Autosomal Dominant Polycystic Kidney Disease
Conditions
Keywords
Kidney Disease, Polycystic Kidney Disease, Autosomal Dominant Polycystic Kidney Disease, PKD, ADPKD
Brief summary
The purpose of this study is to compare the short-term effects of two tolvaptan formulations in patients with ADPKD.
Interventions
Sponsors
Otsuka Pharmaceutical Development & Commercialization, Inc.
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
TRIPLE (Subject, Caregiver, Investigator)
Eligibility
Sex/Gender
ALL
Age
18 Years to 50 Years
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 3. Subjects not planning to become pregnant willing to comply with birth control requirements. 4. Subjects must be in good health as determined by screening tests. 5. 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) 4. Subjects having taken an investigational drug within 30 days preceding randomization on Day 0 5. 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 6. Subjects on antihypertensives that have not been on the same antihypertensive regimen for at least 30 days prior to the first dose of IMP 7. Subjects having contraindications to, or interference with, MRI assessments 8. Subjects with a history of serious mental disorders that, in the opinion of the investigator, would exclude the subject from participating in this trial 9. Subjects with previous exposure to tolvaptan
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| 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
| Measure | Time frame | Description |
|---|---|---|
| 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. |
| 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. |
Countries
United States
Participant flow
Recruitment details
The trial was conducted in 177 participants at 41 trial states in the United States.
Pre-assignment details
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.
Participants by arm
| Arm | Count |
|---|---|
| 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 | 45 |
| 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 | 45 |
| 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 | 44 |
| Placebo Placebo MR capsule and 2 placebo IR tablets (evening) and 1 placebo IR tablet (morning)
Placebo: tablet | 43 |
| Total | 177 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 | FG003 |
|---|---|---|---|---|---|
| Overall Study | Adverse Event | 2 | 0 | 1 | 1 |
| Overall Study | Lost to Follow-up | 0 | 3 | 0 | 2 |
| Overall Study | Participant met withdrawal criteria | 0 | 2 | 0 | 0 |
| Overall Study | Protocol deviation | 1 | 0 | 0 | 0 |
| Overall Study | Withdrawal by Subject | 0 | 0 | 1 | 1 |
Baseline characteristics
| Characteristic | Tolvaptan MR 50 mg | Tolvaptan MR 80 mg | Tolvaptan IR 60/30 mg | Placebo | Total |
|---|---|---|---|---|---|
| Age, Continuous | 34.1 years STANDARD_DEVIATION 10.1 | 35.8 years STANDARD_DEVIATION 7.9 | 32.2 years STANDARD_DEVIATION 7.6 | 33.9 years STANDARD_DEVIATION 8.1 | 34.0 years STANDARD_DEVIATION 8.5 |
| Sex: Female, Male Female | 18 Participants | 23 Participants | 20 Participants | 23 Participants | 84 Participants |
| Sex: Female, Male Male | 27 Participants | 22 Participants | 24 Participants | 20 Participants | 93 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk | EG003 affected / at risk |
|---|---|---|---|---|
| deaths Total, all-cause mortality | 0 / 45 | 0 / 44 | 0 / 44 | 0 / 42 |
| other Total, other adverse events | 27 / 45 | 25 / 44 | 32 / 44 | 18 / 42 |
| serious Total, serious adverse events | 3 / 45 | 1 / 44 | 1 / 44 | 1 / 42 |
Outcome results
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.
Time frame: Baseline to Week 3
Population: Participants who were randomized and had baseline and post-baseline observations in the total renal volume.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Tolvaptan MR 50 mg | Percent Change From Baseline in Total Kidney Volume (TKV) at Week 3 | -2.46 Percentage change | Standard Deviation 4.4 |
| Tolvaptan MR 80 mg | Percent Change From Baseline in Total Kidney Volume (TKV) at Week 3 | -2.55 Percentage change | Standard Deviation 3.85 |
| Tolvaptan IR 60/30 mg | Percent Change From Baseline in Total Kidney Volume (TKV) at Week 3 | -1.17 Percentage change | Standard Deviation 4.52 |
| Placebo | Percent Change From Baseline in Total Kidney Volume (TKV) at Week 3 | 0.09 Percentage change | Standard Deviation 5.31 |
Comparison: 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.p-value: 0.012795% CI: [0.96, 1]ANCOVA
Comparison: 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.p-value: 0.010895% CI: [0.95, 0.99]ANCOVA
Comparison: 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.p-value: 0.015595% CI: [0.96, 1]ANCOVA
Comparison: 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.p-value: 0.241795% CI: [0.97, 1.01]ANCOVA
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.
