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    EudraCT Number:2010-018401-10
    Sponsor's Protocol Code Number:156-08-271
    National Competent Authority:Netherlands - Competent Authority
    Clinical Trial Type:EEA CTA
    Trial Status:Completed
    Date on which this record was first entered in the EudraCT database:2010-10-21
    Trial results View results
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    A. Protocol Information
    A.1Member State ConcernedNetherlands - Competent Authority
    A.2EudraCT number2010-018401-10
    A.3Full title of the trial
    A Multi-center, Open-label, Extension Study to Evaluate the Long-term Efficacy and Safety of Oral Tolvaptan Tablet Regimens in Subjects with Autosomal Dominant Polycystic Kidney Disease (ADPKD)
    A.3.1Title of the trial for lay people, in easily understood, i.e. non-technical, language
    A global clinical research study using a drug that is used in patients for the treatment of multiple cysts which form on the kidneys.
    A.4.1Sponsor's protocol code number156-08-271
    A.7Trial is part of a Paediatric Investigation Plan No
    A.8EMA Decision number of Paediatric Investigation Plan
    B. Sponsor Information
    B.Sponsor: 1
    B.1.1Name of SponsorOtsuka Pharmaceutical Development & Commercialization, Inc
    B.1.3.4CountryUnited States
    B.3.1 and B.3.2Status of the sponsorCommercial
    B.4 Source(s) of Monetary or Material Support for the clinical trial:
    B.4.1Name of organisation providing supportOtsuka Pharmaceutical Development & Commercialization, Inc
    B.4.2CountryUnited States
    B.5 Contact point designated by the sponsor for further information on the trial
    B.5.1Name of organisationMMG, Inc.
    B.5.2Functional name of contact pointMarita Lynott
    B.5.3 Address:
    B.5.3.1Street Address700 King Farm Boulevard
    B.5.3.2Town/ citySuite 500, Rockville
    B.5.3.3Post codeMD 20850
    B.5.3.4CountryUnited States
    B.5.4Telephone number001301.348.1639
    B.5.5Fax number001301.921.4405
    D. IMP Identification
    D.IMP: 1
    D.1.2 and D.1.3IMP RoleTest
    D.2 Status of the IMP to be used in the clinical trial
    D.2.1IMP to be used in the trial has a marketing authorisation Yes
    D. name Samsca
    D. of the Marketing Authorisation holderOtsuka Pharmaceutical Europe Ltd
    D.2.1.2Country which granted the Marketing AuthorisationEuropean Union
    D.2.5The IMP has been designated in this indication as an orphan drug in the Community No
    D.2.5.1Orphan drug designation number
    D.3 Description of the IMP
    D.3.1Product nameTolvaptan
    D.3.2Product code OPC-41061
    D.3.4Pharmaceutical form Tablet
    D.3.4.1Specific paediatric formulation Information not present in EudraCT
    D.3.7Routes of administration for this IMPOral use
    D.3.8 to D.3.10 IMP Identification Details (Active Substances)
    D.3.8INN - Proposed INNTolvaptan
    D.3.9.2Current sponsor codeOPC-41061
    D.3.10 Strength
    D.3.10.1Concentration unit mg milligram(s)
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number15
    D.3.8 to D.3.10 IMP Identification Details (Active Substances)
    D.3.8INN - Proposed INNTolvaptan
    D.3.9.2Current sponsor codeOPC-41061
    D.3.10 Strength
    D.3.10.1Concentration unit mg milligram(s)
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number30
    D.3.11 The IMP contains an:
    D.3.11.1Active substance of chemical origin Yes
    D.3.11.2Active substance of biological/ biotechnological origin (other than Advanced Therapy IMP (ATIMP) No
    The IMP is a:
    D.3.11.3Advanced Therapy IMP (ATIMP) No
    D. cell therapy medicinal product No
    D. therapy medical product No
    D. Engineered Product No
    D. ATIMP (i.e. one involving a medical device) No
    D. on Advanced therapies (CAT) has issued a classification for this product No
    D.3.11.4Combination product that includes a device, but does not involve an Advanced Therapy No
    D.3.11.5Radiopharmaceutical medicinal product No
    D.3.11.6Immunological medicinal product (such as vaccine, allergen, immune serum) No
    D.3.11.7Plasma derived medicinal product No
    D.3.11.8Extractive medicinal product No
    D.3.11.9Recombinant medicinal product No
    D.3.11.10Medicinal product containing genetically modified organisms No
    D.3.11.11Herbal medicinal product No
    D.3.11.12Homeopathic medicinal product No
    D.3.11.13Another type of medicinal product No
    D.8 Information on Placebo
    E. General Information on the Trial
    E.1 Medical condition or disease under investigation
    E.1.1Medical condition(s) being investigated
    Autosomal Dominant Polycystic Kidney Disease (ADPKD)
    E.1.1.1Medical condition in easily understood language
    Kidney cysts (fluid like-filled balloons)
    E.1.1.2Therapeutic area Diseases [C] - Congenital, Hereditary, and Neonatal Diseases and Abnormalities [C16]
    MedDRA Classification
    E.1.2 Medical condition or disease under investigation
    E.1.2Version 17.1
    E.1.2Level LLT
    E.1.2Classification code 10036046
    E.1.2Term Polycystic kidney, autosomal dominant
    E.1.2System Organ Class 100000004850
    E.1.3Condition being studied is a rare disease No
    E.2 Objective of the trial
    E.2.1Main objective of the trial
    To demonstrate whether tolvaptan modifies ADPKD progression as measured by changes in endpoints of total kidney volume (TKV) and
    renal function. Disease modification is evidenced further by the noninferiority of endpoint progression slope during this study for those
    receiving early, continuous treatment with tolvaptan, as compared to those with delayed treatment (ie, whose initial treatment was with
    placebo in trial 156-04-251).
