Beta-blockers or placebo for primary prophylaxis of oesophageal varices trial
| ISRCTN | ISRCTN10324656 |
|---|---|
| DOI | https://doi.org/10.1186/ISRCTN10324656 |
| EudraCT/CTIS number | 2018-002509-78 |
| ClinicalTrials.gov number | NCT03776955 |
| Secondary identifying numbers | HTA 17/32/04; 1.0 |
- Submission date
- 02/11/2018
- Registration date
- 04/12/2018
- Last edited
- 29/08/2024
- Recruitment status
- No longer recruiting
- Overall study status
- Ongoing
- Condition category
- Circulatory System
Plain English Summary
Background and study aims
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. When varices are large they need to be treated with medication called beta-blockers to reduce the pressure in the varices. If the varices are small, it is not certain if they need to be treated with beta-blockers and this study aims to address this uncertainty.
Who can participate?
Patients aged over 18 with cirrhosis and small varices without evidence of previous bleeding
What does the study involve?
Patients are randomly allocated to be treated with either beta-blockers or a placebo (dummy drug). They are observed 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. The patients are reviewed 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. The study also assesses the barriers and facilitators of doctors in primary care (such as General Practitioners) in adjusting the dose of the tablets to improve treatment effects, and assesses patients’ views on taking part in the study, and whether the side effects justify the potential benefits of reducing the risk of bleeding. The impact of beta-blockers on the overall costs to the NHS of caring for people with cirrhosis during the study is measured. The impact of treatment on costs, mortality and quality of life over a patient’s lifetime is estimated, to assess whether any increased costs are justified by better outcomes for patients and represent good value for money for the NHS budget.
What are the possible benefits and risks of participating?
When the study is complete, the results could help advance the use of beta blockers in patients with damaged livers and small oesophageal varices. This would mean that beta-blocker use could be extended to a wider patient population to which there is currently no agreed treatment available. At a patient level, should the patient be allocated to the beta blocker, there is the potential that worsening of varices and progression to variceal bleeding may be prevented or slowed down. This study is relatively non-invasive and uses a well-established drug, therefore few potential risks are foreseen. All tests, apart from a quality of life questionnaire, are standard of care procedures so the usual precautions and standard clinical protocols will be followed. Endoscopies/gastroscopies will be performed by experienced clinicians as standard of care practice following established guidelines. The participants will not know which treatment they are receiving but procedures are in place to reveal this if there are concerning side effects. The researchers do not foresee any reason for the study procedures to cause harm or distress. Should there be any concern or sign of distress being caused due to study involvement, reasons for this will be explored, and referrals to appropriate services made. The study is being carried out in experienced specialist clinical departments with teams that are experienced in research.
Where is the study run from?
King's College Hospital (UK)
When is the study starting and how long is it expected to run for?
September 2018 to December 2026
Who is funding the study?
NIHR Health Technology Assessment Programme (UK)
Who is the main contact?
Dr Vishal Patel
Contact information
Public
Institute of Liver Studies
King’s College Hospital NHS Foundation Trust
Denmark Hill
London
SE5 9RS
United Kingdom
 ORCID ID |
0000-0001-6616-3628 |
|---|---|
| Phone | +44 (0)2032999000 |
| kch-tr.boppptrial@nhs.net |
Study information
| Study design | Multicentre blinded (participant, clinician and analyst) randomized controlled trial |
|---|---|
| Primary study design | Interventional |
| Secondary study design | Randomised controlled trial |
| Study setting(s) | Hospital |
| Study type | Treatment |
| Participant information sheet | Not available in web format, please use contact details to request a participant information sheet |
| Scientific title | Beta-blockers Or Placebo for Primary Prophylaxis of oesophageal varices (BOPPP): a blinded, multi-centre, clinical effectiveness and cost-effectiveness randomised controlled trial |
| Study acronym | BOPPP |
| Study hypothesis | Treating patients with small varices with NSBB for primary prophylaxis of variceal bleeding is clinically and cost-effective. |
| Ethics approval(s) | Approved 20/03/2019, NHS HRA Yorkshire and the Humber – Leeds West (NHSBT Newcastle Blood Donor Centre, Holland Drive, Newcastle upon Tyne, NE2 4NQ; 0207 104 8018; nrescommittee.yorkandhumber-leedswest@nhs.net), ref: 19/YH/0015. |
| Condition | Participants with cirrhosis and small varices without evidence of previous bleeding |
