<clinical_study>
  <!-- This xml conforms to an XML Schema at:
    https://clinicaltrials.gov/ct2/html/images/info/public.xsd -->
  <required_header>
    <download_date>ClinicalTrials.gov processed this data on September 20, 2023</download_date>
    <link_text>Link to the current ClinicalTrials.gov record.</link_text>
    <url>https://clinicaltrials.gov/ct2/show/NCT03776955</url>
  </required_header>
  <id_info>
    <org_study_id>125861</org_study_id>
    <nct_id>NCT03776955</nct_id>
  </id_info>
  <brief_title>Beta-blockers for Oesophageal Varices</brief_title>
  <acronym>BOPPP</acronym>
  <official_title>Beta-blockers or Placebo for Primary Prophylaxis of Oesophageal Varices (BOPPP Trial). A Blinded, Multi-centre, Clinical Effectiveness and Cost-effectiveness Randomised Controlled Trial</official_title>
  <sponsors>
    <lead_sponsor>
      <agency>King's College Hospital NHS Trust</agency>
      <agency_class>Other</agency_class>
    </lead_sponsor>
    <collaborator>
      <agency>King's College London</agency>
      <agency_class>Other</agency_class>
    </collaborator>
    <collaborator>
      <agency>Guy's and St Thomas' NHS Foundation Trust</agency>
      <agency_class>Other</agency_class>
    </collaborator>
    <collaborator>
      <agency>St George's University Hospitals NHS Foundation Trust</agency>
      <agency_class>Other</agency_class>
    </collaborator>
    <collaborator>
      <agency>Cardiff University</agency>
      <agency_class>Other</agency_class>
    </collaborator>
    <collaborator>
      <agency>Brighton and Sussex University Hospitals NHS Trust</agency>
      <agency_class>Other</agency_class>
    </collaborator>
  </sponsors>
  <source>King's College Hospital NHS Trust</source>
  <oversight_info>
    <has_dmc>Yes</has_dmc>
    <is_fda_regulated_drug>No</is_fda_regulated_drug>
    <is_fda_regulated_device>No</is_fda_regulated_device>
  </oversight_info>
  <brief_summary>
    <textblock>
      To determine if carvedilol reduces the rate of variceal haemorrhage in patients with&#xD;
      cirrhosis and small oesophageal varices&#xD;
    </textblock>
  </brief_summary>
  <detailed_description>
    <textblock>
      Cirrhosis or liver scarring is an important problem in healthcare in the United Kingdom.&#xD;
      60,000 patients are living with this disease and about 11,000 people every year will die&#xD;
      because of it. There are several ways in which patients with this severe form of liver&#xD;
      disease become unwell or die and bleeding from the oesophagus or stomach is one. Cirrhosis&#xD;
      causes pressure changes inside the abdomen and swelling of veins in the oesophagus (called&#xD;
      &quot;varices&quot;) which can bleed catastrophically.&#xD;
&#xD;
      The investigators know that when varices are large, treatment can be initiated with&#xD;
      medication called beta-blockers to reduce the pressure in the varices. If the varices are&#xD;
      small, the medical community is not sure if treatment with beta-blockers will work. This&#xD;
      study aims to address this uncertainty.&#xD;
&#xD;
      Patients who are recruited to the study with small varices will be randomised to either&#xD;
      beta-blockers or a placebo. Research sites will observe patients closely for 3 years for&#xD;
      bleeding from their varices or other complications of cirrhosis or side effects of taking&#xD;
      medication. This is the amount of time needed to observe for bleeding when the varices are&#xD;
      small. Research sites will review the patients every 6 months including assessing the varices&#xD;
      by a camera test called an endoscopy at the beginning and each year until the study is&#xD;
      finished.&#xD;
&#xD;
      During the study, patients will be involved with the conduct and management of the research.&#xD;
      Patient will also be notified on the trial results at the end of the study. The barriers and&#xD;
      facilitators in adjusting the dose of the tablets to optimise treatment effects primary care&#xD;
      will be along with patients' views on taking part in the trial, and whether the side effects&#xD;
      justify the potential benefits of reducing the risk of bleeding. The investigators estimate&#xD;
      this risk could be reduced from 20% of patients having significant bleeding to 10% over 3&#xD;
      years.&#xD;
&#xD;
      The investigators will measure the impact of beta-blockers on the overall costs to the&#xD;
      National Health Service (NHS) of caring for people with cirrhosis during the trial, and will&#xD;
      also assess the impact of treatment on both mortality and quality of life using a combined&#xD;
      measure, the Quality Adjusted Life-Year (QALY). The investigators will use a mathematical&#xD;
