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    Summary
    EudraCT Number:2012-000452-34
    Sponsor's Protocol Code Number:3004
    National Competent Authority:Greece - EOF
    Clinical Trial Type:EEA CTA
    Trial Status:Completed
    Date on which this record was first entered in the EudraCT database:2014-03-11
    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 ConcernedGreece - EOF
    A.2EudraCT number2012-000452-34
    A.3Full title of the trial
    Proteomic prediction and Renin angiotensin aldosterone system Inhibition prevention Of early diabetic nephRopathy In TYpe 2 diabetic patients with normoalbuminuria
    A.3.1Title of the trial for lay people, in easily understood, i.e. non-technical, language
    Prediction and prevention of kidney disease in patients with diabetes
    A.3.2Name or abbreviated title of the trial where available
    PRIORITY
    A.4.1Sponsor's protocol code number3004
    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 SponsorSteno Diabetes Center
    B.1.3.4CountryDenmark
    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 supportFP7 Program
    B.4.2CountryEuropean Union
    B.5 Contact point designated by the sponsor for further information on the trial
    B.5.1Name of organisationSteno Diabetes Center
    B.5.2Functional name of contact pointProf. Peter Rossing MD. DMSc
    B.5.3 Address:
    B.5.3.1Street AddressNiels Steensens Vej 2
    B.5.3.2Town/ cityGentofte
    B.5.3.3Post codeDK-2820
    B.5.3.4CountryDenmark
    B.5.4Telephone number+4544437310
    B.5.5Fax number+4544438160
    B.5.6E-mailpro@steno.dk
    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 nameSpironolactone
    D.3.4Pharmaceutical form Film-coated tablet
    D.3.4.1Specific paediatric formulation No
    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 INNSPIRONOLACTONE
    D.3.9.1CAS number 52-01-7
    D.3.9.3Other descriptive nameSPIRONOLACTONE
    D.3.9.4EV Substance CodeSUB10631MIG
    D.3.10 Strength
    D.3.10.1Concentration unit mg milligram(s)
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number25
    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 placeboFilm-coated tablet
    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
    Patients with type 2 diabetes mellitus and normoalbuminuria
    E.1.1.1Medical condition in easily understood language
    Diabetic patients with normal concentration of albumin in urine
    E.1.1.2Therapeutic area Diseases [C] - Nutritional and Metabolic Diseases [C18]
    MedDRA Classification
    E.1.2 Medical condition or disease under investigation
    E.1.2Version 16.1
    E.1.2Level PT
    E.1.2Classification code 10067585
    E.1.2Term Type 2 diabetes mellitus
    E.1.2System Organ Class 10027433 - Metabolism and nutrition disorders
    E.1.3Condition being studied is a rare disease No
    E.2 Objective of the trial
    E.2.1Main objective of the trial
    To confirm that urinary proteomics can predict development of microalbuminuria (as a surrogate marker for the development of overt nephropathy) in a cohort of 3280 type 2 diabetic patients with normal urinary albumin excretion.
    E.2.2Secondary objectives of the trial
    -To investigate if early initiation of preventive therapy with spironolactone 25 mg once daily reduces risk of transition to microalbuminuria in those patients identified by urinary proteomics to be at high risk
    -Assessment of safety in the intervention group
    -To compare the rate of change in UAER in high- vs. low-risk patients (based on the proteomic test), and to compare the effect of spironolactone on rate of change in UACR in the intervention study.
    -In addition, the objective is to study the rate of change in eGFR in relation to urinary marker pattern (CKD 273) and the intervention with spironolactone.
    -To study the ability of urinary proteomic patterns to predict cardiovascular or renal events during the study, as well as response to intervention in relation to study endpoints
    -To establish a biobank that will allow testing of additional putative markers for progression of diabetic nephropathy, development of cardiovascular events and death
    E.2.3Trial contains a sub-study No
    E.3Principal inclusion criteria
    • Written informed consent must be provided before participation. Patient information and consent form must be approved by relevant independent EC. Specifically, all participating patients will be asked to give informed consent for long-term follow-up and collection of follow-up data
    • Male or female patients ≥ 18 years and < 75 years of age at Screening visit
    • Type 2 DM (WHO criteria)
    • Persistent normoalbuminuria (at least 2 of 3 UACR < 30 mg/g samples from ”run in” period)
    • eGFR > 45 ml/min/1.73m2 (MDRD formula) at Screening visit
    • HbA1c ≥ 6.5% (48 mmol / mol) and < 13% (119 mmol / mol) at Screening visit
    • The patient must be willing and able to comply with the protocol for the duration of the study
    • Female without child-bearing potential at the screening visit. Defined as one or more of following:
    - Female patients ≥ 50 years of age at the day of inclusion, who have been postmenopausal for at least 1 year
    - Female patients < 50 years of age at the day of inclusion, who have been postmenopausal for at least 1 year and serum FSH levels > 40 mIU/mL as well as serum estrogen levels < 30 pg/ml or a negative estrogen test
    - 6 weeks after surgical sterilization by bilateral tubal ligation or bilateral ovariectomy with or without hysterectomy
    OR a negative urine pregnancy test at the Screening visit AND one or more of the following:
    - Correct use of reliable contraception methods. This includes one or more ofthe following: hormonal contraceptive (such as injection, transdermal patch, implant, cervical ring or oral) or an intrauterine device (IUD) OR correct use of double barrier with one of the following: barrier methods (diaphragm, cervical cap, Lea contraceptive, femidom or condom) AND in combination with a spermicide
    - General sexual abstinence from the time of screening, during the study until a minimum of 30 days after the last administration of study medication if this is already established as the patient’s preferred and usual lifestyle.
    - Having only female sexual partners
    - Sexual relationship with sterile male partners only

