Condition category
Mental and Behavioural Disorders
Date applied
01/10/2018
Date assigned
02/10/2018
Last edited
18/09/2020
Prospective/Retrospective
Prospectively registered
Overall trial status
Ongoing
Recruitment status
Recruiting

Plain English Summary

Background and study aims
The study is testing the effectiveness of a new approach to treat treatment-resistant depression using pulses of magnetic stimulation applied to the scalp. Treatment-resistant depression is depression that has not improved with at least two previous antidepressant treatments. The treatment that is being tested is called Transcranial Magnetic Stimulation (TMS) and has been recommended for use in the NHS in the UK by the National Institute for Care Excellence (NICE) as a treatment for treatment-resistant depression. There are uncertainties about how to achieve the best results from this procedure, in terms of where it needs to be targeted on the scalp and the pattern of the magnetic pulses. Recent developments in magnetic resonance brain imaging means that a part of the brain can be located in each person where three different brain systems involved in producing depression symptoms meet. Targeting the magnetic pulses at this site, which varies slightly in its position in each person, can be assessed to see if proportion of people who respond to TMS and the length of time they remain well afterwards might be increased. If so then it may be worth people having these brain scans before receiving TMS.

Who can participate?
Patients aged over 18 with moderate to severe treatment-resistant depression

What does the study involve?
The study lasts for 45 months and participant involvement ends after 39 months. Patients are assessed for eligibility and asked to attend an appointment. If still eligible they undergo an MRI brain scan and are randomly allocated to one of two treatment groups, either repetitive TMS (rTMS) standard treatment or the new treatment connectivity guided intermittent theta-burst stimulation (cgiTBS). Patients are asked to attend 20 treatment sessions over 4-6 weeks. They are followed up at 8, 16 and 26 weeks with another MRI scan at 16 weeks.

What are the possible benefits and risks of participating?
Current evidence suggests that 1 in 20 people who receive TMS will experience a side effect. In most cases this is in the form of headache, neck pain or scalp discomfort, while others report light-headedness, watering eyes, tinnitus, muscle tightness and nausea. If any of side effects happen, participants will be advised how to manage these problems. A small proportion (estimated as 1 in 1000) may experience a seizure upon receiving TMS. If participants have a seizure they will be medically reviewed before any further treatment is offered. The researchers cannot promise the study will help participants, but the information from this study may help to determine the most favourable method for administering TMS for the treatment of treatment-resistant depression in the future.

Where is the study run from?
1. Queens Medical Centre (UK)
2. Berrywood Hospital (UK)
3. St Nicholas' Hospital (UK)
4. St Pancras Hospital (UK)

When is the study starting and how long is it expected to run for?
February 2018 to September 2021

Who is funding the study?
National Institute for Health Research (NIHR) (UK)

Who is the main contact?
Mrs Yvette Walters
ylw10@leicester.ac.uk

Trial website

Contact information

Type

Scientific

Primary contact

Mrs Yvette Walters

ORCID ID

Contact details

Leicester Clinical Trials Unit
University of Leicester
Maurice Shock Building
University Road
Leicester
LE1 7RH
United Kingdom
+44 (0)116 229 7245
ylw10@leicester.ac.uk

Additional identifiers

EudraCT number

ClinicalTrials.gov number

Protocol/serial number

39297

Study information

Scientific title

Randomised double-blind controlled trial of connectivity guided theta burst transcranial magnetic stimulation versus repetitive transcranial magnetic stimulation for treatment resistant moderate to severe depression evaluation of efficacy, cost effectiveness and mechanism of action

Acronym

BRIGhTMIND Version 1.0

Study hypothesis

The specific hypotheses for the mechanistic component of the study are:
1. To determine the differential change at 16 weeks between responders and non-responders to treatment (in either treatment arm) in functional connectivity between affective, default and cognitive control networks. The main hypotheses are that connectivity between insula and DLPFC at baseline will distinguish responders from non-responders, and that DLPFC-DMPFC connectivity decrease will be greater in responders than in non-responders.
2. To discern whether DLPFC-DMPFC FC change at 16 weeks is correlated with change in HDRS-17 score at 16 weeks. The hypothesis is that a greater reduction in DLPFC-DMPFC FC is correlated with a greater reduction in HDRS-17.
3. To assess whether prefrontal GABA change at 16 weeks is correlated with change in HDRS-17 score at 16 weeks. The hypothesis is that TBS-induced GABA changes are correlated with a reduction in HDRS-17.
4. To evaluate neurophysiological defined brain signatures at baseline as predictors of depression response or nonresponse to cgiTBS or rTMS. The exploratory hypothesis is that functional connectivity based biotypes can be optimised using advanced computational analytics to individually predict treatment response in TRD patients.
5. To further study the neural mechanisms underlying therapeutic efficacy we will assess interrelations of changes in complex brain network metrics (including the use of graph analysis) with improvement of clinical symptoms. This is an exploratory aim.

