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    Summary
    EudraCT Number:2013-003798-82
    Sponsor's Protocol Code Number:R1578
    National Competent Authority:UK - MHRA
    Clinical Trial Type:EEA CTA
    Trial Status:GB - no longer in EU/EEA
    Date on which this record was first entered in the EudraCT database:2013-12-04
    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 number2013-003798-82
    A.3Full title of the trial
    Multi-centre Randomised Controlled Trial of Angiotensin Converting Enzyme inhibitor (ACEi) / Angiotensin Receptor Blocker (ARB) withdrawal in advanced renal disease;
    The STOP-ACEi Trial
    A.3.1Title of the trial for lay people, in easily understood, i.e. non-technical, language
    Multi-centre randomised controlled trial of Angiotensin Converting Enzyme inhibitor (ACEi) / Angiotensin Receptor Blocker (ARB) withdrawal in advanced renal disease
    A.3.2Name or abbreviated title of the trial where available
    STOP-ACEi
    A.4.1Sponsor's protocol code numberR1578
    A.5.1ISRCTN (International Standard Randomised Controlled Trial) NumberISRCTN62869767
    A.5.4Other Identifiers
    Name:REC ReferenceNumber:13/YH/0394
    Name:Funder referenceNumber:11/30/07
    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 SponsorHull & East Yorkshire Hospitals NHS Trust
    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 supportNIHR and MRC Efficacy and Mechanism Evaluation programme
    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 pointSTOP-ACEi Trial Manager
    B.5.3 Address:
    B.5.3.1Street AddressInstitute of Applied Health Research, Public Health Building, University of Birmingham
    B.5.3.2Town/ cityBirmingham
    B.5.3.3Post codeB15 2TT
    B.5.3.4CountryUnited Kingdom
    B.5.4Telephone number01214159133
    B.5.5Fax number01214159135
    B.5.6E-mailstopacei@trials.bham.ac.uk
    D. IMP Identification
    D.IMP: 1
    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 No
    D.2.1.1.1Trade name Candesartan
    D.2.1.1.2Name of the Marketing Authorisation holderActavis Group PTC ehf.
    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 nameAngiotensin Receptor Blocker (ARB)
    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 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 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 nameAngiotensin Converting Enzyme Inhibitors
    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
    E. General Information on the Trial
    E.1 Medical condition or disease under investigation
    E.1.1Medical condition(s) being investigated
    Progressive, advanced (stage 4 or 5) chronic kidney disease (CKD).

    NB. There was not an appropriate therapeutic area in the drop down menu in E1-1. Have selected 'Male diseases of the urinary and reproductive systems', but this trial is for a disease of the male and female urinary system.
    E.1.1.1Medical condition in easily understood language
    A progressive loss of kidney function from a variety of causes. Patients with stage 4 or 5 CKD have severely reduced kidney function, as measured by glomerular filtration rate (GFR).
    E.1.1.2Therapeutic area Diseases [C] - Male diseases of the urinary and reproductive systems [C12]
    MedDRA Classification
    E.1.2 Medical condition or disease under investigation
    E.1.2Version 20.0
    E.1.2Level PT
    E.1.2Classification code 10064848
    E.1.2Term Chronic kidney disease
    E.1.2System Organ Class 10038359 - Renal and urinary 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 test the hypothesis that stopping ACEi or ARB treatment or a combination of both, compared with continuing on these treatments, improves or stabilises renal function in patients with progressive stages 4 or 5 chronic kidney disease (CKD) based on assessment of renal function using the Modification of Diet in Renal Disease (MDRD) 4-variable estimated Glomerular Filtration Rate (eGFR) over 3 years follow-up.
    E.2.2Secondary objectives of the trial
    To test whether in each of the randomised groups:
    Clinical outcomes
    •Cystatin-C levels differ;
    •Blood pressure control is the same;
    •The number of participants starting renal replacement therapy or sustaining a >50% decline in eGFR differs;
    •There is a difference in the time taken to reach ESRD or need for renal replacement therapy;
    •Hospitalisation rates from any cause are different;
    •Participant quality of life and wellbeing (measured using the KDQOL-SF™ v1.3 questionnaire) differs;
    •Participant physical function (measured using the 6-minute walk test) differs;
    •That withdrawal of these treatments does not cause excess harm (e.g. increased cardiovascular events such as heart failure, hypertension, myocardial infarction, stroke) and is not associated with an increase in adverse effects;
    •Participant survival in each group is similar;

    Mechanistic Outcomes
    •There is a change in urine protein excretion;
    •Discontinuation of ACEi/ARB affects haemoglobin concentration;
    •Discontinuation of
    E.2.3Trial contains a sub-study Yes
    E.2.3.1Full title, date and version of each sub-study and their related objectives
    The MRC START in STOP-ACEi sub-study was introduced as part of Substantial Amendment 04. This sub-study focusses on access and use of the MRC START Multimedia Intervention (MMI), compared to the standard participant information sheet alone. Data from the sub-study will contribute to a programme of research funded by the MRC to expand the relatively small evidence base on an important issue concerning the recruitment of participants to trials. STOP-ACEi acts as a host trial to test the MMI recruitment intervention but the sub-study has no impact on the intervention, outcomes or analysis of STOP-ACEi itself.

