Phase 1, Double-Blind, Placebo-Controlled Assessment of Potential Interactions Between Intravenous Cocaine and Clavulanic Acid
Phase: PHASE1
Conditions: Cocaine Dependence, Cocaine Addiction, Cocaine Abuse, Cocaine-Related Disorders
Sponsor: Temple University

 
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PHASE 1, DOUBLE-BLIND, PLACEBO-CONTROLLED ASSESSMENT OF 
POTENTIAL INTERACTIONS BETWEEN 
INTRAVENOUS COCAINE AND CLAVULANIC ACID NCT02563769 
 
U54 Principal Investigator:  
Kyle M. Kampman, M.D. 
 
Principal Investigator: 
 
Mary F. Morrison, M.D., M.S. 
Project 1 
 
 
 
Professor of Psychiatry 
Lewis Katz School of Medicine 
Temple University 
1316 West Ontario Street, Room 800 
Philadelphia, PA  19140 
T: 215-707-8688 
C: 610-247-2126 
 
Co-Investigator:  
 
 
M. Ingre Walters, M.D. 
 
Co-Investigator 
 
 
 
and Medical Monitor: 
 
Kyle M. Kampman, M.D. 
 
Statistician:   
 
 
Kevin Lynch, Ph.D.  
 
 
 
 
 
Version: 
 
 
 
 
 
 
 
 
  2.3 
 
NIDA Investigators:  
 
[name]  
 
NIDA Study Manager: 
 
[name] 
 
 
 
 
 
National Institute on Drug Abuse 
National Institutes of Health 
6001 Executive Boulevard 
Bethesda, MD 20892 
301/443-3318 
 
Funding Agency: 
 
 
Division of Pharmacotherapies and Medical Consequences 
of Drug Abuse 
National Institute on Drug Abuse (NIDA) 
National Institutes of Health 
Center for Cocaine Medication Development 
University of Pennsylvania 
 
Data Coordinating Center:  
University of Pennsylvania 
 
 
 
 
 
Perelman School of Medicine Department of Psychiatry 
 

 
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2  SYNOPSIS OF STUDY 
Title 
Phase 1, Double-Blind, Placebo-Controlled 
Assessment of Potential Interactions 
Between Intravenous Cocaine and 
Clavulanic Acid 
Short Title 
CLAV and Cocaine Interaction Safety Study 
Phase  
Phase Ib 
Methodology 
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.  
Study Duration 
Approximately 1.5 years. 
Study Center 
Temple Episcopal Hospital.  Centennial 6th 
floor, an inpatient medical unit with telemetry. 
Primary Objective 
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. 
Secondary Objectives 
1. To evaluate whether administration of 
CLAV alters the pharmacokinetics (PK) of 
cocaine or its major metabolite, 
benzoylecgonine (BE). 
2. To determine PK of CLAV during treatment 
at 250 mg/day (low dose) and 500 mg/day 
(medium dose). 
3. To evaluate whether there are significant 
interactions between CLAV treatment 
concurrent with i.v. cocaine infusions of 40 mg 
by measuring the diameter of the pupil using a 
pupillometer. 
Exploratory Objectives 
3. To evaluate whether CLAV treatment alters 
the subjective effects of cocaine, the perceived 
value of the dose of cocaine, and craving.  
4. To assess the effects of clavulanic acid on 
mood and personality and on the abuse 

