rTMS and Cognitive-behavioral Therapy for Cocaine Use Disorder

Official title

Augmenting Cognitive-behavioral Therapy With rTMS of the Medial Prefrontal and Anterior Cingulate Cortices for the Treatment of Cocaine Use Disorder

Overview

The goal of the study is to investigate the feasibility, safety, and effect of rTMS on mPFC/dACC activity using a combination of fMRI and clinical outcome measures, when used as an augmentation to CBT. Our hypothesis is that we will meet the following milestones prior to moving forward to the UH3 phase (a clinical trial for CUD). * Feasibility: At least 75% of participants will receive at least 15 out of 20 rTMS sessions with no participants experiencing a study-related serious adverse event * Mechanism: Compared to baseline, after 1 week of rTMS, participants who received active rTMS will demonstrate a 15% decrease in RSFC (resting state functional connectivity) between the DLPFC (dorsolateral prefrontal cortex) and anterior cingulate * Efficacy: During the final 12 weeks of the trial (weeks 2-13), at least 15% of participants who received active rTMS will demonstrate 3 consecutive weeks of abstinence Participants will: * Have two brain MRI scans; * Undergo 1 week of daily rTMS (or sham) treatments (up to 20 sessions), and; * Have 12 weeks of once-weekly cognitive-behavioral therapy for the treatment of cocaine use disorder. Researchers will compare active (real) rTMS to sham (placebo) rTMS. All participants will receive cognitive-behavioral therapy. The former principle investigator, Dr. Derek Blevins, has vacated his position (February 2025), and has transferred the principle investigator role to Dr. John Mariani, the STARS Clinic Director.

Detailed description

Cocaine use disorder (CUD) is significant public health problem in the U.S. There are no FDA approved medications and many people fail to respond to behavioral therapies, meaning that effective treatment strategies are needed. Previous studies have shown that transcranial magnetic stimulation (rTMS) can reduce cocaine use, although many of these studies have been preliminary and didn't have a control group using sham (placebo) rTMS. Thus, the goal of this study is to use a controlled design to assess rTMS as a treatment. Furthermore, we will use the H-7 coil, which is currently FDA cleared for the treatment for obsessive-compulsive disorder (OCD) and major depressive disorder

The trial will use an accelerated protocol to deliver rTMS, where multiple sessions are delivered in a single day \[Roth et al, 2023, Cole et al. 2022\]. Previous studies delivered up to 10 sessions per day \[Cole et al., 2022\]. In this study, we will deliver up to 5 sessions daily, which has been done previously using the H coil \[Roth et al., 2023\]. Accelerated protocols can decrease the time to improvement from weeks to about 5 days \[Roth et al., 2023\].

This is a randomized, double-blind, sham-controlled trial to evaluate the feasibility, neural mechanism, and clinical efficacy of H-7 coil repetitive transcranial magnetic stimulation (rTMS) in 30 individuals with cocaine use disorder (CUD) when used as an augmentation to standardized cognitive-behavioral therapy (CBT). After informed consent, participants will be randomized 2:1 to active iTBS rTMS (n=20) or sham rTMS (n=10). They will undergo baseline assessments and fMRI scans, followed by 1 week of rTMS (up to 5 sessions a day), followed by 12 weeks of weekly in-person or virtual (telemedicine) CBT, for a total of 13 weeks. fMRI scans will be repeated after the rTMS week and before initiating CBT. One brief phone assessment will be completed at week 17.

Interventions

• Device Active H7-coil repetitive transcranial magnetic stimulation (rTMS)
  A magnetic current created by the device creates an electrical current in the brain to stimulate the medial prefrontal cortex and dorsal anterior cingulate cortex.
• Device Sham H7-coil repetitive transcranial magnetic stimulation (rTMS)
  A sham coil is in the same helmet as the active coil. The sham coil mimics the sound, scalp sensations, and facial muscle activation caused by the active coil, but does not create an electrical current in the brain.

Primary outcome measures

• Percentage of participants receiving at least 15 out of 20 rTMS sessions [Time frame: 1 week]
• Number of participants experiencing an rTMS-emergent serious adverse event [Time frame: 1 week]
• Number of participants with 15% decrease in RSFC (resting state functional connectivity) between the DLPFC (dorsolateral prefrontal cortex) and anterior cingulate. [Time frame: 1 week]
• Percentage of participants who achieve 3 weeks of abstinence during the final 12 weeks of the trial [Time frame: 12 weeks]

Eligibility criteria

Inclusion criteria

• Age 22-65;
• Able to give informed consent and comply with study procedures;
• Meets DSM-5 criteria for current moderate/severe CUD and are treatment-seeking;
• Used cocaine at least 9 days in the past 28 days, with at least weekly cocaine use;
• Agree to no more than moderate alcohol consumption (<15 drinks/week for men and <8 drinks/week for women) and to avoid using amphetamine/methamphetamine and non-prescribed benzodiazepines or barbiturates; and
• Women of childbearing potential must agree to use a method of contraception with proven efficacy and agree to not become pregnant during the study.

