E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
Autosomal Dominant Polycystic Kidney Disease (ADPKD) |
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MedDRA Classification |
E.1.2 Medical condition or disease under investigation |
E.1.2 | Version | 8.1 |
E.1.2 | Level | LLT |
E.1.2 | Classification code | 10036046 |
E.1.2 | Term | Polycystic kidney, autosomal dominant |
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E.1.3 | Condition being studied is a rare disease | No |
E.2 Objective of the trial |
E.2.1 | Main objective of the trial |
Evaluate long-term efficacy of tolvaptan in ADPKD through rate of renal volume change (%) for tolvaptan-treated compared to placebo-treated subjects. |
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E.2.2 | Secondary objectives of the trial |
• Evaluate long-term efficacy of tolvaptan in ADPKD through a composite of ADPKD progression clinical markers (ie, hypertension, renal pain, albuminuria and renal function). • Evaluate long-term efficacy of tolvaptan in ADPKD using single clinical markers of ADPKD progression • Evaluate long-term safety of tolvaptan through standard clinical measures. Evaluate pharmacokinetic (PK), pharmacodynamic (PD) and exploratory parameters for tolvaptan in ADPKD. |
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E.2.3 | Trial contains a sub-study | No |
E.3 | Principal inclusion criteria |
1. Adult subjects providing informed consent: [Defined as men or women ≥ 18 years and ≥ regional legal age of maturity to age 50 years, inclusive who are able to provide informed consent and/or give assent. In the US and Europe, this is generally 18 years, while in Japan it is 20 years, inclusive.] 2. Adult subjects with a diagnosis of ADPKD: [Diagnosis of ADPKD (age 18 or 20-50) requires several cysts in each kidney (3 if by sonography, 5 if by computed tomography (CT) or MRI) in those with a family history of ADPKD and 10 cysts (by any radiologic method) in each kidney and exclusion of other cystic kidney diseases if there is no family history. Conditions to be excluded include: multiple simple renal cysts, renal tubular acidosis, cystic dysplasia of the kidney, multicystic kidney, multilocular cysts of the kidney, medullary cystic kidney and acquired cystic disease of the kidney.] 3. Willing to comply with required reproductive precautions: [Limited to women who are capable of becoming pregnant (ie, not abstinent, not surgically sterile by hysterectomy, bilateral oophorectomy nor those who have been postmenopausal for at least 12 consecutive months). These individuals must be willing to remain abstinent or comply with approved birth control (Protocol Section 5.4) from two-weeks prior to, and for 60 days, after taking investigational product. Further, breast-feeding is not permitted while taking tolvaptan in this trial.] 4. Estimated GFR ≥ 60 mL/min/1.73m2 within -31 days of randomization. [Established using Cockfroft-Gault with correction for gender and race where possible] 5. Rapid estimated rate of renal volume increase based on total renal size ≥750 cc by MRI at randomization. [Excluding, as possible, those clearly meeting criteria solely due to six or fewer predominant cysts.] |
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E.4 | Principal exclusion criteria |
1. Subjects who in the opinion of the trial investigator and/or sponsor present a safety risk. [For example: Subjects having disorders in thirst recognition or inability to access fluids. Subjects who have clinically significant allergic reactions to tolvaptan or chemically related structures such as benzazepines (benzazapril or mirtazapine), those with critical electrolyte imbalances, those with clinically significant anemia, pregnant or breast-feeding women.] 2. Subjects who are unlikely to adequately comply with the trial’s procedures. [For example: Subjects having medical conditions likely to require an extended interruption or discontinuation during the first year of trial, with recurrent recent substance abuse (illicit drugs or alcohol), with a history of persistent non-compliance with anti-hypertensive or other important medical therapy.] 