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
Phase: PHASE1
Conditions: Cocaine Dependence
Sponsor: Temple University

Phase 1B Pharmaco-MRS study of Clavulanic acid after repeated administration. 
 
Page 1 of 60     Protocol V2.7 November 15th 2021 
1) Abstract of the study 
 
STUDY OBJECTIVES: This is a randomized, double blind, placebo controlled, 
tolerability-based, dose escalating inpatient trial to determine the effect and duration of 
multiple doses of clavulanic acid (CLAV) on glutamate (Glu) levels, using neuroimaging, 
in an addiction related brain area (the anterior cingulate cortex [ACC]) in subjects with 
cocaine use disorder (CocUD) who have achieved one week of abstinence.  
 
Primary Objective: The primary objective of this study is to determine whether once-a-
day repeated CLAV 500 (or higher, 750/1000 mg, see dose escalation in study design) 
in patients with CocUD in early remission produces reductions in brain Glu levels at day 
10 compared to baseline, as assessed by Magnetic Resonance Spectroscopy (MRS) in 
the anterior cingulate (ACC).  
 
Secondary Objectives: A) To assess changes in craving-associated neurocircuitry 
(frontal-striatal-thalamic connectivity) using resting state functional Magnetic Resonance 
Imaging (rs-fMRI). Subjects with CocUD will have decreased functional connectivity 
between nodes within the frontal-striatal-thalamic network (Wang et al. 2018) involving 
mesocorticolimbic circuit nodes (Gu et al. 2010). After repeated CLAV, we expect that 
the fronto-striatal-thalamic within network functional connectivity will increase. We also 
will determine whether improved network connectivity as associated with decreased 
craving as determined by the Cocaine Craving Questionnaire (CCQ) and a Visual 
Analog Scale (VAS).  B) To evaluate whether CLAV 500, 750, 1000 mg a day given 
repeatedly for 10 days (to steady state, rationale below) and then stopped, is associated 
with a sustained reduction in brain glutamate concentration measured in the ACC one 
day after cessation of CLAV dosing (to determine the duration of CLAV action on 
glutamate after last dose and to determine the feasibility of once daily CLAV dosing). C) 
To evaluate whether 10 days of treatment with CLAV is associated with increases in 
brain glutamine concentration as assessed by MRS in the ACC. D) To assess CLAV 
500, 750, and 1000 mg/day safety and tolerability by: a) the rates of occurrence of 
adverse events; b) changes in vital signs; c) EKG parameters; and d) laboratory study 
changes.  
Exploratory Objectives: A) To evaluate whether repeated CLAV treatment 500, 750, 
1000 mg/day suppresses cue-induced limbic fMRI activation. B) To evaluate whether 
CLAV treatment 500, 750, 1000 mg/day for 10 days is associated with subjective effects 
measured by Visual Analog Scales (VAS), the Profile of Mood States (POMS). C) To 
evaluate whether CLAV treatment 500, 750,1000 mg/day for 10 days is associated with 
cognitive and executive function deficits as assessed by the Cambridge cognition 
survey batteries. D) To evaluate whether Adverse Childhood Experiences (ACEs) are 
associated with increased outcomes of subjective reports of mood and craving. 
 
STUDY ENDPOINTS:  
Primary Endpoint: Change in brain glutamate concentration in the ACC at Day 10 
compared with baseline.  
Secondary Endpoints:  

Phase 1B Pharmaco-MRS study of Clavulanic acid after repeated administration. 
 
Page 2 of 60     Protocol V2.7 November 15th 2021 
A) Brain connectivity change in the ACC on resting state fMRI.  CCQ and VAS for 
craving.  
B) Change in brain glutamate concentration in the ACC at Day 11 compared with Day 
10.  
C) Change in brain glutamine concentration in the ACC at Day 10 compared with 
baseline.  
D) Safety and tolerance as assessed by the rates of occurrence of adverse events, 
changes in vital signs, Columbia Suicide Severity Rating Scale (C-SSRS), EKG 
parameters and laboratory studies compared with baseline.  
 
Exploratory Endpoints: 
 
A) Suppression of cocaine cue-induced limbic activation during imaging task. 
B) Subjective effects will be compared before and after CLAV 500, 750,1000 mg/day 
for 10 days using the following instruments: Visual Analog Scales (VAS), Profile of 
Mood States (POMS).  
C) Scores from the Cambridge Cognition Cognitive battery at multiple timepoints 
compared with baseline. 
D) Relationship between scores from the Adverse Childhood Experiences (ACE) scale, 
POMS, and VAS. 
STUDY DESIGN: This is a randomized, double-blind, placebo-controlled, parallel group 
inpatient study of clavulanic acid, 500, 750,1000 mg given orally once a day for 10 days. 
Subjects are adults (18-70) in early remission who are seeking treatment for cocaine 
use disorder. In rodents, CLAV 1 mg/kg is associated with a decrease in cocaine intake 
after 5-7 days, which is then maintained and can be considered steady state. A 
conservative estimate for steady state in humans is CLAV administration for 10 days. 
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. For those subjects who can 
tolerate 750mg/day for three days, there will be a forced dose escalation to 1000mg for 
4 days.  Subjects who cannot tolerate an increased dose will return to the last tolerable 
dose for the remainder of the study.  
 
Structural MRI, functional MRI, and MRS will be done before study drug administration 
at baseline, after 3 days of study drug administration (prior to 750mg dose escalation), 
after 6 days of study drug administration (prior to the 1000mg dose escalation) on the 
last day of study drug administration (day 10), and one day after the last dose of study 
drug (day 11). The final MR scan session will be used to gather information on the 
duration of CLAV's effect on anterior cingulate cortex glutamate concentration after 
cessation of CLAV dosing. At the time of each scan, safety of the subject to complete 
the scan will be re-assessed. Subjective and cognitive assessments will be 
administered daily in the inpatient setting. Assessments of adverse effects, blood 
pressure and pulse will also be performed daily. 
 
STUDY DURATION: Study duration is 3 outpatient visits (screening and follow up) and 
11 inpatient days. There will be 5 MRI/MRS studies during the inpatient portion of the 
study. The pre-intake screening will last up to 30 days. After participants are discharged 

Phase 1B Pharmaco-MRS study of Clavulanic acid after repeated administration. 
 
Page 3 of 60     Protocol V2.7 November 15th 2021 
from the inpatient portion of the study, they will be asked to return for the follow up visit 
5-8 days after discharge. The visit will include an assessment of adverse events to 
determine withdrawal symptoms. All adverse events will be followed by study staff until 
resolution. 
 
TREATMENT: The oral administration of CLAV 500,750,1000 mg/day or matched 
placebo for 10 days. Day 1 dosing is 1 capsule (250 mg) twice a day. Participants will 
receive 500mg CLAV in the morning on days 2 and 3 if the day 1 dose is safely 
tolerated. 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 (or matched placebo) for 
3 days. For those subjects who can tolerate 750mg/day (or matched placebo) for three 
days, there will be a forced dose escalation to 1000mg (or matched placebo) for 4 days.  
Participants who are unable to tolerate dose escalation will resume their previously 
tolerated dose. Nine subjects will be randomized to CLAV and 3 to placebo.  
 
2) Protocol Title 
A Phase IB Double Blind, Placebo Controlled, Pharmaco- Magnetic 
Resonance Spectroscopy (MRS) inpatient study of Clavulanic acid 500, 
750,1000 mg daily repeated administration in early remitted cocaine use 
disorder subjects. 
 
3) IRB Review History 
Date:  
03/27/2020 Initial submission to IRB (Modifications required) 
04/17/2020 Modifications required to secure approval submitted (approved) 
07/01/2020 Modification to include Covid Testing and Ace Questionnaire 
submitted (modifications required) 
08/03/2020 Modifications required to secure approval submitted (approved) 
09/17/2020 Modification to change dose self-administration procedures 
submitted (modifications required) 
10/23/2020 Modifications required to secure approval submitted (approved) 
11/02/2020 Modification to change screening and bonus schedule 
(modifications required) 
11/03/2020 RNI (scanning schedule change) submitted 
11/18/2020 Modifications for RNI submitted (approved) 
11/30/2020 Response to modifications required for approval (approved) 
12/01/2020: Modification to split screen into two parts and provide $25 gift 
card compensation for Covid-19 testing (Modifications required) 
12/23/2020: Response to modifications required to secure approval 
(approved) 
03/29/2021: Temple Main Hospital and Jeanes added as back up inpatient 
sites (modifications required) 
04/15/2021: Response to modifications required (approved) 
05/13/2021: Eligibility Criteria Revised (approved) 
 
 

Phase 1B Pharmaco-MRS study of Clavulanic acid after repeated administration. 
 
Page 4 of 60     Protocol V2.7 November 15th 2021 
4) Investigator 
 
Primary Investigator/Medical Monitor:       Mary F. Morrison, M.D., M.S. 
 
 
 
    
 
 
  (Temple University) 
 
Co-Investigator/Imaging Specialist:          Helene Philogene-Khalid, Ph.D. 
 
 
 
     
 
 
  (Temple University) 
 
Co-Investigator/Back up Medical Monitor: M. Ingre Walters, M.D. 
 
 
 
     
 
 
  (Temple University) 
 
 
Other Key Personnel 
 
 
Neuroimaging  
  
 
 
 Huiling Peng Ph.D. 
Supervisor:   
    
 
 
(Temple University) 
 
5) Objectives 
 
STUDY OBJECTIVES: This is a randomized, double blind, placebo controlled, 
tolerability-based, dose escalating inpatient trial to determine the effect and duration of 
multiple doses of clavulanic acid (CLAV) on glutamate (Glu) levels, using neuroimaging, 
in an addiction related brain area (the anterior cingulate cortex [ACC]) in subjects with 
cocaine use disorder (CocUD) who have achieved one week of abstinence.  
 
Primary Objective: The primary objective of this study is to determine whether once-a-
day repeated CLAV 500 (or higher, 750/1000 mg, see dose escalation in study design) 
in patients with CocUD in early remission produces reductions in brain Glu levels at day 
10 compared to baseline, as assessed by Magnetic Resonance Spectroscopy (MRS) in 
the anterior cingulate (ACC).  
 
Secondary Objectives: A) To assess changes in craving-associated neurocircuitry 
(frontal-striatal-thalamic connectivity) using resting state functional Magnetic Resonance 
Imaging (rs-fMRI). Subjects with CocUD will have decreased functional connectivity 
between nodes within the frontal-striatal-thalamic network (Wang et al. 2018) involving 
mesocorticolimbic circuit nodes (Gu et al. 2010). After repeated CLAV, we expect that 
the fronto-striatal-thalamic within network functional connectivity will increase. We also 
will determine whether improved network connectivity as associated with decreased 
craving as determined by the Cocaine Craving Questionnaire (CCQ) and a Visual 
Analog Scale (VAS).  B) To evaluate whether CLAV 500, 750, 1000 mg a day given 
repeatedly for 10 days (to steady state, rationale below) and then stopped, is associated 
with a sustained reduction in brain glutamate concentration measured in the ACC one 
day after cessation of CLAV dosing (to determine the duration of CLAV action on 
glutamate after last dose and to determine the feasibility of once daily CLAV dosing). C) 
To evaluate whether 10 days of treatment with CLAV is associated with increases in 
brain glutamine concentration as assessed by MRS in the ACC. D) To assess CLAV 

Phase 1B Pharmaco-MRS study of Clavulanic acid after repeated administration. 
 
Page 5 of 60     Protocol V2.7 November 15th 2021 
500, 750, and 1000 mg/day safety and tolerability by: a) the rates of occurrence of 
adverse events; b) changes in vital signs; c) EKG parameters; and d) laboratory study 
changes.  
Exploratory Objectives: A) To evaluate whether repeated CLAV treatment 500, 750, 
1000 mg/day suppresses cue-induced limbic fMRI activation. B) To evaluate whether 
CLAV treatment 500, 750, 1000 mg/day for 10 days is associated with subjective effects 
measured by Visual Analog Scales (VAS), the Profile of Mood States (POMS). C) To 
evaluate whether CLAV treatment 500, 750,1000 mg/day for 10 days is associated with 
cognitive and executive function deficits as assessed by the Cambridge cognition 
survey batteries. D) To evaluate whether Adverse Childhood Experiences (ACEs) are 
associated with increased outcomes of subjective reports of mood and craving. 
 
 
STUDY ENDPOINTS:  
Primary Endpoint: Change in brain glutamate concentration in the ACC at Day 10 
compared with baseline.  
 
Secondary Endpoints:  
A) Brain connectivity change in the ACC on resting state fMRI.  CCQ and VAS for 
craving.  
B) Change in brain glutamate concentration in the ACC at Day 11 compared with 
Day 10.  
C) C) Change in brain glutamine concentration in the ACC at Day 10 compared with 
baseline.  
D) D) Safety and tolerance as assessed by the rates of occurrence of adverse 
events, changes in vital signs, Columbia Suicide Severity Rating Scale (C-
SSRS), EKG parameters and laboratory studies compared with baseline.  
 
Exploratory Endpoints: 
 
A) Suppression of cocaine cue-induced limbic activation during imaging task. 
B) Subjective effects will be compared before and after CLAV 500, 750,1000 
mg/day for 10 days using the following instruments: visual Analog Scales (VAS), 
Profile of Mood States (POMS).  
C) Scores from the Cambridge Cognition Cognitive battery at multiple timepoints 
compared with baseline. 
D) Relationship between scores from the Adverse Childhood Experience (ACE) 
scale, POMS, and VAS. 

Phase 1B Pharmaco-MRS study of Clavulanic acid after repeated administration. 
 
Page 6 of 60     Protocol V2.7 November 15th 2021 
STUDY DESIGN: This is a randomized, double-blind, placebo-controlled, parallel group, 
dose-escalating inpatient study of clavulanic acid, 500, 750, 1000 mg given orally once 
a day for 10 days. 
 
In rats, CLAV 1 mg/kg is associated with a 
decrease in cocaine intake after 5-7 days, which 
is then maintained and can be considered steady 
state. A conservative estimate for steady state in 
humans is CLAV administration for 10 days. 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. For 
those subjects who can tolerate 750 mg/day for 
three days (or matched placebo), there will be a 
forced dose escalation to 1000 mg (or matched 
placebo) for 4 days.   
 
Structural MRI and a MRS scan will be done 
before CLAV administration at baseline, on day 3 
of the study prior to the 750mg dose escalation, 
on day 6 of the study before the 1000 mg 
escalation, on day 10 of the study (maximum CLAV dose), and one day after the last 
dose of CLAV to gather information of the duration of CLAV’s effect on brain glutamate 
concentration after cessation of CLAV dosing. Before each scan, safety of the subject to 
complete the scan will be re-assessed. Assessments of subjective and cognitive effects 
will be administered at the beginning of each inpatient study day. In addition, safety 
assessments of adverse effects, blood pressure, and pulse will be performed during 
each study day. The C-SSRS will be conducted at screening, baseline, and on the 
discharge day. A full list of assessments is included in table 1 in section 10: study 
design. A medication questionnaire (Med-Q) will be used to determine whether 
participants believe they have been given study drug or placebo.  
 
STUDY DURATION: Study duration will be 10 days of study drug with 5 MRS scans 
over that time as an inpatient. This is in addition to the pre-intake screening and a follow 
up visit. The pre-intake screening will last up to 30 days. The follow up visit will occur 5-
8 days after discharge. The follow up visit will involve study assessments and an 
evaluation of adverse events to determine any withdrawal symptoms. Subjects with 
adverse events that require further in person assessments may be asked to come in for 
an additional visit.  All adverse events will be followed until resolution. 
 
TREATMENT: The oral administration of CLAV 500, 750, 1000 mg/day or matched 
placebo for 10 days. Day 1 dosing is 1 capsule (250 mg) twice a day. Participants who 
safely tolerate the initial 250 mg dose will be provided the second 250 mg dose for self-
administration.  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 (or matched placebo) for 
3 days. For those subjects who can tolerate 750mg/day (or matched placebo) for three 
Figure 1. CLAV (1.0 mg/kg, 10 mg/kg) increased 
GLT-1 expression in nucleus accumbens. n=5-
6/group; bars are S.E.M. ** and *** indicates 
significance from vehicle as determined by 
Bonferroni posttest p<0.01 and p<0.001 respectively. 

Phase 1B Pharmaco-MRS study of Clavulanic acid after repeated administration. 
 