      prediction model to estimate the impact of treatment on costs, mortality and quality of life&#xD;
      over a patient's lifetime and will assess whether any increased costs are justified by better&#xD;
      outcomes for patients and represent good value for money for the NHS budget.&#xD;
&#xD;
      Finally, the results of the study will be published in the medical literature and discuss the&#xD;
      findings at medical conferences, patient groups and with charities involved in helping&#xD;
      patients with cirrhosis such as the British Liver Trust.&#xD;
    </textblock>
  </detailed_description>
  <overall_status>Recruiting</overall_status>
  <start_date type="Actual">June 17, 2019</start_date>
  <completion_date type="Anticipated">December 2024</completion_date>
  <primary_completion_date type="Anticipated">September 2024</primary_completion_date>
  <phase>Phase 4</phase>
  <study_type>Interventional</study_type>
  <has_expanded_access>No</has_expanded_access>
  <study_design_info>
    <allocation>Randomized</allocation>
    <intervention_model>Parallel Assignment</intervention_model>
    <primary_purpose>Prevention</primary_purpose>
    <masking>Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)</masking>
    <masking_description>Placebo matched control</masking_description>
  </study_design_info>
  <primary_outcome>
    <measure>Variceal bleeding</measure>
    <time_frame>3 years</time_frame>
    <description>Time to first variceal haemorrhage</description>
  </primary_outcome>
  <primary_outcome>
    <measure>Health Economic assessment</measure>
    <time_frame>3 years</time_frame>
    <description>Assess the cost effectiveness of early intervention with non specific beta blockers in this patient population.</description>
  </primary_outcome>
  <secondary_outcome>
    <measure>Variceal bleed rate</measure>
    <time_frame>1 and 3 years</time_frame>
    <description>Number of variceal bleeds by allocation</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Variceal bleeding needing intervention</measure>
    <time_frame>3 years</time_frame>
    <description>Number of patients that progress to medium/large varices requiring clinical intervention</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Composite of variceal bleed rate and bleeding needing intervention</measure>
    <time_frame>3 years</time_frame>
    <description>Composite of variceal bleed rate and bleeding needing intervention. i.e. Unit less measure of rate of ((Number of patients who bled) PLUS (Number of patients who progressed without bleeding)) / (Number of patients in that arm at randomisation) at 3 years ranging from 0 to 1</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Clinical decompensation</measure>
    <time_frame>3 years</time_frame>
    <description>Number of patients with clinical decompensation (spontaneous bacterial peritonitis, new ascites, new hepatic encephalopathy) in the active and inactive IMP groups</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Child Pugh Score for Cirrhosis mortality</measure>
    <time_frame>3 years</time_frame>
    <description>Child Pugh Score for Cirrhosis mortalityin the active and inactive IMP groups. Range 5-15. Higher scores represent worse outcomes.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Model for end-stage liver disease (MELD) score</measure>
    <time_frame>3 years</time_frame>
    <description>MELD score in the active and inactive IMP groups.Range 6-40. Higher scores represent worse outcomes.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Survival (Overall, liver related, cardio-vascular related)</measure>
    <time_frame>3 years</time_frame>
    <description>Survival (Overall, liver related, cardio-vascular related)</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Quality of life assessment</measure>
    <time_frame>3 years</time_frame>
    <description>Quality of life score using EQ5D-5L in the active and inactive IMP groups. Range 5-25. Higher scores represent worse outcomes.</description>
  </secondary_outcome>
  <number_of_arms>2</number_of_arms>
  <enrollment type="Anticipated">1200</enrollment>
  <condition>Cirrhoses, Liver</condition>
  <condition>Oesophageal Varices</condition>
  <arm_group>
    <arm_group_label>Oral Carvedilol</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>6.25 mg or 12.5 mg if tolerated</description>
  </arm_group>
  <arm_group>
    <arm_group_label>Oral Placebo</arm_group_label>
    <arm_group_type>Placebo Comparator</arm_group_type>
  </arm_group>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Carvedilol</intervention_name>
    <description>Oral tablet</description>
    <arm_group_label>Oral Carvedilol</arm_group_label>