 
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liability. 
Outcome Measures 
Primary outcome measure is safety which will 
be measured by AEs, BP, HR, and ECG QTc 
interval. Secondary outcome measures include 
PK parameters of cocaine, PK parameters of 
CLAV, pupillometry.  Exploratory outcome 
measures are subjective effects measurements 
assessed for cocaine in combination with 
CLAV and CLAV alone. Effect on mood 
(POMS), abuse liability (ARCI), and subjective 
effects measurements (VAQ, VAS) will be 
obtained.  The effect of CLAV on cocaine 
craving will be assessed using the CCQ-Brief. 
The DVQ will be used to determine the 
perceived value of each dose of cocaine.  
Number of Participants 
12 completers, 21 estimated to enroll. 
Diagnosis and Main Inclusion Criteria 
Non-treatment seeking adults with cocaine use 
disorder, moderate to severe, ages 18-65. 
Study Product, Dose, Route, Regimen 
Clavulanic acid 250 mg/day (always given 
before 500 mg dose); 500 mg/day or placebo. 
Study drug doses administered on Days 2, 3, 
and 4 in a double-blind fashion.  
Clavulanic acid 750 mg/day dose will always 
be given on Study Day 5 in a single-blind 
fashion if both the low and medium doses are 
well tolerated. 
Duration of Administration 
6 day inpatient study, acute oral dosing of 
CLAV 250 mg/day, 500 mg/day, 750 mg/day 
and matching  placebo 
Reference Therapy 
Placebo 
Statistical Methodology 
Data are gathered from a 3 period, 3 treatment 
crossover design (except 750 mg dose). Our 
primary analyses compare the rates of 
occurrences of adverse events across the first 
three periods (250 mg, 500 mg, placebo) within 
each person using standard mixed effects 
ANOVA models for binary responses. 
 
 
 
 
 
 

 
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3  MODEL STUDY SCHEMA 
    
 
-30 to 0 
 Pre-intake screening 
Screening Infusion #2 – 40 mg cocaine i.v. 
Study Day 
Activity 
 
 
2   
   3   
Treatment Infusion #1 –40 mg cocaine i.v. 
   Discharge 
Screening Infusion  #1– 20 mg cocaine i.v. 
Clavulanic acid/placebo administration 
on days 2 through 4 
 4 
 
 
 
 
 
 
 
6 
     
 
 
5 
 5-8 days after discharge 
1   
Randomization   
Treatment Infusion #2 –40 mg cocaine i.v. 
Treatment Infusion #3 –40 mg cocaine i.v. 
Treatment Infusion #4 –40 mg cocaine i.v. with 
Clavulanic acid administration   
(750 mg, single-blind) if Days 2-4 are well 
tolerated OR Discharge  
-30 to 0 
Follow-up Visit 
Buprenorphine plus naloxone stabilization 
period for opiate-dependent subjects 
Intake and inpatient screening 

 
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4   ABSTRACT 
STUDY OBJECTIVES: This is a human laboratory clinical pharmacology study to assess 
potential interactions between intravenous cocaine and treatment with clavulanic acid (CLAV). 
 
Primary: The primary objective of this study is to determine if there are significant interactions 
between CLAV treatment concurrent with i.v. cocaine infusions of 40 mg by measuring the 
frequency of adverse events and cardiovascular responses [heart rate (HR), blood pressure (BP), 
and electrocardiogram (ECG)] in adult subjects with cocaine use disorder.  
 
Secondary: 
 
1. To evaluate whether the acute administration of CLAV alters the pharmacokinetics (PK) of 
cocaine or its major metabolite, benzoylecgonine (BE) in adult subjects with cocaine use 
disorder. 
2. To determine PK of CLAV in adult subjects with cocaine use disorder during treatment at 
250 mg/day (low dose) and 500 mg/day (medium dose). 
3. To evaluate whether there are significant pharmacodynamic (PD) interactions between 
CLAV treatment (250 mg, 500 mg) concurrent with i.v. cocaine infusions of 40 mg by 
measuring the diameter of the pupil using a pupillometer. 
 
Exploratory: 
 
1. To evaluate whether CLAV treatment alters the subjective effects of cocaine measured by 
Visual Analog Questionnaire (VAQ) and the Visual Analog Scales (VAS), the perceived 
value of the dose of cocaine measured by the Drug Value Questionnaire (DVQ), and craving 
measured by Cocaine Craving Questionnaire-Brief (CCQ-Brief).  
2. To assess the effects of clavulanic acid on mood and personality using the Profile of Mood 
States (POMS) and on the abuse liability using the Addiction Research Center Inventory 
(ARCI).  
3. To evaluate the safety of CLAV treatment concurrent with iv cocaine infusions with subjects 
with combined cocaine and opiate use disorder whose opiate use disorder symptoms are 
stabilized on buprenorphine plus naloxone. 
4. To evaluate the safety and whether there are significant PD interactions between CLAV 
treatment 750 mg concurrent with i.v. cocaine infusions of 40 mg.  
 
