TMS for Exposure Therapy Resistant OCD

Study Overview
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Brief Summary
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TETRO is a multi-center placebo-controlled double-blind randomized controlled trial with an intervention phase of 5-7 weeks and a follow-up phase of 12 months in 250 adult (18 years and older) OCD patients who show no/insufficient response to ERP, aiming to establish the cost-effectiveness of low frequency (1 Hz) rTMS to the pre-SMA (compared to sham rTMS to the pre-SMA) as adjuvant treatment to exposure with response prevention (ERP). The treatment consists of 4 times/week rTMS combined with ERP for at least 5 weeks (20 sessions), with optional extension phase of 1 or 2 weeks (maximum of 28 sessions in total).

Detailed Description
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Rationale: Obsessive-compulsive disorder (OCD) is a serious and disabling mental disorder, characterized by obsessions and compulsions and associated with substantial comorbidity and morbidity (Stein et al. 2019). Approximately 50% of patients treated with standard treatments (exposure therapy with response prevention (ERP) with/without medication) fail to respond fully, resulting in chronicity and poor participation in social and educational/occupational domains. We propose to fill the gap between the standard treatments (exposure therapy with/without medication) on the one side and invasive end-stage strategies (brain surgery) on the other side, using a non-invasive alternative: repetitive transcranial magnetic stimulation (rTMS). Despite proven efficacy (Zhou et al. 2017; Rehn et al. 2018; Fitzsimmons et al. 2022), rTMS for OCD is not yet covered by the Dutch insurance system while rTMS for treatment resistant depression is. This multi-center randomized controlled trial, supported by the 'veelbelovende zorg' grant of Zorg Instituut Nederland (ZIN), aims to establish the added value of rTMS applied over the pre-supplementary motor area (preSMA) when combined with ERP in OCD patients, who show no/insufficient response to ERP (alone or combined with medication). In case of proven cost-effectiveness it will lead to the addition of rTMS as insured health care for patients with OCD. Objective: assess the (cost-)effectiveness of 1Hz rTMS to the pre-SMA as adjuvant treatment to ERP in OCD patients who show no/insufficient response to ERP (alone or combined with medication) Study design: multi-center placebo-controlled double-blind randomized controlled trial with an intervention phase of 5-7 weeks and a follow-up phase of 12 months Study population: 250 adult (18 years and older) OCD patients who show no/insufficient response to ERP Intervention (if applicable): Low frequency (1 Hz) rTMS to the pre-SMA (compared to sham rTMS to the pre-SMA) as adjuvant treatment to ERP, 4 times/week for at least 5 weeks (20 sessions), with optional extension phase of 1 or 2 weeks (maximum of 28 sessions in total) Main study parameters/endpoints: the pre-versus-post-treatment standardized mean difference (SMD) in severity of OCD (Yale-Brown Obsessive-Compulsive Scale - Y-BOCS), version 2. The post-treatment Y-BOCS score will be obtained at the end of treatment, i.e, after 20, 24 or 28 sessions. Secondary study parameters/endpoints: Response (≥35% reduction on Y-BOCS-v2) and remission (Y-BOCS≤12) as established through international expert opinion Standard Mean Difference (SMD) on the Clinical Global Impression (CGI) severity scale Clinical Global Impression (CGI) improvement scale Quality of life (EQ-5D-5L) Societal costs, measured through the iMTA Productivity Cost Questionnaire (iPCQ) and the iMTA Medical Consumption Questionnaire (iMCQ) Depression, measured using the Beck Depression Inventory (BDI) at baseline, post-treatment and follow-up. In addition we will administer a visual analogue scale (VAS) for depression at these same time points, plus every week during treatment, to monitor the effects of treatment on severity of depressive symptoms. Anxiety, measured using the Beck Anxiety Inventory (BAI) and a VAS; following the same procedure and rationale as for depression. Tolerability of the treatment and side effects, using an in-house questionnaire Exploratory outcomes and/or influencing factors: Patient adherence to treatment protocol, as measured using the Patient Exposure and Response Prevention Adherence Scale (PEAS) Difference between responders and non-responders on circadian rhythm and sleep disorders at baseline as defined by the Holland Sleep Disorders Questionnaire (HSDQ). Structural brain network characteristics (using T1 and diffusion weighted scans) to predict treatment response / relapse. Functional resting-state and task-based (during emotional processing) brain network characteristics (using echo-planar imaging) to predict treatment response / relapse. Variation in the exact stimulation location as ascertained and recorded by neuronavigation in relation to treatment outcome. Contribution of demographic and clinical variables (sex, age, medication status) and pre-existing comorbidities (i.e. comorbid tics, depression, anxiety, autism) to the variance in treatment outcome. In OCD patients with comorbid tics: tic severity, measured using the Yale Global Tic Severity Scale (Y-GTSS). Variation in treatment expectancy (7-items credibility and expectancy questionnaire (CEQ)) and blinding success (1-item question 'in which condition do you think you were?') in relation to treatment outcome.

