Dutch-Depression Outcome Trial Comparing 5 Day Multi Daily Neuronavigated Theta Burst Sessions With 6 Weeks rTMS (DDOTT)

April 4, 2024 updated by: Annemiek Dols, MD, PhD, Amsterdam UMC, location VUmc

Higher, Faster, Better: Is an Accelerated Intermittent Theta Burst Stimulation Protocol Compared to Standard 10 Hz Repetitive Transcranial Magnetic Stimulation, More (Cost-) Effective in Patients With Treatment-resistant Depression?

INTRODUCTION Recent findings from three small studies (total n=59) suggest that three changes in repetitive Transcranial Magnetic Stimulation (rTMS) protocols, called the Stanford Neuromodulation Therapy (SNT) protocol, contribute to extreme high overall remission of 79% in patients with treatment resistant depression (TRD), whereas remission using a standard 10 Hz rTMS protocol is 25%. The improvement using the SNT protocol is achieved by combining 1) accelerated treatment with multiple sessions per day, 2) applying a higher overall pulse dose of stimulation, using intermittent Theta Burst Stimulation (iTBS), and 3) precise targeting of the region in the left dorsolateral prefrontal cortex (DLPFC), using functional MRI guided neuronavigation.

OBJECTIVE To determine if the SNT protocol is more (cost-) effective compared to standard 10 Hz rTMS in patients with TRD, even though the number of pulses given in both protocols is equal, i.e., 90,000.

STUDY DESIGN Multicenter randomized controlled trial comparing SNT with standard 10Hz rTMS with a follow-up of 25 weeks.

STUDY POPULATION 108 Patients with TRD (no response to 2 or more evidence-based treatments).

INTERVENTION 50 sessions using the SNT protocol in 5 days. The region of the left DLPFC most anticorrelated with the subgenual anterior cingulate cortex in each participant will be targeted based on subject-specific functional resting state MRI.

COMPARISON 30 standard daily 10 Hz rTMS sessions in six weeks, targeting the left DLPFC based on standard measurement procedures of the skull.

OUTCOME MEASURES

  • Remission, based on the Hamilton depression rating scale
  • Cost effectiveness, based on healthcare resource use
  • Quality of life and positive mental health
  • Tolerability and safety
  • Relapse
  • Description of opportunities and difficulties with regard to implementation

SAMPLE SIZE The investigators will enrol 108 patients (α=0.05, power is 0.80) including adjustment for attrition.

COST EFFECTIVENESS ANALYSIS SNT is faster and possibly more effective than 10Hz rTMS leading to a total cost reduction of 22 million each year considering less expensive healthcare, reduced illness duration and absence from work.

TIME SCHEDULE Within 36 months, the investigators will recruit and treat 108 patients with TRD: each center will recruit 9 patients per year. After the last follow-up assessments, the investigators will finalise the study within 12 months and report the results.

Study Overview

Status

Recruiting

Conditions

Intervention / Treatment

Detailed Description

Rationale: Novel therapies are crucial for patients with unipolar depression since more than 33% of these patients are medication-resistant. As a consequence, there is a high burden of illness for patients with depression, leading to increased suicide rates, inability to maintain proper work and/or social role functions, and reduced quality of life. A promising novel treatment strategy is an intensive five-day course of intermittent Theta Burst Stimulation (iTBS), a form of transcranial magnetic stimulation (rTMS), which could lead to exceptionally high remission rates (79%) in patients with treatment resistant depression. However, it remains unclear whether this novel treatment strategy is more effective in depressed patients when compared to standard 10Hz rTMS (remission 30%).

Hypothesis: 5-day multi daily neuronavigated iTBS sessions (developed by Stanford University and coined, SNT, i.e., Stanford NeuromdulaTion protocol) are more (cost-) effective than standard 10 Hz rTMS in patients with treatment resistant depression.

Objective: To determine remission of depression and cost effectiveness using the SNT protocol, in patients with treatment resistant depression who did not respond to two or more evidence-based treatments.

