Cocaine Dependence
Conditions
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.
Interventions
DRUGClavulanic Acid
Drug will be given in 250mg capsules.
OTHERPlacebo
Placebo
Sponsors
Beth Israel Deaconess Medical Center
University of Pennsylvania
National Institute on Drug Abuse (NIDA)
Temple University
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)
Intervention model description
Randomized, double-blind, placebo-controlled, parallel group inpatient study
Eligibility
Sex/Gender
ALL
Age
18 Years to 70 Years
Healthy volunteers
No
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.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Brain Glutamate Concentration in the Anterior Cingulate Cortex (ACC) in Subjects With Cocaine Use Disorder (CUD) Treated With Escalating Doses of Clavulanate (CLAV) | ACC glutamate and CCQ will be measured and correlated on Day 10 of treatment with CLAV compared with baseline. | Brain glutamate concentration in the ACC (based on Magnetic Resonance Spectroscopy (MRS)) will be correlated with cocaine craving (measured by Cocaine Craving Questionnaire (CCQ)) in subjects receiving escalating doses of CLAV for 10 days. Measurement will be made at baseline and Day 10 of CLAV (1000 mg/day) in subjects with cocaine use disorder. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Changes in Resting State Network Connectivity From Baseline | 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. | Craving-associated neurocircuitry (frontal-striatal-thalamic connectivity) will be examined with resting state functional Magnetic Resonance Imaging (rs-fMRI) and Cocaine Craving Questionnaire (CCQ-45). The CCQ is comprised of five 9-item sub-scales (desire to use cocaine, intention and planning to use cocaine, anticipation of positive outcome from use, anticipation of relief from withdrawal or dysphoria, and lack of control over use) measured on a scale of 1 to 7, total scores ranging from 45 to 315 with higher numbers indicating increased craving.. The rs-fMRI activity and CCQ were assessed in the 9 participants at baseline and at the end of each of 3 periods. rs-fMRI activity and CCQ were correlated using the Spearman Correlation Coefficient calculation. A negative correlation coefficient indicates an inverse relationship between the assessments; higher rs-fMRI activity correlates with lower craving. |
| Craving | CCQ-45 questionnaires were completed daily during the study. Data from day 10 adjusted for baseline score are reported. | Craving will be evaluated by Cocaine Craving Questionnaire (CCQ-45). The CCQ is comprised of five 9-item sub-scales (desire to use cocaine, intention and planning to use cocaine, anticipation of positive outcome from use, anticipation of relief from withdrawal or dysphoria, and lack of control over use) measured on a scale of 1 to 7, total scores ranging from 45 to 315 with higher numbers indicating increased craving. The results are the CCQ scores on day 10 minus the baseline scores before starting study drug. |
| Change in Brain Glutamine From Baseline | 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). | Change in brain glutamine (Gln) concentration in the ACC at Day 10 compared to baseline as assessed by MRS in the ACC. |
| Number of Participants With Treatment-related Adverse Events (AEs) | 1-24 days (during and up to 2 weeks after study dosing period) | Adverse events (AES) will be defined as any clinically significant changes in vital signs, clinically significant change in Electrocardiogram (EKG) from baseline measurement, clinically significant changes in laboratory bloodwork (Complete blood count, comprehensive metabolic panel, urinalysis), or any self reported side effects compared with baseline. AEs will be collected throughout the study and reviewed by a physician. An evaluation of AE severity (mild, moderate, severe) will be evaluated by a physician based on participant self-report. AEs per subject will be listed by organ system, and the number of AEs within the subject population will be totaled. |
Countries
United States
Participant flow
Recruitment details
Recruitment materials included newspapers, facebook, and word of mouth. Participants were recruited from the local community between 9/2020 and 11/2021.
Participants by arm
| Arm | Count |
|---|---|
| Clavulanic Acid 10 participants randomized to the CLAV group
Clavulanic Acid will be given in 250mg capsules according to the 3 Periods | 10 |
| Placebo 3 participants will receive placebo (PBO) and serve as a control group. They will have a dose escalation at the same time as the experimental group, and be given additional placebo pills to match the number given to the experimental group.
