Clinical trial NCT03333460: Transcranial Magnetic Stimulation for Cocaine Addiction
Official title: Cracking Addiction: Does BRAIN Stimulation-induced Neuroplasticity Reverse Prefrontal Cortex Hypoactivity in Cocaine and neW stImulanTs addiCtion in Humans? (BRAIN SWITCH)
Study type: INTERVENTIONAL
Overall status: UNKNOWN
Phase: NA
Conditions: Cocaine Dependence
Substance Use Disorders
Chemical Addiction
Mental Disorder
Cocaine-Related Disorders
Drug Dependence
Keywords: cocaine
addiction
transcranial magnetic stimulation
neuromodulation
neuroimaging
brain stimulation
Lead sponsor: ITAB - Institute for Advanced Biomedical Technologies
Sponsor class: OTHER
First posted: 2017-11-07
Enrollment: 80
Sex: ALL
Minimum age (years): 18
Maximum age (years): 65
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Intervention model description: double blind, randomized, sham-controlled with a 1:1 allocation into 2 parallel arms
Primary purpose: TREATMENT

Brief summary: Background: Cocaine use disorders (CUD) is a complex brain disorder, involving several brain areas and neurocircuits. Effective treatments for CUD are still needed. Repetitive transcranial magnetic stimulation (rTMS) stimulates non-invasively parts of the brain. Preliminary data suggest that rTMS may help reducing cocaine craving and consumption. Researchers want to learn how the brain and the drug-seeking behavior may change with this treatment.

Objectives: To test if rTMS can reduce cocaine craving and use, and also affect several mood, behavioral and cognitive alterations associated with prolonged cocaine use.

Eligibility: Healthy, right-handed adults ages 18-65 who do have cocaine use disorder (moderate to severe).

Design: This is a randomized, double-blind, sham-controlled study. The study includes three phases: 1) a rTMS continued treatment phase; a rTMS follow-up; and a no rTMS follow-up.

Prior to participating, participants will be screened with:

* Questionnaires
* Medical history
* Physical exam
* Urine tests
* MRI (structural)

After being enrolled, baseline behavioral and imaging data will be collected. In particular, participants will undergo:

* Questionnaires
* Functional MRI

During the continued rTMS phase, participants with cocaine use disorder will be randomized to receive real or fake rTMS. Repetitive TMS will be delivered during 10 outpatient treatment days, over 2 weeks (5 days/week). Following this phase, subjects will have 12 follow-up visits (once/weekly), during which they will receive rTMS, and behavioral and imaging assessments will be performed. At the end of the rTMS follow up period, participants will further receive 3 follow up visits (once a month), during which rTMS will not be performed, but behavioral data will be collected.

Treatment includes:

* rTMS: A coil is placed on the head. A brief electrical current passes through the coil. At each visit, participants will receive two rTMS sessions, with a 1hr interval between sessions. At the beginning of each rTMS session, they view cocaine-related images for few minutes.
* MRIs at baseline and at follow-up visit #12: Participants lie on a table that slides into a cylinder that takes pictures of the brain. They respond to images while in the scanner.
* Repeat of screening tests and questionnaires
* Urine toxicological screen

Detailed description: Repetitive transcranial magnetic stimulation (rTMS) has been shown to reduce craving in cocaine addicts. However, the efficacy of rTMS in treating cocaine addiction has not been evaluated in double-blind, sham-controlled studies and also, we lack a full characterization of rTMS effects on other important aspects, including effects on mood, cognition and changes in brain function. The purpose of this study is to investigate the effects of repetitive Transcranial Magnetic Stimulation (rTMS) at 15 Hz frequency on the left dorsolateral prefrontal cortex in cocaine dependent patients and to examine possible changes in mood, cognition, and brain activity and functional connectivity associated with this intervention. For this purpose, the investigators will recruit cocaine dependent patients. After screening and informed consent, participants will undergo active or sham rTMS for two consecutive weeks (twice a day) during the continued treatment phase, and a maintenance intervention (twice a week for 3 months), during the rTMs follow-up phase. Following this phase, participants will be followed for further 3 months, during which no rTMS will be delivered but clinical and imaging data will be collected. The investigators will also measure clinical, cognitive and brain structural and functional connectivity to assess changes related to the intervention in the short and long term (measurements at: baseline, 2 weeks, 3 months, 6 months).

Procedure: The project consists of: Screening Visit (baseline), Part 1 (continued treatment phase), Part 2 (3 months- rTMS follow-up), Part 3 (3 months follow-up without rTMS). First, there will be a screening visit, where a clinical interview will be conducted and questionnaires and tests will be administered to identify study participants who meet the inclusion and exclusion criteria. Baseline clinical, cognitive and neuroimaging data will be acquired. The neuroimaging data will be exploratory, to be associated with the outcome measures. In Part 1, all participants will be randomly assigned to one of the two treatment arms with rTMS (15Hz, 15Hz-Sham). Participants will receive 2 sessions of rTMS (active or sham), twice per day for 10 consecutive days, for a total of 20 rTMS sessions. Following this, the investigators will evaluate the acute effect of treatment on cocaine craving and consumption, mood and cognition. Also, they will collect exploratory neuroimaging data (functional MRI and resting state functional connectivity). In Part 2 of the study, all participants will continue the assigned treatment arm with rTMS (15Hz, 15Hz-Sham) for three months. Participants will receive 2 sessions of rTMS (active or sham) once per week; clinical and cognitive data will be acquired once per month. The investigators will evaluate the effect of treatment on cocaine craving and consumption, mood and cognition. Also, they will collect exploratory neuroimaging data (functional MRI and resting state functional connectivity). In Part 3 of the study, participants will not receive any rTMS session. Clinical and cognitive data will be acquired once per month for three months. The investigators will evaluate the long-term effect of treatment on cocaine craving and consumption, mood and cognition.

