Background:
Depression is highly prevalent in patients with inflammatory bowel disease (IBD) and associated with poor IBD outcomes. Mirtazapine, a tetracyclic antidepressant, is particularly promising in IBD because it has minimal effect on gut motility; has anti-emetic effects; is well absorbed from the gut and carries a low risk of sexual dysfunction. However, mirtazapine has never been trialed in patients with IBD.
Aim:
To test whether it is feasible to carry out a trial of mirtazapine versus placebo - both in addition to treatment-as-usual - for the treatment of depression in patients with IBD, in order to inform the design of a subsequent powered multi-centre randomised controlled trial (RCT).
Objectives:
The primary aim of the research is to test the feasibility of a definitive trial of mirtazapine + treatment-as-usual (TAU) against matched placebo + TAU for depression in adults with IBD. This study will:
1. Establish recruitment, retention, and adherence rates
2. Measure acceptability using treatment adherence and qualitative interview
3. Test the assessment methods and procedures for measuring variables for use in a full trial
4. Test the feasibility of collecting health economic data, including health service use
Study design:
The study is a parallel group, 1:1 feasibility randomised controlled trial (RCT). Participants will be randomised to one of the two treatment arms (mirtazapine + treatment-as-usual (TAU) or matched placebo + TAU) and will complete measures at baseline, 4 weeks, 8 weeks and 12-weeks post randomisation. Blinded treatment will last for 12 weeks, followed by the offer of a 2-3-week tapering off dose. A post-treatment follow-up will take place at 16 weeks post-randomisation.
Recruitment:
From outpatient gastroenterology services, patients aged ≥18 and diagnosed with Crohn's disease or ulcerative colitis, confirmed using clinical notes, will be screened for depression using the Patient Health Questionnaire-9 (PHQ-9) as part of clinical care. For those with at least moderate depression (≥10 on the PHQ-9) - the clinical team will seek the patient's permission to be contacted by the research team. Those who are deemed to be potentially eligible will be invited for a screening assessment with a member of the study team. Final study inclusion and consent will be taken by a member of the study team.
Assignment of interventions:
Participants will be randomly assigned to either mirtazapine or placebo with a 1:1 allocation as per a computer-generated randomisation schedule, which will use a varying permuted block design stratified by diagnosis (Crohn's disease or ulcerative colitis) and sex assigned at birth (male/female). The block sizes will not be disclosed. Participants will be randomised by the clinical team using a web based online randomisation system.
Blinding:
Participants and researchers will be blind to treatment allocation. The blinding will be maintained by opaque over-encapsulation of mirtazapine/placebo. Assessments regarding clinical outcomes will be conducted by an assessor blind to treatment allocation. The trial statistician will become unblind after the first version of the Statistical Analysis Plan is signed.
Intervention:
Half (n=38) will be randomised to 12 weeks of treatment with mirtazapine, which will be blinded through over-encapsulation. The starting dose will be 30mg once at night (ON), which is the minimum therapeutic dose for depression. Treatment with mirtazapine will occur in addition to treatment-as-usual, which is any psychological therapy the patient wishes to access through the National Health Service (NHS) or private therapy services. The patient and assessor will remain blinded to treatment allocation throughout the 12 weeks of treatment. Most benefit from antidepressants is gained within the first 2 weeks after starting treatment, and 12 weeks is a standard treatment duration for antidepressant trials.
After 4 weeks of taking mirtazapine 30mg at night, clinical response will be assessed using the Quick Inventory for Depressive Symptomatology-16. In accordance with British Association of Psychopharmacology clinical guidelines, the dose will be increased to 45mg at night if there is \<20 percent clinical improvement from baseline.
The other half (n=38) will be randomised to a matched placebo, which is a matched capsule filled with lactose. Treatment with placebo will occur in addition to treatment-as-usual, which is any psychological therapy the patient wishes to access through NHS services or private therapy services. After 4 weeks of taking placebo 1 capsule at night, clinical response will be assessed using the Quick Inventory for Depressive Symptomatology-16. The dose will be increased to 2 capsules at night if there is \<20 percent clinical improvement from baseline.