    The main change is to the participant information that is posted out to potential participants.
    For the sub-study, potential participants will receive one of two versions:
    1. The original patient information sheet, or
    2. The original patient information sheet plus information on how to access the MRC START MMI via a website link or QR code.
    The content (i.e. the topics covered) remains the same in the two versions of the patient information sheet, with the only change being that in the second condition the covering letter and information sheet will include references to and the web address for the MRC START web pages.
    E.3Principal inclusion criteria
    •Aged ≥18 years (male or female);
    •CKD stages 4 or 5 (eGFR <30mls/minute using the MDRD equation)and not on dialysis therapy;
    •Progressive deterioration in renal function (fall in eGFR of >2ml/min/year over previous 12-24 months) as measured by linear regression analysis. A simple excel spread sheet for calculation of this will be provided to all sites. A minimum of 3 measurements of eGFR over the previous 12-24 months are required to identify a >2ml/min fall. Last eGFR must be within three months of randomisation.
    •Treatment with either an ACEi or ARB or a combination of both for >6 months with at least 25% of the maximum recommended daily dose on the day of consent;
    •Resting blood pressure (BP) ≤160/90 mmHg when measured in accordance with British Hypertension Society guidelines in clinic or recent home blood pressure readings within the previous month or a 24h ambulatory blood pressure measurement within in the last 3 months are acceptable.
    •At least 3 months of specialist renal follow-up at the time of entry into the trial;
    •Written, signed informed consent to the trial.
    E.4Principal exclusion criteria
    •Aged <18 years;
    •Uncontrolled hypertension (>160/90mmHg) or requirement for 5 or more agents to control BP;
    •Undergoing dialysis therapy;
    •Any condition which, in the opinion of the investigator, makes the participant unsuitable for trial entry due to prognosis/terminal illness with a projected survival of less than 12 months;
    •History of myocardial infarction or stroke in preceding 3 months;
    •Participation in an interventional research study in preceding 6 weeks;
    •Pregnancy, confirmed by positive pregnancy test or breastfeeding;
    •Inability to provide informed consent (e.g. due to cognitive impairment);
    •Immune mediated renal disease requiring disease specific treatment;
    •Known drug or alcohol abuse;
    •Inability to comply with the trial schedule and follow-up.
    E.5 End points
    E.5.1Primary end point(s)
    Renal function measured using MDRD 4-variable eGFR over 3 years.
    E.5.1.1Timepoint(s) of evaluation of this end point
    The primary outcome is the continuous measure eGFR at 3 years. These data will be summarised using means and standard deviations, with differences in means and 95% confidence intervals reported. The two groups will be compared at 3 years using a linear regression model with the baseline eGFR score and all the minimisation variables included in the model as covariates. Longitudinal plots of the data over time will also be constructed for visual presentation of the data. As a secondary analysis, a mixed effects repeated measures analysis, including a treatment by time cross-term, will be carried out on all data across the entire 3 years of follow-up.
    E.5.2Secondary end point(s)
    •Other laboratory measures of renal function including serum creatinine and cystatin C
    •Blood pressure
    •Renal events such as ESRD and the need to start renal replacement therapy (dialysis)
    •Time taken to reach ESRD or requirement for renal replacement therapy
    •Hospitalisation from any cause
    •Participant QOL (using the KDQOL-SF™ v1.3 questionnaire)
    •Physical function using the 6-minute walk test
    •Cardiovascular events such as stroke and myocardial infarction
    •Adverse events
    •All-cause mortality
    •Urine protein excretion (e.g. ACR or PCR)
    •Hb concentration
    •Dose of ESA
    E.5.2.1Timepoint(s) of evaluation of this end point
    Participants will be assessed every 3 months for 3 years and details relating to the secondary end points will be documented at each of these time points. Time-to-event measures will be evaluated as they occur.
    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 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 Yes
    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) 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 concerned39
    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
    The end of the STOP-ACEi trial will be defined as 6 months after the final participant recruited reaches the 3 year (final) follow-up time-point.
    E.8.9 Initial estimate of the duration of the trial
    E.8.9.1In the Member State concerned years7
    E.8.9.1In the Member State concerned months11
    E.8.9.1In the Member State concerned days1
    E.8.9.2In all countries concerned by the trial years7
    E.8.9.2In all countries concerned by the trial months10
    E.8.9.2In all countries concerned by the trial days31
    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: 226
    F.1.3Elderly (>=65 years) Yes
    F.1.3.1Number of subjects for this age range: 185
    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 state410
    F.4.2 For a multinational trial
    F.4.2.1In the EEA 410
    F.4.2.2In the whole clinical trial 410
    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. Treatment at the end of the trial will be wholly determined by the participant’s treating clinician. Since the study treatment is discontinuation of a treatment, there are no issues regarding access to trial treatment after the study ends.
    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 Decision2013-12-12
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion2014-01-29
    P. End of Trial
    P.End of Trial StatusGB - no longer in EU/EEA
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