Eligibility criteria: Inclusion Criteria:

1. Current diagnosis of cocaine use disorder (from moderate to severe), based on the Diagnostic and Statistical Manual of Mental Disorder - Fifth Edition (DSM-5);
2. Abstinence from cocaine for at least 48 hrs.

Exclusion Criteria:

1. Current DSM-5 diagnosis of substance and/or alcohol use disorders other than nicotine;
2. Current DSM-5 diagnosis of schizophrenia, bipolar disorder, or other psychotic disorder;
3. Use in the past 4 weeks of any medication with known pro-convulsant action; or current regular use of any psychotropic medications (benzodiazepines, antipsychotic medications, tricyclic antidepressants, anti-epileptics, mood stabilizers);
4. Any history of any clinically significant neurological disorder, including organic brain disease, epilepsy, stroke, brain lesions, multiple sclerosis, previous neurosurgery, or personal history of head trauma that resulted in loss of consciousness for \> 5 minutes and retrograde amnesia for \> 30 minutes;
5. Any personal or family history (1st degree relatives) of seizures other than febrile childhood seizures;
6. Any psychiatric, medical or social condition whether or not listed above, due to which, in the judgment of the PI and after any consults if indicated, participation in the study is not in the best interest of the patient;
7. For female patients: Pregnancy/breastfeeding.
8. Subjects who have contraindications to MRI. Some of the exclusions are:

   1. Have non-MRI compatible metal in the body, such as a cardiac pacemaker, brain stimulator, shrapnel, surgical metal, clips in the brain or on blood vessels, cochlear implants, artificial heart valves or ferromagnetic fragments in the eye or oral cavity as these make having an MRI unsafe.
   2. Unable to lie flat on the back for the expected length of the experiment (50 minutes).
   3. Have an abnormality on the brain imaging or neurologic examination not related to the diagnosis.
   4. Uncomfortable being in a small space for the expected length of the experiment (50 minutes).
   5. Non-removable body piercing or tattoo posing MRI risk
   6. Pregnancy

Primary outcomes:
measure: Change in the Brief Version of Cocaine Craving Questionnaire (Brief-CCQ) Total score
timeFrame: Baseline, after rTMS treatment: 2 weeks, 3 months, 6 months
measure: Change in cocaine consumption as assessed by Timeline Follow Back (TLFB)
timeFrame: Baseline, after rTMS treatment: 2 weeks, 3 months, 6 months, 12 months
measure: Change in cocaine consumption as assessed by Urine Drug Screen (UDS)
timeFrame: Baseline, after rTMS treatment: 2 weeks, 3 months, 6 months, 12 months
Secondary outcomes:
measure: Changes in 90 Symptom Checklist (SCL-90) Global indices
timeFrame: Baseline, after rTMS treatment: 2 weeks, 3 months, 6 months
measure: Changes in Montgomery-Asberg Depression Scale (MADRS) Total Score
timeFrame: Baseline, after rTMS treatment: 2 weeks, 3 months, 6 months
measure: Changes in Hamilton Rating Scale for Anxiety (HAM-A) Total Score
timeFrame: Baseline, after rTMS treatment: 2 weeks, 3 months, 6 months
measure: Changes in the Frontal Assessment Battery (FAB) Total Score
timeFrame: Baseline, after rTMS treatment: 2 weeks, 3 months, 6 months
measure: Changes in Eriksen Flanker Test
timeFrame: Baseline, after rTMS treatment: 2 weeks, 3 months, 6 months
measure: Changes in the Iowa Gambling Task (IGT) Performance
timeFrame: Baseline, after rTMS treatment: 2 weeks, 3 months, 6 months
measure: Changes in Snaith Hamilton Pleasure Scale (SHAPS) Total Score
timeFrame: Baseline, after rTMS treatment: 2 weeks, 3 months, 6 months
measure: Changes in Temporal experience of Pleasure Scale (TEPS) Total Score
timeFrame: Baseline, after rTMS treatment: 2 weeks, 3 months, 6 months
measure: Changes in Profile of Mood States (POMS), Total Mood Disturbance Score
timeFrame: Baseline, after rTMS treatment: 2 weeks, 3 months, 6 months
Other outcomes:
Locations:
city: Chieti
country: Italy
facility: Department of Neuroscience, Imaging and Clinical Sciences
city: Rome
country: Italy
facility: La Promessa ONLUS
Study officials:
affiliation: Department of Neuroscience, Imaging and Clinical Sciences (ITAB) - University G. d'Annunzio - Chieti (Italy)
name: Massimo di Giannantonio, MD
role: PRINCIPAL_INVESTIGATOR
References:
citation: Martinotti G, Pettorruso M, Montemitro C, Spagnolo PA, Acuti Martellucci C, Di Carlo F, Fanella F, di Giannantonio M; Brainswitch Study Group. Repetitive transcranial magnetic stimulation in treatment-seeking subjects with cocaine use disorder: A randomized, double-blind, sham-controlled trial. Prog Neuropsychopharmacol Biol Psychiatry. 2022 Jun 8;116:110513. doi: 10.1016/j.pnpbp.2022.110513. Epub 2022 Jan 22.
citation: Pettorruso M, Spagnolo PA, Leggio L, Janiri L, Di Giannantonio M, Gallimberti L, Bonci A, Martinotti G. Repetitive transcranial magnetic stimulation of the left dorsolateral prefrontal cortex may improve symptoms of anhedonia in individuals with cocaine use disorder: A pilot study. Brain Stimul. 2018 Sep-Oct;11(5):1195-1197. doi: 10.1016/j.brs.2018.06.001. Epub 2018 Jun 5. No abstract available.