| Intervention | Oral carvedilol 6.25 mg to 12.5 mg once daily vs oral placebo 1 to 2 tablets once daily Patients who are recruited to the study with small varices will be randomised to either beta-blockers (carvedilol) or a placebo. The randomisation sequence will be generated in an ongoing manner using varying permuted blocks of size 4 to 12, within each site in a 1:1 ratio (Carvedilol: Placebo). Participants will be observed 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. The trialists will review the patients every 6 months including assessing the varices by a camera test called an endoscopy at the beginning and of each year until the study is finished. During the study patients will be involved with the conduct and management of the research, and the trialists will feedback to recruited patients the results at the end. They will assess the barriers and facilitators of doctors in primary care - such as General Practitioners - in adjusting the dose of the tablets to optimise treatment effects, and assess patients’ views on taking part in the trial, and whether the side effects justify the potential benefits of reducing the risk of bleeding. It is estimated that this risk could be reduced from 20% of patients having significant bleeding to 10% over 3 years. The trialists will measure the impact of beta-blockers on the overall costs to the NHS of caring for people with cirrhosis during the trial. They will then assess the impact of treatment on both mortality and quality of life using a combined measure, the Quality Adjusted Life-Year (QALY). They will use a mathematical prediction model to estimate the impact of treatment on costs, mortality and quality of life over a patient’s lifetime. They will assess whether any increased costs are justified by better outcomes for patients and represent good value for money for the NHS budget. |
| Intervention type | Drug |
| Pharmaceutical study type(s) | |
| Phase | Phase IV |
| Drug / device / biological / vaccine name(s) | Carvedilol |
| Primary outcome measure | Current primary outcome measure as of 29/08/2024: All-cause decompensation will be assessed through follow-up visits at 6, 12, 18, 24, 30, and 36 months post-randomisation, and also ongoing forms, adverse event forms and patient medical records. Each component (variceal haemorrhage, new or worsening ascites, hepatic encephalopathy, spontaneous bacterial peritonitis, hepatorenal syndrome, increases in Child-Pugh or MELD scores, and liver-related death) will be evaluated at these time points as well as continuously. The event time is defined as the period from randomisation to the first occurrence of any of the all-cause decompensation components listed. For those without events, data will be censored at the last follow-up or medical record review. This approach aligns with the methods used for other primary and secondary outcomes in the current study record, ensuring consistency and comprehensive data collection. Previous primary outcome measure: Time to first variceal haemorrhage, as defined by Baveno IV criteria. Variceal bleed assessed by endoscopy at 6, 12, 18, 24, 30 and 36 months with additional measurement at any ad hoc bleed event (i.e. SAE) and at study completion. |
| Secondary outcome measures | 1. Mortality at 6 weeks, 6, 12, 18, 24, 30 and 36 months with additional measurement at any ad hoc bleed event (i.e. SAE) and at study completion 2. Number of hospitalisations at 6 weeks, 6, 12, 24, and 36 months 3. Oesophageal varices grade, based on UK guidelines of 1 (varices that collapse to inflation of the oesophagus with air), 2 (between grade 1 and 3) and 3 (varices which are large enough to occlude the lumen), at 12, 24, and 36 months 4. Cirrhosis severity, assessed using the Child-Pugh Score for Cirrhosis Mortality at 6, 12, 18, 24, 30 and 36 months with additional measurement at any ad hoc bleed event (i.e. SAE) 5. Severity of end-stage liver disease, assessed using the Model for End-Stage Liver Disease (MELD) score at 6, 12, 18, 24, 30 and 36 months with additional measurement at any ad hoc bleed event (i.e. SAE) 6. Development of hepatic decompensation at 6, 12, 18, 24, 30 and 36 months with additional measurement at any ad hoc bleed event (i.e. SAE), measured using the following: 6.1. Presence of spontaneous bacterial peritonitis (ascitic fluid cell PMN cell count >250/mm3) 6.2. New hepatic encephalopathy (defined by West-Haven Grade >1 [overt HE]) 6.3. New or worsening ascites defined by clinical examination or ultrasound 7. Healthcare usage at 1 week, 6, 12, 18, 24, 30 and 36 months with additional measurement at any ad hoc bleed event (i.e. SAE) and at study completion; cost of treatment and quality adjusted life expectancy (QALE) across trial arms with adjustment for pre-specified baseline characteristics 8. Quality of life assessed using EQ-5D-5L score at randomisation, 6, 12, 18, 24, 30 and 36 months with additional measurement at any ad hoc bleed event (i.e. SAE) |
| Overall study start date | 01/09/2018 |
| Overall study end date | 31/12/2026 |
Eligibility
| Participant type(s) | Patient |
|---|---|
| Age group | Adult |
| Lower age limit | 18 Years |
| Sex | Both |
| Target number of participants | 1,200 |
| Total final enrolment | 763 |