    E.2.2Secondary objectives of the trial
    To determine whether, for placebo-treated subjects from trial 156-04-251, the annual rate of change (slope) in TKV and renal function changes during the crossover from placebo to tolvaptan treatment.

    To explore exposure response relationship among all subjects enrolled in this trial for changes in TKV, renal function and hypertension.
    E.2.3Trial contains a sub-study No
    E.3Principal inclusion criteria
    1) Successful completion (protocol defined completer without early termination) of a previous Phase 1, 2, or 3 tolvaptanADPKD or renal impairment trial, with a confirmed diagnosis of ADPKD (unless approved
    by the sponsor and medical monitor). If early
    termination from the previous trial was due to exceptional circumstances, reinitiation of tolvaptan is judged to be safe, and
    participation is approved by the sponsor and medical monitor, subjects may be enrolled beginning in January 2012.
    2) Estimated GFR ≥ 30 mL/min/1.73m2 within 45 days prior to the baseline visit (calculated using the IDMS-traceable modification of diet
    in renal disease [4 parameter MDRD] equation with correction for gender and race). Subjects with lower estimated GFR (eGFR) may be permitted with documented medical monitor approval prior to enrollment.
    E.4Principal exclusion criteria
    Trial Entry Exclusion Criteria
    1) Inability to provide written informed consent.
    2) Women of childbearing potential, or their partners, who will not adhere to the reproductive
    precautions as outlined in the Informed Consent form.
    3) Positive urine pregnancy test (women only)
    4) Subjects who are pregnant or breast-feeding.
    5) Inability to take oral medications.
    6) Subjects who have clinically significant allergic reactions to tolvaptan or chemically related structures such as benzazepines (benzazepril,
    conivaptan, fenoldopam mesylate or mirtazapine).
    7) Subjects having disorders in thirst recognition or inability to access fluids.
    8) Subjects with critical electrolyte imbalances, as determined by the investigator.
    9) Subjects with or at risk of significant hypovolemia, as determined by investigator.
    10)Subjects with clinically significant anemia, as determined by investigator.
    11)Subjects with a history of substance abuse (within the last 3 years).
    12)Subjects taking other experimental (ie, non-marketed) therapies or current participation in another clinical drug or device trial. Current
    participation in the off-drug follow up period of another ADPKD trial with tolvaptan is permitted.
    Efficacy Analysis Exclusion Criteria
    13)Subjects having contraindications to, or interferance with MRI assessments (eg, ferro-magnetic prostheses, ancurysm clips, severe
    14)Subjects with a history of taking a vasopressin antagonist, outside of
    previous participation in a tolvaptan trial.
    15) Subjects with a history of persistant non-compliance with antihypertensive or other important medical therapy.
    16)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, vasopressin
    antagonists, anti-sense RNA therapies, rapamycin, sirolimus, everolimus, or somatostatin analogs (ie, octreotide, sandostatin), and cyst reduction surgery.
    17)Subjects with advanced diabetes (ie, those with poor glycemic control evidenced by a history of severly elevated hemoglobin AIC, or
    with evidence of advanced retinpathy, nephropathy or peripheral vascular disease due to micro-or-macro vascular disease).
    E.5 End points
    E.5.1Primary end point(s)
    In subjects randomized to tolvaptan and placebo in 156-04-251 and enrolled and treated in 156-08-271 as early treated and delayed treated groups:
    • Change from the 156-04-251 baseline in TKV at Month 24 of 156-08-271
    Percent change from 156-04-251 baseline in Total kidney volume (TKV) at Month 24 in trial 156-08-271 as compared to the percent change in TKV at 156-04-251 Month 36 measured by magnetic resonance imaging (MRI)


    Change in renal function (100x1/Serum Creatinine mg/dl) at Month 24 in trial 156-08-27) as compared to change in renal function at Month 36 in protocol 156-08-251, both relative to 156-04-251 end of titration baseline.