STUDY ENDPOINTS:  
 
Primary endpoint:  Safety and toleration as assessed by the rates of occurrence of adverse 
events across the three study periods within each subject.   In addition, the following 
cardiovascular measures will be assessed during the three study periods: supine vital signs 
measurements (BP, HR) and ECG standard 12-lead monitoring (QTc prolongation).   
 
Secondary endpoints: 
 
1. PK of cocaine alone will be compared statistically with PK when both Cocaine and 
CLAV (250 mg, 500 mg) are present. Both the PK of cocaine and its major metabolite, 

 
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BE, will be evaluated with both doses of CLAV.  PK will be sampled close to Tmax and drug 
levels during combination therapy will be compared with drug levels during treatment with 
each drug alone.  
2. PK of CLAV alone will be compared statistically at both doses of CLAV (250 mg, 500 mg) 
PK will be sampled close to Tmax. If possible, important gender differences in CLAV PK 
will be explored. 
3. PD. Pupil diameter (over time) after Cocaine infusion alone (with PBO) will be compared 
with pupil diameter (over time) after Cocaine infusion with CLAV at both doses (250 mg, 
500 mg). 
Exploratory: 
 
1. Subjective effects of cocaine alone (PBO) will be compared with subjective effects of 
cocaine and CLAV (250 mg, 500 mg, 750 mg) using both the Visual Analog Questionnaire 
(VAQ) and the Visual Analog Scales (VAS) for each condition (COC+PBO vs. 
COC+CLAV). The perceived value of cocaine alone (PBO) will be compared with the 
perceived value of cocaine in combination with CLAV (250 mg, 500 mg, 750 mg) using the 
Drug Value Questionnaire (DVQ) for each condition (COC+PBO vs. COC+CLAV).   
Cocaine craving associated with cocaine alone (PBO) will be compared with the craving 
associated with cocaine and CLAV (250 mg, 500 mg, 750 mg) using measured by Cocaine 
Craving Questionnaire-Brief (CCQ-Brief).  
 
2. The subjective effects of clavulanic acid without cocaine (250 mg, 500 mg, and 750 mg) on 
mood and personality will be assessed using the Profile of Mood States (POMS) score for 
each dose of CLAV compared with the score on PBO. The effects of CLAV on the abuse 
liability using the Addiction Research Center Inventory (ARCI) will be compared at each 
dose of CLAV (250 mg, 500 mg, and 750 mg) compared with PBO score. 
 
3. Safety of clavulanic acid and buprenorphine in combination with cocaine. Safety and 
toleration as assessed by the rates of occurrence of adverse events across the three study 
periods within each subject with comorbid cocaine and opiate use disorder.   In addition, the 
following cardiovascular measures will be assessed during the three study periods: supine 
vital signs measurements (BP, HR) and ECG standard 12-lead monitoring (QTc 
prolongation).  
 
4. Safety of 750 mg clavulanic acid dose.  Safety and toleration as assessed by the occurrence 
of adverse events compared with adverse events on placebo.    In addition, the following 
cardiovascular measures will be assessed and compared with placebo: supine vital signs 
measurements (BP, HR) and ECG standard 12-lead monitoring (QTc prolongation).  
 
STUDY DESIGN: This is a randomized, double-blind, placebo-controlled inpatient cross-over 
study of CLAV for Cocaine Use Disorder (CUD). The crossover study will involve acute oral 
administration of two (2) doses of CLAV (250 mg/day; 500 mg/day); (low and medium) and 
matched oral placebo in 12 (12 completers, 21 enrolled) healthy non-treatment seeking CUD 
adult subjects for each drug. The study is performed in an inpatient medical unit (Centennial 6) 

 
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at Temple-Episcopal Hospital (T-EH) to determine the safety of the CLAV in combination with 
cocaine (COC).  
 
