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    Summary
    EudraCT Number:2013-002636-25
    Sponsor's Protocol Code Number:RG_13-013NS
    National Competent Authority:UK - MHRA
    Clinical Trial Type:EEA CTA
    Trial Status:Completed
    Date on which this record was first entered in the EudraCT database:2013-08-20
    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 ConcernedUK - MHRA
    A.2EudraCT number2013-002636-25
    A.3Full title of the trial
    A Randomised Multicentre Open Label Blinded End Point Trial to Compare the Effects of Spironolactone to Chlortalidone on Left Ventricular Mass and Arterial Stiffness in Stage 3 Chronic Kidney Disease
    A.3.1Title of the trial for lay people, in easily understood, i.e. non-technical, language
    A comparison of the actions of two drugs that lower blood pressure on the heart and arteries of patients with mild kidney disease.
    A.3.2Name or abbreviated title of the trial where available
    SPIRO - CKD
    A.4.1Sponsor's protocol code numberRG_13-013NS
    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 of Birmingham
    B.1.3.4CountryUnited Kingdom
    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 supportBritish Heart Foundation
    B.4.2CountryUnited Kingdom
    B.5 Contact point designated by the sponsor for further information on the trial
    B.5.1Name of organisationBirmingham Clinical Trials Unit
    B.5.2Functional name of contact pointDr Margaret Grant
    B.5.3 Address:
    B.5.3.1Street AddressUniversity of Birmingham
    B.5.3.2Town/ cityBirmingham
    B.5.3.3Post codeB15 2TT
    B.5.3.4CountryUnited Kingdom
    B.5.4Telephone number0121415108
    B.5.5Fax number01214159135
    B.5.6E-mailm.r.grant@bham.ac.uk
    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 Information not present in EudraCT
    D.2.1.1.2Name of the Marketing Authorisation holderActavis UK Limited
    D.2.1.2Country which granted the Marketing AuthorisationIreland
    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 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 nameAldosterone antagonist
    D.3.9.4EV Substance CodeAS5
    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.IMP: 2
    D.1.2 and D.1.3IMP RoleComparator
    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 Information not present in EudraCT
    D.2.1.1.1Trade name Chlortalidone
    D.2.1.1.2Name of the Marketing Authorisation holderAlliance Pharmaceuticals
    D.2.1.2Country which granted the Marketing AuthorisationUnited Kingdom
    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 nameChlortalidone
    D.3.4Pharmaceutical form 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 INNChlortalidone
    D.3.9.1CAS number 77-36-1
    D.3.9.3Other descriptive namethiazide-like diuretic
    D.3.9.4EV Substance CodeAS4
    D.3.10 Strength
    D.3.10.1Concentration unit mg milligram(s)
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number50
    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
    E. General Information on the Trial
    E.1 Medical condition or disease under investigation
    E.1.1Medical condition(s) being investigated
    The condition under investigation is the disease changes that occur in patients with mild kidney disease that cause them to have a high rate of diseases such as heart failure, rhythm disturbance and stroke.
    E.1.1.2Therapeutic area Diseases [C] - Cardiovascular Diseases [C14]
    MedDRA Classification
    E.1.3Condition being studied is a rare disease No
    E.2 Objective of the trial
    E.2.1Main objective of the trial
    Does giving Spironolactone to patients with early stage chronic kidney disease reduce arterial stiffness and left ventricular mass to a greater degree than the standard blood pressure lowering drug treatment, Chlortalidone?
    E.2.2Secondary objectives of the trial
    To see the effect of using spironolactone on:
    1) Frequency of elevated blood potassium concentration.
    2) Blood pressure measured using an arm cuff
    3) The amount of protein leaking out of the kidneys in to the urine
    4) Kidney function measured by blood tests
    5) The occurrence of low blood pressure that might make subjects feel faint
    6) Occurrence of side effects due to treatment
    7) Heart size and pumping function
    8) The level of a hormone in the blood that rises when heart function is poor
    9) Measures of artery function that occur during the treatment period
    E.2.3Trial contains a sub-study Yes
    E.2.3.1Full title, date and version of each sub-study and their related objectives
    Version and dates for all substudies are the same as the main protocol.