Time frame: Baseline to Week 8
Population: Participants who were randomized and had baseline and post-baseline observations in the total renal volume.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Tolvaptan MR 50 mg | Change From Baseline in Total Score of the Autosomal Dominant Polycystic Kidney Disease Urinary Impact Scale (ADPKD-UIS) | Urinary Frequency | 0.74 Unit on a scale | Standard Deviation 0.94 |
| Tolvaptan MR 50 mg | Change From Baseline in Total Score of the Autosomal Dominant Polycystic Kidney Disease Urinary Impact Scale (ADPKD-UIS) | Nocturia | 0.97 Unit on a scale | Standard Deviation 1.28 |
| Tolvaptan MR 50 mg | Change From Baseline in Total Score of the Autosomal Dominant Polycystic Kidney Disease Urinary Impact Scale (ADPKD-UIS) | Urinary Urgency | 0.69 Unit on a scale | Standard Deviation 0.96 |
| Tolvaptan MR 80 mg | Change From Baseline in Total Score of the Autosomal Dominant Polycystic Kidney Disease Urinary Impact Scale (ADPKD-UIS) | Urinary Frequency | 0.82 Unit on a scale | Standard Deviation 0.83 |
| Tolvaptan MR 80 mg | Change From Baseline in Total Score of the Autosomal Dominant Polycystic Kidney Disease Urinary Impact Scale (ADPKD-UIS) | Urinary Urgency | 0.66 Unit on a scale | Standard Deviation 0.77 |
| Tolvaptan MR 80 mg | Change From Baseline in Total Score of the Autosomal Dominant Polycystic Kidney Disease Urinary Impact Scale (ADPKD-UIS) | Nocturia | 1.15 Unit on a scale | Standard Deviation 0.89 |
| Tolvaptan IR 60/30 mg | Change From Baseline in Total Score of the Autosomal Dominant Polycystic Kidney Disease Urinary Impact Scale (ADPKD-UIS) | Urinary Urgency | 1.01 Unit on a scale | Standard Deviation 0.95 |
| Tolvaptan IR 60/30 mg | Change From Baseline in Total Score of the Autosomal Dominant Polycystic Kidney Disease Urinary Impact Scale (ADPKD-UIS) | Urinary Frequency | 0.99 Unit on a scale | Standard Deviation 0.78 |
| Tolvaptan IR 60/30 mg | Change From Baseline in Total Score of the Autosomal Dominant Polycystic Kidney Disease Urinary Impact Scale (ADPKD-UIS) | Nocturia | 1.36 Unit on a scale | Standard Deviation 1.12 |
| Placebo | Change From Baseline in Total Score of the Autosomal Dominant Polycystic Kidney Disease Urinary Impact Scale (ADPKD-UIS) | Nocturia | 0.11 Unit on a scale | Standard Deviation 0.59 |
| Placebo | Change From Baseline in Total Score of the Autosomal Dominant Polycystic Kidney Disease Urinary Impact Scale (ADPKD-UIS) | Urinary Frequency | 0.10 Unit on a scale | Standard Deviation 0.35 |
| Placebo | Change From Baseline in Total Score of the Autosomal Dominant Polycystic Kidney Disease Urinary Impact Scale (ADPKD-UIS) | Urinary Urgency | 0.05 Unit on a scale | Standard Deviation 0.3 |
Comparison: Urinary Frequencyp-value: 0.000295% CI: [0.31, 0.99]ANCOVA
Comparison: Urinary Frequencyp-value: <0.000195% CI: [0.4, 1.08]ANCOVA
Comparison: Urinary Frequencyp-value: <0.000195% CI: [0.58, 1.25]ANCOVA
Comparison: Urinary Urgencyp-value: 0.000495% CI: [0.3, 1.01]ANCOVA
Comparison: Urinary Urgencyp-value: 0.000495% CI: [0.29, 1.01]ANCOVA
Comparison: Urinary Urgencyp-value: <0.000195% CI: [0.63, 1.34]ANCOVA
Comparison: Nocturiap-value: 0.000295% CI: [0.42, 1.3]ANCOVA
Comparison: Nocturiap-value: <0.000195% CI: [0.63, 1.51]ANCOVA
Comparison: Nocturiap-value: <0.000195% CI: [0.8, 1.66]ANCOVA
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.
Time frame: Baseline to Week 8
Population: 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 | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Tolvaptan MR 50 mg | Percent Change From Baseline in TKV at Week 8. | -2.04 Percentage change | Standard Deviation 3.87 |
| Tolvaptan MR 80 mg | Percent Change From Baseline in TKV at Week 8. | -2.02 Percentage change | Standard Deviation 3.54 |
| Tolvaptan IR 60/30 mg | Percent Change From Baseline in TKV at Week 8. | -0.08 Percentage change | Standard Deviation 7.31 |
| Placebo | Percent Change From Baseline in TKV at Week 8. | 2.13 Percentage change | Standard Deviation 7.99 |
Comparison: 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.p-value: 0.020995% CI: [0.94, 0.99]ANCOVA
Comparison: 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 placebop-value: 0.028795% CI: [0.93, 1]ANCOVA
Comparison: 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 placebop-value: 0.029895% CI: [0.93, 1]ANCOVA
Comparison: 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 placebop-value: 0.230695% CI: [0.94, 1.01]ANCOVA