    <arm_group_label>Oral Placebo</arm_group_label>
  </intervention>
  <eligibility>
    <criteria>
      <textblock>
        Inclusion Criteria:&#xD;
&#xD;
          1. Age &gt;18 years&#xD;
&#xD;
          2. Cirrhosis and portal hypertension, defined by any 2 of the following:&#xD;
&#xD;
             A) Characteristic clinical examination findings; one or more of i) liver function&#xD;
             tests ii) haematological panel iii) coagulation profile abnormalities B)&#xD;
             Characteristic radiological findings; one or more of i) heterogeneous, small liver&#xD;
             with irregular contour ii) splenomegaly iii) ascites iv) varices v) recanalized&#xD;
             umbilical vein C) Fibrosis score &gt; stage 4 on liver biopsy D) FibroScan liver&#xD;
             stiffness measurement &gt;15 kilo Pascal without other explanation&#xD;
&#xD;
          3. Small oesophageal varices diagnosed within the last 3 months,- defined as &lt;5 mm in&#xD;
             diameter or varices which completely disappear on moderate insufflation at&#xD;
             gastroscopy.&#xD;
&#xD;
          4. Not received a beta-blocker in the last week&#xD;
&#xD;
          5. Capacity to provide informed consent&#xD;
&#xD;
        Exclusion Criteria:&#xD;
&#xD;
          1. Non-cirrhotic portal hypertension&#xD;
&#xD;
          2. Medium/large oesophageal varices (current or history of), defined as &gt;5 mm in diameter&#xD;
&#xD;
          3. Isolated gastric, duodenal, rectal varices with or without evidence of recent bleeding&#xD;
&#xD;
          4. Previous variceal haemorrhage&#xD;
&#xD;
          5. Red signs accompanying varices at endoscopy&#xD;
&#xD;
          6. Known intolerance to beta blockers&#xD;
&#xD;
          7. Contraindication to beta blocker use i) Heart rate &lt;50 bpm ii) Known 2nd degree or&#xD;
             higher heart block iii) Sick sinus syndrome iv) Systolic blood pressure &lt;85 mm Hg v)&#xD;
             Chronic airways obstruction (asthma/COPD) vi) Floppy Iris Syndrome vii) CYP2D6 Poor&#xD;
             Metaboliser viii) History of cardiogenic shock ix) History of severe hypersensitivity&#xD;
             reaction to beta-blockers x) Untreated phaeochromocytoma xi) Severe peripheral&#xD;
             vascular disease xii) Prinzmetal angina xiii) New York Heart Association IV heart&#xD;
             failure&#xD;
&#xD;
          8. Unable to provide informed consent&#xD;
&#xD;
          9. Child Pugh C cirrhosis&#xD;
&#xD;
         10. Already receiving a beta-blocker for another reason that cannot be discontinued&#xD;
&#xD;
         11. Graft cirrhosis post liver transplantation&#xD;
&#xD;
         12. Evidence of active malignancy without curative therapy planned&#xD;
&#xD;
         13. Pregnant or lactating women&#xD;
&#xD;
         14. Women of child bearing potential not willing to use adequate contraception during the&#xD;
             protocol of IMP dosing&#xD;
&#xD;
         15. Patients who have been on a CTIMP within the previous 3 months&#xD;
      </textblock>
    </criteria>
    <gender>All</gender>
    <minimum_age>18 Years</minimum_age>
    <maximum_age>N/A</maximum_age>
    <healthy_volunteers>No</healthy_volunteers>
  </eligibility>
  <overall_official>
    <last_name>Mark McPhail, BSc, PhD, MB ChB</last_name>
    <role>Study Director</role>
    <affiliation>King's College Hospital NHS Trust</affiliation>
  </overall_official>
  <overall_official>
    <last_name>Ben Carter, BSc, PhD</last_name>
    <role>Study Director</role>
    <affiliation>King's College London</affiliation>
  </overall_official>
  <overall_contact>
    <last_name>Vishal Patel, BSc, MBBS, MRCP, MPhil</last_name>
    <phone>+44 (0)20 3299 3654</phone>
    <email>vishal.patel@nhs.net</email>
  </overall_contact>
  <overall_contact_backup>
    <last_name>Kieran Brack, BSc, PhD</last_name>
    <phone>+44 (0)20 3299 7142</phone>
    <email>kch-tr.boppptrial@nhs.net</email>
  </overall_contact_backup>
  <location>
    <facility>
      <name>Royal Victoria Hospital</name>
      <address>
        <city>Belfast</city>
        <state>Northern Ireland</state>
        <zip>BT12 6BA</zip>
        <country>United Kingdom</country>
      </address>
    </facility>
    <status>Not yet recruiting</status>
    <contact>
      <last_name>Angela Toner</last_name>
      <phone>028 90633197</phone>
      <email>angela.toner@belfasttrust.hscni.net</email>
    </contact>
    <investigator>
      <last_name>Roger McCorry, MB BCh BAO, MRCP</last_name>
      <role>Principal Investigator</role>
    </investigator>
  </location>
  <location>
    <facility>
      <name>Queen Elizabeth Hospital</name>
      <address>
        <city>Birmingham</city>
        <zip>B15 2TT</zip>
        <country>United Kingdom</country>
