TMS for Exposure Therapy Resistant OCD (TETRO)

Amsterdam UMC, location VUmc

Status and phase: Enrolling; Phase 3

Conditions: 1 Hz Sham rTMS to the Pre-SMA; 1 Hz Real rTMS to the Pre-SMA

Treatments: Combination Product: repetitive transcranial magnetic stimulation (rTMS)

Study type: Interventional

Funder types: Other

Identifiers

NCT05331937

2021.0670 - NL78930.029.21

Details and patient eligibility

About

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).

Full description

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.

Enrollment: 250 estimated patients

Sex: All

Ages: 18+ years old

Volunteers: No Healthy Volunteers

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)

Trial design

Primary purpose: Treatment

Allocation: Randomized

Interventional model: Parallel Assignment

Masking: Quadruple Blind

---

250 participants in 2 patient groups

real rTMS

Experimental group

Description:

verum rTMS condition, 1500 continuous 1-Hz pulses to the pre-SMA

Treatment:

Combination Product: repetitive transcranial magnetic stimulation (rTMS)

sham rTMS

Sham Comparator group

Description:

sham rTMS condition, 1500 continuous 1-Hz pulses to the pre-SMA

Treatment:

Combination Product: repetitive transcranial magnetic stimulation (rTMS)