Study design: This study comprises a multicentre, two-phase, randomized clinical trial. Phase 1 comprises a randomized controlled trial. In Phase 1, participants will be assigned to one of the two active treatment conditions, and will receive either treatment using the SNT protocol (5 days of 10 sessions/day, resulting in 50 sessions in total 90000 pulses) or standard 10 Hz left sided rTMS, provided once daily during 6 weeks (30 sessions in total, 90000 pulses). Phase 2 comprises three follow-up measurements, one at 5 weeks, one at 10 weeks and one at 25 weeks after the last treatment with SNT or 10 Hz standard rTMS. Finally, participants who were allocated to standard 10 Hz rTMS will be offered SNT after the end of the study (e.g., 25 weeks after the last rTMS session). Patients allocated to SNT can obtain 10 Hz standard rTMS after SNT has been completed.

Study population: Adult patients with unipolar depression who did not respond to two or more evidence-based treatments for depression, in the current depressive episode, aged 18 years and over.

Sample size: Sample size calculations based on differences in remission suggest that a well-powered trial should consist of 108 patients (for a 2-sided test at alpha=0.05 and with power=0.80).

Intervention: 50 sessions using the SNT protocol in 5 days. The subregion of the left DLPFC most anticorrelated with the subgenual anterior cingulate cortex (sgACC) in each participant will be targeted based on patient-specific functional resting state magnetic resonance imaging .

Comparison: 30 standard daily 10 Hz rTMS sessions in six weeks, targeting the left DLPFC based on standard scalp-based measurement procedures.

Study Type

Interventional

Enrollment (Estimated)

108

Phase

  • Not Applicable

Contacts and Locations

This section provides the contact details for those conducting the study, and information on where this study is being conducted.

Study Contact

Study Contact Backup

Study Locations

Participation Criteria

Researchers look for people who fit a certain description, called eligibility criteria. Some examples of these criteria are a person's general health condition or prior treatments.

Eligibility Criteria

Ages Eligible for Study

  • Adult
  • Older Adult

Accepts Healthy Volunteers

No

Description

Inclusion Criteria:

  • 18 years of age or older;
  • Sufficient level of spoken and written Dutch;
  • Ability to freely provide written informed consent;
  • Current DSM-5 diagnosis of a depressive episode, ascertained by the Mini International Neuropsychiatry Interview (MINI-S).
  • A Hamilton depression rating score (HDRS) of >16 points: this score will be obtained from the SIGH-ADS, a depression rating scale able to determine the HDRS score and a score for atypical depression.
  • have a treatment resistant depression, defined according to the criteria of Conway, that is, lack of remission for eight consecutive weeks after two different evidence-based treatments anti-depressant medication has to be adequately dosed(7,24).
  • Stable anti-depressant medication 6 weeks prior to study. Benzodiazepines may be used up to a dosage equivalent of 3.0 mg lorazepam, and can be lowered over time during the study based on clinical judgement.

Exclusion Criteria:

  • - Bipolar disorder.
  • Current psychotic disorder¸ including psychotic depression, assessed by treating psychiatrist.
  • Suspected dementia, assessed with a dementia screening tool, i.e., the Montreal Cognitive Assessment (MOCA)(25), with a score of less than 20 points, or a clinical suspicion of dementia, or neuroimaging indication for neurodegeneration with a Fazekas > 1 and MTA >1. These cut-offs ensure exclusion of patients with (preclinical) dementia.
  • Active suicidal thoughts and intent to act on it, assessed at the baseline interview and before the start of the trial. This assessment is based on the Columbia suicide severity rating scale, i.e., question 5 is answered positive "Have you started to work out or worked out the details of how to kill yourself? Do you intend to carry out this plan?" (26).
  • Metallic devices implanted above the neck, assessed at the baseline interview.
  • Patients diagnosed with epilepsy, by a neurologist, assessed at the baseline interview.
  • Substance abuse 4 weeks prior to the study, including high dosage of benzodiazepine, a dosage equivalent higher than 3.0 mg lorazepam, assessed at the baseline interview.
  • Inability to understand or comply with study requirements as judged by the investigators, assessed at the baseline interview.
  • Pregnancy

Study Plan

This section provides details of the study plan, including how the study is designed and what the study is measuring.

How is the study designed?