Ethics approval

East Midlands Leicester Central, 30/08/2018, ref: 18/EM/0232

Study design

Randomised; Interventional; Design type: Treatment, Device, Imaging, Psychological & Behavioural, Complex Intervention

Primary study design

Interventional

Secondary study design

Randomised controlled trial

Trial setting

Hospitals

Trial type

Treatment

Patient information sheet

Not available in web format, please use the contact details to request a patient information sheet

Condition

Depression

Intervention

The study is a multicentre parallel group, double blinded randomised controlled trails of efficacy of Connectivity Guided Intermittent theta-burst stimulation (cgiTBS) versus no connectivity guided standard Repetitive Transcranial Magnetic Stimulation (rTMS ); in patients over the age of 18 who have a diagnosis of moderate to severe major depressive disorder and have treatment-resistant depression. The study will look to recruit 368 patients (184 in each treatment group) from 4 sites beginning in Nottingham then Northampton, London and Newcastle. Recruitment will be from both primary and secondary care settings by a letter of invitation requesting a reply slip to be returned to the research team.

Eligibility screening
Interested patients will receive a eligibility screening telephone call, and if eligible they will be invited to attend a baseline assessment.

Baseline assessment
The baseline assessment, which will take a maximum of 2 hours, will be to obtain consent and answer any questions, then to assess their clinical symptoms by the completion of researcher interviews and self-rated questionnaires which will further establish their eligibility to take part. Further checks on medical history may be required.

Baseline MRI scan
Following this they will be invited to attend within 14 days, an MRI scan of the brain which will last for no longer than 1 hour.

Randomisation and treatment
Within 14 days of the scan participants will be invited to attend for their first treatment session, at this stage they will be randomly allocated to one of two treatment groups, either Repetitive Transcranial Magnetic Stimulation (rTMS) Standard Treatment or Connectivity Guided Intermittent theta-burst stimulation (cgiTBS) Novel treatment. TMS machines used for the study will involve placing a device on the surface of the scalp whilst in a seating position. The position of the device will be determined either from the previously obtained brain scan using the standard region for rTMS or optimal location for cgiTBS. Participants will receive a sequence of several short bursts of stimulation via the device, with routine gaps in between or a period of continuous stimulation for nearly 40 minutes, depending on which random group they are allocated to. Allocation of treatment will not be disclosed to the participant. All participants first treatment session will take up to 2 hours,there will be 20 treatment sessions over a 4-6 weeks period, with each treatment session taking 45- 60 minutes for both groups. Both groups will asked if they have any side effects arising from the therapy, after every treatment session or a maximum of 72 hours after. In addition, all groups will have access to email and telephone advice from the research team in case of any problems or side effects arising from the treatments.

Repetitive Transcranial Magnetic Stimulation (rTMS)
Individuals assigned to rTMS will follow the standard US Food and Drug Administration (FDA) approved protocol. A single coil is placed over the left DLPFC. Stimulation is at 120% motor threshold with 75 x 4-second trains of 10Hz interspersed by 26-second intertrain intervals. The site of stimulation will be determined using the Beam F3 method which has been shown to be highly comparable in terms of the site of stimulation to expensive but gold standard MRI neuronavigation methods BeamF3 is an algorithm to provide accurate localization of the F3 electrode site from just three measurements: head circumference, nasion-inion distance, and left tragus-right tragus distance.

Connectivity Guided Intermittent Theta Burst Stimulation (cgiTBS)
Individuals assigned to cgiTBS will receive bursts of 3 pulses (80% motor threshold) at 50Hz applied at a frequency of 5 Hz (i.e. every 200 ms) for 40 seconds duration over a site determined from the assessment of maximal strength of connectivity between the anterior insula and the left dorsolateral prefrontal cortex (DLPFC) from fMRI as described above. The pulses are repeated for a total of 5 runs with 5 minutes rest intervals between runs.

