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    Summary
    EudraCT Number:2017-003864-10
    Sponsor's Protocol Code Number:NL2017HCTMet
    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:2018-03-08
    Trial 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 number2017-003864-10
    A.3Full title of the trial
    Hydrochlorothiazide and metformin cross-over study for attenuating aquaretic side-effects in ADPKD patients treated with tolvaptan
    Hydrochloorthiazide en metformine cross-over studie voor het verminderen van polyurie bij ADPKD-patiënten die tolvaptan gebruiken
    A.3.1Title of the trial for lay people, in easily understood, i.e. non-technical, language
    Medication for excessive urine production in patients treated with tolvaptan
    Medicijnen tegen verhoogde urineproductie bij tolvaptan
    A.4.1Sponsor's protocol code numberNL2017HCTMet
    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 SponsorUniversity Medical Center Groningen
    B.1.3.4CountryNetherlands
    B.3.1 and B.3.2Status of the sponsorNon-Commercial
    B.4 Source(s) of Monetary or Material Support for the clinical trial:
    B.4.1Name of organisation providing supportUniversity Medical Center Groningen
    B.4.2CountryNetherlands
    B.5 Contact point designated by the sponsor for further information on the trial
    B.5.1Name of organisationUniversity Medical Center Groningen
    B.5.2Functional name of contact pointBart J. Kramers
    B.5.3 Address:
    B.5.3.1Street AddressHanzeplein 1; PO Box 30 001
    B.5.3.2Town/ cityGroningen
    B.5.3.3Post code9700RB
    B.5.3.4CountryNetherlands
    B.5.4Telephone number+31503610332
    B.5.5Fax number+31503619067
    B.5.6E-mailb.j.kramers@umcg.nl
    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 No
    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 nameHydrochlorothiazide
    D.3.2Product code HCT
    D.3.4Pharmaceutical form Tablet
    D.3.4.1Specific paediatric formulation No
    D.3.7Routes of administration for this IMPOral use
    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.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 No
    D.3.11.3.4Combination ATIMP (i.e. one involving a medical device) No
    D.3.11.3.5Committee 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.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 No
    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 nameMetformin
    D.3.4Pharmaceutical form Tablet
    D.3.4.1Specific paediatric formulation No
    D.3.7Routes of administration for this IMPOral use
    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.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 No
    D.3.11.3.4Combination ATIMP (i.e. one involving a medical device) No
    D.3.11.3.5Committee 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
    D.8 Placebo: 1
    D.8.1Is a Placebo used in this Trial?Yes
    D.8.3Pharmaceutical form of the placeboTablet
    D.8.4Route of administration of the placeboOral use
    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
    Autosomaal dominante polycysteuze nierziekte
    E.1.1.1Medical condition in easily understood language
    Polycystic kidney disease
    Familiaire cystenieren
    E.1.1.2Therapeutic area Diseases [C] - Symptoms and general pathology [C23]
    MedDRA Classification
    E.1.3Condition being studied is a rare disease Yes
    E.2 Objective of the trial
    E.2.1Main objective of the trial
    To demonstrate whether hydrochlorothiazide or metformin can diminish aquaresis in patients with ADPKD who are treated with tolvaptan as measured by 24-hour urine volume.
    Het doel is om aan te tonen dat hydrochloorthiazide en/of metformine de aquarese kunnen verminderen in patiënten met ADPKD die behandeld worden met tolvaptan, gemeten in 24-uurs urinevolume.
