Clinical trial NCT04411914: Pharmaco-Magnetic Resonance Spectroscopy (MRS) Study of Clavulanic Acid
Official title: A Phase 1B Double Blind, Placebo (PBO) Controlled, Pharmaco- Magnetic Resonance Spectroscopy (MRS) Inpatient Study of Clavulanic Acid (CLAV) 500, 750, 1000 mg Daily Repeated Administration in Early Remitted Cocaine Use Disorder Subjects
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE1
Conditions: Cocaine Dependence
Lead sponsor: Temple University
Sponsor class: OTHER
Collaborators: name: Beth Israel Deaconess Medical Center
name: University of Pennsylvania
name: National Institute on Drug Abuse (NIDA)
First posted: 2020-06-02
Enrollment: 13
Sex: ALL
Minimum age (years): 18
Maximum age (years): 70
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Intervention model description: Randomized, double-blind, placebo-controlled, parallel group inpatient study
Primary purpose: TREATMENT

Brief summary: A dose-escalation study to determine the optimum dose of Clavulanic Acid (CLAV) for effects on craving and efficacy.

Detailed description: This is a randomized, double-blind, placebo-controlled, parallel group inpatient study of clavulanic acid for 10 days in adults (18-65) seeking treatment for cocaine use disorder. For those subjects who can tolerate 500 mg/day for 3 days (or matched placebo), there will be a forced dose escalation to 750 mg/day for 3 days. Subjects who can tolerate 750 mg/day for three days will have a forced dose escalation to 1000 mg/day for 4 days until the study ends.

Thus, there are 3 Periods for each participant:

Period 1: 500 mg CLAV per day for days 1-3; Period 2: 750 mg per day for days 4-6; Period 3: 1000 mg/day for days 7-10.

Subjective, cognitive, and adverse effect assessments, blood pressure and pulse will be performed daily. Structural MRI, resting state MRI (rs-fMRI), functional MRI (fMRI) and Magnetic Resonance Spectroscopy (MRS) scans will be done at baseline and on Days 3, 6 and 10 of the study. At the time of each scan, safety of the subject to complete the scan will be re-assessed. fMRI was not done at baseline.

Eligibility criteria: Inclusion Criteria:

1. Be able to verbalize understanding of consent form
2. Be male or female adult volunteers ages 18-65 inclusive.
3. Have a Diagnostic and Statistical Manual-5 (DSM-5) diagnosis of cocaine use disorder, moderate to severe in early remission
4. Have a Body Mass Index (BMI) of 17.5 to 39.9 kg/m2; and a total body weight of at least 45 kg (99 lbs.)
5. Have a history and brief physical examination that demonstrate no clinically significant contraindication for participating in the study, and/ or significant or unstable medical or psychiatric illness.

Exclusion Criteria:

1. Have a current DSM-5 substance use disorder, mild, moderate, or severe, on any drug of abuse other than nicotine, caffeine, and cocaine use disorder in early remission verified by Urine Drug Screen (UDS). Alcohol use disorder and marijuana use disorder, mild without withdrawal symptoms, will be permitted.
2. Have any previous medically adverse reaction to CLAV, Augmentin, penicillin, Ticarcillin, cephalosporin, or any beta-lactam drug.
3. Have any illness, condition, and use of medications, in the opinion of the principal investigator, sub-investigators which would preclude safe and/or successful completion of the study.
4. Report having human immunodeficiency virus (HIV) infection or test positive for HIV during screening
5. Be pregnant (females).
6. Unable to tolerate MRI scan for duration of 60 minutes for physical or psychological reasons.

Primary outcomes:
measure: Brain Glutamate Concentration in the Anterior Cingulate Cortex (ACC) in Subjects With Cocaine Use Disorder (CUD) Treated With Escalating Doses of Clavulanate (CLAV)
timeFrame: ACC glutamate and CCQ will be measured and correlated on Day 10 of treatment with CLAV compared with baseline.
Secondary outcomes:
measure: Changes in Resting State Network Connectivity From Baseline
timeFrame: Assessment was done at the end of Period 1, 2 and 3 detailed above. Data from the end of Period 3 (Day 10, 1000mg CLAV) are reported.
measure: Craving
timeFrame: CCQ-45 questionnaires were completed daily during the study. Data from day 10 adjusted for baseline score are reported.
measure: Change in Brain Glutamine From Baseline
timeFrame: Brain glutamine will be analyzed at baseline (Day 1 prior to CLAV or PBO dose) and at Day 10 day (having completed Periods 1, 2 and 3 (CLAV 500mg/day for 3 days, 750 mg/day for 3 days and 1000 mg/day for 4 days).
measure: Number of Participants With Treatment-related Adverse Events (AEs)
timeFrame: 1-24 days (during and up to 2 weeks after study dosing period)
Other outcomes:
Locations:
city: Philadelphia
country: United States
facility: Temple University Episcopal Hospital
state: Pennsylvania
Study officials:
References:
citation: Kim J, John J, Langford D, Walker E, Ward S, Rawls SM. Clavulanic acid enhances glutamate transporter subtype I (GLT-1) expression and decreases reinforcing efficacy of cocaine in mice. Amino Acids. 2016 Mar;48(3):689-696. doi: 10.1007/s00726-015-2117-8. Epub 2015 Nov 5.