | Atlanta | Georgia | 30322 | United States |
| Otsuka Investigational Site | Augusta | Georgia | 30901 | United States |
| Otsuka Investigational Site | Peoria | Illinois | 61602 | United States |
| Otsuka Investigational Site | Mishawaka | Indiana | 46545 | United States |
| Otsuka Investigational Site | Kansas City | Kansas | 66160 | United States |
| Otsuka Investigational Site | Paducah | Kentucky | 42003 | United States |
| Otsuka Investigational Site | Shreveport | Louisiana | 71101 | United States |
| Otsuka Investigational Site | Baltimore | Maryland | 21224 | United States |
| Otsuka Investigational Site | Rockville | Maryland | 20850 | United States |
| Otsuka Investigational Site | Boston | Massachusetts | 02111 | United States |
| Otsuka Investigational Site | Detroit | Michigan | 48236 | United States |
| Otsuka Investigational Site | Rochester | Minnesota | 55905 | United States |
| Otsuka Investigational Site | Voorhees Township | New Jersey | 08043 | United States |
| Otsuka Investigational Site | Buffalo | New York | 14215 | United States |
| Otsuka Investigational Site | Chapel Hill | North Carolina | 27599 | United States |
| Otsuka Investigational Site | Cleveland | Ohio | 44106 | United States |
| Otsuka Investigational Site | Bethlehem | Pennsylvania | 18017 | United States |
| Otsuka Investigational Site | Philadelphia | Pennsylvania | 19104 | United States |
| Otsuka Investigational Site | Anderson | South Carolina | 29621 | United States |
| Otsuka Investigational Site | Nashville | Tennessee | 37205 | United States |
| Otsuka Investigational Site | Arlington | Texas | 76015 | United States |
| Otsuka Investigational Site | Mission | Texas | 78572 | United States |
| Otsuka Investigational Site | Charlottesville | Virginia | 22908 | United States |
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
| FG002 | Tolvaptan Immediate Release (IR) 60/30 mg | 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 |
| FG003 | Placebo | Placebo MR capsule and 2 placebo IR tablets (morning) and 1 placebo IR tablet (evening) Placebo: tablet |
| COMPLETED |
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| NOT COMPLETED |
|
|
All participants randomized to treatment.
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| ID | Title | Description |
|---|---|---|
| BG000 | Tolvaptan MR 50 mg | 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 |
| BG001 | Tolvaptan MR 80 mg | 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 |
| BG002 | Tolvaptan IR 60/30 mg | 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 |
| BG003 | Placebo | Placebo MR capsule and 2 placebo IR tablets (evening) and 1 placebo IR tablet (morning) Placebo: tablet |
| BG004 | Total | Total of all reporting groups |
| Units | Counts |
|---|---|
| Participants |
|
| Title | Description | Population Description | Parameter Type | Dispersion Type | Unit of Measure | Calculate Percentage | Denominator Units Selected | Denominators | Classes | ||||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Age, Continuous | Mean | Standard Deviation | years |
| |||||||||||||||
| Sex: Female, Male | Count of Participants | Participants |
|
| Type | Title | Description | Population Description | Reporting Status | Anticipated Posting Date | Parameter Type | Dispersion Type | Unit of Measure | Calculate Percentage | Time Frame | Units Analyzed | Denominator Units Selected | Arm/Group Information | Denominators | Classes | Analyses | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Primary | Percent Change From Baseline in Total Kidney Volume (TKV) at 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. | Participants who were randomized and had baseline and post-baseline observations in the total renal volume. | Posted | Mean | Standard Deviation | Percentage change | Baseline to Week 3 |
|
|
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| Secondary | Change From Baseline in Total Score of the Autosomal Dominant Polycystic Kidney Disease Urinary Impact Scale (ADPKD-UIS) | 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. | Participants who were randomized and had baseline and post-baseline observations in the total renal volume. | Posted | Mean | Standard Deviation | Unit on a scale | Baseline to Week 8 |
| |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Secondary | Percent Change From Baseline in TKV at 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. | 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. | Posted | Mean | Standard Deviation | Percentage change | Baseline to Week 8 |
|
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.
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.
