Clinical trial NCT04956159: TMS in Inflammatory Bowel Disease
Official title: Evaluating the Antidepressant Efficacy of Transcranial Magnetic Stimulation (TMS) in Patients With Inflammatory Bowel Disease (IBD) and Effects on IBD-related Symptoms.
Study type: INTERVENTIONAL
Overall status: TERMINATED
Phase: PHASE2
Conditions: Inflammatory Bowel Diseases
Maladaptive Behavior Associated With Physical Illness
Lead sponsor: University of Calgary
Sponsor class: OTHER
Collaborators: name: IMAGINE (Inflammation, Microbiome, and Alimentation: Gastro-Intestinal and Neuropsychiatric Effects)
First posted: 2021-07-09
Enrollment: 12
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief summary: Transcranial magnetic stimulation (rTMS) has demonstrated diagnostic and therapeutic potential for a number of conditions and is an approved treatment for depression. Inflammatory Bowel Disease (IBD) has a significant impact on mental health, and comorbid maladaptive behaviors and pain are highly prevalent in patients with IBD and are often under-treated.

The investigators predict TMS will improve comorbid maladaptive behavior (heightened interoceptive awareness, sleep, fatigue, catastrophizing, anxiety and depression), reduce pain and improve quality of life in persons with inflammatory bowel disease (IBD). Further, TMS benefits will be associated with changes in gut microbiome as measured by stool, blood and urine samples and normalization of IBD-associated changes in brain structure and/or function as measured by magnetic resonance imaging (MRI).

Detailed description: Background and rationale:

Comorbid maladaptive behaviors and pain are highly prevalent in patients with IBD and are often under-treated. These comorbidities lack effective therapies and thus complicate medical management, adversely impact patient outcome and health, and increase the resource burden on the healthcare system. Development of effective treatment delivery is therefore vital. Repetitive transcranial magnetic stimulation (rTMS) is a noninvasive form of brain stimulation in which an electric pulse generator placed at the scalp produces a rapidly changing magnetic field at biologically relevant frequencies to induce a stimulating electrical current at targeted sites in the brain. rTMS has demonstrated diagnostic and therapeutic potential for a number of conditions, including Alzheimer's disease, autism, bipolar disorder, epilepsy, chronic pain, major depressive disorder, Parkinson's disease, post-traumatic stress disorder (PTSD), schizophrenia (negative symptoms), obsessive-compulsive disorder (OCD), and for the cessation of smoking. To date, however, rTMS has not been used to treat the mental health issues and symptoms observed in persons with IBD. The investigators will develop rTMS interventions for IBD to target comorbid maladaptive behaviors and pain using evidence-based knowledge of TMS effectiveness for other chronic medical conditions.

Research Question:

Compared to sham, does twice daily intermittent theta-burst stimulation rTMS delivered to the left dorsolateral prefrontal cortex for two weeks (20 sessions) improve comorbid maladaptive behavior (heightened interoceptive awareness, sleep, fatigue, catastrophizing, anxiety and depression), reduce pain and improve quality of life in persons with inflammatory bowel disease (IBD)? Further, will TMS benefits be associated with changes in gut microbiome and normalization of IBD-associated changes in brain structure and/or function as measured by magnetic resonance imaging (MRI)?

Methods:

Forty male and female IBD (Chron's Disease (CD) and Ulcerative Colitis (UC)) patients with co-morbid anxiety and depression will be recruited for this study.

Patients will be randomized 1:1 to TMS or sham TMS according to a computer-generated randomization list from eligible patients identified from the cohort study. Randomization will be stratified by type of IBD (UC versus CD). Patients will be randomized 1:1 to 2 weeks of twice-daily active or sham TMS. The investigators will utilize intermittent theta-burst stimulation (iTBS 600 pulses per session delivered as triplets at 50Hz repeated at 5Hz at 80% resting motor threshold) delivered to the left dorsolateral prefrontal cortex (DLPFC) using a MagPro X100 stimulator and a COOL-B70 (active) or MCF-P-B70 (placebo) coil. Participants will receive 20 treatments over two weeks. All participants allocated to the double-blind phase will be offered 2 weeks of open-label twice-daily iTBS to the left DLPFC if they do not achieve 50% reduction in QIDS-SR score during the double-blind phase.