STUDY DURATION: Study duration will include up to six (6) days on an inpatient unit in 
addition to the pre-intake screening and follow up visit. The pre-intake screening will last up to 
30 days. The inpatient period will include: 
 
• One (1) outpatient day of intake and admission screening (Day # -30 – 0)  
• One (1) inpatient day of screening cocaine infusions (Day #1) 
• Four (4) days of inpatient treatment with CLAV or placebo with i.v. cocaine infusions of 
40 mg (Days #2 through #5) 
 
Clinic discharge is on Day #6 unless subject safety precludes them from completing Study Day 
#5. Liver function test results, hematology studies, CPK results, vital signs, and 
occurrence/severity of adverse events (AEs) will be reviewed after Study Day #4 to determine 
eligibility for Study Day #5 at 750 mg.  
 
Subjects will be requested to return for follow-up at 5-8 days after the day of discharge. If 
subjects have a positive urine for cocaine on inpatient admission, they have the option of being 
admitted for observation for 24 hours and commencing Study Day #1 on the next day.  Subjects 
with severe cocaine use disorders have difficulty not using cocaine in their community to obtain 
a negative urine for cocaine. Subjects with combined cocaine and opiate use disorder must have 
a positive urine test for buprenorphine on admission and a negative test for other opiates to be 
eligible for Day #1 screening that day. Subjects with a positive test for buprenorphine as well as 
other opiates will be evaluated on a case by case basis for commencing Study Day #1 after being 
observed for 24 hours in the hospital. 
 
SAMPLE SIZE: Twenty-one (21) subjects are estimated to enroll, with 12 expected to complete 
the study.  Study subjects who complete the inpatient phase of the study will be considered 
completed subjects. Subjects will continue to be screened until the total number (n=12) have 
completed the study. 
 
POPULATION: Volunteer experienced cocaine users, 18-to-65 years of age, who have used 
cocaine by the smoked or i.v. route at least twice a week for at least four (4) of the past six (6) 
weeks and provided a positive urine test for cocaine within two weeks of entering the study. 
 
 
 
 
 
 
 
 
 
 
 
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Figure 1. Schedule for Inpatient CLAV Study 
DAY 2 
DAY 3 
DAY 1 
COCAINE 
20 mg 
COCAINE 
40 mg 
COCAINE 
40 mg 
CLAV 250 mg 
PLACEBO 
CLAV 250 mg 
COCAINE 
40 mg 
CLAV 500 mg 
PLACEBO 
CLAV 250 mg 
DAY 4 
DAY 5 
DAY 6 
COCAINE 
40 mg 
COCAINE 
40 mg 
CLAV 500 mg 
CLAV 500 mg 
PLACEBO 
CLAV 750 mg 
DISCHARGE 
DAY 

 
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TREATMENTS: The initial crossover study will involve acute oral administration of 2 doses of 
CLAV  (250 mg/day; 500 mg/day); (low and medium) and matched oral placebo. Subject will 
potentially have four (4) cocaine infusions after randomization, one with CLAV 250 mg, one 
with CLAV 500 mg (always given after 250 mg dose) and one with placebo (See Figure 1).  If 
subjects tolerate the low and medium dose of cocaine with mild adverse effects, have stable vital 
signs and bloodwork results that indicate it is safe for them to proceed, they are given 750 
mg/day dose on study day #5 on a single blind basis. Subjects will be randomized after the 
screening cocaine infusion of 40 mg i.v. (Day #1) to one of the following arms:          
 
Treatment Arm 1: Day #2: CLAV 250 mg (low dose); Day #3: CLAV 500 mg; Day #4: Placebo; 
Day #5: CLAV 750 mg. 
 
Treatment Arm 2: Day #2: CLAV 250 mg (low dose); Day #3: Placebo; Day #4: CLAV 500 mg; 
Day #5: CLAV 750 mg. 
 
