Conditions: Opioid-use Disorder Opiate Dependence
Allocation: RANDOMIZED | Intervention model: PARALLEL
Enrollment: 112
Healthy volunteers: no

Brief summary:
Individuals with opioid use disorder who are stabilized on buprenorphine or methadone will be randomly assigned to receive placebo or lofexidine for 5 weeks. At the end of five weeks, they will complete a human laboratory stress task and scripted opioid imagery task. Throughout the study a CREMA app (Cue Reactivity Ecological Momentary Assessment) will be used to monitor stress, craving and use in the natural environment.

Detailed description:
Participants will complete a screening visit to determine study eligibility. During the first week, participants will be asked to abstain from opioid use other than buprenorphine. Participants will come to the clinic 2 times that week for urine drug testing. If all 2 tests are negative, participants will be randomly assigned to take either lofexidine or placebo (inactive medication) two to three times a day for 5 weeks. During this time, participants will upload videos of themselves taking their medication. They will come to the clinic 3 times a week for urine drug screens and to have their vital signs measured. They will also participate in "CREMA" sessions (Cue Reactivity Ecologic Momentary Assessment) 3 times a day. These sessions include looking at stressful and neutral pictures and rating stress and craving. At the end of five weeks, participants will return to the clinic and participate in a stress task and a scripted opioid imagery task the following day. For the next five days, participants will taper their medication dose. During this time they will continue to come to clinic to have their vital signs measured and complete a follow-up visit.

Arms:
arm 1: Men will receive lofexidine (Lucemyra) for 5 weeks. Titration schedule is as follows: 0.36 mg on the first two evenings, 0.36 mg in the morning and evening on days 3 and 4; 0.36 mg in the morning, afternoon, and at bedtime on days 5 and 6; 0.36 mg in the morning and afternoon and 0.72 mg at bedtime on days 7 and 8; 0.36 mg in the morning and 0.72 mg in the afternoon and at bedtime on days 9 and 10, and 0.72 mg in the morning, afternoon and at bedtime on Day 11 and throughout the rest of the study. arm 2: Women will receive lofexidine (Lucemyra) for 5 weeks. Titration schedule is as follows: 0.36 mg on the first two evenings, 0.36 mg in the morning and evening on days 3 and 4; 0.36 mg in the morning, afternoon, and at bedtime on days 5 and 6; 0.36 mg in the morning and afternoon and 0.72 mg at bedtime on days 7 and 8; 0.36 mg in the morning and 0.72 mg in the afternoon and at bedtime on days 9 and 10, and 0.72 mg in the morning, afternoon and at bedtime on Day 11 and throughout the rest of the study. arm 3: Men will receive matching placebo for five weeks. arm 4: Women will receive matching placebo for five weeks.

Interventions: intervention 1: Lofexidine intervention 2: Placebo
Intervention descriptions: intervention 1: Lofexidine, sold under the brand name Lucemyra among others, is a medication historically used to treat high blood pressure, but more commonly used to help with the physical symptoms of opioid withdrawal. It is taken by mouth. It is an α2A adrenergic receptor agonist. intervention 2: Placebo comparator.

Protocol document:
Prot_SAP_ICF_000.pdf: 
 
Clinical Trials Cover Sheet 
 
 
Study Title: Impact of Lofexidine on Stress, Craving and Opioid use 
 
IND Number: 141345 
 
Drug Name: Lucemyra (lofexidine) 
  
Sponsor-Investigator: Constance Guille, MD  
 Associate Professor 
 67 President Street 
 Charleston, SC 29425 
 (843) 792-6489 
 (843) 792-3388 
guille@musc.edu 
 
 
 
 
 
 
 
 
 
 