Page 7 of 60     Protocol V2.7 November 15th 2021 
days, there will be a forced dose escalation to 1000 mg (or matched placebo) for 4 
days. Subjects who are unable to tolerate an increased dose will resume the previously 
tolerated dose when medically appropriate (usually the next day).  
 
6) Background 
 
Rationale for CLAV, a GLT-1 Transport Activator 
The glutamate system is critical to understanding and treating CocUD. A large body of 
evidence suggests that inhibiting glutamatergic transmission decreases COC use in 
addiction. Glutamatergic projections from the amygdala and dorsal prefrontal cortex to 
the nucleus accumbens drive drug-seeking following an addiction reinstatement trigger 
(Uys and LaLumiere 2008). Preclinical studies at Temple and elsewhere suggest that 
activation of GLT-1, the dominant astroglial glutamate transporter (Rothstein et al. 2005) 
may provide a breakthrough approach to managing COC addiction. Through a complex 
mechanism, chronic COC use reduces the basal extracellular concentration of 
glutamate. Consequently, during stress- or drug-induced reinstatement of COC seeking, 
there is an increase in synaptic release of glutamate into the nucleus accumbens 
(Kalivas 2009). These effects on glutamate signaling contribute to its reinforcing 
properties, the acquisition of self-administration behavior, and the maintenance, 
extinction, and subsequent reinstatement of drug seeking (Knackstedt and Kalivas 
2009). 
 
Data from animal studies show that CLAV, a component of the commonly used 
antibiotic Augmentin, is an activator of the glutamate transporter GLT-1 (excitatory 
amino acid transporter, EAAT2) (Fig. 1) and reduces COC-seeking behavior (Fig. 2).  
CLAV is a Potent GLT-1 Activator that 
Decreases COC Use.  The data below are 
presented to show that:  1) CLAV is a potent 
GLT-1 activator; 2) CLAV decreases COC 
use in addicted rodents; 3) CLAV is superior 
to available beta-lactam drugs in its potential 
for clinical use.  
 
Figure 2. CLAV 1 mg/kg inhibited motivation to 
self-administer COC (0.56mg/kg/inf) under PR 
schedule of reinforcement.  n=4-6/group. Bars are 
S.E.M. * significantly different from vehicle by 
Bonferroni post-test. 

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Page 8 of 60     Protocol V2.7 November 15th 2021 
GLT-1 activators inhibit COC self-administration. Excessive synaptic glutamate 
activity is buffered by the transport of glutamate into the glial cells via GLT-1 (Rothstein 
et al. 2005). Since glutamate release in nucleus accumbens leads to COC self-
administration, treatments that enhance the activity of GLT-1 might be expected to 
inhibit COC self-administration.  Drugs containing the β-lactam structural motif activate 
GLT-1 and thereby increase glial glutamate uptake. For example, the β-lactam antibiotic 
ceftriaxone (CTX) displayed anti-glutamate 
activity in vitro (Rothstein et al. 2005, 
Chu et al. 2007) and in vivo (Miller et 
al. 2008, Rasmussen et al. 2011). 
CTX (200 mg/kg) decreased COC 
self-administration, with statistically 
significant differences seen by Day 7 
(Ward et al. 2011). As shown in Fig. 
2, CLAV (1 mg/kg) also decreases 
COC self-administration, with 
statistically significant differences 
seen by Day 5 (Kim et al. 2016).  
 
CLAV has glutamate modulating 
properties similar to ceftriaxone 
(CTX). Preclinical experiments from 
the Rawls’ lab provide a proof-of-
principle that CLAV, a β-lactam 
compound structurally related to 
CTX, mimics CTX efficacy against 
neuropsychiatric disorders that result 
from excessive glutamate 
transmission. CLAV also displayed anti-glutamate activity in three different 
neurochemical assays: enhanced GLT-1 expression in nucleus accumbens (Fig. 1), 
increased glutamate uptake in astrocytes (Fig. 3B), and reduced extracellular glutamate 
in nucleus accumbens (data not shown).  This is supported by findings demonstrating 
that CLAV has neuroprotective properties in animal models of neurodegenerative 
diseases (Huh et al. 2010). The β-lactam compounds also display substance abuse-
deterrent properties in animal models. CTX administration inhibited acquisition and 
motivation of COC self-administration in mice (Ward et al. 2011) and prevented relapse 
to COC seeking in rats (Ward et al. 2011, Sari et al. 2009).  In a model of chronic 
cocaine abuse, CTX ameliorated myelin loss in the nucleus accumbens, suggesting 
neuroprotection (Kovalevich et al. 2012).  CTX also inhibited sensitized behavioral 
responses produced by amphetamine in rats (Rasmussen, Unterwald, and Rawls 2011, 
Rawls, Baron, and Kim 2010). Similarly, CLAV inhibits motivational and reinforcing 
properties of COC in mice (Fig. 2).   
 
CLAV may be a more potent GLT-1 activator than CTX.  As shown in Fig. 2 CLAV (1 
mg/kg) had a potent effect on inhibiting COC intake in mice (P<0.05).  Repeated 
administration of CLAV at both 1 mg/kg and 10 mg/kg significantly increased GLT-1 
Figure 3. CLAV is more effective than CTX in 
potentiating glutamate uptake.  Astrocyte 
cultures were bathed in 3H-glutamate and the 
levels (means + S.E.M.) were measured as in 
the text. A, effect of increasing doses of CTX on 
glutamate uptake. B, effect of increasing doses 
of CLAV on glutamate uptake. C, comparison of 
regression dose-response curves between CTX 
and CLAV from the data in A and B.  ** P<0.01, 
* P<0.05 compared to vehicle-treated astrocyte 
controls.  
CLAV Vs. CTX for Glutamate Uptake 

Phase 1B Pharmaco-MRS study of Clavulanic acid after repeated administration. 
 
Page 9 of 60     Protocol V2.7 November 15th 2021 
protein expression in rat nucleus accumbens (Fig. 1). In fact, CLAV (10 mg/kg) 
produced a ~1.4-fold increase in GLT-1 expression, comparable to that detected with a 
much higher dose of CTX (200 mg/kg, 10 days) (Miller et al. 2008, Rasmussen et al. 
2011). Both CLAV and CTX increased glutamate uptake in primary astrocytes (Fig. 3B, 
A). The magnitude of the CLAV effect was actually greater than that of CTX, and 
regression analysis indicated that CLAV displays enhanced anti-glutamate properties 
relative to CTX (Fig. 3C). Additional support for CLAV having greater potency than CTX 
in glutamate-associated disorders was obtained in an invertebrate assay designed to 
screen for anti-epileptic activity (Rawls et al. 2010).  CLAV displayed greater potency 
than did CTX against glutamate- and COC-induced planarian seizure-like activity.  
[(glutamate, COC): (1.44, 0.010 mM for CLAV) and (5.8, 24.5 mM for CTX)].  Thus, both 
vertebrate and invertebrate models demonstrate that CLAV displays anti-glutamate 
properties, but at lower doses than CTX.  
 
CLAV is preferable to CTX for testing the hypothesis that GLT-1 activation can 
prevent COC self-administration and other glutamate-associated toxicities. CTX 
has 3 drawbacks as a drug for human use.  First, it must be given parenterally. Second, 
it is an antibiotic, so its use can give rise to drug resistant bacteria. Third, CTX displays 
poor blood brain barrier (BBB) penetrability, which requires the use of high doses for 
CNS efficacy (typically 200 mg/kg/ day in rodents). These doses equate to about 13 
g/day in a human, approximately 5 times greater than CTX doses used for meningitis. 
Compared with CTX, CLAV displays greater BBB permeability with mean CLAV ratios, 
cerebrospinal fluid to plasma, of ~23% in neurosurgical patients with normal BBB 
(Nakagawa et al. 1994). Chronic cocaine use has been associated with a pro-
inflammatory state, so the BBB permeability of CLAV may be increased in chronic users 
(Fiala et al. 1998). CLAV has negligible antibiotic activity (Saudagar, Survase, and 
Singhal 2008), so there is very low risk of developing drug resistant strains. CLAV is an 
oral drug, which is a practical delivery system for an inpatient study. We hypothesize 
that CLAV, an existing drug that is brain penetrable, safe and orally active offers a 
realistic candidate for cocaine pharmacotherapy. Repeated CTX administration 
produced a dose-dependent reduction in glutamate levels in that persist for up to 20 
days following discontinuation of drug exposure (Rasmussen, Unterwald, and Rawls 
2011). The prolonged reduction in glutamate levels after CTX discontinuation suggest 
that CTX’s effect on glutamate is not a PK-mediated mechanism, since the half-life of 
CTX is short (~ 6 hours). We plan to investigate whether CLAV, given repeatedly for 10 
days, is also associated with reduced glutamate levels after discontinuation of drug 
exposure with an MRS scan 24 hours after the last CLAV dose.  
 
CLAV may be effective for combined cocaine/opiate addiction. Recently, cocaine 
related overdose deaths have increased significantly. In non-treatment samples, much 
of the cocaine use are in combination with opiates (Leeman et al. 2016). CLAV might be 
an effective treatment as a monotherapy or as an adjunctive treatment for comorbid 
cocaine and opioid use disorder based on available preclinical data.  Male rats treated 
with morphine at 4mg/kg demonstrate conditioned place preference (Schroeder et al. 
2014). Co-treatment with either CLAV (10 mg/kg) or the beta-lactam, CTX (200 mg/kg), 
inhibited the development of conditioned place preference associated with morphine by 

Phase 1B Pharmaco-MRS study of Clavulanic acid after repeated administration. 
 
Page 10 of 60     Protocol V2.7 November 15th 2021 
approximately 70%, suggesting efficacy in the treatment of opiate addiction. In a heroin 
study, male rats were trained in heroin self-administration (Shen et al. 2014). After 
extinction, the rats were given 7 days of CTX (200mg/kg) and CTX treatment was 
associated with a reduction in cue associated relapse to heroin seeking. Therefore beta-
lactams appear to have efficacy in two preclinical models of opiate addiction, with one 
study utilizing heroin and another study, morphine. CLAV, an oral beta-lactam, may be 
effective for combined cocaine and opiate addiction.    
 
Pharmacology. Potassium clavulanate is a beta-lactamase inhibitor and is the 
potassium salt of CLAV. CLAV is structurally related to penicillin with a beta-lactam ring.   
 
Pharmacokinetics. The half-life of CLAV is short (between 0.8 and 2 hours) and there 
is no accumulation between doses (Sánchez Navarro 2005).  
 
Previous Human Experience. CLAV is unavailable by itself. CLAV is part of 
Augmentin/Augmentin XR®, along with amoxicillin, which has been FDA approved 
since 1984 for the treatment of patients with acute bacterial sinusitis. Augmentin® is 
considered reasonably safe during pregnancy and lactation (Berkovitch et al. 2004, 
Benyamini et al. 2005). CLAV is not an effective antibiotic and is unlikely to disturb 
bowel flora (Saudagar, Survase, and Singhal 2008). There is no safety data in the 
scientific literature on CLAV alone.  
 
CLAV/COC Interaction Study: CLAV Is Safe to Use in People Who Have Taken 
Concurrent COC. We performed an inpatient, placebo-controlled cocaine interaction 
safety study with 3 acute doses of CLAV (250 mg, 500 mg, and 750 mg (N=5 for 750 
mg dose) in ten subjects (8 men and 2 women). The study report was received by the 
FDA in December 2018. This study was performed under double-blind conditions (for 
the 250 mg and 500 mg doses) and single blind for the 750 mg dose, which was added 
later in the study. There was no indication that any dose of clavulanic acid produced 
medical instability or increased clinical risk in conjunction with COC. No serious or 
severe adverse events occurred during the trial. No clinically significant changes in 
diastolic blood pressure, pulse or electrocardiogram parameters occurred related to 
CLAV. Minor increased systolic blood pressure occurred in the 250mg session 
compared to the placebo and 500mg CLAV sessions. The pharmacokinetic (PK) data 
suggested that CLAV PK levels generally increased from the 40-minute timepoint to the 
70-minute timepoint post dose, as expected. Participant CLAV PK levels had high 
variability between subjects which has been noted in healthy controls (De Velde et al. 
2018). There was no pupillometry evidence to support a pharmacodynamic effect of 
CLAV on cocaine-associated pupil size increase. Thirty-two adverse events (AEs) 
occurred in 10 subjects during the study. Of these AEs, 11 occurred either during the 
safety day (2 doses of cocaine, N=8) or the placebo day (N=3), 4 occurred on the 250 
mg dose of CLAV day, 6 occurred during the 500 mg dose day, and 2 occurred on the 
750 mg dose day, 5 on the day of discharge and 4 at the outpatient follow up visit. The 
AEs deemed to be potentially related to study drug included: headache, nausea, 
indigestion, drowsiness, and minor elevations of serum calcium.  
 

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Page 11 of 60     Protocol V2.7 November 15th 2021 
We performed a phase 1B open label imaging pilot study of CLAV 500mg for 10-day in 
five completed subjects (4 men and 1 woman), with 8 subjects total. No serious or 
severe adverse events occurred during the trial. The AEs deemed to be potentially 
related to study drug included: headache, nausea, hunger, diarrhea, and constipation. 
 
Based on the benign adverse event profile of CLAV in combination with cocaine in our 
cocaine interaction study, and our procedures ensuring careful observation for 
significant blood pressure elevations and arrhythmias during and after cocaine 
administration, the data obtained from the cocaine interaction study provide confidence 
that CLAV 500 mg/day can be safely used in an inpatient setting for 10 days in recent 
cocaine users.  Side effects reported in the Phase I studies of CLAV from the FDA 
approval include: nausea, vomiting, drowsiness, diarrhea, indigestion, headache, 
increased stomach noises, flatulence (passing gas), “very slight increase in liver size” 
with increased liver tests, cholestatic jaundice, and dizziness. In the present study one 
male participant experienced priapism, without pain, for 5 hours after the first day of 
study drug (study drug not unmasked). He informed the study team after resolution. 
During the screening visit, male subjects will be evaluated for priapism risk factors, 
abnormal anatomy of the penis, and previous episodes of unexpected, prolonged 
erections. The PI consulted with Dr. Jack Mydlo, the Temple Chair of Urology, and 
determined that a participant with an erection of 4 hours or longer will be transferred to 
the Emergency Room. Participants experiencing priapism will have their cavernosal 
blood gas evaluated to determine whether the priapism is high or low flow. Emergency 
Room physicians at Temple are familiar with priapism evaluation, and will discuss the 
results with the Urology Resident on call for further management. 
 
Common adverse events for Augmentin include: diarrhea (14.5%), vaginal mycosis 
(3.3%), nausea (2.1%) and loose stools (1.6%). As a beta lactam drug, CLAV has a risk 
of allergic reactions for those with known penicillin allergy.  The risk of hepatitis for 
Augmentin® is estimated at between 1/10,000 to 1/100,000, with an increased risk for 
older males (Gresser 2001). Hepatotoxicity associated with amoxicillin/ CLAV is 
generally self-limited with cessation of medication and generally associated with 
complete recovery (Saudagar, Survase, and Singhal 2008, Gresser 2001, Larrey et al. 
1992). Single dose studies with sodium clavulanate were performed at both 750 mg (5 
subjects) and 1000 mg (2 subjects) (FDA 05/09/1988).  After 750 mg, 4 of 5 subjects 
had symptoms, although they were mild in 3 and consisted of “slight sleepiness, 
borborygmi and a heavy feeling in the epigastrium.  The fourth subject had marked 
malaise, indigestion, and slight headache between ½-2 hours after dosing and later 
epigastric discomfort and diarrhea which persisted for several hours.” The medical 
literature supports the hypothesis that CLAV at doses up to 500 mg/day and CLAV 
given as a chronic medication is generally safe and well tolerated. Combined amoxicillin 
clavulanate (CLAV 250 mg a day) has been given to men to treat actinomycetoma for a 
mean of 9.6 months with no reported side effects (Bonifaz et al. 2007). Combined 
meropenem/clavulanate (CLAV 375 mg a day) has been given to 6 patients with drug-
resistant tuberculosis for up to 36 weeks with no reported side effects (Payen et al. 
2012). Timentin® is an intravenous combination of ticarcillin and CLAV, with 100 mg of 
CLAV in a 3.1 gram infusion of Timentin. In a retrospective study of 127 pediatric cystic 

Phase 1B Pharmaco-MRS study of Clavulanic acid after repeated administration. 
 
