TETRO: TMS for Exposure Therapy Resistant OCD
Study Details
Study Description
Brief Summary
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).
| Condition or Disease | Intervention/Treatment | Phase |
|---|---|---|
|
Phase 3 |
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: 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:
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Response (≥35% reduction on Y-BOCS-v2) and remission (Y-BOCS≤12) as established through international expert opinion
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Standard Mean Difference (SMD) on the Clinical Global Impression (CGI) severity scale
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Clinical Global Impression (CGI) improvement scale
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Quality of life (EQ-5D-5L)
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Societal costs, measured through the iMTA Productivity Cost Questionnaire (iPCQ) and the iMTA Medical Consumption Questionnaire (iMCQ)
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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.
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Anxiety, measured using the Beck Anxiety Inventory (BAI) and a VAS; following the same procedure and rationale as for depression.
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Tolerability of the treatment and side effects, using an in-house questionnaire
Exploratory outcomes and/or influencing factors:
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Patient adherence to treatment protocol, as measured using the Patient Exposure and Response Prevention Adherence Scale (PEAS)
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Difference between responders and non-responders on circadian rhythm and sleep disorders at baseline as defined by the Holland Sleep Disorders Questionnaire (HSDQ).
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Structural brain network characteristics (using T1 and diffusion weighted scans) to predict treatment response / relapse.
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Functional resting-state and task-based (during emotional processing) brain network characteristics (using echo-planar imaging) to predict treatment response / relapse.
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Variation in the exact stimulation location as ascertained and recorded by neuronavigation in relation to treatment outcome.
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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.
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In OCD patients with comorbid tics: tic severity, measured using the Yale Global Tic Severity Scale (Y-GTSS).
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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.
Study Design
Arms and Interventions
| 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:
|
| 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:
|
Outcome Measures
Primary Outcome Measures
- YBOCS-2 [baseline (T0) versus directly post-treatment (5, 6 or 7 weeks post-baseline, dependent on duration of treatment)]
pre-versus-post-treatment standardized mean difference (SMD) in severity of OCD as measured with the Yale-Brown Obsessive-Compulsive Scale (version 2)
Secondary Outcome Measures
- response and remission [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]
response: ≥35% reduction on Y-BOCS | remission: Y-BOCS≤12
- Standard Mean Difference (SMD) on the Clinical Global Impression (CGI) severity scale [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]
global functioning
- Clinical Global Impression (CGI) improvement scale [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]
global improvement
- Quality of life (EQ-5D-5L) [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
- Societal costs, measured through the iMTA Productivity Cost Questionnaire (iPCQ) [baseline (T0) versus directly post-treatment (5, 6 or 7 weeks post-baseline, dependent on duration of treatment) + 6 and 12 months follow-up]
cost effectiveness
- Societal costs, measured through the iMTA Medical Consumption Questionnaire (iMCQ) [baseline (T0) versus directly post-treatment (5, 6 or 7 weeks post-baseline, dependent on duration of treatment) + 6 and 12 months follow-up]
cost effectiveness
- depression, measured through the Beck Depression Inventory [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]
comorbid depression
- anxiety, measured through the Beck Anxiety Inventory [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]
comorbid anxiety
- Tolerability of the treatment and side effects, using an in-house questionnaire [after 1st and last week of treatment]
tolerability and side effects
Other Outcome Measures
- tic severity, measured using the Yale Global Tic Severity Scale (YGTSS) [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]
tic severity (only in OCD patients with comorbid tics)
Eligibility Criteria
Criteria
Inclusion Criteria:
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OCD as current primary diagnosis
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Age 18 and older
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Yale-Brown Obsessive-Compulsive Scale (YBOCS) score of 16 or higher.
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Insufficient response to state-of-the art exposure therapy with response prevention (ERP) and/or drop-out from ERP due to extreme anxiety/avoidance
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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).
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Commitment to actively undergo intensive exposure therapy (both supervised during ERP sessions, as well as unsupervised at home)
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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
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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
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Ability to participate in pre-treatment MRI session (for neuronavigation) at one of the 3 academic sites nearest to their home and/or work
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Capacity for providing informed consent
Exclusion Criteria:
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OCD patients with hoarding as main symptom dimension
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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
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Active suicidal thoughts and intent to act on it
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Chronic use of benzodiazepines is not allowed
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Cochlear implant
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(History of) epilepsy
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Pregnancy
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Extreme claustrophobia or metallic objects in or on the body, preventing from participation in MRI session
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Space-occupying lesion on MRI
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Previous rTMS treatment (for blinding reasons)
Contacts and Locations
Locations
| Site | City | State | Country | Postal Code | |
|---|---|---|---|---|---|
| 1 | Amsterdam UMC, location VU Medical Center | Amsterdam | Noord-Holland | Netherlands | 1081 HZ |
| 2 | GGZ inGeest | Amsterdam | Netherlands | ||
| 3 | Neurocare | Eindhoven | Netherlands | ||
| 4 | Neurocare | Groningen | Netherlands | ||
| 5 | Maastricht UMC+ | Maastricht | Netherlands | ||
| 6 | Mondriaan | Maastricht | Netherlands | ||
| 7 | ProPersona | Nijmegen | Netherlands | ||
| 8 | Radboudumc | Nijmegen | Netherlands |
Sponsors and Collaborators
- Amsterdam UMC, location VUmc
- GGZ inGeest
- Radboud University Medical Center
- ProPersona
- Maastricht University Medical Center
- Mondriaan
- Neurocare
Investigators
None specified.Study Documents (Full-Text)
None provided.More Information
Publications
- 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. Review.
- 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. Review.
- 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. Review.
- 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. Review.
- 2021.0670 - NL78930.029.21