    E.5.1.1Timepoint(s) of evaluation of this end point
    Database lock Feb 2015
    E.5.2Secondary end point(s)
    In subjects randomized to tolvaptan and placebo in 156-04-251 and enrolled and treated in 156-08-271 as early treated and
    delayed treated groups:
    • Change from the 156-04-251 baseline in eGFR
    (Chronic Kidney Disease Epidemiology Collaboration [CKD-EPI]) at Month 24 of 156-08-271
    • Slope of TKV of the 156-08-271 study
    • Slope of eGFR (CKD-EPI) of the 156-08-271 study
    Other Secondary Efficacy Endpoints:
    In prior placebo subjects enrolling from protocol 156-04-251:
    • Rate of change in annual TKV slope when crossing over from placebo to tolvaptan treatment
    • Rate of change in annual slope of renal function (eGFR CKD-EPI) when
    crossing over from placebo totolvaptan treatment
    For all subjects enrolled in this trial:
    • Change from baseline in TKV by exposure group
    • Change from end of titration in renal function (eGFRCKD-EPI) by exposure group
    • For subjects who are taking anti-hypertensive therapy at Baseline in this trial, percentage with clinically sustained decreases of blood
    pressure (BP) leading to a sustained reduction in anti-hypertensive therapy compared to Baseline (while taking investigational product) at
    Months 12 and 24 for hypertensive subjects.
    E.5.2.1Timepoint(s) of evaluation of this end point
    Database lock Feb 2015
    E.6 and E.7 Scope of the trial
    E.6Scope of the trial
    E.6.1Diagnosis No
    E.6.2Prophylaxis No
    E.6.3Therapy No
    E.6.4Safety Yes
    E.6.5Efficacy Yes
    E.6.6Pharmacokinetic Yes
    E.6.7Pharmacodynamic Yes
    E.6.8Bioequivalence No
    E.6.9Dose response No
    E.6.10Pharmacogenetic No
    E.6.11Pharmacogenomic No
    E.6.12Pharmacoeconomic No
    E.6.13Others No
    E.7Trial type and phase
    E.7.1Human pharmacology (Phase I) No
    E.7.1.1First administration to humans No
    E.7.1.2Bioequivalence study No
    E.7.1.3Other No
    E. trial type description
    E.7.2Therapeutic exploratory (Phase II) No
    E.7.3Therapeutic confirmatory (Phase III) Yes
    E.7.4Therapeutic use (Phase IV) No
    E.8 Design of the trial
    E.8.1Controlled No
    E.8.1.1Randomised No
    E.8.1.2Open Yes
    E.8.1.3Single blind No
    E.8.1.4Double blind No
    E.8.1.5Parallel group No
    E.8.1.6Cross over No
    E.8.1.7Other No
    E.8.2 Comparator of controlled trial
    E.8.2.1Other medicinal product(s) Information not present in EudraCT
    E.8.2.2Placebo Information not present in EudraCT
    E.8.2.3Other Information not present in EudraCT
    E.8.2.4Number of treatment arms in the trial3
    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.8.4.1Number of sites anticipated in Member State concerned2
    E.8.5The trial involves multiple Member States Yes
    E.8.5.1Number of sites anticipated in the EEA80
    E.8.6 Trial involving sites outside the EEA
    E.8.6.1Trial being conducted both within and outside the EEA Yes
    E.8.6.2Trial being conducted completely outside of the EEA No
    E.8.6.3If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned
    Russian Federation
    United Kingdom
    United States
    E.8.7Trial 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
    Please refer to the protocol
    E.8.9 Initial estimate of the duration of the trial
    E.8.9.1In the Member State concerned years5
    E.8.9.1In the Member State concerned months0
    E.8.9.1In the Member State concerned days0
    E.8.9.2In all countries concerned by the trial years5
    E.8.9.2In all countries concerned by the trial months0
    E.8.9.2In all countries concerned by the trial days0
    F. Population of Trial Subjects
    F.1 Age Range
    F.1.1Trial has subjects under 18 No
    F.1.1.1In Utero No
    F.1.1.2Preterm newborn infants (up to gestational age < 37 weeks) No
    F.1.1.3Newborns (0-27 days) No
    F.1.1.4Infants and toddlers (28 days-23 months) No
    F.1.1.5Children (2-11years) No
    F.1.1.6Adolescents (12-17 years) No
    F.1.2Adults (18-64 years) Yes
    F.1.2.1Number of subjects for this age range: 750
    F.1.3Elderly (>=65 years) Yes
    F.1.3.1Number of subjects for this age range: 750
    F.2 Gender
    F.2.1Female Yes
    F.2.2Male Yes
    F.3 Group of trial subjects
    F.3.1Healthy volunteers No
    F.3.2Patients Yes
    F.3.3Specific vulnerable populations Yes
    F.3.3.1Women of childbearing potential not using contraception No
    F.3.3.2Women of child-bearing potential using contraception Yes
    F.3.3.3Pregnant women No
    F.3.3.4Nursing women No
    F.3.3.5Emergency situation No
    F.3.3.6Subjects incapable of giving consent personally No
    F.3.3.7Others No
    F.4 Planned number of subjects to be included
    F.4.1In the member state96
    F.4.2 For a multinational trial
    F.4.2.1In the EEA 668
    F.4.2.2In the whole clinical trial 1500
    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)
    Please refer to protocol
    G. Investigator Networks to be involved in the Trial
    N. Review by the Competent Authority or Ethics Committee in the country concerned
    N.Competent Authority Decision Authorised
    N.Date of Competent Authority Decision2010-06-21
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion2011-01-14
    P. End of Trial
    P.End of Trial StatusCompleted
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