Page 12 of 60     Protocol V2.7 November 15th 2021 
fibrosis patients who received Timentin, they received a mean of 450 mg CLAV /day +/- 
227 mg/day for a mean duration of 13.5 days (Zobell et al. 2010). No adverse effects on 
laboratory measures, including liver function tests, were found.  While there is 
substantial clinical experience with Augmentin to treat infections, there is no published 
data on either CLAV or Augmentin in cocaine dependent adults. In our inpatient study of 
3 doses of CLAV in combination with cocaine 40 mg, 10 subjects have received single 
doses of CLAV 500 mg, and 5 subjects have received single doses of CLAV 750 mg in 
combination with cocaine.  All doses have been reasonably well tolerated without 
serious adverse effects. 
 
CLAV 500 mg Decreased Craving with a large effect size compared to PBO. The 
CLAV 500 mg dose, given acutely in the cocaine interaction study, was associated with 
a decrease in craving by -2.1 units on the Cocaine Craving Questionnaire (CCQ). The 
placebo session was associated with an increase in craving by 3.6 units. Thus, craving 
was decreased by 5.7 units in the CLAV 500 mg compared with the placebo group, with 
a calculated effect size of Cohen's d=1.25, representing a large decrease in craving 
associated with CLAV. 
 
MRS Pilot Study of CLAV on 
Brain Glutamate We completed 
an outpatient human MRS 
imaging Pilot study to gather pilot 
data regarding the effect of 10 
days of open label treatment with 
CLAV 500 mg/day on brain Glu 
levels (n=5 completers). The 
levels were obtained from a brain 
area associated with addiction, 
the anterior cingulate (ACC), in 
CocUD subjects with 7+ days of 
abstinence. We present the data 
from Subject 1 in Fig. 4. This 
subject had a decrease in the 
ACC glutamate level compared to 
baseline 30 minutes after the first 
dose of CLAV 250 mg. The 
change in Glu levels was 
sustained after 10 days of CLAV 
500 mg, and slightly attenuated at 
Day 11, 24 hours after the last 
CLAV dose. Thus, on initial study, 
CLAV-associated changes in 
brain Glu in the AC, our biomarker 
for CLAV effect, are reasonably 
stable for 24 hours after the last dose. This supports the idea that CLAV can be dosed 
Baseline 
Pre-Dose 
Baseline 
~30 minutes 
Post 250mg 
Dose 
Day 10 
(last 
500mg 
dose) 
Day 11 ~24 
hours after 
last dose 
Figure 4. Data for Subject 1. Subject was orally 
administered 250mg CLAV 2/day at baseline. On days 2-10 
participants orally administrated 500mg CLAV daily.  

Phase 1B Pharmaco-MRS study of Clavulanic acid after repeated administration. 
 
Page 13 of 60     Protocol V2.7 November 15th 2021 
daily. We also measured whether 10 days of treatment with CLAV is associated with 
increases in brain glutamine concentration (data pending).  
 
We enrolled 8 subjects into the study, and 5 completed the protocol. We utilized the 
pilot study to refine the MRS imaging sequence for the imaging protocol.  
 
There were 21 AEs throughout the course of the study. All AEs were mild and similar to 
those in the inpatient COC interaction study. There were no serious or severe adverse 
events during the study. AEs deemed likely to be study drug related were constipation 
(n=1), hunger (n=1), loose stool (n=1), nausea (n=9), and stomach pain (n=1). 
 
7) Setting of the Human Research 
 
Episcopal Hospital/Health Sciences Center/Jeanes Hospital – Screening and 
inpatient days 
This is an inpatient study to be conducted on a medical unit at the Episcopal Hospital 
campus of the Temple University Health System (T-EH). In the event that space is 
unavailable on C6 for medical reasons, Temple University Hospital Main (TUH-Main) 
and Jeanes Hospital medical floors which can provide nursing staff who are not 
currently assigned Covid patients will serve as back up sites. T-EH,TUH-Main and 
Jeanes are fully equipped hospitals, with 24-hour Emergency Departments. The 
Hospitalist teams for Episcopal Hospital, TUH Main, and Jeanes Hospital will be fully 
briefed on the study. The Chief Medical officer of Episcopal Hospital, Dr. William R. 
Dubin, Executive Vice President and Chief Medical officer of TUH-Main Dr. Tony S. 
Reed, nursing management, nurses on all shifts of the medical unit, pharmacy and 
security will be briefed on the study and will be updated at least every six (6) months 
and more frequently if needed. 
 
Interested candidates between the ages of 18 and 70 who have been determined to be 
cocaine dependent subjects with 7+ days of abstinence, or who express interest in 
remaining abstinent from cocaine, will meet with the investigators/study team by phone 
or in person and receive an explanation of the study purpose and requirements at the 
inpatient sites. If still interested after receiving an explanation of the study, the candidate 
will complete a prescreen questionnaire. Interested candidates who complete the 
prescreen are given an ID and have their data from the prescreen questionnaire stored 
in REDCap. Participant names are not stored in REDCap and are kept separately in a 
password protected excel file on a secure Temple server. If a candidate expresses 
interest in the study but has already completed a prescreen questionnaire, the study 
team will review their prior prescreen to determine whether they were excluded based 
on criteria that may have changed since they last contact the study team. If a participant 
may still be eligible, the study team will ask the candidate if they can update their 
information to determine whether they may be eligible for the study. 
 
Participants who are potentially eligible based on the prescreen questionnaire will be 
given an opportunity to review, inquire about, and sign the study informed consent form 
approved by the Temple University Institutional Review Board (IRB).  Screening of 

Phase 1B Pharmaco-MRS study of Clavulanic acid after repeated administration. 
 
Page 14 of 60     Protocol V2.7 November 15th 2021 
subjects to establish eligibility will occur over the phone or video (for screening part 1) or 
in person (part 1 and 2) at the inpatient unit to establish cocaine use, appropriate age, 
and no excluded medical or psychiatric conditions. 
 
Temple University Main Campus – Scans  
 
MRI scans will be conducted with the Siemens MAGNETOM Prisma 3-Tesla whole-
body MRI scanner in Weiss Hall of the main campus of Temple University. It supports a 
collection of structural MRI, MRS, BOLD fMRI, ASL, perfusion MRI and DTI sequences. 
This instrument provides the strongest commercially available gradient field (80mT/m) in 
combination with the fastest available gradient switching rate (200mT/m/s). The 
magnet’s coil uses an ultra-high-performance cooling and force-compensated design to 
reduce vibrations, which results in a minimization of eddy currents and acoustic noise. 
The advanced fully-dynamic parallel transmit radiofrequency (RF) technology in this 
system integrates all transmit and receive components within the magnet housing, 
providing industry leading signal-to-noise performance and high image stability with 
minimal RF noise artifact. The complete system is equipped with a 64-channel phased-
array parallel transmit and receive RF head/neck coil, providing maximal image quality 
with exceptionally high spatial and temporal resolution for all brain imaging pulse 
sequences. 
 
The scanner is housed within the Temple University Brain Research and Imaging Center 
(TUBRIC), a 3400sf, multi-modal, research imaging center serving the neuroimaging 
research community on Temple’s main campus. TUBRIC is a fully functional research-
dedicated facility with immediately adjacent participant preparation, testing, and 
interview space, furnished with a range of integrated and supplemental research 
instruments to complement basic imaging work. The facility is staffed by a director, a 
neuroimaging supervisor who has a PhD in Biomedical Engineering, and administrative 
and IT support personnel. TUBRIC has a standardized certification process to ensure 
study personnel utilize the scanner and imaging center to maximize subject and 
personnel safety. 
 
 
8) Resources Available to Conduct the Human Research 
INTRODUCTION and rationale 
 
Therapeutic Strategies for Treating Cocaine Use Disorder 
Cocaine (COC) related overdose deaths in non-Hispanic black populations are on par 
with heroin and prescription opioid associated deaths in non-Hispanic white populations 
(Shiels et al. 2018). Cocaine is a consistent and important contributor to deaths in non-
Hispanic white populations and Hispanic populations.  Prevention of cocaine-related 
deaths, which disproportionally affect older non-Hispanic blacks, is urgently needed. A 
variety of neuropharmacological strategies are being pursued in the search for an 
effective treatment for Cocaine Use Disorder (CoCUD). These include: 1) blocking 
cocaine’s effects, 2) restoration of central nervous system homeostasis, 3) reducing 
craving or enhancing the addict’s ability to manage his/her response to craving, 4) 

Phase 1B Pharmaco-MRS study of Clavulanic acid after repeated administration. 
 
Page 15 of 60     Protocol V2.7 November 15th 2021 
treating underlying comorbid conditions that may predispose subpopulations toward 
dependence, and 5) stress reduction to prevent relapse.  
 
Study Site 
This is an inpatient study that will take place at the Episcopal, TUH Main, Jeanes 
Hospital, and Main campus of Temple University. The first part of the screening visit can 
be completed in person or over the phone/video. Inpatient sessions are conducted at 
Centennial 6 at the Episcopal Hospital campus of the Temple University Health System 
(T-EH). In the event that space is unavailable on C6 for medical reasons, Temple 
University Hospital Main (TUH-Main) and Jeanes Hospital medical floors which can 
provide nursing staff who are not currently assigned Covid patients will serve as back 
up sites.  Subject rooms are semi-private (on a unit with other patients) and subjects will 
be able to complete all study surveys privately. 
 
Blood will be drawn at TUBRIC or on the inpatient unit for all study sessions by staff 
who are trained and certified to draw blood for research studies. TUBRIC and the 
inpatient units have a fully equipped blood draw room that will be stocked with all 
necessary blood draw supplies. 
 
Research Staff Training  
Training of research study staff will be conducted by Drs. Morrison, Peng (or 
TUBRIC staff), Khalid and the research specialist.  Training will include 
background on cocaine use disorders, remission and assessing medication 
adherence in substance abuse populations, information about the rationale for 
CLAV, and information about performing MRS studies safely. TUBRIC staff will 
conduct training regarding the TUBRIC scanner and subject safety. The training 
team will ensure that study staff understand and accept the nature of the protocol 
and the requirements for an adequate, safe and ethical study.  Specifically, their 
obligation to conduct the clinical investigation in accordance with Good Clinical 
Practices (GCP) and any other regulations will be reinforced. Study conduct 
training will include protocol review, patient confidentiality, procedures regarding 
study drug administration, procedures with assessments and urine 
testing. Procedures for correctly accounting for and disposing of extra study drug 
will be reviewed. Procedures for assessing and treating adverse events will be 
discussed.  
 
9) Prior Approvals 
The Investigational New Drug (IND) application with the FDA (IND# 113621) was 
approved in 2015. This protocol will be submitted to the FDA concurrently with 
the submission to the Temple IRB. CLAV has been approved for Fast Track 
Designation by the FDA for CocUD.  
 
10) Study Design 
 

Phase 1B Pharmaco-MRS study of Clavulanic acid after repeated administration. 
 
Page 16 of 60     Protocol V2.7 November 15th 2021 
This Phase IB study of 
CLAV will investigate brain 
regional glutamate levels 
before and after repeated 
10-day CLAV dosing to 
determine whether 
glutamate is reduced in the 
ACC after repeated CLAV 
dosing in a dose escalating 
study. The study will be 
performed with 5 imaging 
days (5 MRS scans) over 
11 inpatient study days in 
total with three outpatient 
visits. It will be conducted in 
subjects with moderate to 
severe cocaine use 
disorder in with 1 week or 
more of abstinence.  
 
Structural MRI, functional 
MRI, and MRS will occur before CLAV administration at baseline, after 3 days of study 
drug administration (prior to 750mg dose escalation), after 6 days of study drug 
administration (prior to the 1000mg dose escalation) on the last day of CLAV dosing 
(day 10), and one day after the Cessation of CLAV dosing (day 11). The final MR scan 
session will be used to gather information on the duration of CLAV's effect on ACC Glu 
concentration after cessation of CLAV dosing. Before each scan, safety of the subject to 
complete the scan will be re-assessed. Subjective and cognitive assessments will be 
administered daily in the inpatient setting. Assessments of adverse effects, blood 
pressure and pulse will also be performed daily. 
 
The study will end with a follow up visit 5-8 days after discharge. The follow visit will 
involve an assessment of adverse events to determine withdrawal symptoms. Subjects 
with adverse events that require further in person assessments may be asked to come 
in for an additional visit.  All adverse events will be followed until resolution. 
 
Informed Consent and Screening Part 1 (Approximately 120 minutes, in- person 
or over the phone) 
In-Person Consent and Screening Procedure  
In a private setting, each participant will receive a description by a study staff member of 
the study protocol, its risks, potential benefits, and alternative treatments available. A 
study physician will be present and involved in the consent process. A consent quiz will 
be administered after review of the consent, and prior to when participants sign the 
consent form. Participants will need to understand the answer to all questions correctly 
before signing. Participants who answer questions incorrectly will review those 
questions with research staff, who will explain the sections of the consent form that are 
Figure 5.  Enrollment-Discharge Participant Schedule 
Placebo 
Clavulanic  
Acid  
500 mg 
1 
2
3 
4 
5 
6 
7 
8 
9 
10 
11 
12 
Randomization 
Study Days 
Screening 
Inpatient Treatment 
Outpatient 
Follow up 
 
750 mg dose  
escalation* 
*Participants will have an escalation to 750mg on day 4 of 
the study, and an escalation to 1000mg on day 7 of the study. 
Participants who are unable to tolerate dose escalation will 
resume the previously tolerated dose. 
Study Schematic 
1000 mg dose  
escalation* 

Phase 1B Pharmaco-MRS study of Clavulanic acid after repeated administration. 
 
Page 17 of 60     Protocol V2.7 November 15th 2021 
relevant to the incorrect quiz questions.  Following completion of the consent quiz and 
resolution of any questions, participants who understand the nature of the study and 
consent will be asked to sign the study consent form, which will also be signed by the 
physician present. A copy of the informed consent form will be given to each participant 
and participants will be reminded that the consent expresses willingness to participate 
but that the subsequent screening process will determine final eligibility. Further, each 
participant will be reminded that participation is voluntary, and at any time, s/he may 
withdraw from the study. Following the informed consent process, a research 
coordinator will perform assessments during the outpatient screening visit including: 1) 
collection of demographic information, 2) a timeline follow back (TLFB) interview 
covering the preceding 42 days 3) cocaine use questionnaire, including reactions to 
cocaine, history of other substance use (including cigarettes), number of prior cocaine 
quit attempts and reasons for relapse. A trained coordinator or clinician will perform the 
MINI, a psychiatric diagnostic interview Vital signs will be collected. A study physician 
will take a medical history including drug allergies and medications. 4) Participants who 
are potentially eligible at this stage of the screening will be provided transport to the 
Temple Health Sciences campus to receive a Covid-19 test. Participants who test 
negative will be scheduled for the second half of the screening visit.  
 
 
Phone Consent and Screening Procedures 
Participants who complete the first part of the screen over the phone will review the 
consent with a study physician and complete a consent quiz. After completion of the 
consent quiz, participants will be provided a RedCAP link which will allow them to 
virtually sign the consent form. Participants who sign the consent form virtually will 
complete the same assessments as individuals who complete the screening visit 1 in 
person. At the end of the part 1 screening visit participants will be sent a copy of the 
consent form by e-mail or mail. 
 
Participants who are interested in the study but do not have internet access to complete 
the form can be sent a preaddressed and stamped envelope with a blank consent form, 
which they can return to the research team. The screening visit will be completed at a 
later date when the signed form is received.  
 
If a participant is determined to be eligible for the research study, they will be scheduled 
for a Covid-19 test on the Temple Health sciences campus. Participants who test 
negative will be scheduled for the second half of the screening visit.  
 
 
Screening Part 2 (Approximately 90 minutes, in- person)  
Participants have up to 90 days after the completion of screening part 1 to complete 
screening part 2. Participants who attend screening part 2 more than 30 days after 
screening part 1 will update their medication history, medical history and recent 
substance use information. 
 

Phase 1B Pharmaco-MRS study of Clavulanic acid after repeated administration. 
 