Treatment Arm 3:  Day #2: Placebo; Day #3: CLAV 250 mg (low dose); Day #4: CLAV 500 mg; 
Day #5: CLAV 750 mg. 
Table 1. Cocaine Infusion Session Schedule 
 
Study 
Phase 
Infusion        
Number 
Study 
Day 
Infusion 
Screening 
Stage II 
Safety 
Infusion #1 
1 
Single-blind infusion of COC 20 mg IV  
Screening 
Stage II 
Safety 
Infusion #2 
1 
Single-blind infusion of COC 40 mg IV at least 2 hours 
45 minutes after initial infusion 
Treatment Treatment 
Infusion #1 
2 
Single-blind infusion of COC 40 mg IV 60 minutes post 
CLAV/placebo administration  
Treatment Treatment 
Infusion #2 
3 
Single-blind infusion of COC 40 mg IV 60 minutes post 
CLAV/placebo administration 
Treatment Treatment 
Infusion #3 
4 
Single-blind infusion of COC 40 mg IV 60 minutes post 
CLAV/placebo administration 
Treatment Treatment 
Infusion #4 
5 
Single-blind infusion of COC 40 mg IV 60 minutes post 
single-blind CLAV 750 mg administration 
 
STATISTICAL ANALYSIS PLAN 
5.1  Outcome Measures 
5.1.1  Primary Outcome Measures 
The primary outcome measures are adverse events and cardiovascular responses (HR, BP, ECG 
(QTc prolongation). Safety and toleration as assessed by the rates of occurrence of adverse 
events across the three study periods (250 mg, 500 mg, PBO) within each subject.  
 
5.1.2  Secondary Outcome Measures 
Secondary outcome measures are intended to determine if there are any changes in cocaine 
pharmacokinetics in the presence of clavulanic acid (250 mg, 500 mg) after acute dosing of 

 
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CLAV.  The pharmacokinetics of clavulanic acid at 2 doses (250 mg, 500 mg) will be 
determined in non-treatment seeking adults with cocaine use disorder.  The pharmacodynamic 
effects of clavulanic acid in combination with cocaine will be determined by measuring the 
diameter of the subject’s pupil after the cocaine infusion.  
 
5.1.3  Exploratory Outcome Measures 
 
Exploratory outcome measures are intended to evaluate whether if there are any changes in the 
subjective effects of cocaine in the presence of clavulanic acid (250 mg, 500 mg, 750 mg) after 
acute dosing of CLAV.  The subjective effects of clavulanic acid without cocaine in non-
treatment seeking adults with cocaine use disorder will be assessed at all doses (250 mg, 500 mg, 
750 mg). 
 
5.2   Data Analysis Plan 
5.2.1  Primary Outcome Measures 
 
The primary objective of this study is to assess the safety and tolerability of CLAV in 
combination with cocaine to generate data regarding the safety of the combination of CLAV and 
cocaine in relevant doses of both drugs. This is required prior to an outpatient efficacy study of 
CLAV for cocaine use disorders. Secondary objectives are to assess whether cocaine alters 
serum levels of CLAV and to assess serum levels of CLAV at both doses of CLAV in study 
subjects. Exploratory objectives are to assess the subjective ratings of drug effects with regard to 
craving and mood.  Summary statistics will be provided for all safety, tolerability and subjective 
data.  In addition to the analyses specified below, listings of all data for each patient will be 
provided. 
5.2.1.1 Demographic and Baseline Comparability Analyses 
Demographic variables will be summarized for all for male and female patients. 
5.2.1.2  Primary, Secondary, and Exploratory Analyses 
 
