To investigate the feasibility of proton pump inhibitor (PPI) withdrawal in inflammatory bowel disease (IBD); the data collected will provide valuable information to inform a future multi-centre randomised controlled trial.

Evidence suggests that patients with IBD taking PPIs respond less well to medication and require hospital treatment more frequently than patients not taking PPIs. This may be due to changes in the gut microbiota associated with PPI use.

A future definitive trial is planned to investigate clinical outcomes in patients who stop PPIs compared with those who continue PPIs, in order to determine the safety implications of PPI use in IBD. However, several uncertainties remain which require investigation before such a trial can be undertaken. It is currently unknown how many patients with IBD take PPIs, how many can successfully stop taking PPIs, how many would be willing to stop treatment, and how many would remain off treatment long term. In some cases, withdrawal of PPIs may result in a short-term increase in acid reflux symptoms. The willingness of patients to participate in such a study is also unknown. This study will be conducted in GP practices, a setting in which IBD trials have not previously been undertaken.

The study will recruit 80 participants with IBD aged 16 years and over who have been taking PPIs regularly for more than six months. Half of participants will be randomised to discontinue PPI therapy. Participants will be followed up for 12 months. The study will provide information regarding recruitment rates within GP practices, optimal methods for PPI withdrawal, and whether stopping PPIs affects IBD outcomes.

PURPOSE

The purpose of this study is to explore the feasibility of proton pump inhibitor (PPI) withdrawal in patients with IBD in order to inform the running of a larger scale study.

PRIMARY OBJECTIVES

To understand the feasibility of PPI withdrawal in order to inform a future definitive multi-centre randomised controlled trial by investigating:

How many patients are eligible for this study. What the recruitment rate is - baseline variables predicting non-recruitment from screened patients will be investigated.

What adherence to PPI withdrawal and continuation is - non-adherence amongst recruited participants will be investigated.

What the retention of participants throughout the follow-up period of the trial is.

SECONDARY OBJECTIVES

What is the effect of PPI withdrawal on IBD disease activity?

Effect of withdrawal: For ulcerative colitis, a standardised patient-reported outcome quantifying stool frequency and rectal bleeding scores will be collected. For participants with Crohn's disease, a standardised patient-reported outcome quantifying abdominal pain and stool frequency scores will be collected. Moreover, participants will also be asked to complete the Gastrointestinal Symptom Rating Scale (GSRS) and the Glasgow Dyspepsia Severity Score (GDSS).

TRIAL DESIGN

Parallel-group, open-label randomised controlled trial recruiting participants from primary care. This is an open-label study as it is not possible to blind the clinician delivering the intervention, i.e. the withdrawal of PPI, nor the participant receiving the intervention.

Qualitative study: A semi-structured interview study will be undertaken to investigate the acceptability of and adherence to the study protocol. Interview duration will be up to one hour and will take place online via MS Teams. This may also be available to take place in person, should the participant request this instead. This will allow for further understanding of the underlying mechanisms impacting the study outcomes. This will help inform recruitment processes for downstream research proposals, improving recruitment and attrition. Interviews will follow a semi-structured interview schedule to gain greater clarification through exploration of detailed descriptions of the desired topic from participants. A sample size of approximately 20 participants was chosen. The adequacy of the final sample size will be continually assessed during the data collection process using factors of both 'data saturation' and 'information power'. Data collection and transcription will be undertaken in parallel, and NVivo 12 software will be used to aid data analysis.

