Clavulanic Acid (CLAV) and Cocaine Interaction Safety Study

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

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.

Study Overview

• Status: Completed
• Conditions: Cocaine-Related Disorders; Cocaine Dependence; Cocaine Abuse; Cocaine Addiction
• Intervention / Treatment: Drug: Clavulanic acid; Drug: Intravenous cocaine; Drug: Placebo

Detailed Description

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.

• Study Type: Interventional
• Enrollment (Actual): 10
• Phase: Phase 1

Contacts and Locations

Study Locations

• United States
  • Pennsylvania
    • Philadelphia, Pennsylvania, United States, 19125
      • Temple University Hospital - Episcopal Campus

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 16 years to 63 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Description

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.)

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Crossover Assignment
• Masking: Double

Number of Arms

3

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Clavulanic Acid (CLAV) 250mg; CLAV 500mg then Placebo (PBO); 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; Clavulanic acid will be administered orally in 250mg capsules; Other Names: CLAV; Drug: Intravenous cocaine; 20/40mg Cocaine will be administered by IV; Other Names: Coc; Drug: Placebo; Placebo will be administered orally in capsules identical to CLAV and be filled with crystalline microcellulose; Other Names: PBO
Experimental: CLAV 250mg; PBO; then CLAV 500mg; 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; Clavulanic acid will be administered orally in 250mg capsules; Other Names: CLAV; Drug: Intravenous cocaine; 20/40mg Cocaine will be administered by IV; Other Names: Coc; Drug: Placebo; Placebo will be administered orally in capsules identical to CLAV and be filled with crystalline microcellulose; Other Names: PBO
Experimental: PBO; CLAV 250mg; then CLAV 500mg; 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; Clavulanic acid will be administered orally in 250mg capsules; Other Names: CLAV; Drug: Intravenous cocaine; 20/40mg Cocaine will be administered by IV; Other Names: Coc; Drug: Placebo; Placebo will be administered orally in capsules identical to CLAV and be filled with crystalline microcellulose; Other Names: PBO

What is the study measuring?

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

Collaborators and Investigators

• Sponsor: Temple University
• Collaborators: National Institute on Drug Abuse (NIDA); University of Pennsylvania
• Investigators: Principal Investigator: Kyle M. Kampman, M.D., U54 Principal Investigator - University of Pennsylvania; Principal Investigator: Mary F. Morrison, M.D., M.S., Temple University; Principal Investigator: M. I Walters, M.D., Temple University

Publications and helpful links

General Publications

• Uys JD, LaLumiere RT. Glutamate: the new frontier in pharmacotherapy for cocaine addiction. CNS Neurol Disord Drug Targets. 2008 Nov;7(5):482-91. doi: 10.2174/187152708786927868.
• Rasmussen BA, Baron DA, Kim JK, Unterwald EM, Rawls SM. beta-Lactam antibiotic produces a sustained reduction in extracellular glutamate in the nucleus accumbens of rats. Amino Acids. 2011 Feb;40(2):761-4. doi: 10.1007/s00726-010-0589-0. Epub 2010 Apr 13.
• Ward SJ, Rasmussen BA, Corley G, Henry C, Kim JK, Walker EA, Rawls SM. Beta-lactam antibiotic decreases acquisition of and motivation to respond for cocaine, but not sweet food, in C57Bl/6 mice. Behav Pharmacol. 2011 Aug;22(4):370-3. doi: 10.1097/FBP.0b013e3283473c10.
• Kovalevich J, Corley G, Yen W, Rawls SM, Langford D. Cocaine-induced loss of white matter proteins in the adult mouse nucleus accumbens is attenuated by administration of a beta-lactam antibiotic during cocaine withdrawal. Am J Pathol. 2012 Dec;181(6):1921-7. doi: 10.1016/j.ajpath.2012.08.013. Epub 2012 Sep 29.

Study record dates

Study Major Dates

• Study Start (Actual): October 24, 2016
• Primary Completion (Actual): May 25, 2018
• Study Completion (Actual): May 25, 2018

Study Registration Dates

• First Submitted: August 6, 2015
• First Submitted That Met QC Criteria: September 28, 2015
• First Posted (Estimated): September 30, 2015

Study Record Updates

• Last Update Posted (Actual): November 3, 2023
• Last Update Submitted That Met QC Criteria: October 11, 2023
• Last Verified: October 1, 2023

More Information

Terms related to this study

• Keywords: Cocaine; Clavulanic Acid
• Additional Relevant MeSH Terms: Mental Disorders; Chemically-Induced Disorders; Substance-Related Disorders; Cocaine-Related Disorders; Physiological Effects of Drugs; Neurotransmitter Agents; Molecular Mechanisms of Pharmacological Action; Anti-Infective Agents; Central Nervous System Depressants; Peripheral Nervous System Agents; Enzyme Inhibitors; Sensory System Agents; Anesthetics; Anti-Bacterial Agents; Neurotransmitter Uptake Inhibitors; Membrane Transport Modulators; Dopamine Agents; Anesthetics, Local; Dopamine Uptake Inhibitors; beta-Lactamase Inhibitors; Vasoconstrictor Agents; Clavulanic Acid; Clavulanic Acids; Cocaine
• Other Study ID Numbers: 23222; 1U54DA039002-01 (U.S. NIH Grant/Contract)