5.2.1.2.1  Primary Analyses: Safety is a primary assessment variable.  The number of patients 
reporting each AE by treatment group and severity will be presented.  Adverse events will be 
tabulated by body system and organ class.   In addition, all adverse events (AE’s) noted during 
the study will be listed.  The listings will include each occurrence of the AE, when it was 
reported, the severity and the duration. Adverse event data will be compiled for CLAV at all 
doses (250 mg, 500 mg, 750 mg) and placebo and presented as summary statistics by organ 
system. Our primary analyses will compare the rates of occurrence of adverse events across the 
three-periods within each person. The data are gathered using a 3-period 3-treatment crossover 
design. Safety concerns constrain us to restrict the order of administration of the 2 study drug 
doses of CLAV, so each subject receives the doses in increasing order. Thus, we have three 
sequences: {PBO, Low (250 mg), Medium (500 mg)}, {Low, PBO, Medium}, and {Low, 
Medium, PBO}. One third of the subjects are randomized to each of these sequences. Each 
period is a 1 day session and the periods correspond to days 2, 3, and 4, providing 24 half-lives 
between administrations. The main explanatory variables in the models are: 1) a 3 level within-

 
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subject factor representing drug condition (PBO, study drug low dose (SDlow), study drug 
medium dose (SDmedium), and 2) a three level factor representing period (1, 2, and 3). We use 
standard mixed effects (repeated measures) ANOVA models for binary responses in three-period 
three-treatment crossover designs to test our hypotheses.73 An overall F-test of the condition 
effect will test for differences in response across the three drug doses, and contrasts will 
determine the pattern of differences (if any). Mixed effects models can allow for different error 
variances for different sessions, and other complex error structures as needed. As this study has 
only three repeated measures, a relatively simple covariance structure model (e.g. heterogeneous 
compound symmetry model) should be sufficient to account for within-subject correlations. 
 
Pharmacodynamic parameters (systolic and diastolic blood pressure, heart rate and QTC interval, 
expressed as AUC, 2-minute values and maximal values) will be similarly analyzed.  The COC 
infusions occur on the day of each session, providing three repeated sets of measures of each 
COC related response (change in HR, change in SBP, change in DBP, change in QTc interval,). 
 
HR and BP (systolic BP (SBP) and diastolic BP (DBP)) and QTC induced by cocaine infusion 
will be compared to HR and BP and QTC measurements before the cocaine infusion to assess 
change. BP and HR and QTC changes after infusion given after CLAV (250 mg, 500 mg, 750 
mg) will be compared to those without CLAV. We will compare the distribution of Area Under 
Curve (AUC) summaries of the within-period repeated measures of changes in vital signs (heart 
rate, systolic blood pressure, diastolic blood pressure) across the three-periods within each 
person as described above. 
 
QTC interval measured by the ECG induced by cocaine infusion will be compared to QTC 
interval before the cocaine infusion to assess change. QTC interval changes after infusion given 
after CLAV (250 mg, 500 mg, 750 mg) will be compared to those without CLAV. We will 
compare the distribution of Area Under Curve (AUC) summaries of the within-period repeated 
measures of changes in QTc interval across the three-periods within each person as described 
above. 
 
5.2.1.2.2  Secondary Analyses: The pharmacokinetic parameters will be statistically analyzed 
using a repeated measure analysis of variance model.  
 
5.2.1.2.3  Exploratory Analyses:  Subjective effects of cocaine, as measured by check lists, 
visual analog and rating scales, will be listed for each patient and summarized for each group. 
Adverse events for the CLAV 750 mg group will be analyzed as described above for the lower 
CLAV doses. Adverse events for the subset of subjects stabilized on Buprenorphine will be 
analyzed as described above. 
 
5.2.2  Secondary Outcome Measures 
Secondary outcome measures are intended to determine if there are any changes in cocaine 
pharmacokinetics and pharmacodynamics in the presence of clavulanic acid (250 mg, 500 mg).  
The pharmacokinetics of clavulanic acid will be determined in non-treatment seeking adults with 
cocaine use disorder.  The COC infusions occur on the day of each session, providing four 
repeated sets of measures of each COC related response (PK, PD as determined by change in 

 
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pupil diameter from baseline).  PK curves for single dose CLAV at 250 mg and 500 mg will be 
constructed for all subjects and then for men and women, separately.   
 
5.2.3 Exploratory Outcome Measures 
Data regarding CLAV’s effect on subjective effects and motivation for COC will be considered 
exploratory regarding efficacy, as subjects receive acute treatment.