Clinical Trials Register

Summary
EudraCT Number:	2014-000226-38
Sponsor's Protocol Code Number:	156-13-210
National Competent Authority:	Czechia - SUKL
Clinical Trial Type:	EEA CTA
Trial Status:	Completed
Date on which this record was first entered in the EudraCT database:	2014-11-13
Trial results	View results

Index
A. PROTOCOL INFORMATION
B. SPONSOR INFORMATION
C. APPLICANT IDENTIFICATION
D. IMP IDENTIFICATION
D.8 INFORMATION ON PLACEBO
E. GENERAL INFORMATION ON THE TRIAL
F. POPULATION OF TRIAL SUBJECTS
G. INVESTIGATOR NETWORKS TO BE INVOLVED IN THE TRIAL
N. REVIEW BY THE COMPETENT AUTHORITY OR ETHICS COMMITTEE IN THE COUNTRY CONCERNED
P. END OF TRIAL

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A. Protocol Information

A.1

Member State Concerned

Czechia - SUKL

A.2

EudraCT number

2014-000226-38

A.3

Full title of the trial

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

Multicentrické, placebem kontrolované, dvojitě zaslepené klinické hodnocení fáze 3b s paralelními skupinami a randomizovaným vysazením léku k posouzení účinnosti a bezpečnosti tolvaptanu (45 až 120 mg denně v dělené dávce) u subjektů s chronickým onemocněním ledvin v pozdním stádiu 2 až časném stádiu 4 v důsledku polycystické choroby ledvin autosomálně dominantního typu

A.3.1

Title of the trial for lay people, in easily understood, i.e. non-technical, language

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

A.4.1

Sponsor's protocol code number

156-13-210

A.5.2

US NCT (ClinicalTrials.gov registry) number

NCT02160145

A.7

Trial is part of a Paediatric Investigation Plan

A.8

EMA Decision number of Paediatric Investigation Plan

B. Sponsor Information
B.Sponsor: 1
B.1.1	Name of Sponsor	Otsuka Pharmaceutical Development & Commercialization, Inc.
B.1.3.4	Country	United States
B.3.1 and B.3.2	Status of the sponsor	Commercial
B.4 Source(s) of Monetary or Material Support for the clinical trial:
B.4.1	Name of organisation providing support	Otsuka Pharmaceutical Development & Commercialization, Inc
B.4.2	Country	United States
B.5 Contact point designated by the sponsor for further information on the trial
B.5.1	Name of organisation	Otsuka Pharmaceutical Development & Commercialization, Inc.
B.5.2	Functional name of contact point	Olga Sergeyeva, MD, MPH
B.5.3	Address:
B.5.3.1	Street Address	2440 Research Boulevard
B.5.3.2	Town/ city	Rockville,
B.5.3.3	Post code	Maryland 20850
B.5.3.4	Country	United States
B.5.4	Telephone number	1-609-249-6643
B.5.5	Fax number	1-609-249-0643
B.5.6	E-mail	olga.sergeyeva@otsuka-us.com