    Sub-study (A)
    CMR SPAMM Tissue Tagging. LV dilatation, hypertrophy and dysfunction are common in end-stage kidney disease (ESKD) and are predictors of increased cardiovascular mortality. Overt reduction in systolic function in ESKD is preceded in early CKD by more subtle changes in myocardial deformation, including strain and strain rate. These early changes predict later increased mortality and can be at least in part reversed by treatment with spironolactone. It has been suggested that these effects are directly due tomineralocorticoid receptor blockade, but it is possible they may also simply be a result of lowering blood pressure. The hypothesis of this sub-study is that aldosterone blockade with spironolactone will increase global longitudinal strain and strain rate to a greater extent than chlorthalidone for equivalent blood-pressure lowering effect.
    Sub-study (B)
    T1 Mapping and Inversion Recovery for Late Enhancement. Although patients with CKD are exposed to accelerated atherosclerosis, the increase in heart failure and sudden cardiac death is much higher in stage III-V. LV hypertrophy is present in over 30% of patients with stage 2 (GFR 60-89) and stage 3 CKD, and in 80% of patients at the start of renal replacement therapy. This LV hypertrophy is not simply due to myocyte hypertrophy, since almost a third of those with ESKD have evidence of replacement fibrosis on CMR late gadolinium enhancement (LGE) contrast imaging. Activation of the renin-angiotensin-aldosterone system (RAAS) is a central link in the development of cardio-renal disease and aldosterone plays a leading role in promotion of myocardial fibrosis. While LGE is a useful method for assessment of focal myocardial fibrosis, RAAS activation and the effect of blockade by spironolactone is more likely to be diffuse, requiring CMR techniques that are able to detect and quantify global myocardial changes in extracellular volume expansion, such as T1 mapping by modified look-locker inversion recovery (MOLLI). The hypothesis of this sub-study is that aldosterone blockade with spironolactone will reduce both focal and diffuse myocardial fibriosis identified by CMR LGE and MOLLI.
    Sub-study (C)
    Stress/Rest Perfusion. While tissue tagging measures the mechanical effects of myocardial fibrosis and MOLLI quantifies the relative size of the extracellular space, these CMR techniques assess only one aspect of RAAS activation in cardio-renal disease. RAAS activation is one of several factors that also promote both atherosclerosis and arteriosclerosis in patients with CKD. The pro-atherogenic effect of RAAS activation may be compounded by the effect of CKD in promoting aortic stiffness, which in turn is associated with increased afterload and the promotion of left ventricular hypertrophy. As a result of increased afterload, wall stress within the hypertrophied ventricle increases and subendocardial perfusion falls, an effect thought to result in reduction in longitudinal function as a marker of subendocardial ischaemia. Myocardial blood flow and myocardial perfusion reserve can both be quantified by assessment of signal intensity from the first pass of gadolinium contrast into the myocardium, using contrast within the ventricular cavity as a measure of input. The hypothesis of this sub-study is that aldosterone blockade with spironolactone will increase myocardial blood flow reserve compared to anti-hypertensive treatment with chlorthalidone on MBF estimation by first-pass CMR.
    E.3Principal inclusion criteria
    - Aged over 18 years
    - Diagnosis of stage 3 CKD (eGFR by 4 variable MDRD of 30-59 ml/min/1.73m2 on 2 occasions, at least 3 months apart)
    - Well controlled blood pressure (office reading of <150/90 mmHg, i.e. within 10 mmHg of the systolic level recommended in the Renal Association Clinical Practice Guideline, Fifth edition)
    4) On established (>6 weeks) treatment with ACE inhibitors or ARBs.
    5) Written informed consent.