Follow up visits 8 and 16 weeks post randomisation
Follow up Visits will take place at 8, 16 after randomisation, participant’s clinical symptoms will be reassessed with repeated completion of researcher interviews and self-rated questionnaires from the baseline assessment. If at 16 weeks there has been no improvements the participants Clinical Care will be reviewed, by a clinical expert in treatment resistant depression to assess whether further changes to their treatment regime is required

MRI scan - 16 weeks
Within 14 days of the 16 week follow up appointment participants will also have another MRI brain scan, this will help us in estimating the lasting effects of TMS on the brain, so we can assess predictors of treatment response. This appointment will last 60 minutes.

Follow up assessment at 26 weeks
26 weeks post randomisation a final assessment will be completed and disclosure to the participant of what treatment they have received will be made. All participants will have their clinical care reviewed by a clinical expert in treatment resistant depression. This will complete the participants involvement in the study.

Intervention type

Device

Phase

Drug names

Primary outcome measure

The efficacy of cgiTBS at 16 weeks (primary clinical outcome, 50% drop in HDRS-17 score from baseline to 16 weeks) and 26 weeks compared with standard rTMS; in people with TRD ; Timepoint(s): 16 and 26 weeks post randomisation

Secondary outcome measures

1. Depression is measured using Hamilton Depression Rating Scale (HDRS)-17 at baseline (repeated at before treatment is exceeds 4 weeks from baseline), 8, 16 and 26 weeks post randomisation
2. Treatment resistant depression is measured using Massachusetts Generalised Hospital scale at baseline (MGH)
3. Information on socio-demographics, diagnosis measured using Socio Demographics (SCID-11) at baseline
4. Childhood emotional trauma measured using Childhood Trauma Questionnaire (CTQ) at baseline
5. Characteristic attitudes and symptoms of depression are measured using Beck Depression Inventory (BDI-2) at baseline and 8, 16 and 26 weeks post randomisation
6. Symptoms of depression measured using Patient Health Questionnaire (PHQ-9) at baseline and 8, 16 and 26 weeks post randomisation
7. Health utility and quality of life measured using EuroQol-5D-5L Questionnaire (EQ-5D-5l) at baseline and 8, 16 and 26 weeks post randomisation
8. Anxiety and depression measured using Generalised Anxiety and Depression scale (GAD-7) at baseline and 8, 16 and 26 weeks post randomisation
9. Cognitive functioning in patients with major depression measured using Thinc –Integrated Tool (Thinc-It) at baseline and 8, 16 and 26 weeks post randomisation
10. Impairment in functioning measured using Work and Social Adjustment (WSAS) at baseline and 8, 16 and 26 weeks post randomisation
11. Acceptability of recruitment and barriers assessed using Patient Rating Acceptability after every treatment session and at 8, 16 and 26 weeks post randomisation
12. Health economics measured using specially designed Client Resource Proforma at baseline and 16 and 26 weeks post randomisation
13. Side effects measured using side effect checklist after every treatment session and at 8 weeks post randomisation
14. Mechanisms of therapeutic efficacy using multimodal MRI at baseline and 16 weeks pot randomisation

Overall trial start date

01/02/2018

Overall trial end date

31/01/2023

Reason abandoned (if study stopped)

Eligibility

Participant inclusion criteria

1. Adults > 18 years
2. Diagnosis of MDD (defined according to DSM-5) that is treatment resistant (defined as scoring 2 or more on the Massachusetts General Hospital Treatment Resistant Depression staging score)
3. Capacity to provide informed consent before any trial related activities

Participant type

Patient

Age group

Adult

Gender

Both

Target number of participants

Planned Sample Size: 368; UK Sample Size: 368

Participant exclusion criteria

Current exclusion criteria as of 02/07/2019:
1. History of bipolar disorder (due to risk of mania) or depression secondary to other mental disorder
2. Neurological conditions e.g. brain neoplasm, cerebrovascular events, epilepsy, neurodegenerative disorders, and prior brain surgery
3. Standard contradictions to MRI i.e. irremovable metal objects in and around body e.g. cardiac pacemaker, implanted medication pump and pregnancy (any doubt resolved by pregnancy test, women of childbearing age taking precautions against pregnancy). This will include other potential complicated factors such as red tattoos which consist of iron on the head, neck and back and claustrophobia (we offer mock scanner testing and training in some sites)
4. Major unstable medical illness requiring further investigation or treatment
5. Change in prescribed medication 2 weeks before baseline assessment
6. Prescription of lamotrigine, gabapentin, pregabalin in the 2 weeks prior to baseline assessment
7. Daily prescription of benzodiazepine above 5 mg diazepam equivalents, zopiclone above 7.5 mg, zolpidem above 10 mg or zaleplon above 10 mg. These drugs should not be used intermittently in the 2 weeks before baseline assessment
8. Current substance abuse or dependence (defined by DSM-5 criteria)
9. Prior TMS treatment
10. At risk of suicidality
11. Potential complicated factors relating to the TMS treatment i.e hairstyles which would impair magnetic transmission and piercings (participants would only be excluded if they chose to not make the changes required to ensure effective treatment)
12. Involved with any other clinical trial at the time of consent or 6 months prior
13. Unable to read or understand English