    E.4Principal exclusion criteria
    • Average of systolic BP < 110 or > 160 mm Hg at baseline
    • Average of diastolic BP > 100 mm Hg at baseline
    • Type 1 DM (WHO criteria)
    • Current in treatment with more than one RAAS blocking agent (Angiotensin Converting Enzyme inhibitor, Angiotensin Receptor Blocker or Direct Renin Inhibitor)
    • Current lithium treatment
    • Known or suspected hypersensitivity to Spironolactone or to any of its excipients
    • Current use of potassium sparing diuretics, such as: Spironolactone, Eplerenone or amiloride etc
    • Screening (week -6) plasma (or serum) potassium level >5.0 mmol/L
    • Hyponatriemia determine by the investigator
    • Current cancer treatment or within five years from baseline (except basal cell skin cancer or squamous cell skin cancer)
    • Any clinically significant disorder, except for conditions as-sociated with type 2 DM history, which in the Investigators opinion could interfere with the results of the trial
    • Cardiac disease defined as: Heart failure (NYHA class III-IV) and/or diagnosis of unstable angina pectoris and/or MI, stroke, PTCA or CABG within the last 3 months
    • Body mass index < 18.5 or > 40 kg/m2
    • Diagnosis of non-Diabetic CKD current or in the past
    • Diagnosis of liver cirrhosis with current impaired liver function within the last 3 years.
    • Diagnosis of Addison's disease
    • Being lactating
    • Intend to become pregnant within the duration of the study or not use adequate birth control.
    • Known or suspected abuse of alcohol or narcotics
    • Not able to understand informed consent form
    • Participation in any other intervention trial than PRIORITY or a related sub-study is not allowed within 30 days before inclusion or concurrent to this study
    E.5 End points
    E.5.1Primary end point(s)
    Development of confirmed microalbuminuria UACR >30 mg/g in at least two out of three first morning voids with ≥ 30% increase in UACR from "run-in" period samples.
    E.5.1.1Timepoint(s) of evaluation of this end point
    Every 13 weeks and week 156 or early termination (treatment group)
    Every 52 weeks and week 156 or early termination (observational group)
    E.5.2Secondary end point(s)
    In the following paragraphs patients in the intervention group, (group B) and observation group (group A) will be compared