3. Subjects having contraindications to, or interference with MRI assessments [For example: ferromagnetic metal prostheses, aneurysm clips, severe claustrophobia, gadolinium reactions, large abdominal/back tattoos, etc.] 4. Subjects having concomitant illnesses likely to confound endpoint assessments [For example: advanced diabetes (ie, fasting glucose >126 and glycosuria by dipstick), evidence of significant renal disease (ie, currently active glomerular nephritidies), renal cancer, single kidney, recent (within last 3 years) renal surgery etc.] 5. Subjects taking other experimental therapies, with previous exposure to tolvaptan, or taking approved therapies for the purpose of affecting PKD cysts [For example: tolvaptan, anti-sense RNA therapies, rapamycin, somatostatin analogs, recent (within 3 years) or anticipated cyst decompression, etc.] |
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E.5 End points |
E.5.1 | Primary end point(s) |
• Primary Efficacy Endpoint: Rate of renal volume (total, both kidneys) change (normalized as percentage) for tolvaptan (combining all doses) relative to placebo. • Safety Endpoints: Safety endpoints to be analyzed will include a descriptive summary of: 1. Reported Adverse Events 2. Vital signs 3. Clinical laboratory tests 4. ECGs. • Pharmacokinetic Endpoints: Sparse samples will be taken for determination of tolvaptan and metabolite plasma concentrations (DM-4103 and DM- 4107). • Pharmacodynamic Endpoints: For tolvaptan compared to placebo: 1. For urine, trough spot osmolality, and MCP-1 concentrations. 2. For blood, cystatin C concentrations and BUA |
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E.6 and E.7 Scope of the trial |
E.6 | Scope of the trial |
E.6.1 | Diagnosis | No |
E.6.2 | Prophylaxis | No |
E.6.3 | Therapy | Yes |
E.6.4 | Safety | Yes |
E.6.5 | Efficacy | Yes |
E.6.6 | Pharmacokinetic | Yes |
E.6.7 | Pharmacodynamic | Yes |
E.6.8 | Bioequivalence | No |
E.6.9 | Dose response | No |
E.6.10 | Pharmacogenetic | No |
E.6.11 | Pharmacogenomic | No |
E.6.12 | Pharmacoeconomic | No |
E.6.13 | Others | No |
E.7 | Trial type and phase |
E.7.1 | Human pharmacology (Phase I) | No |
E.7.1.1 | First administration to humans | No |
E.7.1.2 | Bioequivalence study | No |
E.7.1.3 | Other | No |
E.7.1.3.1 | Other trial type description | |
E.7.2 | Therapeutic exploratory (Phase II) | No |
E.7.3 | Therapeutic confirmatory (Phase III) | Yes |
E.7.4 | Therapeutic use (Phase IV) | No |
E.8 Design of the trial |
E.8.1 | Controlled | Yes |
E.8.1.1 | Randomised | Yes |
E.8.1.2 | Open | No |
E.8.1.3 | Single blind | No |
E.8.1.4 | Double blind | Yes |
E.8.1.5 | Parallel group | Yes |
E.8.1.6 | Cross over | No |
E.8.1.7 | Other | No |
E.8.2 | Comparator of controlled trial |
E.8.2.1 | Other medicinal product(s) | No |
E.8.2.2 | Placebo | Yes |
E.8.2.3 | Other | No |
E.8.3 |
The trial involves single site in the Member State concerned
| No |
E.8.4 | The trial involves multiple sites in the Member State concerned | Yes |
E.8.4.1 | Number of sites anticipated in Member State concerned | 9 |
E.8.5 | The trial involves multiple Member States | Yes |
E.8.5.1 | Number of sites anticipated in the EEA | 39 |
E.8.6 Trial involving sites outside the EEA |
E.8.6.1 | Trial being conducted both within and outside the EEA | Yes |
E.8.6.2 | Trial being conducted completely outside of the EEA | Information not present in EudraCT |
E.8.6.3 | If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned |
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E.8.7 | Trial has a data monitoring committee | Yes |
E.8.8 |
Definition of the end of the trial and justification where it is not the last
visit of the last subject undergoing the trial
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The End of Trial Date is defined as the last Date of Contact or the Date of Final Contact Attempt from the Post-Treatment Follow-up or withdrawing from the trial. |
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E.8.9 Initial estimate of the duration of the trial |
E.8.9.1 | In the Member State concerned years | 5 |
E.8.9.1 | In the Member State concerned months | |
E.8.9.1 | In the Member State concerned days | |
E.8.9.2 | In all countries concerned by the trial years | 5 |