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.