This is a study to evaluate the safety and effectiveness of Tolvaptan in adults with chronic kidney disease

• Register: EUCTR
• Last refreshed on: 3 July 2017
• Main ID: EUCTR2014-000226-38-HU
• Date of registration: 21/08/2014
• Prospective Registration: Yes
• Primary sponsor: Otsuka Pharmaceutical Development & Commercialization, Inc.
• Public title: This is a study to evaluate the safety and effectiveness of Tolvaptan in adults with chronic kidney disease
• Scientific title: A Phase 3b, Multi-center, Randomized-withdrawal, Placebo-controlled, Double-blind, Parallel-group Trial to Compare the Efficacy and Safety of Tolvaptan (45 to 120 mg/day, Split-dose) in Subjects with Chronic Kidney Disease Between Late Stage 2 to Early Stage 4 Due to Autosomal Dominant Polycystic Kidney Disease
• Date of first enrolment: 03/11/2014
• Target sample size: 1300
• Recruitment status: Not Recruiting
• URL: https://www.clinicaltrialsregister.eu/ctr-search/search?query=eudract_number:2014-000226-38
• 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 Number of treatment arms in the trial: 2
• Phase: Human pharmacology (Phase I): no Therapeutic exploratory (Phase II): no Therapeutic confirmatory - (Phase III): yes Therapeutic use (Phase IV): no

Countries of recruitment

Argentina, Australia, Belgium, Brazil, Canada, Chile, Colombia, Czech Republic, Denmark, France, Germany, Hungary, Israel, Italy, Korea, Republic of, Malaysia, Mexico, Netherlands, Norway, Peru, Poland, Romania, Russian Federation, South Africa, Spain, Sweden, Switzerland, Taiwan, Turkey, United Kingdom, United States

Contacts

• Name: Olga Sergeyeva, MD, MPH
• Affiliation: Otsuka Pharmaceutical Development & Commercialization, Inc.

• Name: Olga Sergeyeva, MD, MPH
• Affiliation: Otsuka Pharmaceutical Development & Commercialization, Inc.

Key inclusion & exclusion criteria

Inclusion criteria:
1. Male and female subjects age 18 to 55 years of age (inclusive) with eGFR between 25 and 65
mL/min/1.73m2 -OR-
2. Male and female subjects age 56 to < 66 years of age with eGFR between 25 and
44 mL/min/1.73m2 (with evidence of ADPKD progression, ie, eGFR decline of
>2.0 mL/min/1.73 m2 per year, based on historical eGFR data and medical monitor discretion).
3. Male and female subjects who are tolvaptan naïve.
4. Diagnosis of ADPKD by modified Pei-Ravine criteria18 19:
? With family history: several cysts per kidney (3 if by sonography, 5 if by CT or MRI)
? Without family history: 10 cysts per kidney (by any radiologic method, above) and exclusion
of other cystic kidney diseases. 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.
? Distribution and number of cysts consistent with the observed level of renal function deficit
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 1270
F.1.3 Elderly (>=65 years) yes
F.1.3.1 Number of subjects for this age range 30

Exclusion criteria:
1. Women of childbearing potential (WOCBP) who do not agree to practice 2 different methods of
birth control or remain abstinent during the trial and for 30 days after the last dose of IMP. If
employing birth control, 2 of the following precautions must be used: vasectomy of partner, tubal
ligation, vaginal diaphragm, intrauterine device, birth control pill, birth control implant, birth
control depot injection, condom, or sponge with spermicide.
2. Women who are breast-feeding and/or who have a positive pregnancy test result prior to receiving
IMP.
3. Need for chronic diuretic use.
4. Hepatic impairment or liver function abnormalities other than that expected for ADPKD with
typical cystic liver disease during the pre-randomization period.
5. Subjects with advanced diabetes (eg, glycosylated hemoglobin [HgbA1c] > 7.5, and/or glycosuria
by dipstick, significant proteinuria, retinopathy), evidence of additional significant renal
disease(s) (ie, currently active glomerular nephritides), renal cancer, single kidney, or recent
(within last 6 months) renal surgery or acute kidney injury.
6. Subjects with contraindications to required trial assessments.
7. Subjects who, in the opinion of the trial investigator or medical monitor, have a medical history or
medical findings inconsistent with safety or compliance with trial assessments.


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

Health Condition(s) or Problem(s) studied

Autosomal Dominant Polycystic Kidney Disease (ADPKD)
MedDRA version: 18.0 Level: LLT Classification code 10036046 Term: Polycystic kidney, autosomal dominant System Organ Class: 100000004850

Therapeutic area: Diseases [C] - Congenital, Hereditary, and Neonatal Diseases and Abnormalities [C16]

Intervention(s)

Product Name: Tolvaptan 15mg
Pharmaceutical Form: Tablet
INN or Proposed INN: Tolvaptan
Current Sponsor code: OPC-41061
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 30mg
Pharmaceutical Form: Tablet
INN or Proposed INN: Tolvaptan
Current Sponsor code: OPC-41061
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)

Primary end point(s): Treatment difference in the change of eGFR from pre-treatment baseline to posttreatment
follow-up, annualized (divided) by each subject’s IMP treatment duration.

Secondary Objective: To compare the efficacy of tolvaptan treatment in
reducing the decline of annualized eGFR slope, as compared
with placebo, in subjects with late-stage CKD due to ADPKD
who tolerate tolvaptan during an initial run-in period.
To compare overall and hepatic safety of tolvaptan with
placebo and to compare incidence of ADPKD complications
(outcomes) during the trial.

Timepoint(s) of evaluation of this end point: Throughout study up to the Follow up period (3 week post treatment end). The eGFR values will be calculated from the central-laboratory serum creatinine concentrations taken at screening and during every trial visit including follow up visit.

Main Objective: To compare the efficacy of tolvaptan treatment in
reducing the change in estimated glomerular filtration rate
(eGFR) from pre-treatment baseline to post-treatment followup,
as compared with placebo, in subjects with late-stage
chronic kidney disease (CKD) due to ADPKD who tolerate
tolvaptan during an initial run-in period.

Secondary Outcome(s)

Secondary end point(s): Key Secondary Efficacy Endpoint
Treatment difference in annualized slope of eGFR calculated for individual subjects using an appropriate baseline and available, post-randomization, on-treatment assessments.

Safety Endpoints
Safety endpoints to be analyzed will include a descriptive summary of:
1) AEs
2) Vital signs
3) Clinical laboratory tests, including serum transaminases, BT, ALP, and serum sodium

Pharmacokinetic/Pharmacodynamic Endpoints
PK Endpoints: Determination of plasma tolvaptan and metabolite(s), including DM-4103 concentrations.
PD Endpoints: Uosm and urine specific gravity

Timepoint(s) of evaluation of this end point: Efficacy and Safety endpoints will be assessed throughout study up to
and including the Follow up period (3 week post treatment end).
PK endpoint assessed:
End of the tolvaptan run-in period (Day -1)
During the double-blind, randomized treatment period at Months 3, 6, 9,
12/EoTx,
At the last follow-up visit
PD endpoint assessed:
second visit of the screening period
end of the placebo run-in period (Day -36)
end of the tolvaptan titration period (Day -22)
end of the tolvaptan run-in period (Day -1)
during the double-blind, randomized treatment period at Months 3, 6, 9,
and 12/EoTx
at the last follow-up visit.

Secondary ID(s)

NCT02160145

156-13-210

2014-000226-38-GB

Source(s) of Monetary Support

Otsuka Pharmaceutical Development & Commercialization, Inc