Page 18 of 60     Protocol V2.7 November 15th 2021 
Upon arrival for the part 2 visit, participants will be asked to show legal picture 
identification. Participants who completed the first part of the screen virtually will be 
asked to sign a physical copy of the informed consent and will be provided a copy. A 
physician will perform a physical exam. Laboratory assessments (blood & urine) will be 
checked including a comprehensive metabolic panel, CBC, infectious disease panel, 
including human immunodeficiency virus (HIV) type 1 and 2, and urine tests for drugs of 
abuse, pregnancy (women) and urinalysis. Approximately 15ml (1 tablespoon) of blood 
will be collected at this visit. A breathalyzer test will be completed. An EKG will be 
performed and reviewed.  
 
If a participant can be scheduled for admission within 96 hours, they will be provided 
transport to the Temple Health Sciences campus to receive a Covid-19 test. If 
participants cannot be scheduled for admission within 96 hours at the time of the 
screening part 2 visit, they will be scheduled for a test within 96 hours prior to their 
admission date. 
 
Participants can receive up to 2 additional Covid-19 tests (4 total) as needed to account 
for unanticipated scheduling changes, and increase scheduling flexibility for admission. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

Phase 1B Pharmaco-MRS study of Clavulanic acid after repeated administration. 
 
Page 19 of 60     Protocol V2.7 November 15th 2021 
 Table 1: Study Assessments 
 
Baseline and Intake (Approximately 180 minutes)  
After determination of eligibility on the screening day, the subject will be scheduled for a 
baseline visit (Day1) at TUBRIC. Subjects are instructed to refrain from non-prescription 
drugs and alcohol prior to the baseline/intake visit. Upon arrival, participants will be 
asked to complete a breathalyzer test and provide a urine sample to confirm abstinence 
 
1 Vital signs will only be taken at screening visit 1 if it is conducted in person. 
 
Screenin
g visit 1 
 
(-30 to 0 
days) 
Screening 
Visit 2 
(-30 to 0 
days) 
Day 1 
Baseline 
Day 
2 
Day 
3 
 
Day 
4 
Days 
5 
 
Day 
6 
Days 
7-9 
 
Day 
10 
 
Day 
11 
 
 
Follow 
Up  
(Day 16 - 
19) 
ICF with HIPAA 
X 
 
 
 
 
 
 
 
 
 
 
 
Cocaine Use Questionnaire 
X 
 
 
 
 
 
 
 
 
 
 
 
Illicit Drug Use TLFB (preceding 
30 days or less on follow up) 
X 
 
X 
 
 
 
 
 
 
 
 
X 
Medical record review 
X 
 
 
 
 
 
 
 
 
 
 
 
Demographics 
X 
 
 
 
 
 
 
 
 
 
 
 
Vital signs 
X1 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Medical History 
X 
 
 
 
 
 
 
 
 
 
 
 
Nasopharyngeal swab 
(Covid-19 test) 
X 
X 
 
 
 
 
 
 
 
 
 
 
Physical Exam 
 
X 
 
 
 
 
 
 
 
 
 
 
Labs (CBC, Metabolic Panel) 
 
X 
 
 
X 
 
 
X 
 
X 
 
 
Labs (Hepatitis B, C, HIV) 
 
X 
 
 
 
 
 
 
 
 
 
 
EKG 
 
X 
 
 
 
 
 
 
 
X 
 
 
Breathalyzer 
 
X 
X 
 
 
 
 
 
 
 
 
 
Urine Drug Screen 
 
X 
X 
 
 
 
 
 
 
 
 
X 
Urine Pregnancy 
 
X 
X 
 
 
 
 
 
 
 
 
X 
Urinalysis 
 
X 
 
 
 
 
 
 
 
X 
 
 
MINI 
X 
 
 
 
 
 
 
 
 
 
 
 
ASI 
X 
 
 
 
 
 
 
 
 
 
 
 
Adverse Childhood Experiences 
(ACEs) Scale 
X 
 
 
 
 
 
 
 
 
 
 
 
MRS scan 
 
 
X 
 
X 
 
 
X 
 
X 
X 
 
Craving Assessments (CCQ-
Brief, Craving VAS) 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Subjective Assessments (POMS, VAS) 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
CANTAB (Cognitive Tests) 
 
 
X 
 
X 
 
 
X 
 
X 
X 
 
C-SSRS scale 
X 
 
X 
 
 
 
 
 
 
X 
 
 
MED-Q 
 
 
 
 
X 
 
 
 
 
X 
 
 
Assessment of AEs 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Assessment for Dose Escalation 
 
 
 
 
X 
 
 
X 
 
 
 
 

Phase 1B Pharmaco-MRS study of Clavulanic acid after repeated administration. 
 
Page 20 of 60     Protocol V2.7 November 15th 2021 
from illicit substances. Participants who have a positive urine drug test will not be 
admitted to the study with an exception for marijuana with either a diagnosis of mild use 
disorder or no use disorder. Participants who have a positive breathalyzer test will be 
reevaluated by the PI to determine alcohol dependence and study eligibility. Participants 
will not conduct study activities prior to providing negative breathalyzer test. 
 
Female participants will have a pregnancy test. Female participants who have a positive 
pregnancy test will not be enrolled into the study and will be offered referrals to 
appropriate health care services. 
 
Participants will also complete a TLFB covering the time back to the screening visit, and 
complete assessments including the C–SSRS, CCQ-Brief, POMS-SF, VAS, ACEs, and 
CANTAB cognition tests will be performed before scan.  
 
After the assessments, the study team will perform the first MR scan session.  
 
After the completion of the MR scan the study team will accompany participants to the 
inpatient unit for intake. Upon arrival, participants will need to provide a photo ID so they 
can be registered as an inpatient on the unit. Potential candidates will need to provide 
any of the following government issued photo identification:  
 
• 
Driver’s license 
• 
Non-driver ID 
• 
Passport 
• 
Military ID 
 
Alternatively, potential candidates can provide non-governmental photo ID supported by 
additional documentation (social security card or birth certificate) that includes the same 
name on the photo ID.  
 
Inpatient sessions are conducted at Centennial 6 at the Episcopal Hospital campus of 
the Temple University Health System (T-EH). In the event that space is unavailable on 
C6 for medical reasons, Temple University Hospital Main (TUH-Main) and Jeanes 
Hospital medical floors which can provide nursing staff who are not currently assigned 
Covid patients will serve as back up sites. Subjects are oriented to the rules of the 
medical unit during intake screening. After participants have been admitted to the 
medical unit, they will self-administer the first dose of study drug CLAV 250 mg dose (1 
capsule). Participants will self-administer under study personnel supervision the second 
250mg dose later in the day if the initial dose is tolerated. 
 
Aside from the times participants need to travel to TUBRIC, participants will remain on 
the inpatient unit until discharge. A study team member will remain with the participant 
during travel times. 

Phase 1B Pharmaco-MRS study of Clavulanic acid after repeated administration. 
 
Page 21 of 60     Protocol V2.7 November 15th 2021 
 
Study Day 2 
This session includes adverse events assessment, craving assessments, and 
subjective assessments (Table 1). Vital signs (BP, pulse) will be obtained. Subjects self-
administer study drug. This session will take approximately 30 minutes. 
 
Study Day 3 
This session includes MR scan session 2, laboratory tests, adverse events assessment, 
and subjective/craving assessments. The MR scan takes 1 hour. Laboratory tests will 
include a complete blood count with differential, and a comprehensive metabolic panel. 
Approximately 15ml (1 tablespoon) of blood will be collected at this session. Vital signs 
(BP, pulse) will be obtained. Staff members supervise subject self-administration of 
study drug. This session will take approximately 3 hours. 
 
Subjects who have safely tolerated the study drug will have a forced escalation to 
750mg on study day 4. 
 
Study Day 4-5 
This session includes Adverse events assessment, and subjective/craving 
assessments. Vital signs (BP, Pulse) will be obtained. Subjects will self-administer study 
drug under staff supervision. This session will take approximately 30 minutes. 
 
Study Day 6 
This session includes MR scan session 3, laboratory tests, adverse events assessment, 
and subjective/craving assessments. Laboratory tests will include a complete blood 
count with differential, and a comprehensive metabolic panel. The MR scan takes 1 
hour. Approximately 15ml (1 tablespoon) of blood will be collected at this session. Vital 
signs (BP, pulse) will be obtained. Subjects self-administer study drug under staff 
supervision.  This session will take approximately 3 hours. 
 
Subjects who have safely tolerated the study drug will have a forced escalation to 1000 
mg on study day 7. 
 
Study Days 7-9 
These sessions include adverse events assessment and subjective/craving 
assessments. Vital signs (BP, pulse) will be obtained. Subjects self-administer study 
drug under staff supervision. These sessions will take approximately 30 minutes. 
 
Study Day 10 
This session includes MR scan session 4, adverse events assessment, and 
subjective/craving assessments. Vital signs (BP, Pulse) will be obtained. Subjects self-
administer the final dose of study drug under staff supervision. An EKG will be 
performed and reviewed. Laboratory tests will include a complete blood count with 
differential, and a comprehensive metabolic panel. Approximately 15ml (1 tablespoon) 
of blood will be collected at this session. This session will take approximately 2 hours. 

Phase 1B Pharmaco-MRS study of Clavulanic acid after repeated administration. 
 
Page 22 of 60     Protocol V2.7 November 15th 2021 
 
Study Day 11 
This session includes MR scan session 5, adverse events assessment, 
subjective/craving/C-SSRS assessments, and laboratory assessments. Vital signs (BP, 
Pulse) will be obtained. This session will take approximately 3 hours and will occur 
before and after the subject is discharged from the hospital. 
 
Follow up Visit 
5-8 days after discharge, participants will return for a follow up visit. The visit will involve 
an assessment of adverse events to determine any withdrawal symptoms. Participants 
will complete subjective/craving assessments, the TLFB covering the time back to 
discharge, and will have a UDS.  This visit will take approximately 1 hour. 
 
All adverse events will be followed until resolution. 
 
Early Termination Procedures 
Participants who are discharged from the study early will complete the day 11 discharge 
procedures, including scan, laboratory tests, and CANTAB cognitive test battery. 
Participants will be compensated at the day 11 discharge rate ($230).  Participants will 
then be scheduled for a follow up visit. Participants may be scheduled for additional 
follow up visits and bloodwork if a study physician determines they are needed to 
monitor subject AEs. Unscheduled follow up visits will take appropriately 30 minutes. 
 
At the early termination visit participants will receive the final payment for time and 
travel for the study in the form of gift cards, cash, or Greenphire ClinCard. Participants 
are given the option to choose which form of compensation they would prefer. There is 
no monetary difference between the compensation methods. The early termination (end 
of study) visit will take approximately 1 hour.  
 
Study Drug Supply Description 
CLAV will be supplied in 250mg capsules. CLAV will be made at the Investigational 
Drug Service (IDS) pharmacy at the University of Pennsylvania in Philadelphia, 
Pennsylvania, as 250mg capsules. Matching placebo pills will also be made at IDS at 
UPENN. Bulk CLAV has been procured from BOC Sciences (Shirley NY).  Stability 
testing completed by Protoform (Westampton, NJ) for the clavulanic acid pills 
demonstrated that the current formulation of clavulanic acid is stable at room 
temperature in a space with controlled humidity for 6 months. Controlling humidity is 
important to clavulanic acid stability. To ensure stability, both the medication 
manufacturer, Investigational Drug Services (IDS), and the Temple Pharmacy, keep the 
study drug at room temperature in a space with controlled humidity.  All new batches of 
pills manufactured by IDS are tested by Protoform before release. 
 
Study medication will be stored at room temperature until dispensed for distribution to 
participants in the Episcopal Hospital Pharmacy.  
 
Table 2.Treatment Regimen 

Phase 1B Pharmaco-MRS study of Clavulanic acid after repeated administration. 
 
Page 23 of 60     Protocol V2.7 November 15th 2021 
 
Participants will receive CLAV at the end of Day 1 after MRS scans. The first dose of 
CLAV will be 1 capsule or 250 mg.  A second dose (one 250 mg capsule) will be taken 
later that day if the first dose is safely tolerated. On days 2-3, participants will receive 2 
capsules (500 mg) each day. Forced dose escalation will occur on days 4 (750 mg, 3 
capsules) and 7 (1000 mg. 4 capsules). 
 
Staff will provide study drug for self-administration each day. Medication dispensing will 
be done directly by the research nurse, physician, or research staff (trained and 
supervised by the nurse or physicians), who will ensure that the patient understands the 
medication regimen. Study personnel will not administer the study drug but will dispense 
study drug to participants for self-administration. Study staff will assess participants 
after self-administration for AEs. Participants and inpatient staff are reminded that the 
primary investigator is available at the 24-hour emergency number listed on the first 
page of the consent form.  
 
Randomization 
The TUHS Investigational Research Pharmacist will supply the Temple-Episcopal Chief 
Pharmacist, Dr. Kim, with pre-coded envelopes with treatment assignments and study 
medication obtained from IDS. On study day #1, the investigator or study coordinator 
will obtain the study medication from the Episcopal Pharmacist. Codes linking 
randomization number to actual treatment will be secured in a sealed, opaque envelope 
and maintained in the Episcopal Hospital Pharmacy. The Episcopal Pharmacist will 
dispense the coded bottle/blister pack of investigational agent for the subject to the 
investigator/research specialist. The nurse or trained research staff will observe 
ingestion of the study drug to ensure medication adherence. Nine subjects will be 
randomized to CLAV and 3 to placebo. 
 
Blinding.  
Subjects, investigators, nursing and research staff are blinded to study drug allocation. 
The subject and investigator will be assessed on study days 3, 6, and 10, regarding 
study drug allocation to determine whether blinding was successful with the MED-Q and 
Med-Q-Investigator developed at the University of Pennsylvania.  
a) Recruitment Methods 
Research staff will advertise in media, including online classifieds such as Craigslist, 
newspapers (print and online), magazines, radio, and social media. Staff will post and 
distribute recruitment material in community settings with public posting areas or other 
means of providing community access to materials (such as substance abuse treatment 
centers, town halls, public libraries, YMCAs, health fairs). Staff will obtain permission at 
select locations before distributing or posting the approved recruitment materials 
Dosing Schedule 
Dose 
Baseline-Day3 
Day 4-6 
Days 7-10 
500 mg 
X 
 
 
750 mg (if tolerated) 
 
X 
 
1000 mg (if tolerated) 
 
 
X 

Phase 1B Pharmaco-MRS study of Clavulanic acid after repeated administration. 
 
Page 24 of 60     Protocol V2.7 November 15th 2021 
(ensuring compliance with other institutions guidelines, including seeking IRB approval 
as needed to conduct recruitment activities). Study staff will review clinical records of 
potentially eligible subjects who have expressed interest in the research study through 
the EPIC system. EPIC will only be accessed by IRB approved study staff and will not 
be accessed unless potential participants initiate contact and express an interest in the 
study. Staff will conduct a brief in-person pre-screening questionnaire and a screening 
interview over the phone or in-person at the participant’s clinic to assess study eligibility 
criteria. Participants will be contacted by phone or e-mail. Prospective participants who 
appear to meet eligibility criteria for the study will be scheduled for an in-person 
Informed Consent and Screening visit. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

Phase 1B Pharmaco-MRS study of Clavulanic acid after repeated administration. 
 
Page 25 of 60     Protocol V2.7 November 15th 2021 
 Table 3. Participant compensation schedule 
 
 
* Subjects will be compensated for reasonable travel costs [up to a maximum of $100 per subject 
over the course of study with qualifying receipts or given tokens (or equivalent) for local travel on 
mass transit.  
 
 
 
 
 
 
 
 
 
 
 
 
 
2 Covid-19 Test compensation will be in gift cards 
Visit 
 Visit 
Compensation 
Blood Sample 
Compensation 
MRI 
Compensation 
Survey 
Compensation 
Participant 
Compensation 
Outpatient 
screen-Visit -1 
$20 
$0 
$0 
$0 
$20 
Outpatient Visit 2 
$0 
$20 
$0 
$0 
$20 
Covid-19 Test 
1+2 
$252 
$0 
$0 
$0 
$25 
Day 1 
$30 
$0 
$150 
$30 
$210 
Day 2 
$30 
$0 
$0 
$30 
$60 
Day 3 
$30 
$20 
$150 
$30 
$230 
Day 4 
$30 
$0 
$0 
$30 
$60 
Day 5 
$30 
$0 
$0 
$30 
$60 
Day 6 
$30 
$20 
$150 
$30 
$230 
Day 7 
$30 
$0 
$0 
$30 
$60 
Day 8 
$30 
$0 
$0 
$30 
$60 
Day 9 
$30 
$0 
$0 
$30 
$60 
Day 10 
$30 
$0 
$150 
$30 
$210 
Day 11 
$30 
$20 
$150 
$30 
$230 
Outpatient 
Follow up visit 
$70 
$0 
$0 
$30 
$100 
Study Completion Bonus 
$730 
Total Payment 
for Full 
Participation  
 
 
 
 
$2340 

Phase 1B Pharmaco-MRS study of Clavulanic acid after repeated administration. 
 