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| ID | Title | Description | Deaths (Affected) | Deaths (At Risk) | Serious Events (Affected) | Serious Events (At Risk) | Other Events (Affected) | Other Events (At Risk) |
|---|---|---|---|---|---|---|---|---|
| EG000 | Tolvaptan MR 50 mg | 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 | 0 | 45 | 3 | 45 | 27 | 45 |
| EG001 | Tolvaptan MR 80 mg | 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 | 0 | 44 | 1 | 44 | 25 | 44 |
| EG002 | Tolvaptan IR 60/30 mg | 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 | 0 | 44 | 1 | 44 | 32 | 44 |
| EG003 | Placebo | Placebo MR capsule and 2 placebo IR tablets (AM) and 1 placebo IR tablet (PM) Placebo: tablet | 0 | 42 | 1 | 42 | 18 | 42 |
| Term | Organ System | Source Vocabulary | Assessment Type | Notes | Statistical Information |
|---|---|---|---|---|---|
| Sinus tachycardia | Cardiac disorders | MedDRA 15.0 | Non-systematic Assessment |
| |
| Alanine aminotransferase increased | Investigations | MedDRA 15.0 | Non-systematic Assessment |
| |
| Blood creatinine increased | Investigations | MedDRA 15.0 | Non-systematic Assessment |
| |
| Hepatic enzyme increased | Investigations | MedDRA 15.0 | Non-systematic Assessment |
| |
| Liver function test abnormal | Investigations | MedDRA 15.0 | Non-systematic Assessment |
| |
| Dehydration | Metabolism and nutrition disorders | MedDRA 15.0 | Non-systematic Assessment |
| |
| Renal pain | Renal and urinary disorders | MedDRA 15.0 | Non-systematic Assessment |
|
| Term | Organ System | Source Vocabulary | Assessment Type | Notes | Statistical Information |
|---|---|---|---|---|---|
| Dry mouth | Gastrointestinal disorders | MedDRA 15.0 | Non-systematic Assessment |
| |
| Nausea | Gastrointestinal disorders | MedDRA 15.0 | Non-systematic Assessment |
| |
| Fatigue | General disorders | MedDRA 15.0 | Non-systematic Assessment |
| |
| Thirst | General disorders | MedDRA 15.0 | Non-systematic Assessment |
| |
| Polydipsia | Metabolism and nutrition disorders | MedDRA 15.0 | Non-systematic Assessment |
| |
| Headache | Nervous system disorders | MedDRA 15.0 | Non-systematic Assessment |
| |
| Nocturia | Renal and urinary disorders | MedDRA 15.0 | Non-systematic Assessment |
| |
| Pollakuria | Renal and urinary disorders | MedDRA 15.0 | Non-systematic Assessment |
| |
| Polyuria | Renal and urinary disorders | MedDRA 15.0 | Non-systematic Assessment |
| |
| Nasopharyngitis | Infections and infestations | MedDRA 15.0 | Non-systematic Assessment |
| |
| Renal pain | Renal and urinary disorders | MedDRA 15.0 | Non-systematic Assessment |
| |
| Hypertension | Vascular disorders | MedDRA 15.0 | Non-systematic Assessment |
|
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.
| Title | Organization | Phone | Extension | |
|---|---|---|---|---|
| Global Medical Affairs | Otsuka Pharmaceutical Development and Commercialization, Inc. | 800 562-3974 |
| ID | Term |
|---|---|
| D016891 | Polycystic Kidney, Autosomal Dominant |
| D007674 | Kidney Diseases |
| D007690 | Polycystic Kidney Diseases |
| ID | Term |
|---|---|
| D052177 | Kidney Diseases, Cystic |
| D014570 | Urologic Diseases |
| D052776 | Female Urogenital Diseases |
| D005261 | Female Urogenital Diseases and Pregnancy Complications |
| D000091642 | Urogenital Diseases |
| D052801 | Male Urogenital Diseases |
| D000015 | Abnormalities, Multiple |
| D000013 | Congenital Abnormalities |
| D009358 | Congenital, Hereditary, and Neonatal Diseases and Abnormalities |
| D000072661 | Ciliopathies |
| D030342 | Genetic Diseases, Inborn |
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| ID | Term |
|---|---|
| D000077602 | Tolvaptan |
| ID | Term |
|---|---|
| D001552 | Benzazepines |
| D006574 | Heterocyclic Compounds, 2-Ring |
| D000072471 | Heterocyclic Compounds, Fused-Ring |
| D006571 | Heterocyclic Compounds |
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| Male |
|
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. |
| ANCOVA |
| 0.0108 |
| Ratio of geometric means |
| 0.97 |
| 2-Sided |
| 95 |
| 0.95 |
| 0.99 |
| Superiority or Other |
| 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. | ANCOVA | 0.0155 | Ratio of geometric means | 0.98 | 2-Sided | 95 | 0.96 | 1.00 | Superiority or Other |
| 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. | ANCOVA | 0.2417 | Ratio of geometric means | 0.99 | 2-Sided | 95 | 0.97 | 1.01 | Superiority or Other |
| OG003 | Placebo | Placebo MR capsule and 2 placebo IR tablets (AM) and 1 placebo IR tablet (PM) Placebo: tablet |
|
|
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| OG003 | Placebo | Placebo MR capsule and 2 placebo IR tablets (AM) and 1 placebo IR tablet (PM) Placebo: tablet |
|
|
|