    1) Comparison of composite fatal and non-fatal cardiovascular outcome (MI, stroke, CABG, PTCA, hospitalization for heart failure and CVD), and all cause mortality during the study
    2) Comparison of incidence of retinopathy and frequency of laser treatment. Data collected from self-reported AEs
    3) In addition to the categorical analysis of urinary albumin excretion, an analysis will be performed with changes in geometric mean albuminuria throughout the study period in all patients by assessing the slope of albuminuria changes and absolute changes from inclusion to end of trial
    4) Development of microalbuminuria (UACR >30 mg/g) in at least one morning void urine sample will be used as a secondary outcome instead of confirmed microalbuminuria
    5) Development of macroalbuminuria (UACR >300 mg/g) in 2 out 3 first morning void urine samples)
    6) For patients with eGFR ≥ 60 at baseline, development of eGFR<60 ml/min/1.73m2. eGFR will be measured from serum creatinine (standardized traceable method) on blood samples tested in local laboratories. Serum creatinine (mg/dL) will be recorded on eCRFs and used to calculate estimated glomerular filtration rate using the MDRD equation [eGFR ml/min/ 1.73m2 =186 x serum creatinine-1.154 x age-0.203 x (1.210 if black) x (0.742 if female)]
    7) Change in eGFR (slope and absolute from baseline and from 3 month post-baseline to end of study)


    In the following paragraphs patients receiving active medication will be compared to placebo treatment.

    8) Comparison of composite fatal and non-fatal cardiovascular outcome (MI, stroke, CABG, PTCA, hospitalization for heart failure and CVD) and all cause mortality during the study
    9) Comparison of incidence of retinopathy and frequency of laser treatment. Data collected from AEs
    10) Development of microalbuminuria (UACR > 30 mg/g) in at least one morning void urine sample will be used as a secondary outcome instead of con-firmed microalbuminuria
    11) Development of macroalbuminuria (UACR > 300 mg/g in 2 out 3 first morning void urine samples)
    12) For patients with eGFR ≥ 60 at baseline, development of eGFR<60 ml/min/1.73m2
    13) Change in eGFR (slope and absolute from baseline and from 3 month post-baseline to end of study)

    14) Assessment of safety
    The assessment of safety will be based primarily on the frequency of eCRF-documented AEs, laboratory abnormalities, and SAEs. Occurrence and frequency of eCRF-documented AEs, SAEs and laboratory abnormalities will be summarized by treatment group.
    In addition AEs leading to death and AEs leading to discontinuation of study medication and/or withdrawal will be summarized for the two treatment groups.
    E.5.2.1Timepoint(s) of evaluation of this end point
    1), 8) during the study
    2), 9) Data collected from self-reported AEs
    3), throughout the study
    4), 5), 10), 11), run-in period, every 13 weeks, week 156 or early termination (treatment group), run-in period, every 52 weeks, week 156 or early termination (observational group)
    6),12) screening/baseline, Visit 1, every 13 weeks, week 156 or early termination (treatment group); every 52 weeks and week 156 or early termination (observational group)
    7), 13) baseline, every 13 weeks and week 156 or early termination (treatment group); every 52 weeks and week 156 or early termination (observational group)
    14) baseline, every Visit, prolonged until all AEs are resolved or until the investigator assess the adverse events as “chronic” or “stable”.
    E.6 and E.7 Scope of the trial
    E.6Scope of the trial
    E.6.1Diagnosis No
    E.6.2Prophylaxis Yes
    E.6.3Therapy Yes
    E.6.4Safety Yes
    E.6.5Efficacy Yes
    E.6.6Pharmacokinetic No
    E.6.7Pharmacodynamic No
    E.6.8Bioequivalence No
    E.6.9Dose response No
    E.6.10Pharmacogenetic No
    E.6.11Pharmacogenomic No
    E.6.12Pharmacoeconomic No
    E.6.13Others Yes
    E.6.13.1Other scope of the trial description
    Predictive value of the urinary proteomics test in regards to renal and cardiovascular events
    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) Yes
    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 No
    E.8.1.7Other Yes
    E.8.1.7.1Other trial design description
    Randomized, double blind, placebo-control trial and prospective observational study
    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 trial2
    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 Yes
    E.8.5.1Number of sites anticipated in the EEA9
    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
    Denmark
    France
    Greece
    Italy
    Netherlands
    Czech Republic
    Germany
    Spain
    Macedonia, the former Yugoslav Republic of
    Switzerland
    United Kingdom
    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
    LVLS
    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: 60
    F.1.3Elderly (>=65 years) Yes
    F.1.3.1Number of subjects for this age range: 40
    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 state100
    F.4.2 For a multinational trial
    F.4.2.1In the EEA 2680
    F.4.2.2In the whole clinical trial 3280
    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)
    None
    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 Decision2014-04-08
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion2014-06-27
    P. End of Trial
    P.End of Trial StatusCompleted
    P.Date of the global end of the trial2018-10-29
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