Placebo: Placebo | 3 |
| Total | 13 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| CLAV 500mg/Day for Days 1-3 | Adverse Event | 1 | 0 |
Baseline characteristics
| Characteristic | Clavulanic Acid | Placebo | Total |
|---|---|---|---|
| Age, Continuous | 54.2 years | 57.8 years | 55.6 years |
| Education Left formal education at 16 | 0 Participants | 1 Participants | 1 Participants |
| Education Left formal education at 17-18 | 5 Participants | 2 Participants | 7 Participants |
| Education Undergraduate or Equivalent | 4 Participants | 0 Participants | 4 Participants |
| Education unknown | 1 Participants | 0 Participants | 1 Participants |
| Ethnicity (NIH/OMB) Hispanic or Latino | 0 Participants | 0 Participants | 0 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 10 Participants | 3 Participants | 13 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants |
| Handedness left-handed | 0 Participants | 1 Participants | 1 Participants |
| Handedness right-handed | 10 Participants | 2 Participants | 12 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Black or African American | 7 Participants | 3 Participants | 10 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) White | 3 Participants | 0 Participants | 3 Participants |
| Region of Enrollment United States | 10 participants | 3 participants | 0 participants |
| Sex: Female, Male Female | 3 Participants | 1 Participants | 4 Participants |
| Sex: Female, Male Male | 7 Participants | 2 Participants | 9 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk | EG003 affected / at risk |
|---|---|---|---|---|
| deaths Total, all-cause mortality | 0 / 10 | 0 / 9 | 0 / 9 | 0 / 3 |
| other Total, other adverse events | 6 / 10 | 5 / 9 | 2 / 9 | 1 / 3 |
| serious Total, serious adverse events | 0 / 10 | 0 / 9 | 0 / 9 | 0 / 3 |
Outcome results
Primary
Brain Glutamate Concentration in the Anterior Cingulate Cortex (ACC) in Subjects With Cocaine Use Disorder (CUD) Treated With Escalating Doses of Clavulanate (CLAV)
Brain glutamate concentration in the ACC (based on Magnetic Resonance Spectroscopy (MRS)) will be correlated with cocaine craving (measured by Cocaine Craving Questionnaire (CCQ)) in subjects receiving escalating doses of CLAV for 10 days. Measurement will be made at baseline and Day 10 of CLAV (1000 mg/day) in subjects with cocaine use disorder.
Time frame: ACC glutamate and CCQ will be measured and correlated on Day 10 of treatment with CLAV compared with baseline.
Population: Glutamate (Glu) level (MR-Spectroscopy) in the ACC (9 scans at baseline and 9 scans at Day 10, adjusted for baseline) are correlated with CCQ results (9 baseline questionnaires and 9 day 10 questionnaires). Spearman Correlation Coefficients were calculated. Higher concentrations of ACC glutamate on day 10 correlated with decreased cocaine craving.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Clavulanic Acid Day 10 | Brain Glutamate Concentration in the Anterior Cingulate Cortex (ACC) in Subjects With Cocaine Use Disorder (CUD) Treated With Escalating Doses of Clavulanate (CLAV) | -0.9000 Spearman Correlation Coefficient |
| Clavulanic Acid Baseline | Brain Glutamate Concentration in the Anterior Cingulate Cortex (ACC) in Subjects With Cocaine Use Disorder (CUD) Treated With Escalating Doses of Clavulanate (CLAV) | 0.3333 Spearman Correlation Coefficient |
p-value: 0.0009Spearman Correlation Coefficient
Secondary
Change in Brain Glutamine From Baseline
Change in brain glutamine (Gln) concentration in the ACC at Day 10 compared to baseline as assessed by MRS in the ACC.
Time frame: 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).