Page 26 of 60     Protocol V2.7 November 15th 2021 
Inclusion and Exclusion Criteria 
Inclusion Criteria 
In order to participate in the study, subjects must: 
 
1.  Be able to verbalize understanding of consent form, able to provide written 
informed consent, and verbalize willingness to complete study procedures 
 
2. Be male or female adult volunteers ages 18-70 inclusive. 
 
3. Have a DSM-5 diagnosis of cocaine use disorder, moderate to severe in early 
remissionB with a duration of regular (weekly or more) cocaine (either snorted, 
smoked or injected) for at least one year, with at least 1 week(or more) 
without cocaine use, verified by UDS.  
 
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. 
 
6. If female: have a negative pregnancy test within 48 hours prior to receiving 
the first dose of investigational agent and agree to use an effective method of 
birth control for a minimum of 30 days after study participation, or be 
postmenopausal, or have had a hysterectomy, or have been sterilized, or be 
male.  Effective forms of birth control include: 
 
a) 
complete abstinence from sexual intercourse  
b) 
oral contraceptives, Depo-Provera, Norplant, or intrauterine progesterone 
contraceptive system and condom by partner 
c) 
diaphragm and condom by partner 
d) 
intrauterine device and condom by partner 
e) 
sponge and condom by partner 
 
7. Be able to comply with protocol requirements, rules and regulations of the 
study, and be likely to complete the entire study. 
 
8. Must remain local for at least 2 months  
 
 
 
Exclusion Criteria 
In order to participate in the study, subjects must not: 
 
 
B Early remission is defined as 7 or more days of cocaine abstinence and will be determined through a 
timeline follow back calendar that is completed at screen and updated at the baseline visit. 

Phase 1B Pharmaco-MRS study of Clavulanic acid after repeated administration. 
 
Page 27 of 60     Protocol V2.7 November 15th 2021 
1. Have a current DSM-V substance use disorder, of any drug of abuse other 
than nicotine, caffeine, cocaine, alcohol, marijuana use disorder verified by 
UDS. Alcohol use disorder and marijuana use disorder are not permitted if 
there are seizures or psychotic symptoms associated with withdrawal or 
medication is required to treat withdrawal symptoms from alcohol or 
marijuana use. 
 
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. Have moderate to severe liver disease or current elevation of aspartate 
aminotransferase (AST) or alanine aminotransferase (ALT) exceeding 2.0 
times the upper limit of normal (> 2.0 X ULN).  
 
5. Have a diagnosis of adult (i.e., 21 years or older) asthma, or chronic 
obstructive pulmonary disease (COPD), with an exacerbation of their 
asthma/COPD within last six (6) weeks before study enrollment that required 
medication treatment.  
 
6. Report having human immunodeficiency virus (HIV) infection or test positive 
for HIV during screening 
 
7. Be pregnant (females). 
 
8. Have participated in another investigational medication or device study within 
12 weeks. 
 
9. Have systolic blood pressure ≥ 150 after three (3) measurements or have 
diastolic blood pressure ≥ 95 after three (3) measurements. 
 
10. Have any current DSM-5 defined unstableC major psychiatric illness.  
 
11. Have a suicide attempt in the past year, or score high risk (17 or greater) on 
the suicidality MINI module, or answer “yes’ on Questions 4 or 5 on Columbia 
Suicide Severity Rating Scale (C-SSRS) 
 
12. Any implanted object in their body as described on the Temple Magnetic 
Resonance Environment Screening Form for individuals. 
 
 
C Prone to change significantly in the two weeks before assessment and including severe symptoms 

Phase 1B Pharmaco-MRS study of Clavulanic acid after repeated administration. 
 
Page 28 of 60     Protocol V2.7 November 15th 2021 
13. Previous injury to any part of the body (including the eye) involving a metallic 
object, metallic slivers, or foreign body which left behind ferrous magnetic 
metal. 
 
14. Chronically taking a medication that is associated with changes in glutamate, 
glutamine, GABA. Common medications excluded by this criterion include 
beta lactams, N-acetylcysteine, tiagabine, and lorazepam. A comprehensive 
list of prohibited medications is included as part of this protocol as Appendix I.  
 
15. Be taking any herbal supplements that are associated with changes in 
glutamate, glutamine, GABA, including kava and other herbals listed in 
Appendix I. 
 
16. Unable to tolerate MRI scan for duration of 60 minutes for physical or 
psychological reasons.  
 
17. Have a history of head injury with loss of consciousness greater than five (5) 
minutes. 
 
18. Have any impending incarceration or be in a treatment facility in accordance 
with a court mandate 
 
b) Number of Subjects 
 
SAMPLE SIZE: 12 subjects will complete the study. Dropouts will be replaced.  
 
POPULATION: Subjects are adult male and female volunteers, 18-to-70 years of age, 
who have cocaine use disorder in early remission. 
 
c) Study-Wide Number of Subjects 
Same as above. 
 
d) Study Timelines 
 Submit Final Protocol to Temple IRB and FDA 
 First Patient Entered, recruitment ~1.5 patients/month 
 start intellectual property review with VistaGen 
 Last Patient Entered, 12 study completers 
 Final Data Set, drafting FDA study report 
 Data Analysis complete, Milestone discussion with NIDA 
 Study Report Complete 
 
e) Study Endpoints 
 
Primary Endpoint: Change in brain glutamate concentration in the ACC at Day 10 
compared with baseline.  
 

Phase 1B Pharmaco-MRS study of Clavulanic acid after repeated administration. 
 
Page 29 of 60     Protocol V2.7 November 15th 2021 
Secondary Endpoints:  
A) Brain connectivity change in the ACC on resting state fMRI. 
B) Change in brain glutamate concentration in the ACC at Day 11 compared with 
Day 10  
C) Change in brain glutamine concentration in the ACC at Day 10 compared with 
baseline.  
D) Safety and tolerance as assessed by the rates of occurrence of adverse events, 
changes in vital signs, Columbia Suicide Severity Rating Scale (C-SSRS), EKG 
parameters and laboratory studies compared with baseline.  
 
Exploratory Endpoints: 
 
A) Suppression of cocaine cue-induced limbic activation during imaging task. 
B) Subjective effects will be compared before and after CLAV 500,750, 1000 
mg/day for 10 days using the following instruments: the Visual Analog Scales 
(VAS), Profile of Mood States (POMS) (Curran, Andrykowski, and Studts 1995 ), 
and the scores from the Cambridge Cognition Cognitive battery at multiple 
timepoints compared with baseline  
C) Relationship between scores from the Adverse Childhood Experience (ACE) 
scale, POMS, and VAS. 
 
Procedures Involved in the Human Research 
 
Before the MR scan, subjects will have the option to go inside a mock scanner to have a 
feeling of the MR setting to reduce anxiety. Before each scan, subjects will have to fill 
out a safety screen form. In addition to the safety screen form, subjects will be scanned 
with a wand to detect any ferromagnetic materials. For the actual imaging session, 
subjects will be asked to lie down on a platform that can be slid into the bore of the 
magnet. Because of beeping and hammering sounds made by the machine, it is 
somewhat noisy inside the magnet. Disposable earplugs will be provided to diminish the 
noise. A 64 channel MRI imaging coil will be placed around the subject’s head. This coil 
is simply a number of wires covered in plastic. Subjects will not come into direct contact 
with the coil during the MRI study. Foam pads will be placed around the subject’s head 
to limit movement during the study. Subjects will then be slid into the magnet and will be 
asked to lie still for approximately one hour, during which several images will be 
acquired. During the study, a physician will be available for any medical questions or 
problems. The technicians involved in the study will advise subjects on the progress of 
the study. Subjects will be able to contact staff at any time if they feel uncomfortable or 
do not wish to continue study activities. 

Phase 1B Pharmaco-MRS study of Clavulanic acid after repeated administration. 
 
Page 30 of 60     Protocol V2.7 November 15th 2021 
Imaging. Participants will undergo MR scans 
at 3 T using MR scanner on Main Campus, 
Temple University. There will be 5 MR scans 
performed for each subject. (Table 4) For any 
MR scan, there is no injection of exogenous 
contrast agent or interventions other than 
CLAV, which is described previously in this 
protocol. Imaging procedures are detailed in 
Fig. 6 and specific scan information is detailed 
below 
 
1) Localizer scan. Fast MRI along the x, y, 
and z direction will be performed to 
define the physical imaging space in 
order to locate placement of the 
following scans. This will take 
approximately 25-30 secs.  
 
2) Structural MRI. High resolution 
anatomical scan will be performed with 
a T1-weighted 3D MPRAGE product 
sequence from Siemens with 160 
slices, 1.0 mm thickness, 22cm field-of-
view (FOV), 192x256 matrix, TI/TR/ 
TE=1100/1630/3 ms. Parallel imaging 
with 2-fold acceleration will be used to 
shorten acquisition time. The scan time 
will be around 5.3 mins.  
 
3) MR spectroscopy (MRS). MRS will be 
performed using the Siemens product 
single-voxel spin-echo point-resolved 
spectroscopy (PRESS) sequence using 
short TE (30ms) with 128 averages and 
water suppression to measure Glutamate, Glutamine and other metabolites 
(Ramadan, Lin, & Stanwell, 2013). In addition, a special 32-echo multiecho 
PRESS sequence (8 averages, TE = 30ms to 185ms, with increments of 5ms) 
will also be used for selective detection of glutamate and glutamine signal. For 
each sequence, the un-suppressed water signal will be acquired for absolute 
quantification of metabolites using water scaling. The 2 x 2 x 2 cm3 (8 ml) MRS 
voxel will be positioned in the ACC. This region will take 20 minutes.  
 
4) Resting State fMRI. Resting state fMRI will be performed using Siemens product 
Gradient-Echo EPI with multiband factor of 3. 60 axial slices with gap of 0.1mm, 
2.0 mm thickness, FOV is 200 x 200 mm2, 100 x 100 matrix, TR/TE= 2000/29 
ms., 2 x 2 x 2 mm3 voxel resolution, 180 volumes per run will be used to 
Imaging Procedures 
Figure 6: Imaging and safety procedures for 
each scan day 

Phase 1B Pharmaco-MRS study of Clavulanic acid after repeated administration. 
 
Page 31 of 60     Protocol V2.7 November 15th 2021 
measure functional connectivity of ACC while subjects are instructed to relax, 
keep eyes open and stare at a cross. Data will be acquired in 2 runs of 6 minutes 
each. This scan will take 12 minutes.  
 
5) Limbic Cue Associated fMRI Activation. After the resting state scan, a brief cue 
will be presented, either a cocaine related cue or a neutral cue from the Childress 
laboratory. Subjects will then be crossed over to receive exposure to the other 
cue (cocaine or neutral). This scan will take 18 minutes.  
 
 
 
 
 
 
 
 
Methods for Assessment of Secondary and Exploratory Outcome Measures 
 
The secondary outcome measure craving for cocaine is assessed using CCQ-Brief, and 
VAS for craving. Exploratory outcomes are measured using psychological, mood, and 
personality tests including the POMS, VAS, ACE scale, and Cambridge Cognition 
Cognitive Battery. Refer to Table 1 as well for schedule of Assessments.  
 
1) Cocaine Craving Questionnaire-Brief (CCQ-Brief)  
 
The CCQ-Brief is a self-administered assessment that asks the subject to 
rate his or her craving for cocaine. The CCQ-Brief used for this study is a 
modification of the Cocaine Craving Questionnaire-Now (Sussner et al. 
2006). This measure will be completed every inpatient study day.  
 
2) Visual Analog Scales (VAS)-Craving 
The Visual Analog craving scale is a 0-100 scale asking participants to self-report 
their current feelings of craving. Subjects will complete this form every inpatient 
study day. 
Table 4: Timetable for Pharmaco-MRI study of Clavulanic Acid for Cocaine Use 
Disorder 
Imaging 
Study 
Day 
 
Scan 1 
(Day 1) 
 
Scan 2 
(Day 3) 
 
Scan 3 
(Day 6) 
 
Scan 4 
(Day 
10) 
 
Scan 5 
(Day 
11) 
MRS 
scan 
X 
X 
X 
X 
X 
CLAV 
No dose 
given 
prior to 
scan 
500 mg 
given prior 
to scan 
750mg 
given prior 
to scan 
1000 
mg 
given 
prior to 
scan 
No 
CLAV 
given 

Phase 1B Pharmaco-MRS study of Clavulanic acid after repeated administration. 
 
Page 32 of 60     Protocol V2.7 November 15th 2021 
 
3) Profile of Mood States Short Form (POMS-SF) 
 
The POMS-SF is shortened version of the POMS questionnaire that measures 
dimensions of affect or mood and has comparable internal consistency to the 
standard POMS assessment (Curran, Andrykowski, and Studts 1995 ). The 
POMS-SF consists of 37 adjectives to which the client responds according to a 
5-point scale ranging from “not at all” to “extremely” (Curran, Andrykowski, and 
Studts 1995 ). Subjects will complete this measure every inpatient day.  
 
4) Columbia Suicide Severity Rating Scale (C-SSRS) 
 
Columbia Suicide Severity Rating Scale (C-SSRS) will be assessed at screening, 
baseline, and on the discharge day. The C-SSRS uses a series or probes to help 
physicians determine the presence of suicidal ideation (Posner et al. 2008).  The 
physician’s judgment of subject responses will determine the presence of suicidal 
behavior or ideation. Validity studies support the C-SSRS’s use in research and 
clinical settings (Posner et al. 2011). 
 
5) Cambridge Cognition Cognitive Battery 
 
CANTAB tasks are computerized measures of cognition which will be assessed 
every scan day. 
 
 
6) Visual Analog Scales (General) 
 
The VAS will be assessed at every inpatient day. VAS is a battery of 21 
computerized visual analog scales with items related to psychological response 
and will be administered with a continuous scale of 0 to 100. 
 
7) Adverse Childhood Experience (ACE) scale 
 
The ACE is a 10-item measure of adverse childhood experiences that will be 
administered at baseline (Felitti et al. 1998).  
 
a. Data Banking 
 
Following completion of an imaging session, the raw data will immediately be 
transferred to electronic storage by the study staff/MR technician for later processing. 
This storage is in a locked room with access limited to the investigators and data 
processors. Subjective and physiological data are likewise kept in a locked area 
accessible only to the investigators/data processors. Subjective assessments (besides 
Cognitive tasks), C-SSRS, adverse events, and morning blood pressure and pulse will 
be collected through REDCap. No personal health information will be entered into 
REDCap.  

Phase 1B Pharmaco-MRS study of Clavulanic acid after repeated administration. 
 
Page 33 of 60     Protocol V2.7 November 15th 2021 
 
Cognitive data will be captured electronically, encrypted at source and processed using 
a study-specific build of the CANTAB data management software. 
 
Participants will be given a unique ID code. The key to the ID codes will be stored 
electronically in an encrypted and password protected document on a Temple 
University computer. Only the study staff will have access to the document that links 
participant IDs to a participant’s personal health information. 
 
Cases are coded by a number detached from the patient's name. No published or 
presented materials will identify subjects by names, initials, or any other means that 
could be used to identify the participant. Whenever possible, designated team members 
will only see de-identified information during the study. 
 
Research study records may only be accessed by staff engaged in the research project 
or clinical care of the subjects, or by representatives of the National Institute on Drug 
Abuse, the Food and Drug Administration, or other government agencies as required 
and permitted by law. 
 
Already collected data will not be destroyed if a subject withdraws or is discharged from 
the study. 
 
b. Data Management  
 
Data and Safety Monitoring  
Every two months, the PI or a specially designated Investigator will check the active 
research charts for compliance with the research protocol and with Good Clinical 
Practice procedures. Corrective actions will be taken as needed, and results of the 
monitoring will be included in our regular updates to the Temple IRB and Data Safety 
Monitoring Board. Any safety concerns arising from the review will be immediately 
reported to the regulatory bodies. 
 
