TMS for Exposure Therapy Resistant OCD (TETRO)

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

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).

Study Overview

• Status: Recruiting
• Conditions: 1 Hz Real rTMS to the Pre-SMA; 1 Hz Sham rTMS to the Pre-SMA
• Intervention / Treatment: Combination product: repetitive transcranial magnetic stimulation (rTMS)

Detailed 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

• Study Type: Interventional
• Enrollment (Estimated): 250
• Phase: Phase 3

Contacts and Locations

• Study Contact: Name: Odile A van den Heuvel, MD PhD; Phone Number: +31-20-4444444; Email: oa.vandenheuvel@amsterdamumc.nl
• Study Contact Backup: Name: Tjardo S Postma, MD; Phone Number: +31-20-4444444; Email: tetro@amsterdamumc.nl

Study Locations

• Netherlands
  • Amsterdam, Netherlands
    • Recruiting
    • GGz inGeest
    • Contact: Neeltje M Batelaan, MD PhD; Phone Number: +31-20-788 4641; Email: n.batelaan@ggzingeest.nl
  • Eindhoven, Netherlands
    • Not yet recruiting
    • Neurocare
    • Contact: Iris van Oostrom, PhD; Phone Number: +31-24-7503507; Email: iris.vanoostrom@neurocaregroup.com
  • Groningen, Netherlands
    • Not yet recruiting
    • Neurocare
    • Contact: Iris van Oostrom, PhD; Phone Number: +31-24-7503507; Email: iris.vanoostrom@neurocaregroup.com
  • Maastricht, Netherlands
    • Not yet recruiting
    • Maastricht UMC+
    • Contact: Alexander Sack, PhD; Email: a.sack@maastrichtuniversity.nl
  • Maastricht, Netherlands
    • Not yet recruiting
    • Mondriaan
    • Contact: Koen Schruers, MD PhD; Phone Number: +31-88-5066262; Email: koen.schruers@maastrichtuniversity.nl
  • Nijmegen, Netherlands
    • Not yet recruiting
    • Radboudumc
    • Contact: Indira Tendolkar, MD PhD; Phone Number: +31-24-3613489; Email: indira.tendolkar@radboudumc.nl
  • Nijmegen, Netherlands
    • Not yet recruiting
    • ProPersona
    • Contact: Gert-Jan Hendriks, MD PhD; Phone Number: +31-06-13 578578; Email: g.hendriks@propersona.nl
  • North Holland
    • Amsterdam, North Holland, Netherlands, 1081 HZ
      • Recruiting
      • Amsterdam UMC, location VU Medical Center
      • Contact: Odile A van den Heuvel, MD PhD; Phone Number: +31-20-4444444; Email: oa.vandenheuvel@amsterdamumc.nl
      • Principal Investigator: O A van den Heuvel, MD PhD

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Description

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)

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Quadruple

Number of Arms

2

Arms and Interventions

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

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Y-BOCS	The severity of OCD as measured by the Yale-Brown Obsessive-Compulsive Scale Y-BOCS I	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.

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

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
tic severity, measured using the Yale Global Tic Severity Scale (YGTSS)	tic severity (only in OCD patients with comorbid tics)	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

Collaborators and Investigators

• Sponsor: Amsterdam UMC, location VUmc
• Collaborators: Radboud University Medical Center; Maastricht University Medical Center; GGZ inGeest; Neurocare; Mondriaan; ProPersona

Publications and helpful links

General Publications

• Rehn S, Eslick GD, Brakoulias V. A Meta-Analysis of the Effectiveness of Different Cortical Targets Used in Repetitive Transcranial Magnetic Stimulation (rTMS) for the Treatment of Obsessive-Compulsive Disorder (OCD). Psychiatr Q. 2018 Sep;89(3):645-665. doi: 10.1007/s11126-018-9566-7.
• Zhou DD, Wang W, Wang GM, Li DQ, Kuang L. An updated meta-analysis: Short-term therapeutic effects of repeated transcranial magnetic stimulation in treating obsessive-compulsive disorder. J Affect Disord. 2017 Jun;215:187-196. doi: 10.1016/j.jad.2017.03.033. Epub 2017 Mar 18.
• Stein DJ, Costa DLC, Lochner C, Miguel EC, Reddy YCJ, Shavitt RG, van den Heuvel OA, Simpson HB. Obsessive-compulsive disorder. Nat Rev Dis Primers. 2019 Aug 1;5(1):52. doi: 10.1038/s41572-019-0102-3.
• Fitzsimmons SMDD, van der Werf YD, van Campen AD, Arns M, Sack AT, Hoogendoorn AW; other members of the TETRO Consortium; van den Heuvel OA. Repetitive transcranial magnetic stimulation for obsessive-compulsive disorder: A systematic review and pairwise/network meta-analysis. J Affect Disord. 2022 Apr 1;302:302-312. doi: 10.1016/j.jad.2022.01.048. Epub 2022 Jan 15.

Study record dates

Study Major Dates

• Study Start (Actual): May 16, 2022
• Primary Completion (Estimated): December 1, 2027
• Study Completion (Estimated): December 1, 2027

Study Registration Dates

• First Submitted: March 29, 2022
• First Submitted That Met QC Criteria: April 15, 2022
• First Posted (Actual): April 18, 2022

Study Record Updates

• Last Update Posted (Actual): March 4, 2026
• Last Update Submitted That Met QC Criteria: March 1, 2026
• Last Verified: March 1, 2026

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Therapeutics; Behavior Therapy; Psychotherapy; Behavioral Disciplines and Activities; Magnetic Field Therapy; Desensitization, Psychologic; Transcranial Magnetic Stimulation; Implosive Therapy
• Other Study ID Numbers: 2021.0670 - NL78930.029.21

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No