Exclusion criteria

• Meets DSM-5 criteria for current moderate/severe major depressive episode, OCD, bipolar disorder, schizophrenia or any psychotic disorder other than transient psychosis due to substance use;
• Hamilton Depression Rating Scale score > 17;
• Young Mania Rating Scale score >10;
• Meets DSM-5 criteria for current moderate/severe other substance use disorder (aside from tobacco use disorder; physiologic dependence on any other substance other than nicotine, including alcohol, is exclusionary);
• Heavy weekly alcohol drinking as defined by an average of >14 drinks/week for men or >7 drinks/week for women on average during the past 28 days;
• Prior alcohol, benzodiazepine, or barbiturate withdrawal that resulted in hospitalization, medical detoxification, or resulted in seizures or delirium tremens;
• More than twice weekly use of non-prescribed medications/drugs that may change the seizure threshold, including benzodiazepines, barbiturates, GHB/GBL, amphetamines/methamphetamine;
• Any other current DSM-5 psychiatric disorder(s) that in the investigator's judgment are unstable, would be disrupted by study procedures, or are likely to require pharmacotherapy or psychotherapy during the study period;
• Significant current risk of suicide, indicated by either: (1) "yes" response on #3, #4, or #5 on the C-SSRS and a psychiatric risk assessment indicating a moderate or high risk of suicide or (2) suicidal behavior in the past year that, in the opinion of the clinician, increases risk of future suicidal behavior over the study period (note: non-suicidal self-injurious behavior is not exclusionary).
• Females with a positive urine pregnancy test and/or breast feeding
• Clinically significant abnormal cardiac functioning per electrocardiogram (ECG) (required for any participant age 60 years and older);
• Seizure history including: seizure disorder/epilepsy, alcohol/drug withdrawal seizure, or seizure deemed by the study physician to be related to cocaine intoxication/withdrawal (note: febrile seizures are not exclusionary)
• Other conditions associated with seizure: epilepsy and the following acute or subacute neurologic disorders: stroke (ischemic or hemorrhagic), multiple sclerosis, traumatic brain injury (moderate or severe), neurosurgery, meningoencephalitis, increased intracerebral pressure, or intracerebral abscess, neurodegenerative disorders, and parenchymal or leptomeningeal brain tumors (per the TMS core guidelines which is attached).

Participants with a history of metabolic abnormalities (hyponatremia, hypocalcemia, hypomagnesemia, hypo or hyperglycemia, renal failure/uremia, liver failure), recent infection with fever, and serious alcohol withdrawal will be assessed by the MD/NP to ensure these conditions have resolved and are not currently present (per the TMS core guidelines which is attached).

In this protocol, we will also exclude glaucoma, severe migraine (particularly complicated migraines with significant aura and hemiparesis, and severe vertebrobasilar migraines, that may lead to brainstem infarctions).

• Medications that lower seizure threshold and in the opinion of the investigator impose significant seizure risk for the individual (including tricyclic antidepressants, monoamine oxidase inhibitors, bupropion, clozapine, and anticholinergics). The use of lithium, antipsychotics (other than clozapine), antibiotics, antihistamines, selective serotonin reuptake inhibitors, and serotonin-norepinephrine reuptake inhibitors will be carefully assessed by the physician
• Cognitive disorder (MMSE <25);
• Disqualifying response on the TMS Adult Safety Screen (TASS);
• Implanted devices or stimulators (cardiac pacemakers, vagus nerve stimulators, spinal cord stimulators, cochlear implant, implanted brain stimulators)
• Currently taking ototoxic medications (aminoglycosides, cisplatin);
• Metal implants or paramagnetic objects in the body that prohibits MR scanning;
• Claustrophobia that prohibits MR scanning; or
• Legally mandated (e.g., to avoid incarceration or other penalties) to participate in SUD treatment program.
• Moderate to severe heart disease

Criteria are shown verbatim from the registry (in English). Final eligibility is always assessed by the study center.

Healthy volunteers: No

Study design

Allocation

Randomized

Model

Parallel assignment

Masking

Quadruple blind

Primary purpose

Treatment

Study locations

United States · 1 center

• New York State Psychiatric Institute (NYSPI) / Substance Treatment and Research Service (S — New York

Identifiers

NCT: NCT05974202 · 8483/Pro00076502 · UG3DA056138-01A1

Primary sources (government registries)

• ClinicalTrials.gov (US NIH)

View this study on ClinicalTrials.gov ↗