Statistical Plan 
 
Primary Outcome Measures 
 
The primary outcome measures are changes in brain glutamate concentration in the 
anterior cingulate (ACC) after 10 days (steady state) of CLAV 500, 750, 1000 mg/day in 
subjects with cocaine use disorder compared with baseline. To normalize MRS data, an 
unsuppressed water signal acquired prior to or after the water-suppressed MRS scan in 
addition to the total creatine resonance will be used. The molecules present will be 
determined using the area under the curve corresponding to the concentration of the 
metabolite. Dr. Bolo, Harvard University, will supervise and perform the data analysis of 
the imaging data. 
 

Phase 1B Pharmaco-MRS study of Clavulanic acid after repeated administration. 
 
Page 34 of 60     Protocol V2.7 November 15th 2021 
Secondary Outcome Measures 
 
Secondary objectives are to:  
A) To assess changes in craving-associated neurocircuitry (frontal-striatal-thalamic 
connectivity) using resting state functional Magnetic Resonance Imaging (rs-fMRI). 
Subjects with CocUD will have decreased functional connectivity between nodes within 
the frontal-striatal-thalamic network (Wang et al. 2018) involving mesocorticolimbic 
circuit nodes (Gu et al. 2010). After repeated CLAV, we expect that the fronto-striatal-
thalamic within network functional connectivity will increase. We also will determine 
whether improved network connectivity as associated with decreased craving as 
determined by the Cocaine Craving Questionnaire (CCQ) (Sussner et al. 2006) and a 
Visual Analog Scale (VAS). B) To evaluate whether CLAV 500, 750, 1000 mg a day 
given repeatedly for 10 days (to steady state, rationale below) and then stopped, is 
associated with a sustained reduction in brain glutamate concentration measured in the 
ACC one day after cessation of CLAV dosing (to determine the duration of CLAV action 
on glutamate after last dose and to determine the feasibility of once daily CLAV dosing). 
C) To evaluate whether 10 days of treatment with CLAV is associated with increases in 
brain glutamine concentration as assessed by MRS in the AC. D) To assess CLAV 500, 
750, and 1000 mg/day safety and tolerability by: a) the rates of occurrence of adverse 
events; b) changes in vital signs; c) EKG parameters; and d) laboratory study changes.  
 
Exploratory Outcome Measures 
 
Exploratory objectives are to:  A) To evaluate whether repeated CLAV treatment 
500, 750, 1000 mg/day suppresses cue-induced limbic fMRI activation. B) To 
evaluate whether CLAV treatment 500, 750, 1000 mg/day for 10 days is 
associated with subjective effects measured by the Visual Analog Scales (VAS), 
the Profile of Mood States (POMS). C) To evaluate whether CLAV treatment 500, 
750, 1000 mg/day for 10 days is associated with cognitive and executive function 
deficits as assessed by the Cambridge cognition survey batteries.  
  
Data Statistical Analysis Plan 
 
Demographic and Baseline Comparability Analyses 
 
Demographic variables will be summarized both separately and together for all male 
and female patients. 
 
Primary Analyses:  
 
ACC glutamate concentrations at days 0, 10 and 11 are the primary assessment 
variables. Glu level differences assessed by MRS in the ACC after 10 days of CLAV 
dosing 500, 750, 1000 mg/day will be compared with baseline and presented. The MRS 
raw data will be taken directly from the scanner and the software package, TARQUIN 
(http://tarquin.sourceforge.net/) will be used to measure the quantities of metabolites 
present in the AC. The software recognizes scanning parameters from the data and 

Phase 1B Pharmaco-MRS study of Clavulanic acid after repeated administration. 
 
Page 35 of 60     Protocol V2.7 November 15th 2021 
generates model basis set of MRS signals for the following 17 metabolites: alanine, 
aspartate, creatine (Cr), phosphocreatine (PCr), gamma-aminobutyric acid (GABA), 
glycerophosphocholine (GPC), phosphocholine (PCh), glucose, glutamine, glutathione, 
Glu, myo-inositol, lactate, Nacetylaspartate (NAA), N-acetylaspartate-glutamate 
(NAAG), scyllo-inositol and taurine as well as the combinations of Glu and glutamine 
(Glx), Cr and PCr (total creatine or TCr), of GPC and PCh (cholines or Cho), and 
macromolecules. After several iterations of data preprocessing, it fits the model basis 
set to the data and calculates the absolute concentration of each metabolite in mM 
taking the area under the corresponding fitted curve scaled to the water signal in the 
voxel. Processing of the multi-echo MRS data set allows precise measurement of Glu 
from the selective TE-averaged Glu signal, and can take into account T2 relaxation 
effects in the voxel. Water concentration in the voxel will be estimated by calculating the 
fractions of grey and white matter and cerebrospinal fluid in the voxel after 
segmentation of the T1-weighted structural MRI (Gasparovic et al., 2006; Kreis, Ernst, & 
Ross, 1993). Dr. Bolo and/or his assistant will perform the MRS data processing. 
Glutamate level will then be compared between pre and post study drug administration. 
Changes in ACC glutamate level will be compared between the CLAV and placebo 
group using a one-sided Mann-Whitney-Wilcoxon Test at a significance level set to 
0.05. 
 
For all variables, first, preliminary and descriptive analyses will be conducted to assess 
data quality and integrity by descriptive statistical and graphical methods. Balances in 
terms of the demographic or disease characteristic variables between the groups will be 
empirically examined. Any systematic differences so identified will be noted in the study 
report of this proposal. Note that given the dramatically reduced new group sizes, all 
data analyses will be mostly descriptive and hypothesis generating in nature, and the 
results will be used primarily to guide the decision-making for the next step of this 
project. 
 
Using the intent-to-treat framework, the data will be reported using descriptive summary 
statistics such as mean, median, range, quartiles and standard deviation for a 
continuous variable and frequency and percentage for a categorical variable overall as 
well as by study group. Whenever appropriate, both point estimates and confidence 
intervals will be reported on the study endpoints of interest (e.g., changes in brain 
glutamate concentration and glutamate/creatine ratio). Differences for continuous 
variables will be assessed using t-tests (with unequal variances if appropriate) or the 
Wilcoxon rank sum test if the distributional assumption is violated for two-group 
comparisons. Proportions will be compared using the chi-square test or Fisher’s exact 
tests. Multiple comparison adjustments will not be made due to the small sample size. 
Demographics and medical history variables (e.g., age, gender, and race) may be 
correlated to the study endpoints of interest, if strongly warranted. Some exploratory 
statistical approaches (e.g., Pearson/Spearman correlation coefficients, and linear 
regression for continuous variables) may be considered, if absolutely indicated by the 
study, to explore possible associations between the study endpoints and various 
covariates. We do recognize, however, due to small group sizes, such approaches 

Phase 1B Pharmaco-MRS study of Clavulanic acid after repeated administration. 
 
Page 36 of 60     Protocol V2.7 November 15th 2021 
(correlation and regression analyses) may be not feasible to implement. Such analyses 
will not be employed unless absolutely warranted. To safeguard a possible departure 
from the normal distribution assumption, the appropriate nonparametric methods such 
as Wilcoxon rank sum test and Spearman correlation will be employed for analysis in 
addition to the usual parametric data analyses methods. SAS version 9.4 or higher will 
be used for all the data analyses. 
 
Secondary Analyses 
 
Assessment of ACC Glu level one day after the last CLAV dose will be compared with 
the level on the last day of CLAV dosing. Resting state fMRI data preprocessing and 
analyses will be performed using statistical parametric mapping (SPM) 
(http://www.fil.ion.ucl.ac.uk/spm) based custom batch scripts (Wang et al. 2015, Wang 
et al. 2017, Li, Kadivar, et al. 2012, Li, Zhu, et al. 2012). Seed region-based functional 
connectivity (SRFC) will be calculated as the correlation coefficient (CC) of the resting 
state fMRI signal from a seed and any voxel in the rest of the brain. A Priori seeds will 
be defined in anterior cingulate (ACC), amygdala, ventral striatum (VS), insula, 
ventromedial prefrontal cortex (VMPFC), posterior cingulate cortex (PCC), and lateral 
prefrontal cortex (PFC). These regions are known to be affected by cocaine addiction, 
suggesting that their connections to other regions may be impaired as shown in (Gu et 
al. 2010) and may be predictive of relapse (Adinoff et al. 2015).  ACC Regions of 
Interest (ROI) in the Montreal Neurological Institute (MNI) standard brain will be defined 
based on the previous SRFC work in cocaine addiction (Gu et al. 2010). Other seeds 
will be based on suprathreshold clusters from the literature or manually defined using 
the SPM Pickatlas utility (Maldjian et al. 2003). The individual subjects’ FC maps will be 
first registered into the image space of the T1-weighted structural MRI and then 
registered into the MNI standard brain using SPM (version 12). The registration 
transform will be derived from the projection from the T1-weighted structural MRI to the 
MNI space.  
There will be an assessment of glutamate level one day after the last dose compared 
with the last day of dosing after last dose.   
 
Assessments for glutamine will be similar to those for glutamate.    
 
Adverse events will be tabulated overall as well as by study group, and by body system 
and organ class if desired. 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 and 
placebo and presented as summary statistics. Subjective craving effects of CLAV from 
the visual analog scale and CCQ will be evaluated similarly as described in the above 
for glutamate. 
 
Exploratory Analyses:   
Cue reactivity task will be analyzed using a standard general linear model (GLM) with 
the task design function convolved with a generic hemodynamic response function as 
the regressors for brain activity during each task condition; an  ANOVA may be used to 

Phase 1B Pharmaco-MRS study of Clavulanic acid after repeated administration. 
 
Page 37 of 60     Protocol V2.7 November 15th 2021 
examine treatment group (CLAV vs. placebo) and cue condition effects in a second 
level analysis (Young et al. 2014). The hemodynamic response function convolution 
allows for correction of hemodynamic delay.  
 
Subjective effects of CLAV, as measured by check lists, rating scales, and cognitive 
tests will be listed for each patient and summarized for each group. 
 
Rationale for Sample Size:  
Sample sizes are derived based on a 12% difference between CLAV and placebo 
groups in the mean changes in Glu in anterior cingulate cortex from a human crossover 
MRS imaging study of N-acetylcysteine, another (weaker) GLT-1 activator (Schmaal et 
al. 2012). Summary glutamate data on changes in glutamate with reference to the 
unsuppressed water signal were reported by Schmaal et al, 2012. Specifically, based 
on this article, we assume the mean change (SD) in Glu for the placebo group is 8.39 
(0.76) while the mean (SD) is 7.38 (0.76) for the CLAV group. Note that the standard 
deviations (estimated based on the SEM and number of subjects) are relatively small 
and the target 12% difference is relatively large. Because of budget reductions, the 
proposed sample size has been reduced to 12, with 9 subjects allocated to CLAV and 3 
to placebo. Group sample sizes of 3 and 9 achieve 63% power to detect a difference of 
-1.01 between the null hypothesis mean difference of 0.0 and the actual mean 
difference of 1.01 at the 0.05 significance level (alpha) using a one-sided Wilcoxon Test 
(the actual alpha=0.075). However, if the actual group difference is 20% instead of 12%, 
group sample sizes of 3 and 9 achieve 94% power to detect a difference of -1.68 
between the null hypothesis mean difference of 0.0 and the actual mean difference of 
1.68 at the 0.05 significance level (alpha) using a one-sided Wilcoxon Test (the actual 
alpha=0.085). These results are based on 2000 Monte Carlo samples from the null 
distributions: Normal(M0 S) and Normal(M0 S), and the alternative distributions: 
Normal(M0 S) and Normal(M1 S). Randomization assignment tables will be generated 
by study statistician Dr. Daohai Yu and stratification on sex and last use of cocaine (≤1 
month vs. > 1 month) will be considered. 
c. Confidentiality   
 
Confidentiality of Data 
 
Particular attention is drawn to the regulations promulgated by the Food and Drug 
Administration under the Freedom of Information Act providing, in part, that proprietary 
information furnished to clinical investigators and Institutional Review Boards will be 
kept confidential by the Food and Drug Administration only if maintained in confidence 
by the clinical investigator and Institutional Review Board. 
 

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Confidentiality of Patient Records 
 
To maintain subject confidentiality, all laboratory specimens shipped outside the Temple 
Health System, reports and other records will be identified by a coded study subject 
number only. Research and clinical records will be stored securely. Only research staff 
and sponsor or sponsor’s representative will have access to the records. Subject 
information will not be released without written permission, except as necessary for 
monitoring by the FDA or sponsor. Upon approval of the study by the IRBNIH 
automatically grants a certificate of confidentiality. 
 
By signing the protocol, the investigator agrees that within local regulatory restrictions 
and ethical considerations, the sponsor or any regulatory agency may consult and/or 
copy study documents in order to verify case report form data. 
 
d. Provisions to Monitor the Data to Ensure the Safety of subjects 
 
Participant Compliance Monitoring 
 
Study staff will be present for the self-administration of all study drug/placebo doses. 
Participants will be closely observed during self-administration and asked to open their 
mouths and lift their tongue to the roof of their mouths to confirm the dose was 
swallowed.  
 
Compliance with NIDA Policy on Monitoring Plans:  
 
In June 2000, the National Institutes of Health (NIH) issued a policy that extended the 
requirement for inclusion of monitoring plans to phase 1 and 2 clinical trials.  
(http://grants.nih.gov/grants/guide/notice-files/NOT-OD-00-038.html)  That Further 
Guidance followed the policy issued in June 1998 on data and safety monitoring 
(http://grants.nih.gov/grants/guide/notice-files/not98-084.html), which required the 
establishment of Data and Safety Monitoring Boards (DSMBs) for all NIH-supported or -
conducted multi-site clinical trials involving interventions that entail potential risk to the 
participants.  NIH requires each Institute to have a system of oversight of the conduct of 
clinical trials to ensure the safety of participants and the validity and integrity of the data. 
 
This protocol complies with that policy. The procedures for reporting Serious Adverse 
Events (SAEs) to NIDA, the IRB and FDA are contained under the adverse events 
reporting section below. A DSMB will be reviewing the data and safety information from 
this trial. Please see the attached Data Safety and Monitoring Plan for complete details 
regarding safety monitoring. A safety monitoring board has been established with the 
following purpose (according to NIDA guidelines): to assure that the safety of study 
subjects is protected while the scientific goals of the ongoing studies are being met. 
Specifically, the DSMB is charged with monitoring the safety of participants and the 
quality of the data, as well as the appropriate termination of studies either when 
significant benefits or risks have been uncovered.   
 

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All board members meet NIDA requirements regarding background and experience, 
and none will have ethical conflicts, including financial interest related to study outcome.  
Individuals invited to serve on the board disclose any potential conflicts in writing. The 
board meets every 3-4 months (unless more frequent meeting is deemed necessary) 
and is chaired by Huaqing Zhao, Ph.D. Huaqing Zhao, Ph.D., is an Associate Professor 
of Biostatistics at Lewis Katz School of Medicine at Temple University. Other members 
include (Jaakko Lappalainen PhD, M.D) who is the chief of addiction psychiatry at the 
Crozer-Chester Medical center, and Mark Weiner MD is the deputy chief information 
officer for health system and research analytics at Cornell University. The current study 
is reviewed using a DSMB Progress Report reviewed in an open session, followed by a 
closed session under the direction of Dr. Zhao.  Issues related to recruitment, subject 
safety and efficacy, whether the primary study question is being answered, conflict of 
interest, confidentiality, and ongoing study review (including AEs, SAEs, and regulatory 
issues) are assessed. Following each DSM Board meeting, Dr. Zhao will make 
recommendations to Dr. Morrison, and a final report (edited by all Board members) will 
be prepared and submitted to NIDA and the Temple IRB (and if required the FDA), 
according to each bodies’ reporting requirements.  
 
Definitions 
 
Adverse Event 
 
An adverse event (AE) is any symptom, sign, illness or experience that develops or 
worsens in severity during the study.  Intercurrent illnesses or injuries should be 
regarded as adverse events.  Abnormal results of diagnostic procedures are considered 
adverse events if the abnormality: 
 results in study withdrawal 
 is associated with a serious adverse event 
 is associated with clinical signs or symptoms 
 leads to additional treatment or to further diagnostic tests 
 is considered by the investigator to be of clinical significance 
Adverse Events Reporting 
 
In accordance with FDA reporting requirements, all AEs occurring during the clinical trial 
will be collected, documented, and reported by the principal investigator or sub-
investigators according to the specific instructions detailed in this section of the protocol. 
 