      </address>
    </facility>
    <status>Not yet recruiting</status>
    <contact>
      <last_name>Emma Burke</last_name>
      <phone>0121 3718451</phone>
      <email>Emma.Burke@uhb.nhs.uk</email>
    </contact>
    <contact_backup>
      <phone>07770 827573</phone>
    </contact_backup>
    <investigator>
      <last_name>Dhiraj Tripathi, MBChB, MD</last_name>
      <role>Principal Investigator</role>
    </investigator>
  </location>
  <location>
    <facility>
      <name>Royal London Hospital (Barts)</name>
      <address>
        <city>London</city>
        <zip>E1 1FR</zip>
        <country>United Kingdom</country>
      </address>
    </facility>
    <status>Not yet recruiting</status>
    <contact>
      <last_name>James Hand</last_name>
      <phone>020 3594 6773</phone>
      <email>James.Hand@nhs.net</email>
    </contact>
    <investigator>
      <last_name>Vikram Sharma, MBBS, MRCP, PhD, FRCP</last_name>
      <role>Principal Investigator</role>
    </investigator>
  </location>
  <location>
    <facility>
      <name>King's College Hosptial NHS Foundation Trust (Denmark Hill)</name>
      <address>
        <city>London</city>
        <country>United Kingdom</country>
      </address>
    </facility>
    <status>Recruiting</status>
    <contact>
      <last_name>Ruhuma Uddin, BSc</last_name>
      <phone>020 3299 7142</phone>
      <email>kch-tr.boppptrial@hs.uk</email>
    </contact>
    <investigator>
      <last_name>Mark McPhail</last_name>
      <role>Principal Investigator</role>
    </investigator>
  </location>
  <location_countries>
    <country>United Kingdom</country>
  </location_countries>
  <verification_date>October 2019</verification_date>
  <study_first_submitted>November 30, 2018</study_first_submitted>
  <study_first_submitted_qc>December 13, 2018</study_first_submitted_qc>
  <study_first_posted type="Actual">December 17, 2018</study_first_posted>
  <last_update_submitted>October 1, 2019</last_update_submitted>
  <last_update_submitted_qc>October 1, 2019</last_update_submitted_qc>
  <last_update_posted type="Actual">October 3, 2019</last_update_posted>
  <responsible_party>
    <responsible_party_type>Sponsor</responsible_party_type>
  </responsible_party>
  <condition_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Liver Cirrhosis</mesh_term>
    <mesh_term>Esophageal and Gastric Varices</mesh_term>
    <mesh_term>Varicose Veins</mesh_term>
  </condition_browse>
  <intervention_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Carvedilol</mesh_term>
  </intervention_browse>
  <patient_data>
    <sharing_ipd>Undecided</sharing_ipd>
    <ipd_description>To be decided</ipd_description>
  </patient_data>
  <!-- Results have not yet been posted for this study                                          -->
</clinical_study>


download date: ClinicalTrials.gov processed this data on September 20, 2023
link text: Link to the current ClinicalTrials.gov record.
url: https://clinicaltrials.gov/ct2/show/NCT03776955
org study id: 125861
nct id: NCT03776955
lead sponsor: 
collaborator: 
collaborator: 
collaborator: 
collaborator: 
collaborator: 
has dmc: Yes
is fda regulated drug: No
is fda regulated device: No
To determine if carvedilol reduces the rate of variceal haemorrhage in patients with
      cirrhosis and small oesophageal varices
Cirrhosis or liver scarring is an important problem in healthcare in the United Kingdom.
      60,000 patients are living with this disease and about 11,000 people every year will die
      because of it. There are several ways in which patients with this severe form of liver
      disease become unwell or die and bleeding from the oesophagus or stomach is one. Cirrhosis
      causes pressure changes inside the abdomen and swelling of veins in the oesophagus (called
      "varices") which can bleed catastrophically.

      The investigators know that when varices are large, treatment can be initiated with
      medication called beta-blockers to reduce the pressure in the varices. If the varices are
      small, the medical community is not sure if treatment with beta-blockers will work. This
      study aims to address this uncertainty.

      Patients who are recruited to the study with small varices will be randomised to either
      beta-blockers or a placebo. Research sites will observe patients closely for 3 years for
      bleeding from their varices or other complications of cirrhosis or side effects of taking
      medication. This is the amount of time needed to observe for bleeding when the varices are
      small. Research sites will review the patients every 6 months including assessing the varices
      by a camera test called an endoscopy at the beginning and each year until the study is
      finished.