Continuity of care:
The investigators will ask participants if they wish to continue mirtazapine through their General Practitioner (GP) after their participation in the trial has finished. For those not wishing to continue treatment after the trial, participants will be able to down-titrate and stop treatment.
Concomitant medications:
Participants will agree not to start any other antidepressants during the trial. The investigators will also exclude participants where there is a planned or expected change in IBD treatment in the next 12 weeks. The investigators will record concomitant medications for IBD, mental health or pain (strong or weak opioids) during this time.
Treatment stopping rules:
Treatment will be stopped for an individual participant if they develop any of the following:
* Active suicidal thoughts.
* Pregnancy
* Any Serious Adverse Event (SAE), Serious Adverse Reaction (SAR) or Unexpected Serious Adverse Reaction (USAR), which, in the view of the investigators, necessitates treatment cessation.
Every effort will be made to ensure the patient outcomes are continued to be collected even if their treatment has been stopped.
Withdrawal:
Participants have the right to withdraw from the study at any time for any reason. The investigators also have the right to withdraw participants from the study in the event of inter-current illness, adverse events, protocol or treatment non-compliance or administrative reasons. Should a participant withdraw from the intervention, efforts will be made to continue to obtain follow-up data, with the permission of the patient.
Measures collected at baseline:
Socio-demographic variables: age, sex, ethnicity, occupational status, duration of education, marital status, current employment status and smoking status.
Psychiatric history: previous episodes of depression or anxiety, medication history, previous psychological therapies and psychiatric comorbidities.
IBD variables: IBD diagnosis, disease type using the Montreal classification, IBD duration, current/previous medications, current analgesia, presence/absence of fistulae, current stoma (colostomy, ileostomy, jejunostomy), current or previous parenteral nutrition or intravenous fluid support, previous surgery and number of IBD flares in the last 2 years.
Anthropometrics: Height and weight for participants attending in person.
Primary feasibility outcomes:
These are described in detail elsewhere.
Secondary outcomes (baseline, 4 weeks, 8 weeks, 12 weeks and 16 weeks post-randomisation):
Participants will complete a questionnaire schedule that includes key psychological measures, typically completed within 30 minutes by patients themselves. The investigators will repeat the range of questionnaires at follow-up and estimate the completeness, variance and estimate standardised effect sizes (see Outcomes section), as well as faecal calprotectin, C-reactive protein and inflammatory cytokines. Effects on gut microbiome, gut metabolome and serum metabolome will also be captured and reported outside of the main trial analysis.
Qualitative interview (subset of participants, after completion of the trial):
We will also assess feasibility using a one-off post-treatment interview, conducted between 12- and 16 weeks after initial randomisation. The investigators will approach all patients who begin treatment but discontinue, exploring their reasons and any barriers they encountered. A purposive sample of treatment completers will also be invited to individual post-treatment interviews.
End of study definition:
The end of the trial will be defined as the date when all participants have made their final visits, the data entered into the database and all queries resolved and the database locked.
Sample size:
As a feasibility study, power calculations for a treatment effect are not applicable. The target sample size is 64 participants (32 per group), which is sufficient to generate robust variance estimates. To account for an estimated 15% attrition, the investigators will recruit 76 participants to the study. Based on this sample size, a two-sided confidence interval will extend no more than 10% 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.
Exploratory analysis:
To explore potential mediators of treatment response in a future powered trial (reduction in peripheral inflammatory cytokines, improvement in sleep quality, improvement in irritable bowel syndrome symptoms, improvement in functional dyspepsia symptoms), exploratory analysis will report the mediation analysis. Significant findings will be interpreted cautiously, acknowledging the issue of multiple testing, need for replication and low statistical power.
Qualitative data analysis:
For the qualitative analysis of post-treatment interviews, the investigators will use pragmatic thematic analysis to code and report the interview data. Two researchers will perform preliminary analysis to identify themes, which will then be discussed and agreed with all authors if appropriate.
Dissemination policy:
Findings of this feasibility study will be disseminated through international conferences, peer-reviewed journals, charities, educational seminars in acute trusts and through appropriate social media channels. If the study is feasible, it will support an application for a powered trial of mirtazapine for depression in IBD.