All AEs, including clinically significant abnormal findings on laboratory evaluations, 
regardless of severity, will be followed by study investigators until satisfactory 
resolution. AEs should be reported up to 2 weeks following completion of, or termination 
from treatment. 
 
Serious Adverse Event 
 
Adverse events are classified as serious or non-serious.  Based on the seriousness of 
the adverse event or reaction appropriate reporting procedures will be followed. The 

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Page 40 of 60     Protocol V2.7 November 15th 2021 
International Conference on Harmonization (ICH) Guideline for Industry: Clinical Safety 
Data Management: Definitions and Standards for Expedited Reporting, ICH-E2A March 
1995, as implemented by the U.S. Food and Drug Administration states that a serious 
adverse event is any AE that is:  
 fatal 
 life-threatening 
 requires or prolongs hospital stay 
 results in persistent or significant disability or incapacity 
 a congenital anomaly or birth defect 
 an important medical event 
 
Important medical events are those that may not be immediately life threatening but are 
clearly of major clinical significance. They may jeopardize the participant wellbeing and 
may require intervention to prevent one of the other serious outcomes noted above.  For 
example, drug overdose or abuse, a seizure that did not result in inpatient 
hospitalization, or intensive treatment of bronchospasm in an emergency department 
would typically be considered serious.  
 
All adverse events that do not meet any of the criteria for serious should be regarded as 
non-serious adverse events.  
 
Any SAEs due to any cause, which occur during the course of this investigation, 
whether or not related to the investigational agent, must be reported within 24-hours by 
telephone or e-mail to: all study physicians, the NIDA Study Medical Monitor, NIDA 
grant Program Officer and the Temple IRB. 
 
24-hour Reporting Requirements 
 
Any serious adverse event, including death due to any cause, which occurs to any 
subject from the time of admission through discharge whether related to the study 
drug/placebo, must be reported within 24 hours. 
 
The following information must be provided with the initial report of an SAE or 
unexpected AE: 
 
 Name of person reporting the SAE/unexpected AE 
 Subject's I.D. number 
 Name of the principal investigator and institution 
 Description of the SAE/unexpected AE 
 Date and time of Onset 
 Date/time of administration of last dose of study agent/placebo prior to the 
SAE/unexpected AE 
 Severity of the SAE/unexpected AE 
 Investigator's assessment of the relationship of the SAE/unexpected AE to study 
drug (related, possibly related, probably related, unlikely related, not related) 

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 Any action taken with the study drug, alteration to protocol defined schedule, 
diagnostics, and treatments secondary to the SAE/unexpected AE. 
 
The telephone/e-mail report is to be followed by submission of a completed SAE Form 
within 3 days with demographic information and a narrative explanation of the event. 
Supporting documentation is listed below. All serious medical events are to be reported 
to the Temple IRB within 3 days.  All study investigators will be also notified of any 
serious and unexpected AE requiring submission to the FDA in an IND safety report. 
 
3-day Supporting Documentation Requirements 
 
Written documentation for all SAEs/unexpected AEs must be received by the NIDA 
Program Officer and Science Officer , the Temple IRB and the DSMP within 3 days of 
reporting the event and will be in narrative form. Required documents that must be 
submitted to NIDA include the following: 
 
 SAE Form 
 Concomitant Medication CRF pages  
 Adverse Events CRF pages 
 Copies of source documents pertinent to the event (lab reports, EKG tracings, 
medical chart notes, etc.) 
 Any other relevant information necessary to facilitate the investigator’s judgment 
regarding the SAE’s relatedness to the severity OR by request of the Medical 
Monitor/Alternate 
 
Follow-Up of All Adverse Events/Serious Adverse Events 
 
All adverse medical events must be followed until they are resolved, or until all attempts 
to determine the resolution of the AE/SAE are exhausted. This may require an extended 
inpatient period. All treatments, outcomes and information regarding whether the 
subject was referred to their Primary Care Provider for additional follow-up must be 
recorded in the source document. All serious and unexpected adverse events occurring 
30 days after administration of the last dose of study drug/placebo must be reported.   
 
The investigator is required to provide the NIDA Medical Monitor/Alternate with all 
relevant follow-up information necessary to facilitate a thorough understanding of the 
event and judgment regarding the relationship to the study drug/placebo. 
 
Reporting to the FDA 
 
The IND sponsor, Dr. Morrison, is required to report SAEs to the FDA: 
 
 in 7 days if the SAE is unexpected (or, if expected, unusually serious or rarely 
seen), life-threatening or lethal, and at least possibly related to the study agent, 
with a follow-up written report in 8 days; 
 

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 in 15 days if the SAE is unexpected (or, if expected, unusually serious or rarely 
seen), but not immediately life-threatening; and  
 
 in an annual report in all other cases. 
 
Any fatal or life-threatening SAE that is investigational agent related and unexpected 
must be reported initially to the FDA within 7 calendar days via telephone, facsimile or 
e-mail. A follow-up written report must be submitted in 8 days to the FDA.  All AEs that 
are both serious and unexpected but not life-threatening or lethal must be reported to 
the FDA, in writing, within 15 calendar days of notification of the sponsor of the SAE. All 
other SAEs will be reported in an annual report or more frequently as necessary. Any 
additional clinical information that is obtained must be reported to the FDA, as it 
becomes available in the form of an information amendment. Dr. Morrison and study 
physicians/personnel will inform NIDA of all SAEs that occur during the study.   
 
If a study subject withdraws from the study or if an investigator decides to discontinue 
the subject from the study because of a SAE, the subject must have appropriate follow-
up medical monitoring. If the subject is hospitalized, medical monitoring will consist of 
not less than daily evaluation by physical examination, vital signs, laboratory 
evaluations, and if applicable, EKG monitoring for significant treatment-emergent 
abnormalities. Monitoring will continue until the problem prompting hospitalization has 
resolved or stabilized with no further change expected or is discovered to be clearly 
unrelated to study medication or progresses to death. 
 
Pre-existing Condition 
A pre-existing condition is one that is present at the start of the study. A pre-existing 
condition should be recorded as an adverse event if the frequency, intensity, or the 
character of the condition worsens during the study period. 
 
At screening, any clinically significant abnormality or disorder should be recorded as a 
pre-existing condition. At the end of the study, any new clinically significant 
findings/abnormalities or disorder that meets the definition of an adverse event must 
also be recorded and documented as an adverse event.  
 
Post-study Adverse Event 
 
All unresolved adverse events will be followed by the investigator until the events are 
resolved, the participant is lost to follow-up, or the adverse event is otherwise explained.  
At the last scheduled visit, the investigator should instruct each participant to report any 
subsequent event(s) that the participant, or the participant’s personal physician, 
believes might reasonably be related to participation in this study. The investigator 
should notify the IRB of any adverse event occurring at any time after a participant has 
discontinued or terminated study participation that may reasonably be related to this 
study. The IRB will also be notified if the investigator should become aware of the 
development of cancer or of a congenital anomaly in a subsequently conceived 
offspring of a participant that has participated in this study.  

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Other Safety Considerations 
 
No patients with allergies to penicillins, cephalosporins and beta-lactam related drugs 
will be enrolled in the study. Subjects will not be allowed to take concomitant over the 
counter (OTC) medications without the permission of the investigator.  Any medication 
with effects on glutamate or GABA such as N-acetylcysteine, tiagabine, or lorazepam is 
excluded. A table of excluded medication is provided in Appendix I. For an urgent 
medical problem after working hours after inpatient discharge, please contact the study 
doctor using the 24-Hour phone number at 610-247-2126. 
 
Covid-19 Safety Procedures 
Participants who are determined to be potentially eligible from the prescreen 
questionnaire will complete an illness screening questionnaire. Participants who 
endorse Covid-19 related symptoms within the past 14 days will be asked to seek 
appropriate care and will have their screening visit scheduled a minimum of 14 days 
after their symptoms resolve. Covid PCR testing will be recommended for participants 
with symptoms, and participants with negative tests will be scheduled for a screening 
visit. 
 
Participants who are scheduled for a screening visit will be asked to contact the study 
team should they develop any symptoms related to Covid-19. Participants who develop 
Covid-19 related symptoms will be asked to reschedule their visit a minimum of 14 days 
after their symptoms resolve. 
 
Participants will have their temperature taken and be provided a surgical mask prior to 
starting study procedures. Session rooms will be arranged so that participants can 
maintain a 6-foot social distance when possible, and rooms will be disinfected between 
participants.  
 
Eligible participants will receive a Covid-19 test prior to screening visit part 2, and 
receive a Covid-19 PCR viral test within 96 hours prior to the baseline visit. Participants 
who test positive for Covid-19 will be instructed to seek appropriate medical care and 
will have their visit rescheduled a minimum of 14 days after their symptoms resolve. 
 
e. Withdrawal from Study 
 
Early Withdrawal of Participants 
 
1. When and How to Withdraw Participants 
 
Participants who experience severe psychological symptoms (e.g., suicidal thoughts), 
fail to adhere to protocol requirements, or withdraw consent will be withdrawn from the 
study and, if applicable, referred for appropriate clinical care. Participants who report 
active suicidal ideation (determined by MINI or C-SSRS) will be referred to the crisis 
center or the outpatient clinic for evaluation. Participants will be reminded that they will 

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be responsible for any costs related to treatment. Any participant experiencing a serious 
adverse event that the Principal Investigator believes to be related to study drug and a 
potential threat to the health and safety of the participant will be withdrawn from the 
study.  
 
Participants will be informed about any new information that may affect their health, 
welfare, or choice to stay in this research.  
 
2. Data Collection and Follow-up for Withdrawn Participants 
 
We will make a strong effort (via phone calls and alternative contact information) to 
obtain follow-up information on all participants who are prematurely withdrawn from the 
project. 
 
 
11. 
Risks to Subjects 
 
MRI and MRS have proven to be of great value in the noninvasive diagnosis and 
understanding of neuropsychiatric brain disorders. The overall risk to subjects from 
participation in MRS research scans is minimal.  The levels of energy used to make 
magnetic resonance measurements is far less than is used in a single X-ray, and many 
patients have been safely studied using magnetic resonance techniques. However, 
some people become uncomfortable or claustrophobic while inside the magnet.  If 
subjects become uncomfortable inside the magnet, they may withdraw immediately 
from the study.    
 
The greatest risk from an MRS scan is a metallic object flying toward the magnet and 
hitting them. To reduce this risk, we require that all people involved with the study 
remove all metal from their clothing and all metal objects from their pockets. Subjects 
are scanned wearing clothing provided by TUBRIC though they retain their underpants.  
No metal objects are allowed in the magnet room at any time. In addition, once a 
subject is in the magnet, the door to the room will be closed so that no one inadvertently 
walks into the magnet. 
 
During some of the MRI scans, subjects have occasionally reported “tingling” or 
“twitching” sensations in their arms or legs, especially when their hands are clasped 
together. Further, because of the strong magnetic field, people with pacemakers, metal 
fragments in the eye, or certain metallic implants cannot participate in this study. Subjects 
are given a checklist before entering the MRI room at each scan which is reviewed so 
that subjects do not encounter this problem. All women of childbearing potential are to 
take a pregnancy test (urine) to verify that they are not pregnant before they are enrolled 
in the study. Clavulanic Acid by itself is not FDA approved and its current use in this study 
is experimental. The medication could pose an unknown risk to a fetus or embryo, and 
pregnant women will be excluded from this study to mitigate this risk. While there are no 
known harmful effects to embryos of multiple brain MRIs within a couple weeks, there is 

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Page 45 of 60     Protocol V2.7 November 15th 2021 
no clear unique knowledge or benefit gained from including this population in the current 
study. 
 
This study may include the use of custom manufactured head coils and experimental 
imaging sequences that are not FDA-approved but are considered non-significant risks. 
 
The primary risks of this study are those of possible adverse reaction to the study drug, 
CLAV. There is substantial safety data on Augmentin, but it is not known whether CLAV 
alone confers increased medical risk to cocaine dependent people who have 7+ days of 
cocaine abstinence. Our experience with our cocaine interaction study and outpatient 
imaging study with CLAV does not suggest serious risk of multiple dose CLAV 500 mg 
in the cocaine dependent population.  CLAV is a beta-lactamase inhibitor and is the 
potassium salt of CLAV. CLAV is part of Augmentin/Augmentin XR®, along with 
amoxicillin.  Augmentin® has been FDA approved since 1984 for the treatment of 
patients with community-acquired pneumonia or acute bacterial sinusitis and has been 
used globally for the treatment of infectious diseases. Augmentin® is considered 
reasonably safe during pregnancy and lactation (Berkovitch et al. 2004, Benyamini et al. 
2005). CLAV is not an effective antibiotic and is unlikely to disturb bowel flora 
(Saudagar, Survase, and Singhal 2008). CLAV levels in tissue are too low to affect 
human flora in healthy subjects (Earnshaw et al. 1987, Finlay, Miller, and Poupard 
2003).  However, one report of an experimental murine model suggested that CLAV 
may have efficacy for the treatment for Acinetobacter baumannii, a gram negative rod 
that is an opportunistic pathogen in immunocompromised patients (Beceiro et al. 2009). 
CLAV is unavailable by itself, without amoxicillin. Thus, there is no safety data in the 
scientific literature on CLAV alone. The Augmentin approval package includes single 
dose data on CLAV 750 mg and 1,000 mg (FDA 05/09/1988). Side effects reported in 
the Phase I studies of CLAV from the FDA approval data include: nausea, vomiting, 
drowsiness, fatigue, diarrhea, indigestion, headache, increased stomach noises, 
nausea (sometimes with increased heart rate), flatulence (passing gas), “very slight 
increase in liver size” with increased liver tests, cholestatic jaundice, and dizziness. In 
the present study one male participant experienced priapism without pain for 5 hours 
after the first day of study drug (study drug not unmasked). During the screening visit 
male subjects will be evaluated for priapism risk factors, abnormal anatomy of the penis, 
and previous episodes of unexpected prolonged erections. The PI consulted with Dr. 
Jack Mydlo, the Temple Chair of Urology, and determined that a participant with an 
erection of 4 hours or longer will be transferred to the Emergency Room. Participants 
experiencing priapism will have their cavernosal blood gas evaluated to determine 
whether the priapism is high or low flow. Emergency Room physicians at Temple are 
familiar with priapism evaluation, and will discuss the results with the Urology Resident 
on call for further management.  
 
Common adverse events for Augmentin include: diarrhea (14.5%), vaginal mycosis 
(3.3%), nausea (2.1%) and loose stools (1.6%). As a beta lactam drug, CLAV has a risk 
of allergic reactions both for those with known penicillin allergy, as well as for those with 
no known allergy. No patients with allergies to penicillins, cephalosporins and beta-
lactam related drugs will be enrolled in the study.  The risk of hepatitis for Augmentin® 

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Page 46 of 60     Protocol V2.7 November 15th 2021 
is estimated at between 1/10,000 to 1/100,000, with an increased risk for older males 
(Gresser 2001). Hepatotoxicity associated with amoxicillin/ CLAV is generally self-
limited with cessation of medication and generally associated with complete recovery 
(Saudagar, Survase, and Singhal 2008, Gresser 2001, Larrey et al. 1992). The medical 
literature supports the hypothesis that CLAV at doses up to 500 mg/day and CLAV 
given as a chronic medication is generally safe and well tolerated. Combined amoxicillin 
clavulanate (CLAV 250 mg a day) has been given to men to treat actinomycetoma for a 
mean of 9.6 months with no reported side effects (Bonifaz et al. 2007). Combined 
meropenem/clavulanate (CLAV 375 mg a day) has been given to 6 patients with drug-
resistant tuberculosis for up to 36 weeks with no reported side effects (Payen et al. 
2012).  Timentin® is an intravenous combination of ticarcillin and CLAV, with 100 mg of 
CLAV in a 3.1-gram infusion of Timentin. In a retrospective study of 127 pediatric cystic 
fibrosis patients who received Timentin, they received a mean of 450 mg CLAV /day +/- 
227 mg/day for a mean duration of 13.5 days (Zobell et al. 2010). No adverse effects on 
laboratory measures, including liver function tests, were found. While there is 
substantial clinical experience with Augmentin to treat infections, there is no published 
data on either CLAV or Augmentin in cocaine dependent adults.   
 