Baseline characterization will include demographic information, self-reported measures of comorbid maladaptive behaviors and pain, neurocognitive tests, analysis of IBD symptoms, microbiome analysis

Participants will undergo an MRI of the brain prior to receiving treatment for localization of the DLPFC, as well as characterization of volumetric imaging, white matter imaging, resting state activity and inflammation imaging. A second MRI will be repeated characterizing these same parameters after the conclusion of the sham-controlled treatment (week 2).

Stool, blood and urine samples will be collected at baseline, after the conclusion of the sham-controlled treatment (week 2) and 4 weeks follow up (week 6). These will be used for assessment of fecal calprotectin, fecal bacterial and fungal microbiome, inflammatory markers and metabolomic analysis.

Brief, computerized neurocognitive tests will be administered at baseline, after TMS treatment (week 2) and 4 week follow up (week 6)

Eligibility criteria: Inclusion Criteria:

* confirmed diagnosis of IBD, demonstrated to be in endoscopic remission (Mayo Endoscopic Subscore \[for UC\] 0 or 1, or Simple Endoscopic Score for CD ≤4) or biomarker remission (fecal calprotectin \<250 ug/g) within 6 months of randomization
* ≥8 on the Hospital Anxiety and Depression Scale
* on stable IBD-related and psychotropic medications for the four weeks preceding randomization

Exclusion Criteria:

* severely active IBD (Mayo score \> 9, HBI \> 16)
* require systemic corticosteroids
* initiated biologic treatment within the preceding three months
* suicidal ideation
* psychosis
* having failed ECT
* previous rTMS treatment (for blinding integrity)
* contraindications for MRI
* Use of benzodiazepines or GABA agonists