D. IMP Identification
D.IMP: 1
D.1.2 and D.1.3	IMP Role	Test
D.2	Status of the IMP to be used in the clinical trial
D.2.1	IMP to be used in the trial has a marketing authorisation	No
D.2.5	The IMP has been designated in this indication as an orphan drug in the Community	Yes
D.2.5.1	Orphan drug designation number	EU/3/13/1175
D.3 Description of the IMP
D.3.1	Product name	Tolvaptan 15mg
D.3.4	Pharmaceutical form	Tablet
D.3.4.1	Specific paediatric formulation	No
D.3.7	Routes of administration for this IMP	Oral use
D.3.8 to D.3.10 IMP Identification Details (Active Substances)
D.3.8	INN - Proposed INN	Tolvaptan
D.3.9.2	Current sponsor code	OPC-41061
D.3.9.4	EV Substance Code	SUB31691
D.3.10	Strength
D.3.10.1	Concentration unit	mg milligram(s)
D.3.10.2	Concentration type	equal
D.3.10.3	Concentration number	15
D.3.11 The IMP contains an:
D.3.11.1	Active substance of chemical origin	Yes
D.3.11.2	Active substance of biological/ biotechnological origin (other than Advanced Therapy IMP (ATIMP)	No
	The IMP is a:
D.3.11.3	Advanced Therapy IMP (ATIMP)	No
D.3.11.3.1	Somatic cell therapy medicinal product	No
D.3.11.3.2	Gene therapy medical product	No
D.3.11.3.3	Tissue Engineered Product	No
D.3.11.3.4	Combination ATIMP (i.e. one involving a medical device)	No
D.3.11.3.5	Committee on Advanced therapies (CAT) has issued a classification for this product	No
D.3.11.4	Combination product that includes a device, but does not involve an Advanced Therapy	No
D.3.11.5	Radiopharmaceutical medicinal product	No
D.3.11.6	Immunological medicinal product (such as vaccine, allergen, immune serum)	No
D.3.11.7	Plasma derived medicinal product	No
D.3.11.8	Extractive medicinal product	No
D.3.11.9	Recombinant medicinal product	No
D.3.11.10	Medicinal product containing genetically modified organisms	No
D.3.11.11	Herbal medicinal product	No
D.3.11.12	Homeopathic medicinal product	No
D.3.11.13	Another type of medicinal product	No
D.IMP: 2
D.1.2 and D.1.3	IMP Role	Test
D.2	Status of the IMP to be used in the clinical trial
D.2.1	IMP to be used in the trial has a marketing authorisation	No
D.2.5	The IMP has been designated in this indication as an orphan drug in the Community	Yes
D.2.5.1	Orphan drug designation number	EU/3/13/1175
D.3 Description of the IMP
D.3.1	Product name	Tolvaptan 30mg
D.3.4	Pharmaceutical form	Tablet
D.3.4.1	Specific paediatric formulation	No
D.3.7	Routes of administration for this IMP	Oral use
D.3.8 to D.3.10 IMP Identification Details (Active Substances)
D.3.8	INN - Proposed INN	Tolvaptan
D.3.9.2	Current sponsor code	OPC-41061
D.3.9.4	EV Substance Code	SUB31691
D.3.10	Strength
D.3.10.1	Concentration unit	mg milligram(s)
D.3.10.2	Concentration type	equal
D.3.10.3	Concentration number	30
D.3.11 The IMP contains an:
D.3.11.1	Active substance of chemical origin	Yes
D.3.11.2	Active substance of biological/ biotechnological origin (other than Advanced Therapy IMP (ATIMP)	No
	The IMP is a:
D.3.11.3	Advanced Therapy IMP (ATIMP)	No
D.3.11.3.1	Somatic cell therapy medicinal product	No
D.3.11.3.2	Gene therapy medical product	No
D.3.11.3.3	Tissue Engineered Product	No
D.3.11.3.4	Combination ATIMP (i.e. one involving a medical device)	No
D.3.11.3.5	Committee on Advanced therapies (CAT) has issued a classification for this product	No
D.3.11.4	Combination product that includes a device, but does not involve an Advanced Therapy	No
D.3.11.5	Radiopharmaceutical medicinal product	No
D.3.11.6	Immunological medicinal product (such as vaccine, allergen, immune serum)	No
D.3.11.7	Plasma derived medicinal product	No
D.3.11.8	Extractive medicinal product	No
D.3.11.9	Recombinant medicinal product	No
D.3.11.10	Medicinal product containing genetically modified organisms	No
D.3.11.11	Herbal medicinal product	No
D.3.11.12	Homeopathic medicinal product	No
D.3.11.13	Another type of medicinal product	No

D.8 Information on Placebo
D.8 Placebo: 1
D.8.1	Is a Placebo used in this Trial?	Yes
D.8.3	Pharmaceutical form of the placebo	Tablet
D.8.4	Route of administration of the placebo	Oral use

E. General Information on the Trial

E.1 Medical condition or disease under investigation

E.1.1

Medical condition(s) being investigated

Autosomal Dominant Polycystic Kidney Disease (ADPKD)

E.1.1.1

Medical condition in easily understood language

ADPKD is an inherited condition (passed from ones parents) that causes cysts (fluid filled sacs) to develop on the kidneys. It causes the kidneys to get bigger over time and for the kidneys to fail.

E.1.1.2

Therapeutic area

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

MedDRA Classification

E.1.2 Medical condition or disease under investigation

E.1.2	Version	18.0
E.1.2	Level	LLT
E.1.2	Classification code	10036046
E.1.2	Term	Polycystic kidney, autosomal dominant
E.1.2	System Organ Class	100000004850

E.1.3

Condition being studied is a rare disease

Yes

E.2 Objective of the trial

E.2.1

Main objective of the trial

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.