RANDOMISATION AND BLINDING

The Randomisation Scheme

Participants will be randomly assigned in a 1:1 ratio to one of two study arms using a random minimisation algorithm, stratified by IBD type (50% Crohn's disease, 50% ulcerative colitis), and current use of advanced therapy (yes/no). Randomisation will be conducted through an online randomisation system, with participants allocated to one of the following groups:

Continue PPI therapy

Withdraw PPI therapy

The randomisation system will be provided by the Derby CTSU. Randomisation will be undertaken by the University of Nottingham research team using the online randomisation tool 'Sealed Envelope' hosted by Derby CTSU. Participants will be contacted by the research team at the University of Nottingham by phone or email to explain their treatment allocation. Participants will also receive a letter via DocMail to confirm their treatment allocation, and a letter (sent via electronic mail) will be sent to the GP explaining participant enrolment and treatment allocation for entry into the medical records.

This is an open-label study as it is not possible to blind the clinician delivering the intervention, i.e. the withdrawal of PPI. The data analyses will be undertaken by the research team, who will be blinded to participant allocation.

TRIAL MANAGEMENT

The trial will be managed by the study team at the University of Nottingham. There is a Trial Manager based at the University of Nottingham.

Derby CTSU will provide a web-based randomisation service and statistical services during the development, conduct, analysis and reporting stages of the feasibility trial. TCR Nottingham will be responsible for setting up the study database and data management while the team at the University of Nottingham will lead trial management, qualitative analyses and overall project delivery.

The TMG will report to the independent TSC, which will be responsible for oversight of the trial including safety oversight. Membership will include patient representation and relevant expertise. The TSC will meet (in person) prior to commencement of the trial to agree the protocol, and then at least annually (in person or by telephone conference) until completion of the trial. The TSC will be responsible for approving the trial protocol, reviewing trial progress and resolving problems brought to it by the co-ordinating centre. Reflecting the feasibility nature of this study, there will be no data monitoring committee.

The Chief Investigator has overall responsibility for the study and shall oversee all study management.

The data custodian will be the Chief Investigator.

DURATION OF THE TRIAL / STUDY AND PARTICIPANT INVOLVEMENT

Participant Duration: From the point of enrolment, participants will be invited to take part in the study for 12 months. Follow-up time points are questionnaire completion at 3, 6 and 12 months and these will be undertaken online or over the phone. Data related to outcomes 3-6 will be collected at these time points. After 3 months in the trial, participants will be invited to take part in the qualitative sub-study, which is a one-off qualitative interview study of up to one hour duration. Participants reach the end of their study participation after their month 12 follow-up is complete.

Study Duration: The planned total study duration is 24 months.

End of the Trial

Once the last 12-month follow-up is completed, the qualitative interviews for those participants who adhered to the study protocol will take place. Therefore, the end of the study is the last interview of the last fully completed participant.

SELECTION AND WITHDRAWAL OF PARTICIPANTS

Recruitment

Routinely collected data will be used to identify patients, making this data-driven trial cost-effective.

Inclusion Criteria:

• Aged 16 years or older.
• An IBD diagnosis as defined through SNOMED codes in primary care databases [Appendix 5]
• Taking a PPI regularly for >6 months prior to enrolment
• Patient-confirmed compliance with PPI therapy (>75% of prescribed doses)
• Able to give full, independent valid Informed consent
• Stable disease as defined by no change in medication or IBD-related surgery for the last 3 months.

Exclusion Criteria:

• Unable to participate fully in all aspects of the clinical trial.
• Barrett's oesophagus
• Peptic disease at a recent upper GI endoscopy
• Zollinger-Ellison Syndrome
• Eosinophilic oesophagitis
• Chronic NSAID usage
• Pulmonary fibrosis.
• Declined consent to data sharing
• History of dementia
• Terminal illness
• Present malignancy
• Active history of mental illness
• In a care home
• Alcohol misuse
• Illicit drug misuse

The data will be shared with and analysed only by staff from the University of Nottingham and Derby CTSU De-identified pre-analysed data may be shared with collaborators at other UK institutions for the purposes of writing up results and dissemination. All transfers will be via encrypted file transfer.

Data generated as part of the outputs of the project (published manuscripts, published protocols) will be freely available and appropriately licensed for re-use under a CC-BY or CC-BY-NC licence.