Clavulanic Acid (CLAV) and Cocaine Interaction Safety Study

Study Overview
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Brief Summary
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The main purpose of this study is to determine if it is safe to use the study drug, clavulanic acid, in combination with cocaine. In this study, subjects will receive intravenous (i.v.) cocaine and the study drug, clavulanic acid. The safety of clavulanic acid is being studied so future studies can be done to find out if this drug is helpful in treating cocaine dependence. Currently, there is no available medication treatment for cocaine dependence.

Detailed Description
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This is a prospective, placebo controlled inpatient crossover safety study of 3 doses (250 mg/day, 500 mg/day, 750 mg/day) of CLAV with an intravenous infusion of cocaine 40 mg. Subjects will be non-treatment seeking experienced cocaine dependent adults, ages 18-65 (N=12 completers, 21 estimated to enroll). Subjects will undergo a washout of the study drug for 5 half-lives between study drug administration sessions. The primary objective will be to determine whether there are clinically significant adverse interactions between CLAV (250 mg/day; 500 mg/day; 750 mg/day) and intravenously administered cocaine in healthy, non-treatment seeking adults with cocaine use disorder.

Official Title
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Phase 1, Double-Blind, Placebo-Controlled Assessment of Potential Interactions Between Intravenous Cocaine and Clavulanic Acid

Conditions
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Cocaine Dependence, Cocaine Addiction, Cocaine Abuse, Cocaine-Related Disorders

Intervention / Treatment
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* Drug: Clavulanic acid
* Drug: Intravenous cocaine
* Drug: Placebo


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Meet Diagnostic and Statistical Manual of Mental Disorders Fifth Edition criteria for cocaine use disorder, moderate to severe. Be a non-treatment seeking cocaine user. If female and of childbearing potential, must have a negative pregnancy test within 48 hours of beginning the study and be willing to use acceptable contraception or be abstinent for 14 days prior to study, through the entire study and 30 days after study participation. Exclusion Criteria: Be seeking treatment for substance abuse. (For full inclusion/exclusion criteria or for more information, please contact the site directly.)

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 65 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Crossover Assignment
Masking: Double


