Ignite Creation Date:
2024-05-06 @ 8:15 PM
Last Modification Date:
2024-10-26 @ 3:23 PM
Study NCT ID:
NCT06309472
Status:
RECRUITING
Last Update Posted:
2024-03-13
First Post:
2024-02-27
Brief Title:
Trial of Mirtazapine for Depression in IBD
Sponsor:
Kings College London
Organization:
Kings College London
Study Overview
Official Title:
A Multi-centre Double-blind Randomised Controlled Trial to Compare Mirtazapine Versus Placebo Over 12 Weeks in Patients With Multimorbid Major Depression and Inflammatory Bowel Disease MD-IBD a Feasibility Study
Status:
RECRUITING
Status Verified Date:
2024-08
Last Known Status:
None
Delayed Posting:
No
If Stopped, Why?:
Not Stopped
Has Expanded Access:
False
If Expanded Access, NCT#:
N/A
Has Expanded Access, NCT# Status:
N/A
Acronym:
MDIBD
Brief Summary:
This study will test whether it is feasible to conduct a clinical trial of mirtazapine an antidepressant tablet in patients who have both depression and inflammatory bowel disease IBD The study design 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 76 patients with both depression and IBD
The investigators will recruit outpatients aged 18 or over with a diagnosis of any IBD attending gastroenterology clinics Either in person or remotely patients will complete a brief screening questionnaire for depression Those scoring positive for depression will be invited for a 15-minute interview for clinical depression Those with clinical depression will be invited to take part Participants will be randomly allocated by a computer to take either 1 mirtazapine tablet once at night for 12 weeks or 2 placebo dummy tablet once at night for 12 weeks The study is blinded meaning neither patients nor the study team will know which medication they are taking Throughout participants will be able to access other treatments for depression such as talking therapies
The investigators will measure how many people join the study how many remain in the trial how many complete treatment how many tablets people take and assess overall acceptability of the trial Participants will complete brief questionnaires to measure their mental health and IBD symptoms after 4 weeks 8 weeks 12 weeks and 16 weeks Participants will also provide blood samples and faecal samples to measure inflammation
If successful this trial will support an application for a larger version of the study
The investigators will recruit outpatients aged 18 or over with a diagnosis of any IBD attending gastroenterology clinics Either in person or remotely patients will complete a brief screening questionnaire for depression Those scoring positive for depression will be invited for a 15-minute interview for clinical depression Those with clinical depression will be invited to take part Participants will be randomly allocated by a computer to take either 1 mirtazapine tablet once at night for 12 weeks or 2 placebo dummy tablet once at night for 12 weeks The study is blinded meaning neither patients nor the study team will know which medication they are taking Throughout participants will be able to access other treatments for depression such as talking therapies
The investigators will measure how many people join the study how many remain in the trial how many complete treatment how many tablets people take and assess overall acceptability of the trial Participants will complete brief questionnaires to measure their mental health and IBD symptoms after 4 weeks 8 weeks 12 weeks and 16 weeks Participants will also provide blood samples and faecal samples to measure inflammation
If successful this trial will support an application for a larger version of the study
Detailed Description:
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 11 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 Crohns 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 patients 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 11 allocation as per a computer-generated randomisation schedule which will use a varying permuted block design stratified by diagnosis Crohns disease or ulcerative colitis and sex assigned at birth malefemale 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 mirtazapineplacebo 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 n38 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 n38 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 currentprevious medications current analgesia presenceabsence 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 hisher 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
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 11 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 Crohns 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 patients 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 11 allocation as per a computer-generated randomisation schedule which will use a varying permuted block design stratified by diagnosis Crohns disease or ulcerative colitis and sex assigned at birth malefemale 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 mirtazapineplacebo 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 n38 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 n38 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 currentprevious medications current analgesia presenceabsence 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 hisher 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
Study Oversight
Has Oversight DMC:
None
Is a FDA Regulated Drug?:
False
Is a FDA Regulated Device?:
False
Is an Unapproved Device?:
None
Is a PPSD?:
None
Is a US Export?:
None
Is an FDA AA801 Violation?:
None