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: OCD severity at post-treatment, as measured by the Yale-Brown Obsessive-Compulsive Scale (Y-BOCS, v1). The primary endpoint is the difference between the active and sham intervention groups in post-treatment severity of OCD, estimated using an ANCOVA model that adjusts for pre-treatment severity of OCD. The intervention effect will also be reported as a standardized mean difference.

Secondary outcomes - Clinical

• Response (=35% reduction on Y-BOCS v1)
• Remission (Y-BOCS v1 <12)
• The severity of OCD, as measured using the newer version of the Yale-Brown Obsessive-Compulsive Scale - Y-BOCS v2. A combined version of the Y-BOCS v1 and v2 is administered pre-treatment and post-treatment. Additionally, Y-BOCS-v2 severity scores are collected weekly during treatment and at all follow-up sessions, enabling comparison between the two versions and potentially supporting further implementation of the newer Y-BOCS v2.
• The Clinical Global Impression (CGI) severity scale
• Comorbid depression symptoms, measured using the Beck Depression Inventory (BDI) at baseline, post-treatment and follow-up. In addition we administer a VAS for depression at these same time points, plus every week during treatment, to monitor treatment response on mood. The simultaneous administration of VAS and BDI at baseline and post-treatment will allow us to scale and validate the VAS relative to the BDI, while offering a much quicker and simpler assessment for the participants
• Anxiety, measured using the Beck Anxiety Inventory (BAI) and a VAS; following the same procedure and rationale as for depression.
• For participants with comorbid tics, as identified using the Yale Global Tic Severity Scale (YGTSS), tic severity will be assessed using the same scale.

Tolerability of the treatment and side effects, using an in-house questionnaire developed as part of our previous TIPICCO trial.

Secondary outcomes - Cost-effectiveness

• Societal costs will be measured using the iMTA Productivity Cost Questionnaire (iPCQ) and the iMTA Medical Consumption Questionnaire (iMCQ).
• Quality of life (EQ-5D-5L). Quality-Adjusted Life-Years (QALYs) are the most important outcome measure for healthcare decision makers when deciding about the reimbursement of healthcare interventions.

Secondary outcomes - Neuroplasticity

• Blood sampling at baseline, directly post-treatment and at 3 months follow-up is performed to establish markers of treatment-induced neuroplasticity and predictors of treatment response.
• Pre- and post-treatment MRI scans to analyse ERP and rTMS-induced effects on multiple levels in the brain, using innovative multi-modal neuroimaging.
• Pre-treatment structural and functional MRI scans to assess brain structure and network activation and connectivity to predict treatment response.

Exploratory variables:

• Patient adherence to treatment protocol, as measured using the Patient Exposure and Response Prevention Adherence Scale (PEAS) and its relationship to treatment outcome. This scale is carried out by the therapists as part of usual treatment.
• Difference between responders and non-responders on circadian rhythm and other sleep disorders at baseline as defined by the Holland Sleep Disorders Questionnaire (HSDQ), as a possible prognostic marker for response.
• The relationship of demographic and clinical variables (gender, age, medication status) and pre-existing comorbidities (i.e. comorbid tics, depression, anxiety, autism) to the treatment outcome. A simplified Dutch version of the Mini-International Neuropsychiatric Interview (M.I.N.I.) for DSM-5-diagnoses is used to confirm OCD diagnosis and establish current comorbidity. To specifically evaluate symptoms of comorbid autism spectrum disorder, the Dutch version of the Autism Spectrum Questionnaire (AQ-NL) is administered.
• The Y-BOCS symptom checklist is used to categorize symptom dimensions and examine treatment effects and underlying mechanisms in different OCD subgroups.
• Measuring the exact stimulation location as ascertained and recorded by neuronavigation on three separate sessions (session 1, 10 and 20) will allow us to map the variation in achieved location in relation to treatment outcome.
• Variation in treatment expectancy (7-items credibility and expectancy questionnaire) 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

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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)