E.2.2

Secondary objectives of the trial

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.

E.2.3

Trial contains a sub-study

E.3

Principal 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

E.4

Principal 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.

E.5 End points

E.5.1

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.

E.5.1.1

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.

E.5.2

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

E.5.2.1

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.

E.6 and E.7 Scope of the trial

E.6

Scope of the trial

E.6.1

Diagnosis

E.6.2

Prophylaxis

E.6.3

Therapy

E.6.4

Safety

Yes

E.6.5

Efficacy

Yes

E.6.6

Pharmacokinetic

Yes

E.6.7

Pharmacodynamic

Yes

E.6.8

Bioequivalence

E.6.9

Dose response

E.6.10

Pharmacogenetic

E.6.11

Pharmacogenomic

E.6.12

Pharmacoeconomic

E.6.13

Others

E.7

Trial type and phase

E.7.1

Human pharmacology (Phase I)

E.7.1.1

First administration to humans

E.7.1.2

Bioequivalence study

E.7.1.3

Other

E.7.1.3.1

Other trial type description

E.7.2

Therapeutic exploratory (Phase II)

E.7.3

Therapeutic confirmatory (Phase III)

Yes

E.7.4

Therapeutic use (Phase IV)

E.8 Design of the trial

E.8.1

Controlled

Yes

E.8.1.1

Randomised

Yes

E.8.1.2

Open

E.8.1.3

Single blind

E.8.1.4

Double blind

Yes

E.8.1.5

Parallel group

Yes

E.8.1.6

Cross over

E.8.1.7

Other

E.8.2

Comparator of controlled trial

E.8.2.1

Other medicinal product(s)

E.8.2.2

Placebo

Yes

E.8.2.3

Other

E.8.2.4

Number of treatment arms in the trial

E.8.3

The trial involves single site in the Member State concerned

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

E.8.5

The trial involves multiple Member States

Yes

E.8.5.1

Number of sites anticipated in the EEA

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

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

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

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

The end of trial date is defined as the last date of last contact with the subject.

E.8.9 Initial estimate of the duration of the trial

E.8.9.1

In the Member State concerned years

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

E.8.9.2

In all countries concerned by the trial months

F. Population of Trial Subjects

F.1 Age Range

F.1.1

Trial has subjects under 18

F.1.1.1

In Utero

F.1.1.2

Preterm newborn infants (up to gestational age < 37 weeks)

F.1.1.3

Newborns (0-27 days)

F.1.1.4

Infants and toddlers (28 days-23 months)

F.1.1.5

Children (2-11years)

F.1.1.6

Adolescents (12-17 years)

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:

F.2 Gender

F.2.1

Female

Yes

F.2.2

Male

Yes

F.3 Group of trial subjects

F.3.1

Healthy volunteers

F.3.2

Patients

Yes

F.3.3

Specific vulnerable populations

Yes

F.3.3.1

Women of childbearing potential not using contraception

F.3.3.2

Women of child-bearing potential using contraception

Yes

F.3.3.3

Pregnant women

F.3.3.4

Nursing women

F.3.3.5

Emergency situation

F.3.3.6

Subjects incapable of giving consent personally

F.3.3.7

Others

F.4 Planned number of subjects to be included

F.4.1

In the member state

F.4.2

For a multinational trial

F.4.2.1

In the EEA

688

F.4.2.2

In the whole clinical trial

1300

F.5

Plans for treatment or care after the subject has ended the participation in the trial (if it is different from the expected normal treatment of that condition)

Patients who complete treatment will be offered entry into the 211
Open Label Extension study. Patients who do not enter the 211 OLE
will be treated as directed by their physician.

G. Investigator Networks to be involved in the Trial

N. Review by the Competent Authority or Ethics Committee in the country concerned

Competent Authority Decision

Authorised

Date of Competent Authority Decision

2015-01-21

Ethics Committee Opinion of the trial application

Favourable

Ethics Committee Opinion: Reason(s) for unfavourable opinion

Date of Ethics Committee Opinion

2015-01-21

P. End of Trial
P.	End of Trial Status	Completed
P.	Date of the global end of the trial	2017-04-14

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