    E.2.2Secondary objectives of the trial
    -To assess change in glomerular filtration rate (as measured with the iohexol plasma clearance technique)
    -To assess change in plasma copeptin
    -To assess tolerability of the study medication
    -De effecten onderzoeken van studiemedicatie op verandering in glomerulaire filtratie snelheid (GFR) (zoals gemeten met de iohexol plasma klaringstechniek)
    -De effecten onderzoeken van studiemedicatie op verandering in copeptin
    -De effecten onderzoeken van studiemedicatie op verdraagbaarheid van de studiemedicatie
    E.2.3Trial contains a sub-study No
    E.3Principal inclusion criteria
    1. Diagnosis of ADPKD, based upon modified Ravine criteria
    2. Using tolvaptan 120mg daily
    3. Age between 18 and 50 years
    4. ≥45 eGFR (CKD-EPI)
    5. Providing informed consent
    1. Diagnose ADPKD, gebaseerd op de gemodificeerde Ravine criteria
    2. Gebruikt tolvaptan 120mg per dag
    3. Leeftijd tussen de 18 en 50 jaar
    4. ≥45 eGFR (CKD-EPI)
    5. Informed consent getekend
    E.4Principal exclusion criteria
    1. Patients who, in the opinion of the investigator may present a safety risk
    2. Patients who are unlikely to adequately comply to the trial’s procedures (due for instance to medical conditions likely to require interruption or discontinuation, history of substance abuse or non-compliance)
    3. a. Patients taking medication likely to confound endpoint assessments (e.g. NSAID or diuretics such as furosemide or spironolactone)
    3. b. Patients having concomitant illnesses likely to confound endpoint assessments such (e.g. diabetes mellitus for which medication is needed or diabetes insipidus)
    4. Women who are pregnant or breastfeeding
    5. Patients with known contra indications to the study medication such as
    5. a. Hydrochlorothiazide: gout, hepatic impairment, illnesses that cause potassium loss, history of hypokalaemia, known allergy to hydrochlorothiazide
    5. b. Metformin: Illnesses that can cause tissue hypoxia (e.g. recent myocardial infarction, heart failure, respiratory failure), known allergy to metformin
    1. Patiënten die naar mening van de onderzoekers een veiligheidsrisico kunnen lopen
    2. Patiënten waarvan het onwaarschijnlijk is dat zij zich adequaat aan de studieprocedures zullen houden (bijvoorbeeld door medische aandoeningen die ingrijpen of niet voortzetten van studiemedicatie behoeven, middelenmisbruik in de voorgeschiedenis, of non-compliantie)
    3. a. Patiënten met medicatie die waarschijnlijk eindpunten verstoren (zoals NSAIDs of diuretica zoals furosemide of spironolacton)
    3. b. Patiënten met andere aandoeningen die waarschijnlijk eindpunten verstoren (zoals diabetes mellitus waarvoor medicatie gebruikt dient te worden of diabetes insipidus)
    4. Vrouwen die zwanger zijn of borstvoeding geven
    5.Patiënten met contraindicaties voor de medicatie zoals
    5. a. Hydrochloorthiazide: jicht, leverfalen, ziektes die leiden tot kaliumverlies, hypokaliëmieën, bekende allergie voor hydrochloorthiazide
    5. b. Metformine: Ziekten die tot weefselhypoperfusie kunnen leiden (zoals recent myocardinfarct, hartfalen, respiratoir falen), bekende allergie voor metformine
    E.5 End points
    E.5.1Primary end point(s)
    Change in 24-hour urine volume
    Verandering in 24-uurs urinevolume
    E.5.1.1Timepoint(s) of evaluation of this end point
    Baseline, and the end of each 2-week treatment period
    Baseline en aan het einde van elke behnadelperiode van twee weken
    E.5.2Secondary end point(s)
    -Change in glomerular filtration rate (as measured with the iohexol plasma clearance technique)
    -Change in plasma copeptin
    -Tolerability of the study medication
    -Verandering in glomerulaire filtratie snelheid (GFR) (zoals gemeten met de iohexol plasma klaringstechniek)
    -Verandering in copeptin
    -Verdraagbaarheid van de studiemedicatie
    E.5.2.1Timepoint(s) of evaluation of this end point
    Baseline, and the end of each 2-week treatment period. Adverse events: during entire study period
    Baseline en aan het einde van elke behnadelperiode van twee weken. Bijwerkingen: Gedurende de hele studieperiode
    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 Yes
    E.6.4Safety Yes
    E.6.5Efficacy Yes
    E.6.6Pharmacokinetic No
    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 Yes
    E.8.1.1Randomised Yes
    E.8.1.2Open No
    E.8.1.3Single blind No
    E.8.1.4Double blind Yes
    E.8.1.5Parallel group No
    E.8.1.6Cross over Yes
    E.8.1.7Other No
    E.8.2 Comparator of controlled trial
    E.8.2.1Other medicinal product(s) No
    E.8.2.2Placebo Yes
    E.8.2.3Other No
    E.8.2.4Number of treatment arms in the trial3
    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.8.5The 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 No
    E.8.7Trial has a data monitoring committee No
    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
    LVLS
    LVLS
    E.8.9 Initial estimate of the duration of the trial
    E.8.9.1In the Member State concerned years
    E.8.9.1In the Member State concerned months
    E.8.9.1In the Member State concerned days
    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: 12
    F.1.3Elderly (>=65 years) No
    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 state12
    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)
    During the study and after the study the patients will visit his/her own physician according to the routine terms of patient care.
    Gedurende de studie en na de studie zal de patiënt door zijn/haar eigen arts gezien worden, zoals normaal gesproken ook de afspraken gepland staan.
    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 Decision2018-03-08
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion2018-05-02
    P. End of Trial
    P.End of Trial StatusCompleted
    P.Date of the global end of the trial2022-03-21
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