    E.4Principal exclusion criteria
    - Diabetes mellitus
    - Clinical evidence of hypovolaemia
    - Recent (<6 months) acute myocardial infarction or other major adverse cardiovascular event
    - Established diagnosis of left ventricular dysfunction or heart failure
    - Active malignant disease with a life expectancy of <5 years
    - Previous hyperkalaemia (K+ ≥6.0 mmol/l without precipitating cause)
    - Serum K+ ≥5.0 mmol/l at entry
    - Serum sodium <132 mmol/l at entry
    - Atrial fibrillation on screening ECG
    - Use of a thiazide or loop diuretic in the 6 weeks prior to enrolment
    - Pregnancy
    - Known alcohol or drug abuse
    - Active chronic diarrhoeal illness
    - Recent active gout (within 3 months)
    - Episode of acute kidney injury within 3 months
    - Documented Addison’s disease
    - Current treatment with fludrocortisone or co-trimoxasole
    - Office blood pressure <115 mmHg systolic or <50 mmHg diastolic
    E.5 End points
    E.5.1Primary end point(s)
    a) Change in arterial stiffness measured by carotid-femoral pulse wave velocity

    b) Change in LV mass measured by cardiac magnetic resonance imaging
    E.5.1.1Timepoint(s) of evaluation of this end point
    a) At rand and at weeks 4, 24, 40 & 46 by SphygmoCor

    b) At rand and at week 40 by CMR
    E.5.2Secondary end point(s)
    a) Incidence of hyperkalaemia
    b) Change in blood pressure
    c) Change in urinary albumin:creatinine ratio
    d) Decline in renal function (requiring discontinuation from trial therapy)
    e) Symptomatic hypotension (requiring discontinuation from trial therapy)
    f) Incidence of side-effects (requiring discontinuation from trial therapy)
    g) Changes in left ventricular volumes and systolic function
    h) Changes in plasma NT-pro-BNP
    i) Changes in arterial stiffness measures including pulse wave velocity, augmentation index and central blood pressure (measured at 24 weeks)
    E.5.2.1Timepoint(s) of evaluation of this end point
    a)
    b) Measured at rand and at weeks 1, 2, 4, 8, 24, 40 & 46.
    c)
    d)
    e)
    f)
    g)
    h) Measured at rand and at weeks 4, 24, 40 & 16
    i)
    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 No
    E.6.5Efficacy No
    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 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) No
    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 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 Yes
    E.8.1.7.1Other trial design description
    PROBE design
    E.8.2 Comparator of controlled trial
    E.8.2.1Other medicinal product(s) Yes
    E.8.2.2Placebo No
    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 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 concerned4
    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 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 years3
    E.8.9.1In the Member State concerned months0
    E.8.9.1In the Member State concerned days1
    E.8.9.2In all countries concerned by the trial years3
    E.8.9.2In all countries concerned by the trial months0
    E.8.9.2In all countries concerned by the trial days1
    F. Population of Trial Subjects
    F.1 Age Range
    F.1.1Trial has subjects under 18 No
    F.1.1Number of subjects for this age range: 0
    F.1.1.1In Utero No
    F.1.1.1.1Number of subjects for this age range: 0
    F.1.1.2Preterm newborn infants (up to gestational age < 37 weeks) No
    F.1.1.2.1Number of subjects for this age range: 0
    F.1.1.3Newborns (0-27 days) No
    F.1.1.3.1Number of subjects for this age range: 0
    F.1.1.4Infants and toddlers (28 days-23 months) No
    F.1.1.4.1Number of subjects for this age range: 0
    F.1.1.5Children (2-11years) No
    F.1.1.5.1Number of subjects for this age range: 0
    F.1.1.6Adolescents (12-17 years) No
    F.1.1.6.1Number of subjects for this age range: 0
    F.1.2Adults (18-64 years) Yes
    F.1.2.1Number of subjects for this age range: 0
    F.1.3Elderly (>=65 years) Yes
    F.1.3.1Number of subjects for this age range: 0
    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 No
    F.3.3.1Women of childbearing potential not using contraception No
    F.3.3.2Women of child-bearing potential using contraception No
    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 state350
    F.4.2 For a multinational trial
    F.4.2.1In the EEA 350
    F.4.2.2In the whole clinical trial 350
    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. Without evidence of prognostic benefit, we do not feel it is justified to continue treatment with either spironolactone or chlortalidone after the research has finished.
    G. Investigator Networks to be involved in the Trial
    G.4 Investigator Network to be involved in the Trial: 1
    N. Review by the Competent Authority or Ethics Committee in the country concerned
    N.Competent Authority Decision Authorised
    N.Date of Competent Authority Decision2013-09-11
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion2013-09-09
    P. End of Trial
    P.End of Trial StatusCompleted
    P.Date of the global end of the trial2019-03-18
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