Design Details

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

Arms and Interventions

Participant Group / Arm
Intervention / Treatment
Experimental: intermittent theta burst transcranial magnetic stimulation (iTBS)
5-day multi daily neuronavigated intermittent theta burst sessions (developed by Stanford University) and coined, SNT, i.e., Stanford NeuromdulaTion protocol
Device: iTBS
neuronavigated intermittent theta burst transcranial-magnetic-stimulation
Active Comparator: 10 Hz repetitive-transcranial-magnetic-stimulation (rTMS)
6-weeks standard 10 Hz rTMS
Device: rTMS
10 Hz repetitive-transcranial-magnetic-stimulation

What is the study measuring?

Primary Outcome Measures

Outcome Measure
Measure Description
Time Frame
Remission
Time Frame: After 1 week.
Clinical outcome is remission, which is defined as a score of 7 or lower on the clinician-rated HDRS-17 (17-itemHamilton Depression Rating Scale, scores 0-52 with higher score indicating worse outcome) measured one week after the last treatment session.
After 1 week.

Secondary Outcome Measures

Outcome Measure
Measure Description
Time Frame
Health-related quality of life
Time Frame: After 1-, 5-, 10- and 25-weeks.
Health-related quality of life determined with the EQ 5D-5L (EuroQol 5 Dimension 5 Level, scores 5-25, with higher scores indicating worse outcome).
After 1-, 5-, 10- and 25-weeks.
Self-rated depressive symptoms
Time Frame: After 1-, 5-, 10- and 25-weeks.
Percentual reduction of depressive symptoms as measured with self-rated HDRS-6 (self-rated 6-item Hamilton Depression Rating Scale, scores 0-18 with higher score indicating worse outcome).
After 1-, 5-, 10- and 25-weeks.
Relapse
Time Frame: After1-, 5-, 10- and 25-weeks.
Relapse, at 5-, 10- and 25-weeks post-treatment. Relapse is defined as a HDRS-17 (17-item Hamilton Depression Rating Scale, scores 0-52 with higher score indicating worse outcome) total score of 15 or higher for 2 consecutive assessments separated by 5 to 15 days or hospitalization for depression
After1-, 5-, 10- and 25-weeks.
Side-effects
Time Frame: After 1- and 6- weeks.
Establish tolerability of the treatment and side effects, of SNT and rTMS.
After 1- and 6- weeks.
Remission
Time Frame: 5-, 10- and 25-weeks after the last treatment session.
Clinical outcome is remission, which is defined as a score of 7 or lower on the clinician-rated HDRS-17 (17-item Hamilton Depression Rating Scale, scores 0-52 with higher score indicating worse outcome) measured directly after the last treatment session.
5-, 10- and 25-weeks after the last treatment session.

Collaborators and Investigators

This is where you will find people and organizations involved with this study.

Sponsor

Amsterdam UMC, location VUmc

Collaborators

Radboud University Medical Center
Maastricht University Medical Center
Academisch Medisch Centrum - Universiteit van Amsterdam (AMC-UvA)
Maastricht University
Trimbos
Donders Centre for Neuroscience

Study record dates

These dates track the progress of study record and summary results submissions to ClinicalTrials.gov. Study records and reported results are reviewed by the National Library of Medicine (NLM) to make sure they meet specific quality control standards before being posted on the public website.

Study Major Dates

Study Start (Actual)

November 15, 2023

Primary Completion (Estimated)

April 1, 2027

Study Completion (Estimated)

December 1, 2027

Study Registration Dates

First Submitted

May 10, 2023

First Submitted That Met QC Criteria

June 7, 2023

First Posted (Actual)

June 12, 2023

Study Record Updates

Last Update Posted (Actual)

April 5, 2024

Last Update Submitted That Met QC Criteria

April 4, 2024

Last Verified

April 1, 2024

More Information

Terms related to this study

Keywords

Additional Relevant MeSH Terms

Other Study ID Numbers

  • 10390012110079

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

product manufactured in and exported from the U.S.

No

This information was retrieved directly from the website clinicaltrials.gov without any changes. If you have any requests to change, remove or update your study details, please contact register@clinicaltrials.gov. As soon as a change is implemented on clinicaltrials.gov, this will be updated automatically on our website as well.

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