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Clavulanic Acid (CLAV) 250mg; CLAV 500mg then Placebo (PBO)<br>Clavulanic acid OR Placebo to be given in combination with intravenous cocaine; Day #2: Clavulanic Acid 250 mg (low dose); Day #3: Clavulanic Acid 500 mg; Day #4: Placebo | Drug: Clavulanic acid<br>* Clavulanic acid will be administered orally in 250mg capsules<br>* Other names: CLAV;Drug: Intravenous cocaine<br>* 20/40mg Cocaine will be administered by IV<br>* Other names: Coc;Drug: Placebo<br>* Placebo will be administered orally in capsules identical to CLAV and be filled with crystalline microcellulose<br>* Other names: PBO;|
| Experimental: CLAV 250mg; PBO; then CLAV 500mg<br>Clavulanic acid OR Placebo to be given in combination with intravenous cocaine; Day #2: Clavulanic Acid 250 mg (low dose); Day #3: Placebo; Day #4: Clavulanic Acid 500 mg | Drug: Clavulanic acid<br>* Clavulanic acid will be administered orally in 250mg capsules<br>* Other names: CLAV;Drug: Intravenous cocaine<br>* 20/40mg Cocaine will be administered by IV<br>* Other names: Coc;Drug: Placebo<br>* Placebo will be administered orally in capsules identical to CLAV and be filled with crystalline microcellulose<br>* Other names: PBO;|
| Experimental: PBO; CLAV 250mg; then CLAV 500mg<br>Clavulanic acid OR Placebo to be given in combination with intravenous cocaine; Day #2: Placebo; Day #3: Clavulanic Acid 250 mg (low dose); Day #4: Clavulanic Acid 500 mg | Drug: Clavulanic acid<br>* Clavulanic acid will be administered orally in 250mg capsules<br>* Other names: CLAV;Drug: Intravenous cocaine<br>* 20/40mg Cocaine will be administered by IV<br>* Other names: Coc;Drug: Placebo<br>* Placebo will be administered orally in capsules identical to CLAV and be filled with crystalline microcellulose<br>* Other names: PBO;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of Participants With Severe Adverse Events (AEs) | Rates of occurrence of serious adverse events across the different treatments: Day 1-IV cocaine only; Day 2.3 and 4 treatment with either PBO, CLAV 250mg or CLAV 500mg depending on randomization; Day 5 CLAV 750mg, Day 10 Follow-up appointment See Adverse Event section for reporting of mild-moderate AEs. | 6 Days (Study Days 1, 2, 3, 4, 5, 10) | 
| Change in Heart Rate in Response to IV Cocaine Infusion With and Without CLAV Dosing | IV cocaine was infused 1 hour following the dosing of PBO or CLAV 250mg, CLAV 500mg and CLAV 750 mg and vital signs were checked at -15min,-10min, -5 min preinfusion of IV cocaine and then every 2 min for the first 30 minutes, then every 15min through 150 minutes post-infusion. The mean heart rate (HR) at 2 minutes post IV cocaine infusion and the maximum (max) change in heart rate from baseline pre-infusion are reported (peak heart rate post-infusion minus baseline heart rate pre-infusion) are reported. | 4 Days (Study Days 2, 3, 4, 5) | 
| Changes in Blood Pressure in Response to IV Cocaine With and Without CLAV Dosing | IV cocaine was infused 1 hour following the dosing of PBO or CLAV 250mg, CLAV 500mg and CLAV 750 mg and vital signs were checked at -15min,-10min, -5 min pre-infusion of IV cocaine and then every 2 min for the first 30 minutes, then every 15min through 150 minutes post-infusion. The mean systolic blood pressure (SBP) and diastolic blood pressure (DBP) at 2 minutes post IV cocaine infusion are reported. Also, the maximum (max) change in SBP snd DBP from baseline pre-infusion are reported (peak SBP or DBP post-infusion minus baseline SBP or DBP pre-infusion) are reported. | 4 Days (Study Days 2, 3, 4, 5) | 
| Electrocardiogram (ECG) Following IV Cocaine With and Without CLAV Dosing | ECG was done 15 min after IV cocaine infusion (following the dosing of PBO or CLAV 250mg, CLAV 500mg and CLAV 750 mg). The interval between the Q wave and the T wave, corrected (QTc) is reported. | 4 Days (Study Days 2, 3, 4, 5) | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Pharmacokinetic (PK) Parameter of Cocaine-concentration | Cocaine concentrations are reported at 10 min and 30 minutes after cocaine infusion (70 and 90 minutes after administration of placebo (PBO), CLAV 250mg or CLAV 500mg). | 3 Days (Study Days 2, 3, 4) | 
| Clavulanic Acid (CLAV) Concentrations Following CLAV 250mg and CLAV 500mg Doses | CLAV concentrations were measured 40 min and 70 min after ingestion of CLAV 250 mg or 500 mg. (The 70 min time point is 10 min after the IV cocaine infusion).The 250mg dose and the 500mg dose were given on different days per the randomization protocol: the 250mg dose was given on either day 2 or 3 and the 500mg dose was given on either day 3 or 4. The lowest level of detection of CLAV is 40ng/ml. A non-detectable level is reported as 0. | 3 Days (Study Days 2, 3, 4) | 
| Difference in CLAV Concentrations Between the 250mg and 500mg CLAV Doses | The CLAV concentration after ingestion of 250mg CLAV minus the CLAV PK level after the 500 mg dose is reported at 40min and 70 min after ingestion | 3 days (Day 2, 3, 4) | 
| Pupil Pharmacodynamic Effects of Cocaine With Clavulanic Acid | Pupil Diameter (mm) was measured 10 minutes pre-infusion and 10, 15, 30 and 45 min after cocaine infusion. Cocaine infusion was done 1 hour following ingestion of placebo (day 2), CLAV 250 mg (day3), or CLAV 500 mg (day 4). Results are reported as median pupil diameter (mm) with interquartile range at different time points relative to the cocaine infusion as noted. | 10 minutes pre-infusion and 10, 15, 30 and 45 min after cocaine infusion on Study Days 2, 3, and 4 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Cocaine, Clavulanic Acid