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    Summary
    EudraCT Number:2010-019025-33
    Sponsor's Protocol Code Number:156-09-284
    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:2010-07-27
    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
    Expand All   Collapse All
    A. Protocol Information
    A.1Member State ConcernedNetherlands - Competent Authority
    A.2EudraCT number2010-019025-33
    A.3Full title of the trial
    A Phase IIa, Single-Center Study, Investigating the Short-Term Renal Hemodynamic Effects, Safety and Pharmacokinetics/Pharmacodynamics of Oral Tolvaptan (OPC-41061) in Subjects with Autosomal Dominant Polycystic Kidney Disease at Various Stages of Renal Function
    A.4.1Sponsor's protocol code number156-09-284
    A.7Trial is part of a Paediatric Investigation Plan Information not present in EudraCT
    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 support
    B.4.2Country
    B.5 Contact point designated by the sponsor for further information on the trial
    B.5.1Name of organisation
    B.5.2Functional name of contact point
    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.2.1.1.1Trade name Samsca 15 mg tablets
    D.2.1.1.2Name 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 15 mg tablets
    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.3.11 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) Information not present in EudraCT
    D.3.11.3.1Somatic cell therapy medicinal product No
    D.3.11.3.2Gene therapy medical product No
    D.3.11.3.3Tissue Engineered Product Information not present in EudraCT
    D.3.11.3.4Combination ATIMP (i.e. one involving a medical device) Information not present in EudraCT
    D.3.11.3.5Committee on Advanced therapies (CAT) has issued a classification for this product Information not present in EudraCT
    D.3.11.4Combination product that includes a device, but does not involve an Advanced Therapy Information not present in EudraCT
    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 Information not present in EudraCT
    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.IMP: 2
    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.2.1.1.1Trade name Samsca 30 mg tablets
    D.2.1.1.2Name 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 30 mg tablets
    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 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) Information not present in EudraCT
    D.3.11.3.1Somatic cell therapy medicinal product No
    D.3.11.3.2Gene therapy medical product No
    D.3.11.3.3Tissue Engineered Product Information not present in EudraCT
    D.3.11.3.4Combination ATIMP (i.e. one involving a medical device) Information not present in EudraCT
    D.3.11.3.5Committee on Advanced therapies (CAT) has issued a classification for this product Information not present in EudraCT
    D.3.11.4Combination product that includes a device, but does not involve an Advanced Therapy Information not present in EudraCT
    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 Information not present in EudraCT
    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)
    MedDRA Classification
    E.1.2 Medical condition or disease under investigation
    E.1.2Version 12.1
    E.1.2Level LLT
    E.1.2Classification code 10036046
    E.1.2Term Polycystic kidney, autosomal dominant
    E.1.3Condition being studied is a rare disease No
    E.2 Objective of the trial
    E.2.1Main objective of the trial
    To determine the effect of maximally tolerated doses of tolvaptan at steady state on the measured glomerular filtration rate (GFR), renal plasma flow (RPF), and filtration fraction in subjects with ADKPD, including those with severely impaired renal function.
    E.2.2Secondary objectives of the trial
    To determine the effect of maximally tolerated doses of tolvaptan at steady state in subjects with ADPKD, including those with severely impaired renal function.

    To assess the short-term hemodynamic safety of tolvaptan.

    To determine the effect of tolvaptan on urine osmolality (spot, 2-hour and 24 hour collections), urine volume (2-hour and 24-hour collections), plasma or serum concentrations of albumin, sodium, creatinine, potassium, uric acid, cystatin C, plasma renin activity, angiotensin II, copeptin, aldosterone and osmoles, urine concentrations of sodium, potassium, creatinine, osmoles, and albumin, the urine albumin/creatinine ratios, and free water, sodium , potassium, urea, uric acid, osmolar and creatinine clearances.

    To determine the effect of tolvaptan on mean arterial blood pressure.

    To characterize tolvaptan plasma concentrations.
    E.2.3Trial contains a sub-study No
    E.3Principal inclusion criteria
    1) Males and females between 18 and 70 years of age, inclusive

    2) Diaganosis of ADPKD by Ravine criteria:
    With family history: several cysts per kidney (3 if by sonography, 5 if by CT or MRI)
    Without family history: 10 cysts (by an radiologic method) per kidney and exclusion of other cystic kidney diseases

    3) eGFR as assessed by the MDRD equation based on an average of 2 measurements (one may be historical within 3 months prior to enrollment) that falls into one of the following strata:
    Group A must have an eGFR of > 60 mL/min * 1.73 m2
    Group B must have an eGFR of 30-60 ml/min * 1.73 m2
    Group C must have an eGFR of < 30 ml/min * 1.73m2

    4) Must have a negative serum pregnancy test prior to the first dose for all women of child-bearing potential (WOCBP)

    5) Must have a body mass index (BMI) between 19-32 kg/m2

    6) Must be in good health as determined by medical history, physical examination, ECG, serum/urine biochemistry , hematology and serology tests

    7) Subjects using diuretics may be eligible to participate if, after signing the informed consent , diuretic use is discontinued and the subject's blood pressure is stabilized on new antihypertension medication prior to the baseline visit

    8) Ability to provide written, informed consent prior to initiation of any study-related procedures, and ability, in the opinion of the principle investigator, to comply with all requirements of the study.
    E.4Principal exclusion criteria
    1. Men or women who will not adhere to the reproductive precautions as outlined in the informed consent form.