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Clavulanic Acid Day 10 | Change in Brain Glutamine From Baseline | 1.5 mmol/kg | Standard Deviation 1 |
| Clavulanic Acid Baseline | Change in Brain Glutamine From Baseline | 2.1 mmol/kg | Standard Deviation 2 |
| Female CLAV Subjects--CCQ Score Day 10 | Change in Brain Glutamine From Baseline | 0.8 mmol/kg | Standard Deviation 0.3 |
| Femaile PBO Subjects--CCQ Scores Day 10 | Change in Brain Glutamine From Baseline | 0.7 mmol/kg | Standard Deviation 0.6 |
Secondary
Changes in Resting State Network Connectivity From Baseline
Craving-associated neurocircuitry (frontal-striatal-thalamic connectivity) will be examined with resting state functional Magnetic Resonance Imaging (rs-fMRI) and Cocaine Craving Questionnaire (CCQ-45). The CCQ is comprised of five 9-item sub-scales (desire to use cocaine, intention and planning to use cocaine, anticipation of positive outcome from use, anticipation of relief from withdrawal or dysphoria, and lack of control over use) measured on a scale of 1 to 7, total scores ranging from 45 to 315 with higher numbers indicating increased craving.. The rs-fMRI activity and CCQ were assessed in the 9 participants at baseline and at the end of each of 3 periods. rs-fMRI activity and CCQ were correlated using the Spearman Correlation Coefficient calculation. A negative correlation coefficient indicates an inverse relationship between the assessments; higher rs-fMRI activity correlates with lower craving.
Time frame: 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.
Population: 9 participants completed Period 1 (3 days of CLAV 500mg) Period 2 (3 days of CLAV 750mg) and then Period 3 (4 days of CLAV 1000mg). The rs-fMRI activity in the executive control network and CCQ were correlated using the Spearman Correlation calculation at the end of this course of study drug (Day 10) and are reported.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Clavulanic Acid Day 10 | Changes in Resting State Network Connectivity From Baseline | -0.8333 Spearman Correlation Coefficient |
p-value: 0.0053Spearman Correlation Coefficient
Secondary
Craving
Craving will be evaluated by Cocaine Craving Questionnaire (CCQ-45). The CCQ is comprised of five 9-item sub-scales (desire to use cocaine, intention and planning to use cocaine, anticipation of positive outcome from use, anticipation of relief from withdrawal or dysphoria, and lack of control over use) measured on a scale of 1 to 7, total scores ranging from 45 to 315 with higher numbers indicating increased craving. The results are the CCQ scores on day 10 minus the baseline scores before starting study drug.
Time frame: CCQ-45 questionnaires were completed daily during the study. Data from day 10 adjusted for baseline score are reported.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Clavulanic Acid Day 10 | Craving | 7 difference in score on a scale | Standard Deviation 16 |
| Clavulanic Acid Baseline | Craving | -22 difference in score on a scale | Standard Deviation 10 |
| Female CLAV Subjects--CCQ Score Day 10 | Craving | -15 difference in score on a scale | Standard Deviation 21 |
| Femaile PBO Subjects--CCQ Scores Day 10 | Craving | 49 difference in score on a scale | Standard Deviation 0 |
Secondary
Number of Participants With Treatment-related Adverse Events (AEs)
Adverse events (AES) will be defined as any clinically significant changes in vital signs, clinically significant change in Electrocardiogram (EKG) from baseline measurement, clinically significant changes in laboratory bloodwork (Complete blood count, comprehensive metabolic panel, urinalysis), or any self reported side effects compared with baseline. AEs will be collected throughout the study and reviewed by a physician. An evaluation of AE severity (mild, moderate, severe) will be evaluated by a physician based on participant self-report. AEs per subject will be listed by organ system, and the number of AEs within the subject population will be totaled.
Time frame: 1-24 days (during and up to 2 weeks after study dosing period)
Population: see adverse events report; Blood Pressure, heart rate, EKG were not statistically different between the two groups.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Clavulanic Acid Day 10 | Number of Participants With Treatment-related Adverse Events (AEs) | 6 Participants |
| Clavulanic Acid Baseline | Number of Participants With Treatment-related Adverse Events (AEs) | 1 Participants |