Modafinil For Fatigue in IBD: A Feasibility Randomised Controlled Trial

Design: The current study is a randomised controlled trial (a study in which people are allocated by chance to receive different interventions). The trial will compare mirtazapine against a placebo (dummy) tablet in 70 patients with both severe fatigue and IBD. This is a feasibility study, meaning that it is testing whether it will be possible to do a larger version of this study.

Setting: Consent and assessments will take placebo in clinic rooms or clinical research facilities at Imperial College Healthcare National Health Service (NHS) Foundation Trust, King's College Hospital, St Mark's Hospital and Guy's and St Thomas' Hospital, or online if the patient prefers this. The latter is important in maximising participation to the study for participants who may find it difficult to access hospitals, which is a common problem in inflammatory bowel disease (IBD) due to issues like pain and incontinence.

Recruitment: Consecutive patients aged ≥18 with diagnosed IBD and significant fatigue will be identified from outpatient clinics and biologics infusion suites. If possible, clinicians will use the IBD Fatigue Scale to identify people scoring ≥11. If necessary, patients will be identified from screening of endoscopy schedules and IBD multidisciplinary team meetings. The clinical team will seek the patient's permission to be contacted by the research team.

If they agree, the research team will then contact the patient - either in the clinic or over the phone - and provide the patient information sheet. The research team will check some basic pre-screening questions: confirming IBD diagnosis, duration of fatigue, whether they are planned to change any IBD treatments in the next 12 weeks, and the 5- question IBD Fatigue Assessment Scale if not already completed. Before pre-screening, the research team will advise patients that the fatigue information they provide will be passed onto their clinical team - with their permission - even if they decide not to take part in the study. They will be advised that any other information about their IBD will not be retained by the study team if they do not wish to take part. If anyone has an elevated fatigue score but does not wish to take part in the study, the research team will seek the patient's permission to relay the fatigue score to their clinical team.

Those who are deemed to be potentially eligible after pre-screening will be invited for a full screening assessment with a member of the study team. Final study inclusion and consent will be taken by a study doctor.

Study procedures: There will be 4 main study visits. At the first visit, the researcher will explain the study in detail. They will answer any questions the participant has. They will ask the participant some brief questions about their mental health and gut health. They will complete the IBD Fatigue Scale if not already done to ensure they score ≥11/20. The research team will confirm that their fatigue is at least 6 months in duration. If eligible according to screening criteria, the research team will invite them to participate and to sign a consent form.

The researchers will check that the participant meets all the inclusion criteria and none of the exclusion criteria. They will ask the participant more detailed questions about fatigue and mental health (the National Institute for Health and Care Excellent (NICE) criteria for chronic fatigue syndrome, Mini Neuropsychiatric Interview for depression) and will complete further questionnaires lasting around 20 minutes. They will also be asked to have height and weight measured and to provide a blood sample (though these are not compulsory). They will have their hand grip strength tested. If female and of childbearing age, the researcher will take a blood pregnancy test. If they are eligible to take part, the participant will then be randomised by computer to one of the 2 treatments (modafinil or placebo). The tablets for both groups are made to look the same. Neither participant nor the research team will know in which treatment group they are allocated to.

Participants will be given medication the same day or will receive it via recorded post.

The 2 treatment arms are:

1. Modafinil (a stimulant medication) If randomised to this group, the participant will be asked to take a modafinil capsule once in the morning. If their fatigue does not improve much, they can add a second tablet after 2 weeks. If needed, they can then add a third tablet after 4 weeks. The total treatment lasts 12 weeks.
2. Placebo If randomised to this group, the participant will take a placebo tablet once per day for 12 weeks. If their fatigue does not improve much, they can add a second tablet after 2 weeks. If needed, they can then add a third tablet after 4 weeks. The total treatment lasts 12 weeks. Participants will not know which treatment (modafinil or placebo) they are taking.

The participant will meet with the research team again at 6 and 12 weeks after starting treatment. This can be in person or online. These appointments will last for around 30 minutes and will involve:

• Repeating most of the questionnaires completed at the beginning
• A review of general health and other medications
• Repeat blood tests and weight measurement (12 weeks only)
• Repeat hand grip strength measurement (12 weeks only)

Although they will finish treatment after 12 weeks, the investigators will participants whether they can attend a final visit 6 weeks later. This is not compulsory. It will involve repeating most of the questionnaires. Throughout, participants will still be able to access any talking therapies for depression or fatigue, though should not start any other antidepressants.

Progression criteria: The milestones for progression to a full efficacy clinical trial will be based on the proportion-to-target of patients randomised overall; % completing 12 weeks of treatment; % of participants taking at least 75% of prescribed mediation; % of planned data and samples collected at 12 weeks; and % participants describing the treatment as acceptable (≥6/10 on 0-10 scale).

Sample size: As a feasibility study, power calculations for a treatment effect are not applicable. The investigators will recruit 70 participants (35 per group), which is sufficient to generate robust variance estimates. Based on 70 patients and an anticipated follow-up rate of 80%, a two-sided confidence interval will extend no more than 12% of the observed proportion.

Data management:

Data will be collected on paper case report form (CRF) and then transferred to an electronic case report form (eCRF). The type of activity that an individual user may undertake is regulated by the privileges associated with his/her user identification code and password. All forms and tapes related to study data will be kept in locked cabinets. Access to the study data will be restricted. The database will be password-protected.

Statistical methods:

A statistical analysis plan (SAP) will be approved by the Trial Steering Committee independent statistician. The analysis population will use intention-to-treat principles. A recruitment plot of predicted vs. actual recruitment will be generated on a monthly basis.

Participant flow through the study will be presented. Descriptive data will be presented in the form of means and standard deviations; medians and ranges; or percentages with 95% confidence intervals, as appropriate depending on the data being described. The investigators will use linear mixed models to estimate the between group adjusted mean difference (aMD) between mirtazapine and placebo groups at week 12 after adjustment for baseline scores, time, and a treatment-by-time-interaction. Associated 95% confidence intervals will be presented alongside the aMD without p-values. More details will be provided in the statistical analysis plan.

Timeline: This 24-month study includes up to 5 months for setup and approval, 12 months for recruitment (plus 3 months' contingency), 4 months for follow-up visits (including post-treatment follow-ups) and 3 months for write-up and dissemination.