Previous exclusion criteria:
1. History of bipolar disorder (due to risk of mania) or depression secondary to other mental disorder
2. Neurological conditions e.g. brain neoplasm, cerebrovascular events, epilepsy, neurodegenerative disorders, and prior brain surgery
3. Standard contradictions to MRI i.e. irremovable metal objects in and around body e.g. cardiac pacemaker, implanted medication pump and pregnancy (any doubt resolved by pregnancy test, women of childbearing age taking precautions against pregnancy). This will include other potential complicated factors such as red tattoos which consist of iron on the head, neck and back and claustrophobia (we offer mock scanner testing and training in some sites)
4. Major unstable medical illness requiring further investigation or treatment
5. Change in prescribed medication in the 2 weeks preceding the start of TMS trial or prescription of lamotrigine, pregabalin, gabapentin or benzodiazepines that act on brain glutamate or GABA (only occasional use of other hypnotic drugs zopiclone, zolpidem, zoleplon and promethazine will be allowed)
6. Current substance abuse or dependence (defined by DSM-5 criteria)
7. Prior TMS treatment
8. At risk of suicidality
9. Potential complicated factors relating to the TMS treatment i.e hairstyles which would impair magnetic transmission and piercings (participants would only be excluded if they chose to not make the changes required to ensure effective treatment)
10. Involved with any other clinical trial at the time of consent or 6 months prior
11. Unable to read or understand English

Recruitment start date

15/10/2018

Recruitment end date

31/01/2022

Locations

Countries of recruitment

United Kingdom

Trial participating centre

Queens Medical Centre
Bridge Room ECT clinic A Floor, South Block Derby Road
Nottingham
NG7 2UH
United Kingdom

Trial participating centre

Berrywood Hospital
Centre for Neuromodulation Quayside Duston
Northampton
NN5 6UD
United Kingdom

Trial participating centre

St Nicholas' Hospital
Gibside Ward Gosforth
Newcastle upon Tyne
NE3 3XT
United Kingdom

Trial participating centre

St Pancras Hospital
TMS Clinic Camley Centre 4 St Pancras Way
London
NW1 0PE
United Kingdom

Sponsor information

Organisation

Nottinghamshire Healthcare NHS Foundation Trust

Sponsor details

The Resource
Trust HQ
Duncan Macmillan House
Porchester Road
Nottingham
NG3 6AA
United Kingdom
+44 (0)1156961300
RandIenquiries@nottshc.nhs.uk

Sponsor type

Hospital/treatment centre

Website

Funders

Funder type

Government

Funder name

NIHR Evaluation, Trials and Studies Co-ordinating Centre (NETSCC); Grant Codes: 16/44/22

Alternative name(s)

Funding Body Type

Funding Body Subtype

Location

Results and Publications

Publication and dissemination plan

All participants will be sent a report summary of the results. Publication plans will be approved by the Trial Steering Committee will be written by the TMG during the study with the sponsor and funder approvals. It is envisaged that the results of the study will be published in the relevant peer-reviewed journals. Acknowledgement of any supporting organisations, including funders, and the Nottinghamshire Healthcare NHS Foundation Trust and the LCTU, will be included.

IPD sharing statement
The datasets generated and/or analysed during the current study during this study will be included in the subsequent results publication.

Intention to publish date

31/01/2024

Participant level data

Other

Basic results (scientific)

Publication list

2020 protocol in https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7342821/ (added 18/09/2020)

Publication citations

Additional files

Editorial Notes

18/09/2020: The following changes have been made: 1. Recruitment has resumed. 2. The recruitment end date has been changed from 30/09/2020 to 31/01/2022. 3. The overall trial end date has been changed from 30/09/2021 to 31/01/2023. 4. The intention to publish date has been changed from 30/09/2022 to 31/01/2024. 5. Publication reference added. 23/04/2020: Due to current public health guidance, recruitment for this study has been paused. 02/07/2019: The exclusion criteria were updated. 28/03/2019: The condition has been changed from "Specialty: Mental Health, Primary sub-specialty: Depression; Health Category: Mental health; Disease/Condition: Mood [affective] disorders" to "Depression" following a request from the NIHR.