A Phase 3, Multi-center, Double-blind, Placebo-controlled, Parallel-arm Trial to Determine Long-term Safety and Efficacy of Oral Tolvaptan Tablet Regimens in Adult Subjects with Autosomal Dominant Polycystic Kidney Disease - -

• Register: EUCTR
• Last refreshed on: 20 May 2013
• Main ID: EUCTR2006-002768-24-DK
• Date of registration: 29/11/2006
• Prospective Registration: Yes
• Primary sponsor: Otsuka Pharmaceutical Development & Commercialization, Inc.
• Public title: A Phase 3, Multi-center, Double-blind, Placebo-controlled, Parallel-arm Trial to Determine Long-term Safety and Efficacy of Oral Tolvaptan Tablet Regimens in Adult Subjects with Autosomal Dominant Polycystic Kidney Disease - -
• Scientific title: A Phase 3, Multi-center, Double-blind, Placebo-controlled, Parallel-arm Trial to Determine Long-term Safety and Efficacy of Oral Tolvaptan Tablet Regimens in Adult Subjects with Autosomal Dominant Polycystic Kidney Disease - -
• Date of first enrolment: 26/01/2007
• Target sample size: 1500
• Recruitment status: Not Recruiting
• URL: https://www.clinicaltrialsregister.eu/ctr-search/search?query=eudract_number:2006-002768-24
• Study type: Interventional clinical trial of medicinal product
• Study design: Controlled: yes Randomised: yes Open: no Single blind: no Double blind: yes Parallel group: yes Cross over: no Other: no If controlled, specify comparator, Other Medicinial Product: no Placebo: yes Other: no

Countries of recruitment

Denmark, France, Germany, Italy, United Kingdom

Key inclusion & exclusion criteria

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 within -31 days of randomization. [Established using Cockcroft-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 those meeting volumetric criteria solely due to six or fewer predominant cysts.]
Are the trial subjects under 18? no
Number of subjects for this age range:
F.1.2 Adults (18-64 years) yes
F.1.2.1 Number of subjects for this age range
F.1.3 Elderly (>=65 years) no
F.1.3.1 Number of subjects for this age range

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 (benzazepril, conivaptan, fenoldopam mesylate or mirtazapine), those with critical electrolyte imbalances, or low blood volume, 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 a history of substance abuse (within the last 3 years), 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, large abdominal/back tattoos, etc.]
4. Subjects taking medications or having concomitant illnesses likely to confound endpoint assessments [For example: chronic use of diuretics, advanced diabetes (ie, those with poor glycemic control evidenced by a history of severely elevated hemoglobin A1C, or with evidence of advanced retinopathy, nephropathy or peripheral vascular disease due to micro-or-macro vascular disease), 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 (ie, non marketed) therapies, or taking approved therapies for the purpose of affecting PKD cysts, or those taking or have a history of taking tolvaptan. [For example: tolvaptan, anti-sense RNA therapies, rapamycin, sirolimus, everolimus, somatostatin analogs ( ie, octreotide,sandostatin), recent (within 3 years) or anticipated cyst decompression, etc.]


Age minimum:
Age maximum:
Gender:
Female: yes
Male: yes

Health Condition(s) or Problem(s) studied

Autosomal Dominant Polycystic Kidney Disease (ADPKD)
MedDRA version: 8.1 Level: LLT Classification code 10036046 Term: Polycystic kidney, autosomal dominant

Intervention(s)

Product Name: Tolvaptan (OPC-41061)
Product Code: Tolvaptan (OPC-41061)
Pharmaceutical Form: Tablet
INN or Proposed INN: Tolvaptan
Current Sponsor code: OPC-41061, OPC-156
Concentration unit: mg milligram(s)
Concentration type: equal
Concentration number: 15-
Pharmaceutical form of the placebo: Tablet
Route of administration of the placebo: Oral use

Product Name: Tolvaptan (OPC-41061)
Product Code: Tolvaptan (OPC-41061)
Pharmaceutical Form: Tablet
INN or Proposed INN: Tolvaptan
Current Sponsor code: OPC-41061, OPC-156
Concentration unit: mg milligram(s)
Concentration type: equal
Concentration number: 30-
Pharmaceutical form of the placebo: Tablet
Route of administration of the placebo: Oral use

Primary Outcome(s)

Main Objective: Evaluate long-term efficacy of tolvaptan in ADPKD
through rate of renal volume change (%) for tolvaptan-treated
compared to placebo-treated subjects.

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

Secondary Objective: • 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.

Secondary ID(s)

156-04-251