Primary outcomes:
measure: Change in depressive and anxiety symptoms with active iTBS-rTMS as compared to sham treatment group
timeFrame: Measured at baseline, halfway through rTMS treatment (week 1), end of rTMS treatment (week 2) and 4 weeks post treatment (week 6)
Secondary outcomes:
measure: Change in depressive symptoms as measured by Montgomery-Åsberg Depression Rating Scale (MADRS) score from baseline to week-2 (post rTMS treatment) with iTBS-rTMS as compared to sham treatment group
timeFrame: Measured at baseline, halfway through rTMS treatment (week 1), end of rTMS treatment (week 2) and 4 weeks post treatment (week 6)
measure: Change in mood from baseline to week 2 (post rTMS treatment) with iTBS-rTMS as compared to sham treatment group
timeFrame: Measured at baseline, halfway through rTMS treatment (week 1), end of rTMS treatment (week 2) and 4 weeks post treatment (week 6)
measure: Change in IBD symptoms with active iTBS rTMS compared to sham rTMS
timeFrame: Measured at baseline, halfway through rTMS treatment (week 1), end of rTMS treatment (week 2) and 4 weeks post treatment (week 6)
measure: Change in quality of life in persons with IBD with active iTBS rTMS compared to sham rTMS
timeFrame: Measured at baseline, halfway through rTMS treatment (week 1), end of rTMS treatment (week 2) and 4 weeks post treatment (week 6)
measure: Change in self reported anxiety symptoms in persons with IBD with active iTBS rTMS compared to sham rTMS
timeFrame: Measured at baseline, halfway through rTMS treatment (week 1), end of rTMS treatment (week 2) and 4 weeks post treatment (week 6)
measure: Change in self reported depressive symptoms in persons with IBD with active iTBS rTMS compared to sham rTMS as measured by the Patient Health Questionaire.
timeFrame: Measured at baseline, halfway through rTMS treatment (week 1), end of rTMS treatment (week 2) and 4 weeks post treatment (week 6)
measure: Change in self reported depressive symptoms in persons with IBD with active iTBS rTMS compared to sham rTMS as measured by the Quick Inventory of Depressive Symptomatology
timeFrame: Measured at baseline, halfway through rTMS treatment (week 1), end of rTMS treatment (week 2) and 4 weeks post treatment (week 6)
measure: Change in self reported physical, mental and social health and well-being in persons with IBD with active iTBS rTMS compared to sham rTMS
timeFrame: Measured at baseline, halfway through rTMS treatment (week 1), end of rTMS treatment (week 2) and 4 weeks post treatment (week 6)
measure: Change in self reported symptoms of gastrointestinal pain in persons with IBD with active iTBS rTMS compared to sham rTMS
timeFrame: Measured at baseline, halfway through rTMS treatment (week 1), end of rTMS treatment (week 2) and 4 weeks post treatment (week 6)
measure: Change in interoceptive awareness with active iTBS rTMS compared to sham rTMS in persons with IBD.
timeFrame: Measured at baseline, halfway through rTMS treatment (week 1), end of rTMS treatment (week 2) and 4 weeks post treatment (week 6)
measure: Change in catastrophizing thoughts and feelings in persons with IBD with active iTBS rTMS compared to sham rTMS
timeFrame: Measured at baseline, halfway through rTMS treatment (week 1), end of rTMS treatment (week 2) and 4 weeks post treatment (week 6)
measure: Change in quality of sleep with active iTBS rTMS compared to sham rTMS in persons with IBD.
timeFrame: Measured at baseline, halfway through rTMS treatment (week 1), end of rTMS treatment (week 2) and 4 weeks post treatment (week 6)
measure: Change in self reported fatigue in persons with IBD with active iTBS rTMS compared to sham rTMS
timeFrame: Measured at baseline, halfway through rTMS treatment (week 1), end of rTMS treatment (week 2) and 4 weeks post treatment (week 6)
measure: Change in cognitive function with active iTBS rTMS compared to sham rTMS in persons with IBD.
timeFrame: tests will also be administered at baseline and at the conclusion of the 2 week double-blind phase, and at 4 weeks post treatment (week 6)
measure: Stool samples- Individual microbial analysis
timeFrame: Stool will be collected at baseline, at the conclusion of the 2 week double-blind phase, and at 4 weeks post treatment (week 6)
measure: Stool samples- Microbial community measurements
timeFrame: Stool will be collected at baseline, at the conclusion of the 2 week double-blind phase, and at 4 weeks post treatment (week 6)
measure: 16S and ITS2 rRNA gene sequencing.
timeFrame: Stool, urine, and blood samples will be collected at baseline, at the conclusion of the 2 week double-blind phase, and at 4 weeks post treatment (week 6)
measure: Implicit Suicidal Thoughts
timeFrame: tests will also be administered at baseline, at the conclusion of the 2 week double-blind phase, and at 4 weeks post treatment (week 6)
measure: Functional Magnetic Resonance Imaging (fMRI)
timeFrame: Subjects will undergo MRI at 0 (baseline) and at the completion of the blinded phase (week 2)
measure: Magnetic Resonance (MR) spectroscopy
timeFrame: Subjects will undergo MRI at 0 (baseline) and at the completion of the blinded phase (week 2)
measure: Magnetic Resonance Imaging (MRI)- Volumetric imaging.
timeFrame: Subjects will undergo MRI at 0 (baseline) and at the completion of the blinded phase (week 2)
measure: Magnetic Resonance Imaging (MRI)- White matter imaging
timeFrame: Subjects will undergo MRI at 0 (baseline) and at the completion of the blinded phase (week 2)
measure: Magnetic Resonance Imaging (MRI)- Inflammation imaging.
timeFrame: Subjects will undergo MRI at 0 (baseline) and at the completion of the blinded phase (week 2)
Other outcomes:
measure: Side Effects
timeFrame: Measured at baseline, halfway through rTMS treatment (week 1), end of rTMS treatment (week 2) and 4 weeks post treatment (week 6)
Locations:
city: Calgary
country: Canada
facility: University of Calgary
state: Alberta
Study officials:
References: