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    Summary
    EudraCT Number:2018-002509-78
    Sponsor's Protocol Code Number:BOPPP
    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:2019-01-24
    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 ConcernedUK - MHRA
    A.2EudraCT number2018-002509-78
    A.3Full title of the trial
    Beta-blockers Or Placebo for Primary Prophylaxis of oesophageal varices (BOPPP Trial). A blinded, UK multi-centre, clinical effectiveness and cost-effectiveness randomised controlled trial.
    A.3.1Title of the trial for lay people, in easily understood, i.e. non-technical, language
    Comparing Carvedilol versus Placebo on the rate of variceal haemorrhage in patients with cirrhosis of the liver and small oesophageal varices
    A.3.2Name or abbreviated title of the trial where available
    Beta-blockers or placebo for primary prophylaxis (BOPPP) of oesophageal varices trial.
    A.4.1Sponsor's protocol code numberBOPPP
    A.5.1ISRCTN (International Standard Randomised Controlled Trial) NumberISRCTN10324656
    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 SponsorKings College Hospital NHS Foundation 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 supportNational Institute for Health Research Health Technology Assessment Board
    B.4.2CountryUnited Kingdom
    B.5 Contact point designated by the sponsor for further information on the trial
    B.5.1Name of organisationKings College Hospital NHS Foundation Trust
    B.5.2Functional name of contact pointDr Vishal Patel
    B.5.3 Address:
    B.5.3.1Street AddressInstitute of Liver Studies, Denmark Hill
    B.5.3.2Town/ cityLondon
    B.5.3.3Post codeSE5 9RS
    B.5.3.4CountryUnited Kingdom
    B.5.4Telephone number+44020 3299 3713
    B.5.5Fax number+440203299 3014
    B.5.6E-mailvishal.patel@nhs.net
    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 Carvedilol EG 6.25mg tablets
    D.2.1.1.2Name of the Marketing Authorisation holderEG (Eurogenerics) SA
    D.2.1.2Country which granted the Marketing AuthorisationBelgium
    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 nameCarvedilol EG 6.25mg tablets
    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
    Liver cirrhosis with small oesophageal varices
    E.1.1.1Medical condition in easily understood language
    Liver disease with scarring of the liver tissue; and swelling of the veins within the gullet due to raised blood pressure of the main blood vessels carrying blood to the liver.
    E.1.1.2Therapeutic area Body processes [G] - Digestive System and Oral Physiological Phenomena [G10]
    MedDRA Classification
    E.1.2 Medical condition or disease under investigation
    E.1.2Version 20.0
    E.1.2Level LLT
    E.1.2Classification code 10024667
    E.1.2Term Liver cirrhosis
    E.1.2System Organ Class 100000004871
    E.1.2 Medical condition or disease under investigation
    E.1.2Version 21.1
    E.1.2Level LLT
    E.1.2Classification code 10055489
    E.1.2Term Esophageal varices in cirrhosis of liver
    E.1.2System Organ Class 100000004856
    E.1.3Condition being studied is a rare disease No
    E.2 Objective of the trial
    E.2.1Main objective of the trial
    1.To determine the clinical effectiveness of the reduction in variceal haemorrhage in patients treated with carvedilol versus placebo at 3 years.
    2.To determine the cost-effectiveness of Carvedilol in patients with small oesophageal varices.
    E.2.2Secondary objectives of the trial
    1.At 1-year after participant recruitment opens, to assess feasibility of: recruitment, retention acceptability, with progression criteria outlined in internal pilot 1.
    2.At 2.5-years, to estimate the control arm 1-year variceal bleed rate, with progression criteria outlined in internal pilot 2.
    3.To determine additional clinical benefits of Carvedilol versus placebo for: reduction of variceal size progression, need to initiate endoscopic management of varices (endoscopic band ligation (EBL)), deterioration in liver function (assessed by MELD score and Child-Pugh grade) and all-cause mortality.
    4.To investigate how this is best delivered in primary care, by general practice, using qualitative approaches and GP interviews to examine barriers and enablers to implementation.
    E.2.3Trial contains a sub-study Yes
    E.2.3.1Full title, date and version of each sub-study and their related objectives
    Mechanism of beta-blockade on bacterial translocation in portal hypertension (MBOP) study.
    Version 1, 22Nov2019
    Primary Objective: To characterise bacterial translocation and the microbial-immuno-metabolic response in patients with cirrhosis and small varices receiving carvedilol or placebo with the aim of demonstrating a reduction in bacterial translocation and inflammatory response due to carvedilol resulting in reduced all cause decompensation.
    E.3Principal inclusion criteria
    o Age 18 years and over

    o Cirrhosis and portal hypertension, defined by any 2 of the following:
    1) Characteristic clinical examination findings; one or more of:
    Characteristic liver function tests
    •Haematological panel
    •Coagulation profile abnormalities
    2)Characteristic radiological findings; one or more of
    •Heterogeneous liver with irregular contour
    •splenomegaly
    •ascites
    •varices
    •recanalized umbilical vein
    3) FibroScan liver stiffness measurement >15 kPa without other explanation
    4) Fibrosis score > stage 4 on liver biopsy (presence of a relevant fibrosis score by biopsy does not require additional clinical examination / radiological / FibroScan supporting evidence)

    oSmall oesophageal varices diagnosed within the last 6 months, defined as ≤5 mm in diameter or varices which completely disappear on moderate insufflation at gastroscopy.