Blood being drawn is a risk of the study. Blood drawn from all subjects should be 
considered infectious and extreme caution will be used to avoid needle sticks and direct 
contact with blood or plasma. 
 
The nasoparyngeal Covid-19 swab is a risk of the study. The swab can be 
uncomfortable and some participants experience mild bleeding from their nose 
afterwards (5-8% patients). Headache and ear discomfort after the swab test are rarely 
experienced (1-5% patients). Participants will be instructed to hold very still to ensure 
the swab is properly administered and does not cause further discomfort. The swab 
should be considered infectious after administration, and staff will use extreme caution 
to avoid direct contact with the swab. 
 
Questions from the ACE scale include information about childhood abuse, neglect, and 
other adverse childhood experiences. Participants may find some of the questions from 
the ACE scale distressing to answer. Participants will be reminded their participation is 
voluntary, and they can refuse to answer any question that is asked in the 
questionnaire. Staff will provide emotional support to participants who are distressed by 
the questionnaire, and if necessary, referrals will be provided for outpatient care. 
 
There is the risk of a breach of confidentiality regarding study records, but this is 
unlikely, since staff is well trained in this area. 
 
Note: "Minimal risk" means that the risks of harm anticipated in the proposed research 
are not greater, considering probability and magnitude, than those ordinarily 
encountered in daily life or during the performance of routine physical and psychological 
examinations or tests. 
 
12. 
Potential Benefits to Subjects 

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Although there is little immediate benefit to the subjects who undergo this study 
including MRI imaging, there is great potential for the study of drug abuse, which 
remains a major source of social, economic, and medical disability in the United States 
and elsewhere. Increasing knowledge about the brain response to a drug being studied 
for cocaine addiction may aid in the development of therapeutic strategies for this 
addiction. Furthermore, the technical development is also expected to lead to valuable 
methodologies for all studies of behavioral state and will have general applicability in 
basic and clinical neuroscience. If the study staff observes a brain abnormality during 
the scan, a professionally licensed radiologist will be consulted at no cost to the 
participant. If the radiologist recommends clinical follow-up, the team will inform the 
participant of the recommendation, make images from the scan session available to 
them, and provide a referral to a professional upon the subject’s request. Participants 
are reminded that the study team is not responsible for any medical costs related to the 
incidental finding. Subjects may experience benefit from having a medical history, 
physical, laboratory testing and associated counselling performed. These potential 
benefits can be contemplated as the risk of participation in the study is considered.  
 
13. 
Privacy and Confidentiality 
 
Privacy is a subject’s ability to control how other people see, touch, or obtain information 
about the subject.   
 
Research study records may only be accessed by staff engaged in the research project 
or clinical care of the subjects, or by representatives of the National Institute on Drug 
Abuse, the Temple IRB, the Food and Drug Administration, or other government 
agencies as required and permitted by law. 
 
The following data may be collected. It contains protected health information (PHI)  
 Name 
 Street address, city, 
county, precinct, zip 
code, and equivalent 
geocode 
 date of 
birth/age/gender 
 Personal information 
regarding past medical 
or drug therapies to 
ensure eligibility for 
inclusion in the study 
 Telephone numbers 
 Electronic mail 
addresses 
 
 
 Social security 
numbers (for payment 
processing) 
 Health plan ID 
numbers to register 
subjects in Temple 
systems for MRI if 
there is a need 
 Brain images/lab test 
results 
 Responses to study 
safety questionnaires  
 
 

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14. 
Compensation for Research-Related Injury 
 
There will be no compensation for research-related injury. The study team will 
help arrange appropriate medical care, but participants will be informed there is 
no commitment by Temple University, Temple University Health System or its 
subsidiaries to provide monetary compensation or free medical care in the event 
of a research-related injury. Participants will be given the contact information for 
Dr. Mary F. Morrison or the study physician covering the study. 
 
15. 
Economic Burden to Subjects 
 
The study drug will be provided to participants for no charge. Participants will 
receive compensation for time and transportation. There are no charges to 
subjects for participating in this research study. 
 
16. 
Consent Process 
 
All study personnel will follow Temple University’s SOP “INVESTIGATOR 
GUIDANCE: Informed Consent (HRP-802).”  
 
Non-English-Speaking Subjects 
We will not be enrolling non-English speaking subjects at this time. 
 
Waiver or Alteration of the Consent Process (consent will not be 
obtained, required information will not be disclosed, or the research 
involves deception) 
Not Applicable. 
 
Subjects who are not yet adults (infants, children, teenagers) 
Not Applicable. 
 
Cognitively Impaired Adults  
Cognitively impaired adults are not appropriate for enrollment in the study. 
 
Adults Unable to Consent 
If the adult is deemed unable to provide consent, then they will not be 
included in this study. 
 
17. 
Process to Document Consent in Writing 
 
All study personnel will follow Temple University’s SOP “INVESTIGATOR 
GUIDANCE: Documentation of Informed Consent (HRP-803).” 
 
18. 
Vulnerable Populations 
 

Phase 1B Pharmaco-MRS study of Clavulanic acid after repeated administration. 
 
Page 49 of 60     Protocol V2.7 November 15th 2021 
No vulnerable populations will be included in this study. All subjects will be told 
that they may choose not to participate in this study and their decision will not 
have any impact on their current care if they choose not to participate in the 
study. We will not use coercive language before, during or after the consent 
process and study procedures. 
 
19. 
Drugs or Devices 
 
The study drug (CLAV) will be stored in the Episcopal inpatient pharmacy. The 
trained research staff will observe ingestion of each study drug dose by the 
participant to ensure medication adherence.  
 
The initial dose of CLAV (250 mg) for the first day was picked to be higher than 
10 mg/kg CLAV (in rodents or ~162 mg in humans). In addition, 500 mg dose has 
been reasonably well-tolerated in the cocaine interaction study and MRS pilot 
study. 750 mg was tolerated in the cocaine interaction study. 1000 mg will be 
tested. The Augmentin NDA, the published literature, and our studies support the 
safety of testing these doses for 10 days on an inpatient basis with daily 
evaluations.   
 
20. 
Dose Justification.  
 
The range of 1 -10 mg/kg CLAV was associated with behavioral changes 
suggesting efficacy for substance abuse disorders in our rodent models at 
Temple (S Rawls’ lab). One way to translate rodent doses to humans is to match 
the net systemic exposure of CLAV in each species. A single intravenous dose of 
10 mg/kg in rats gave an AUC (area under the curve) of 7.9 mg.h/L (Woodnutt, 
Kernutt, and Mizen 1987). A single oral dose of 125 mg in humans gave an AUC 
of 6.1 mg.h/L (Sánchez Navarro 2005). Linear PK is assumed, based on data in 
the Augmentin NDA (New Drug Application to the FDA) and the scientific 
literature (FDA 05/09/1988). We then calculate that a single oral dose of 16.2 mg 
in a 70 kg human would achieve comparable systemic exposure to a single 
1mg/kg IV/IP (intraperitoneal) dose in rats (and 162 mg ~10mg/kg). The initial 
dose of CLAV (250 mg) was picked to be higher than 10 mg/kg CLAV (in rodents 
or ~162 mg in humans). For this study, we plan to study a minimum of 500 
mg/day (2 capsules) for 10 days to maximize the possibility of detecting any 
change in the concentration of glutamate in the ACC brain regions after repeated 
administration using what may be an efficacious dose of CLAV, based on 
efficacious doses found in rodents. The maximum tested dose in the Augmentin 
New Drug Application (NDA) was 1000 mg in healthy volunteers, but it is not 
clear whether this is the maximum tolerated dose (Augmentin New Drug 
Application to the FDA). For safety purposes participants will receive 250mg of 
CLAV on the first day of dosing. Participants who safely tolerate the 250 mg dose 
will be instructed to self-administer the second 250mg dose later in the day under 
staff supervision. Participants will take a 500mg dose (2 capsules) at a single 
time for the next 2 days. Participants who tolerate the 500mg dose will be 

Phase 1B Pharmaco-MRS study of Clavulanic acid after repeated administration. 
 
Page 50 of 60     Protocol V2.7 November 15th 2021 
escalated to a 750mg dose for 3 days. Participants who tolerate the 750mg dose 
will be escalated to the 1000mg. Participants will be administered the 750mg and 
1000mg doses to maximize the possibility of detecting any adverse 
pharmacodynamic effect, using what may be an efficacious dose of CLAV. 
Participants who are unable to tolerate dose escalation will resume their 
previously tolerated dose. No MTD in healthy controls or cocaine dependent 
subjects has been established. For a drug development program for CLAV in the 
cocaine disorder population, it is reasonable to study a higher dose under close 
supervision in case higher doses are needed for efficacy. The inpatient clinical 
trial examining IV cocaine in combination with CLAV had 10 subjects who have 
been exposed to the 500 mg dose, 5 subjects have been exposed to a 750 mg 
dose with no severe side effects. No adverse pharmacodynamic interactions 
between CLAV or Augmentin and cocaine have been reported.   
 
21. 
Multi-Site Human Research 
 
Not Applicable. 
 
22. 
Sharing of Results or Incidental Findings with Subjects 
 
 The MRI will not be reviewed by a neuroradiologist.  Results will only be shared 
with subjects if they ask for the results of the study. Study results will be 
published without identifying information. If a subject is interested in knowing the 
results from the study, they will be directed to the publication and the published 
results may be discussed. No individual results will be discussed regarding the 
study. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

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Page 51 of 60     Protocol V2.7 November 15th 2021 
APPENDIX I: Table of Glutamate/GABA Affecting Drugs 
 
Glutamate/GABA 
Affecting Drugs 
Chronic Use 
Episodic UseD 
 
Acamprosate 
N 
N 
Acetazolamide 
N 
Y 
Agmatine 
N 
N 
Alcohols (including 
ethanol) 
N 
Y 
Amantadine 
N 
N 
Antidepressants (SSRI, 
SNRI, Wellbutrin) 
N 
N 
Atomoxetine 
N 
N 
Baclofen 
N 
Y 
Barbiturates 
N 
N 
Benzodiazepines 
N 
Y 
Beta-Lactam Drugs 
N 
N 
Bromides 
N 
N 
Buprenorphine 
N 
N 
Cannabinoids (including 
marijuana) 
N 
Y once only. 
Negative UDS 
for entry. 
Carbamates 
(carisoprodol (SOMA), 
meprobamate) 
N 
N 
Chloral hydrate 
N 
Y 
Chloroform 
N 
Y 
D-cycloserine 
N 
N 
Delucemine 
N 
N 
Dexoxadrol: etoxadrol 
 
N 
N 
Dextromethorphan 
N 
Y 
Dextrorphan 
N 
N 
Diphenidine 
N 
N 
Eliprodil 
N 
Y 
Etifoxine 
N 
N 
Eszopiclone 
N 
Y 
Etoxadrol: similar to 
PCP. 
N 
N 
Felbamate 
N 
N 
Gabamide 
N 
N 
Gabapentin 
N 
N 
Gaboxadol 
N 
N 
 
D Episodic Use is defined as use 1-2 times a week and no use 3 days prior to the scan 

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Page 52 of 60     Protocol V2.7 November 15th 2021 
Gammahydroxybutyrate 
(GHB) 
N 
N 
Glutamine 
N 
N 
Huperzine A 
N 
N 
Ibogaine 
N 
N 
Ibotenic Acid 
N 
N 
Ivermectin and other 
avermectins 
N 
N 
Kavalactones  
N 
N 
Ketamine 
N 
N 
Kratom 
N 
N 
Lamotrigine 
N 
N 
Levetiracetam 
N 
N 
Loreclezole 
N 
N 
Magnesium 
N 
Y 
Memantine 
N 
N 
Meprobamate 
N 
N 
Methadone 
N 
N 
Minocycline 
N 
N 
Muscimol 
N 
N 
N-acetylcysteine 
N 
N 
Neramexane 
N 
N 
Neuroactive steroids 
(such as 
allopregnanolone) 
N 
N 
Nitromemantine 
N 
N 
Nitrous oxide 
N 
Y 
Opioids 
N 
Y 
Perampanel 
N 
N 
Phencyclidine 
N 
N 
Phenibut 
N 
Y 
Picamilon 
N 
N 
Pregabalin 
N 
N 
Progabide 
N 
N 
Propofol 
N 
Y 
Primidone 
N 
N 
Remacemide 
N 
N 
Retigabine 
N 
N 
Riluzole 
N 
N 
Selegiline 
N 
N 
Tiagabine 
N 
N 
Topiramate 
N 
N 
Tricyclic 
antidepressants 
N 
Y 
Valerian 
N 
Y 

Phase 1B Pharmaco-MRS study of Clavulanic acid after repeated administration. 
 
Page 53 of 60     Protocol V2.7 November 15th 2021 
Vigabatrin 
N 
N 
Zaleplon 
N 
Y 
Zolpidem 
N 
Y 
 

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Page 54 of 60     Protocol V2.7 November 15th 2021 
APPENDIX II:  Certificate of Confidentiality 
 
The only people who will know the identity of the subjects are members of the research 
team and, if appropriate the physicians and nurses.  No information about the subjects, 
or provided by the subjects during the research, will be disclosed to others without the 
subjects’ written permission, except:  
 
- 
if necessary to protect subjects’ rights or welfare, or 
- 
if required by law. 
 
When the results of the research are published or discussed in conferences, no 
information will be included that would reveal subjects’ identity.  Authorized 
representatives of the FDA and NIDA study monitors may need to review records of 
individual subjects.  As a result, they may know subjects’ names, but they are bound by 
rules of confidentiality not to reveal their identity to others.  The results of this study 
including laboratory results and clinical information collected during this study will be 
submitted to the FDA and may be used for research purposes.  The results of this study 
may be published but will not personally identify any subjects.  All records will be kept in 
locked storage locations that will be accessible only to authorized study personnel.  
 
Effective October 1, 2017 Certificates of Confidentiality (COCs) will be issued 
automatically for any NIH-funded project using identifiable, sensitive information that 
was on-going on/after December 13, 2016. 
 
The CoC will be issued as a term and condition of award and there will be no physical 
certificate issued. 
 
The study subjects should be informed that a Certificate is in effect and be given a fair 
and clear explanation of the protection it affords, including the limitations and 
exceptions. This information will be included in the informed consent. Please see below 
some suggested wording: 
 
“We have received a Certificate of Confidentiality from the National Institute on Drug 
Abuse, which will help us protect your privacy. The Certificate protects against the 
involuntary release of information about your participation in this study. The researchers 
involved in this project cannot be forced to disclose your identity or your participation in 
this study in any legal proceedings at the federal, state, or local level, regardless of 
whether they are criminal, administrative, or legislative proceedings. However, you or 
the researcher may choose to voluntarily disclose the protected information under 
certain circumstances. For example, if you or your guardian requests disclosure of your 
participation, the researchers will provide research data. The Certificate does not 
protect against that voluntary disclosure. 
 
Furthermore, federal agencies may review our records under limited circumstances, 
such as a DHHS request for information for an audit or program evaluation or a Food 
and Drug Administration request under the Food, Drug and Cosmetics Act.” 

Phase 1B Pharmaco-MRS study of Clavulanic acid after repeated administration. 
 
Page 55 of 60     Protocol V2.7 November 15th 2021 
 
          
 
 
 
 
or  
 
“A Certificate of Confidentiality has been obtained from the Federal Government for this 
study to help insure your privacy. This Certificate means that the researchers cannot be 
forced to tell people who are not connected with the study, including courts, about your 
participation, without your written consent. If we see [learn] something that would 
immediately endanger you, your child, or others, we may discuss it with you, if possible, 
or seek help.” 
 
A Certificate of Confidentiality is a legal defense against a subpoena or court order and 
is to be used by the researcher to resist disclosure. The researcher should seek legal 
counsel from his or her institution if legal action is brought to  
release personally identifying information protected by a certificate. The Office of  
General Counsel for DHHS is willing to discuss the regulations with the researcher's 
attorney. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

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APPENDIX III:  MRI Safety Questionnaire 

Phase 1B Pharmaco-MRS study of Clavulanic acid after repeated administration. 
 
Page 57 of 60     Protocol V2.7 November 15th 2021 
 
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