| Participant inclusion criteria | 1. Age >18 years 2. Cirrhosis and portal hypertension, defined by any two of the following: 2.1. Characteristic clinical examination findings; one or more of: 2.1.1. Jaundice, ascites, caput medusae, spider naevi, palmar erythema, asterixis 2.2. Characteristic liver function tests, haematological panel and coagulation profile abnormalities 2.2.1. hyperbilirubinaemia (serum total bilirubin > 30 umol/l) 2.2.2. thrombocytopenia (platelet count <120 x109 / L) 2.2.3.international normalised raio (INR) > 1.5 NB These blood tests may be normal in well compensated cirrhosis – if cirrhosis is confirmed on other investigations, normal blood tests suggest well compensated disease. 2.3. Characteristic radiological findings; one or more of: 2.3.1. Heterogeneous, small liver with irregular contour 2.3.2. Splenomegaly 2.3.3. Ascites 2.3.4. Varices 2.3.5. Recanalized umbilical vein 2.4. Fibrosis score > stage 4 on liver biopsy 2.5. FibroScan liver stiffness measurement >15 kPa without other explanation 3. Small oesophageal varices – defined as <5mm in diameter or completely disappear on moderate insufflation at gastroscopy within the last 3 months 4. Not received a beta-blocker in the last week 5. Capacity to provide informed consent 6. Fluent in the English Language |
| Participant exclusion criteria | 1. Non-cirrhotic portal hypertension 2. Medium/large oesophageal varices (current or history of) 3. Isolated gastric, duodenal, rectal varices with or without evidence of recent bleeding 4. Previous variceal haemorrhage 5. Known intolerance to beta blockers 6. Contraindication to beta blocker use: 6.1. Heart rate <50 bpm 6.2. Known 2nd degree or higher heart block 6.3. Sick sinus syndrome 6.4. Systolic blood pressure <85mm Hg 6.5. Chronic airways obstruction (asthma/COPD) 6.6. Floppy Iris Syndrome 6.7. CYP2D6 Poor Metaboliser 6.8. Cardiogenic shock 6.9. History of severe hypersensitivity reaction to beta blockers 6.10. Untreated phaeochromocytoma 6.11. Severe peripheral vascular disease 6.12. Prinzmetal angina 6.13. NYHA IV heart failure 7. Unable to provide informed consent 8. Child Pugh C cirrhosis 9. Already receiving a beta-blocker for another reason that cannot be discontinued 10. Pregnant or lactating women 11. Graft cirrhosis post liver transplantation 12. Evidence of active malignancy without curative therapy planned |
| Recruitment start date | 01/04/2019 |
| Recruitment end date | 19/07/2024 |
Locations
Countries of recruitment
- England
- United Kingdom
Study participating centre
Denmark Hill
London
SE5 9RS
United Kingdom
Sponsor information
Hospital/treatment centre
King’s Health Partners Clinical Trials Office
King’s College Hospital
London
SE5 9RS
England
United Kingdom
| Website | https://www.khpcto.co.uk |
|---|---|
"ROR" |
https://ror.org/01n0k5m85 |
Funders
Funder type
Government
Government organisation / National government
- Alternative name(s)
- NIHR Health Technology Assessment Programme, HTA
- Location
- United Kingdom
Results and Publications
| Intention to publish date | 31/12/2027 |
|---|---|
| Individual participant data (IPD) Intention to share | No |
| IPD sharing plan summary | Data sharing statement to be made available at a later date |
| Publication and dissemination plan | It is intended that the results of the study will be reported and disseminated at international conferences and in peer-reviewed scientific journals and by Open Access credentialing. The protocol will be published in a clinical trials journal prior to trial commencement. No professional writers will be used. The trialists will disseminate the results to patients via the BOPPP website, and they will discuss the findings at patient groups and with charities involved in helping patients with cirrhosis such as the British Liver Trust. |
| IPD sharing plan | The data sharing plans for the current study are unknown and will be made available at a later date. |
Study outputs
| Output type | Details | Date created | Date added | Peer reviewed? | Patient-facing? |
|---|---|---|---|---|---|
| Other publications | results of the embedded qualitative study | 03/02/2022 | 04/02/2022 | Yes | No |
| Other publications | results of the embedded qualitative study | 17/10/2022 | 18/10/2022 | Yes | No |
| HRA research summary | 28/06/2023 | No | No | ||
| Protocol article | 16/04/2024 | 17/04/2024 | Yes | No | |
| Plain English results | version 3.0 | 31/05/2023 | 29/08/2024 | No | Yes |
| Protocol file | version 4.0 | 31/05/2023 | 29/08/2024 | No | No |
Additional files
Editorial Notes
29/08/2024: The following changes were made to the study record:
1. The target number of participants was changed from 1200 to 740.
2. The primary outcome measure was updated.
3. The recruitment end date was changed from 30/11/2021 to 19/07/2024.
4. Total final enrolment added.
5. The overall study end date was changed from 01/08/2024 to 31/12/2026.
6. The intention to publish date was changed from 01/10/2024 to 31/12/2027.
7. Protocol and plain English results added.
17/04/2024: Publication reference added.
18/10/2022: Publication reference added.
04/02/2022: Publication reference added.
17/09/2021: Internal review.
01/04/2021: The recruitment end date has been changed from 01/04/2021 to 30/11/2021.
23/06/2020: The primary contact details were changed.
28/04/2020: Due to current public health guidance, recruitment for this study has been paused.
10/01/2020: ClinicalTrials.gov number added.
12/07/2019: The ethical approval was added.