    oNot received a beta-blocker in the last week

    oCapacity to provide informed consent
    E.4Principal exclusion criteria
    o Non-cirrhotic portal hypertension
    o Medium/large oesophageal varices (current or history [decreasing in size without curative therapy), defined as >5 mm in diameter
    o Gastric (IGV and GOV2), duodenal, rectal varices with or without evidence of recent bleeding. For gastric varices, this includes:
     IGV-1 and IGV-2 (isolated gastric varices)
     GOV2 (gastric varices continuing into the cardia)
     Note GOV1 (gastric varices continuing into the lesser curve) are not an exclusion if present with small oesophageal varices
    o Previous variceal haemorrhage
    o Previous band ligation or glue injection of oesophageal and/or gastric varices
    o Red signs accompanying varices at endoscopy
    o Known intolerance to beta blockers
    o Contraindications to beta blocker use:
    • Heart rate <50 bpm
    • Known 2nd degree or higher heart block
    • Sick sinus syndrome
    • Systolic blood pressure <85 mmHg
    • Chronic airways obstruction (asthma/COPD)
    • Floppy Iris Syndrome
    • CYP2D6 Poor Metaboliser
    • History of cardiogenic shock
    • History of severe hypersensitivity reaction to beta-blockers
    • Untreated phaeochromocytoma
    • Severe peripheral vascular disease
    • Prinzmetal angina
    • NYHA IV heart failure
    o Unable to provide informed consent
    o Child Pugh C cirrhosis
    o Already receiving a beta-blocker for another reason that cannot be discontinued
    o Graft cirrhosis post liver transplantation
    o Evidence of active malignancy without curative therapy planned
    o Pregnant or lactating women
    o Women of child bearing potential not willing to use adequate contraception during the period of IMP dosing (1 week washout period)
    o Patients who have been on a CTIMP within the previous 3 months
    E.5 End points
    E.5.1Primary end point(s)
    1. Time to first variceal haemorrhage (as defined by Baveno IV criteria).
    2. Cost-utility of NSBB over trial follow-up to 3 years.
    E.5.1.1Timepoint(s) of evaluation of this end point
    Baseline to 3 years
    E.5.2Secondary end point(s)
    1. Estimation of the 1, and 3-year oesophogeal variceal bleed rate by allocation, and associated number needed to treat.
    2. Progression to oesophageal medium/large varices at gastroscopy requiring clinical intervention.
    3. Development of gastric, duodenal or ectopic varices
    4. Composite of oesophageal progression in variceal size and bleeding as per 1 and 2 by 3 years.
    5. Progression of gastric, duodenal or ectopic varices
    6. Survival (Overall, liver-related, cardiovascular-related).
    7. Quality of life, EQ-5D-5L.
    8. Decompensation as evidenced by one or more of the following:
    • Spontaneous bacterial peritonitis (ascitic fluid cell PMN cell count >250/mm3).
    • New hepatic encephalopathy (Defined by West-Haven Grade >1 (overt HE)).
    • New or worsening ascites defined by clinical examination or ultrasound.
    9. Progression in Child Pugh grade.
    10. Progression in MELD score.
    E.5.2.1Timepoint(s) of evaluation of this end point
    Baseline to 3 years unless explicitely stated above
    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 No
    E.6.4Safety No
    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) No
    E.7.4Therapeutic use (Phase IV) Yes
    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 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
    Triple blind (participant, investigator, analyst)
    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 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
    Database lock
    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 months9
    E.8.9.1In the Member State concerned days
    E.8.9.2In all countries concerned by the trial years5
    E.8.9.2In all countries concerned by the trial months9
    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: 1200
    F.1.3Elderly (>=65 years) Yes
    F.1.3.1Number of subjects for this age range: 1200
    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 state1200
    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)
    Patient will continue with standard of care procedures and monitoring once the study has been completed.
    G. Investigator Networks to be involved in the Trial
    G.4 Investigator Network to be involved in the Trial: 1
    G.4.1Name of Organisation South London Clinical Research Network
    G.4.3.4Network Country United Kingdom
    N. Review by the Competent Authority or Ethics Committee in the country concerned
    N.Competent Authority Decision Authorised
    N.Date of Competent Authority Decision2019-04-23
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion2019-04-24
    P. End of Trial
    P.End of Trial StatusGB - no longer in EU/EEA
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