      During the study, patients will be involved with the conduct and management of the research.
      Patient will also be notified on the trial results at the end of the study. The barriers and
      facilitators in adjusting the dose of the tablets to optimise treatment effects primary care
      will be along with patients' views on taking part in the trial, and whether the side effects
      justify the potential benefits of reducing the risk of bleeding. The investigators estimate
      this risk could be reduced from 20% of patients having significant bleeding to 10% over 3
      years.

      The investigators will measure the impact of beta-blockers on the overall costs to the
      National Health Service (NHS) of caring for people with cirrhosis during the trial, and will
      also assess the impact of treatment on both mortality and quality of life using a combined
      measure, the Quality Adjusted Life-Year (QALY). The investigators will use a mathematical
      prediction model to estimate the impact of treatment on costs, mortality and quality of life
      over a patient's lifetime and will assess whether any increased costs are justified by better
      outcomes for patients and represent good value for money for the NHS budget.

      Finally, the results of the study will be published in the medical literature and discuss the
      findings at medical conferences, patient groups and with charities involved in helping
      patients with cirrhosis such as the British Liver Trust.
allocation: Randomized
intervention model: Parallel Assignment
primary purpose: Prevention
masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
masking description: Placebo matched control
measure: Variceal bleeding
time frame: 3 years
description: Time to first variceal haemorrhage
measure: Health Economic assessment
time frame: 3 years
description: Assess the cost effectiveness of early intervention with non specific beta blockers in this patient population.
measure: Variceal bleed rate
time frame: 1 and 3 years
description: Number of variceal bleeds by allocation
measure: Variceal bleeding needing intervention
time frame: 3 years
description: Number of patients that progress to medium/large varices requiring clinical intervention
measure: Composite of variceal bleed rate and bleeding needing intervention
time frame: 3 years
description: Composite of variceal bleed rate and bleeding needing intervention. i.e. Unit less measure of rate of ((Number of patients who bled) PLUS (Number of patients who progressed without bleeding)) / (Number of patients in that arm at randomisation) at 3 years ranging from 0 to 1
measure: Clinical decompensation
time frame: 3 years
description: Number of patients with clinical decompensation (spontaneous bacterial peritonitis, new ascites, new hepatic encephalopathy) in the active and inactive IMP groups
measure: Child Pugh Score for Cirrhosis mortality
time frame: 3 years
description: Child Pugh Score for Cirrhosis mortalityin the active and inactive IMP groups. Range 5-15. Higher scores represent worse outcomes.
measure: Model for end-stage liver disease (MELD) score
time frame: 3 years
description: MELD score in the active and inactive IMP groups.Range 6-40. Higher scores represent worse outcomes.
measure: Survival (Overall, liver related, cardio-vascular related)
time frame: 3 years
description: Survival (Overall, liver related, cardio-vascular related)
measure: Quality of life assessment
time frame: 3 years
description: Quality of life score using EQ5D-5L in the active and inactive IMP groups. Range 5-25. Higher scores represent worse outcomes.
arm group label: Oral Carvedilol
arm group type: Experimental
description: 6.25 mg or 12.5 mg if tolerated
arm group label: Oral Placebo
arm group type: Placebo Comparator
intervention type: Drug
intervention name: Carvedilol
description: Oral tablet
arm group label: Oral Carvedilol
arm group label: Oral Placebo
criteria: 
gender: All
minimum age: 18 Years
maximum age: N/A
healthy volunteers: No
last name: Mark McPhail, BSc, PhD, MB ChB
role: Study Director
affiliation: King's College Hospital NHS Trust
last name: Ben Carter, BSc, PhD
role: Study Director
affiliation: King's College London
last name: Vishal Patel, BSc, MBBS, MRCP, MPhil
phone: +44 (0)20 3299 3654
email: vishal.patel@nhs.net
last name: Kieran Brack, BSc, PhD
phone: +44 (0)20 3299 7142
email: kch-tr.boppptrial@nhs.net
facility: 
status: Not yet recruiting
contact: 
investigator: 
facility: 
status: Not yet recruiting
contact: 
contact backup: 
investigator: 
facility: 
status: Not yet recruiting
contact: 
investigator: 
facility: 
status: Recruiting
contact: 
investigator: 
country: United Kingdom
responsible party type: Sponsor
mesh term: Liver Cirrhosis
mesh term: Esophageal and Gastric Varices
mesh term: Varicose Veins
mesh term: Carvedilol
sharing ipd: Undecided
ipd description: To be decided