Official Title
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Transcranial Magnetic Stimulation (TMS) for Patients With Exposure Therapy-resistant Obsessive-compulsive Disorder (OCD): TETRO - a Multicenter Randomized Controlled Trial

Conditions
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1 Hz Real rTMS to the Pre-SMA, 1 Hz Sham rTMS to the Pre-SMA

Intervention / Treatment
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* Combination Product: repetitive transcranial magnetic stimulation (rTMS)


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: OCD as current primary diagnosis Age 18 and older Yale-Brown Obsessive-Compulsive Scale (YBOCS) score of 16 or higher. Insufficient response to state-of-the art exposure therapy with response prevention (ERP) and/or drop-out from ERP due to extreme anxiety/avoidance The following comorbid disorders are allowed (as long as OCD is the current primary diagnosis): depression, other anxiety disorders, ADHD, tic/Tourette's disorder, eating disorders, personality disorders, autism spectrum disorder (when this does not dominate the clinical profile, i.e. is not main diagnosis). Commitment to actively undergo intensive exposure therapy (both supervised during ERP sessions, as well as unsupervised at home) Unmedicated (for at least 8 weeks) or stable dosage of psychotropic medication (for at least 8 weeks), involving serotonergic antidepressants (SSRI, SNRI, clomipramine). Other psychotropic medication that is allowed (provided dosage is stably established for at least 8 weeks): methylphenidate, mood stabilizers, antipsychotic drugs Ability to participate in frequent treatment sessions (4 days/week, for 5 (or 6, or 7) weeks) at one of the 5 sites nearest to their home and/or work Ability to participate in pre-treatment MRI session (for neuronavigation) at one of the 3 academic sites nearest to their home and/or work Capacity for providing informed consent Exclusion Criteria: OCD patients with hoarding as main symptom dimension The following comorbid disorders (current diagnosis) are not allowed: psychotic disorders, bipolar disorder, autism spectrum disorder (when this dominates the clinical profile, i.e. is diagnosed as main disorder), substance use disorder Active suicidal thoughts and intent to act on it Chronic use of benzodiazepines is not allowed Cochlear implant (History of) epilepsy Pregnancy Extreme claustrophobia or metallic objects in or on the body, preventing from participation in MRI session Space-occupying lesion on MRI Previous rTMS treatment (for blinding reasons)

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Interventional Model Description: multi-center placebo-controlled double-blind randomized controlled trial with an intervention phase of 5-7 weeks and a follow-up phase of 12 months
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: real rTMS<br>verum rTMS condition, 1500 continuous 1-Hz pulses to the pre-SMA | Combination Product: repetitive transcranial magnetic stimulation (rTMS)<br>* rTMS (real versus sham) is used as adjuvant to ERP<br>* Other names: exposure therapy with response prevention (ERP);|
| Sham Comparator: sham rTMS<br>sham rTMS condition, 1500 continuous 1-Hz pulses to the pre-SMA | Combination Product: repetitive transcranial magnetic stimulation (rTMS)<br>* rTMS (real versus sham) is used as adjuvant to ERP<br>* Other names: exposure therapy with response prevention (ERP);|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| YBOCS-2 | pre-versus-post-treatment standardized mean difference (SMD) in severity of OCD as measured with the Yale-Brown Obsessive-Compulsive Scale (version 2) | baseline (T0) versus directly post-treatment (5, 6 or 7 weeks post-baseline, dependent on duration of treatment) | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| response and remission | response: ≥35% reduction on Y-BOCS | remission: Y-BOCS≤12 | baseline (T0) versus directly post-treatment (5, 6 or 7 weeks post-baseline, dependent on duration of treatment) + 3, 6 and 12 months follow-up | 
| Standard Mean Difference (SMD) on the Clinical Global Impression (CGI) severity scale | global functioning | baseline (T0) versus directly post-treatment (5, 6 or 7 weeks post-baseline, dependent on duration of treatment) + 3, 6 and 12 months follow-up | 
| Clinical Global Impression (CGI) improvement scale | global improvement | baseline (T0) versus directly post-treatment (5, 6 or 7 weeks post-baseline, dependent on duration of treatment) + 3, 6 and 12 months follow-up | 
| Quality of life (EQ-5D-5L) | quality of life | baseline (T0) versus directly post-treatment (5, 6 or 7 weeks post-baseline, dependent on duration of treatment) + 3, 6 and 12 months follow-up | 
| Societal costs, measured through the iMTA Productivity Cost Questionnaire (iPCQ) | cost effectiveness | baseline (T0) versus directly post-treatment (5, 6 or 7 weeks post-baseline, dependent on duration of treatment) + 6 and 12 months follow-up | 
| Societal costs, measured through the iMTA Medical Consumption Questionnaire (iMCQ) | cost effectiveness | baseline (T0) versus directly post-treatment (5, 6 or 7 weeks post-baseline, dependent on duration of treatment) + 6 and 12 months follow-up | 
| depression, measured through the Beck Depression Inventory | comorbid depression | baseline (T0) versus directly post-treatment (5, 6 or 7 weeks post-baseline, dependent on duration of treatment) + 3, 6 and 12 months follow-up | 
| anxiety, measured through the Beck Anxiety Inventory | comorbid anxiety | baseline (T0) versus directly post-treatment (5, 6 or 7 weeks post-baseline, dependent on duration of treatment) + 3, 6 and 12 months follow-up | 
| Tolerability of the treatment and side effects, using an in-house questionnaire | tolerability and side effects | after 1st and last week of treatment |