    2. Subject who is pregnant or breast-feeding.
    3. Inability to take oral medications.
    4. Subjects who have clinically significant allergic reactions to tolvaptan or chemically related structures such as benzazepines (benzazepril, conivaptan, fenoldopam mesylate or mirtazapine)
    5. Subjects with a history of substance abuse (within the last 3 years).
    6. Subjects taking other experimental (ie, nonmarketed) therapies or current participation in another clinical drug or device trial within 30 days prior to dosing.
    Efficacy Endpoint Specific Exclusion
    7. Subjects on any form of renal replacement therapy (e.g. dialysis, renal transplantation)
    8. Subjects taking approved therapies for the purpose of affecting PKD cysts, including but not limited to, anti-sense RNA therapies, rapamycin, sirolimus, everolimus, or somatostatin analogs ( ie, octreotide, sandostatin).
    9. Prior use of a vasopressin antagonist for greater than 10 days or within 6 months of randomization.
    10. Previous exposure to tolvaptan.
    11. Subjects with a history of renal cystic disease likely to call into question the diagnosis of ADPKD, including 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.
    12. Subjects with evidence of significant renal disease other than ADPKD, such as currently active glomerular nephritidies, renal cancer, single kidney.
    13. Subjects with significant risk-factors for renal impairment other than ADPKD, such as 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), use of nephrotoxic drugs.
    14. Subjects having recent (within last 6 months) renal surgery
    15. Subjects with a history of persistent non-compliance with anti-hypertensive or other important medical therapy.
    16. Subjects who may not safely be discontinued from diuretic medication for any reason.
    17. Consumption of alcohol and/or food and beverages containing methyl xanthines within 24 hours of renal function testing and grapefruit, grapefruit juice, Seville oranges or Seville orange juice within 72 hours prior to dosing.
    18. Exposure to any substances known to stimulate hepatic microsomal enzymes within 30 days prior to screening through the end of the study (eg, occupational exposure to pesticides, organic solvents, etc).
    Patient Safety Specific Exclusion
    19. Allergy to iodine.
    20. Subjects with diabetes mellitus (fasting glucose > 126 mg/dL or on treatment with insulin or oral hypoglycemics).
    21. Any history of significant coagulation defects or hemorrhagic diathesis (ie, von Willebrand disease).
    22. A history of difficulty in donating blood.
    23. Donation of blood or plasma within 30 days prior to dosing.
    23. History of or current hepatitis or acquired immunodeficiency syndrome (AIDS) or carriers of hepatitis B surface antigen (HBsAg) and/or hepatitis C antibodies (anti-HCV), or human immunodeficiency virus (HIV) antibodies.
    24. Urine cotinine concentrations > 200 ng/mL or serum cotinine concentrations > 20 ng/mL at screening or upon admission to the study center.
    25. Subjects having disorders in thirst recognition or inability to access fluids.
    26. Subjects with critical electrolyte imbalances.

    27. Subjects with low blood volume.

    28. Subjects with clinically significant anemia, as determined by investigator.
    29. Subjects with uncontrolled hypertension.

    30. Any subject who, in the opinion of the sponsor or the principle investigator, should not participate in the study.
    E.5 End points
    E.5.1Primary end point(s)
    Primary Outcome Variables:
    Pharmacodynamics: GFR as determined by iothalamate clearance and RPF as determined by para-amino-hippurate (PAH) clearance and magnetic resonance imaging (MRI) and filtration fraction (GFR/RPF)
    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.7.1.3.1Other trial type description
    E.7.2Therapeutic exploratory (Phase II) Yes
    E.7.3Therapeutic confirmatory (Phase III) No
    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 No
    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.8.3 The trial involves single site in the Member State concerned Yes
    E.8.4 The trial involves multiple sites in the Member State concerned No
    E.8.4.1Number of sites anticipated in Member State concerned1
    E.8.5The trial involves multiple Member States No
    E.8.6 Trial involving sites outside the EEA
    E.8.6.1Trial being conducted both within and outside the EEA No
    E.8.6.2Trial being conducted completely outside of the EEA Information not present in EudraCT
    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 protocol
    E.8.9 Initial estimate of the duration of the trial
    E.8.9.1In the Member State concerned years0
    E.8.9.1In the Member State concerned months3
    E.8.9.1In the Member State concerned days0
    E.8.9.2In all countries concerned by the trial years0
    E.8.9.2In all countries concerned by the trial months3
    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.1.3Elderly (>=65 years) Yes
    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 For clinical trials recorded in the database before the 10th March 2011 this question read: "Women of childbearing potential" and did not include the words "not using contraception". An answer of yes could have included women of child bearing potential whether or not they would be using contraception. The answer should therefore be understood in that context. This trial was recorded in the database on 2010-07-27. Yes
    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 state36
    F.4.2 For a multinational trial
    F.4.2.1In the EEA 36
    F.4.2.2In the whole clinical trial 36
    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 Decision2010-07-26
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion2010-08-31
    P. End of Trial
    P.End of Trial StatusCompleted
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