V20 7.25.23 
Impact of lofexidine on stress, craving and opioid use 
 
A. Significance 
A.1.  Opioid Epidemic in Women.  Opioid use disorder (OUDs) are increasing at alarming rates in the United 
States and the prevalence in women is substantial. While the number of opioid-dependent men in the US remains 
larger than the number of opioid-dependent women, there are some disturbing trends. Between 1999 and 2015, 
overdose deaths from prescription pain drugs increased 471 percent in women compared to an increase of 218 
percent in men (CDC, 2018). Although nonmedical use of prescription opioids among women has generally been 
decreasing since 2010 (Jones, 2016), heroin use among women increased faster in women than men and 
between 2002 and 2013, heroin use among women increased 100% compared to an increase of 50% among 
men (Cicero et al., 2014). Disturbingly, there has been an enormous increase in the rates of synthetic opioid-
related deaths, with an 850 percent increase in deaths for women between 1999 and 2015 (CDC, 2018).   
 A.2.  Gender Differences in Substance Use Disorders (SUDs).  There is growing recognition that biological 
and psychosocial differences between men and women influence the prevalence, presentation, comorbidity and 
treatment of SUDs.  For example, women tend to use smaller amounts of drugs or alcohol for a shorter amount 
of time before seeking treatment, a phenomenon known as “telescoping” (Brady and Randal, 2007).  A similar 
trend is seen in OUDs; an analysis of data from a multisite clinical trial demonstrated that women progressed to 
opioid dependence more quickly and experienced more craving as compared to men (Back et al., 2011). Women 
with SUDs are also more likely to have comorbid depression and anxiety disorders (Brady et al., 1993; Brady 
and Randall, 1999) and are more likely to attribute use and relapse to negative emotional states and 
interpersonal conflict (Connors et al., 1998; Back et al., 2011) as compared to men.  There is also evidence of 
gender differences in neurocognitive and brain responses in drug-dependent individuals. An fMRI study 
examining gender differences in neural correlates of stress- and drug cue exposure found greater corticostriatal-
limbic reactivity in cocaine-dependent women during stress exposure, but higher reactivity in these regions 
during drug cue exposure in cocaine-dependent men suggesting greater neural stress sensitization in women 
(Potenza et al., 2012). Another study found psychological and emotional distress were identified as risk factors 
for hazardous prescription opioid use among women, but not men (Back et al., 2011).  
A.3.  Stress and Relapse: Sex and Gender Differences. Etiologic theories of SUDs suggest that stress plays 
an important role in vulnerability and motivation to abuse addictive substances (Higgins and Marlatt, 1975; Koob 
and LeMoal, 2001; Russell and Mehrabian, 1975). Animal studies demonstrate that exposure to stress facilitates 
both initiation and reinstatement of drug use after a period of abstinence (Koob et al., 2004; Stewart, 2000). The 
brain circuitry (including amygdala and hippocampus) underlying cognitive processing of stress is sexually 
dimorphic in humans and animals (Kudielka and Kirschbaum, 2005).  In addition, hormonal regulation contributes 
to sexual dimorphism in stress response (Patchev and Almeida, 1998), with estrogen and progesterone acting 
as modulators of stress regulation (Windle et al., 2006). Corticotropin-releasing factor (CRF), an important 
mediator of the stress response through the hypothalamic-pituitary-adrenal (HPA) axis and extra-hypothalamic 
systems, has been implicated in the pathophysiology of stress-induced relapse (Koob et al., 2014). Preclinical 
studies have demonstrated significant sex differences in CRF systems. For example, female rodents have higher 
basal levels of CRF in the hypothalamus (Viau et al., 2005; Dunko et al., 2001) and significantly greater 
adrenocorticotropin hormone (response) to CRF (Kuhn and Francis, 1997). 
 
One focus of our previous SCOR work was the neural circuitry and mechanistic connection between 
stress and vulnerability to relapse in cocaine dependence.  Preclinical studies by our group and others 
demonstrated that CRF agonists can initiate reinstatement of cocaine-seeking in rodent models (Shaham et al., 
2003; Lu et al., 2003).  Our SCOR group was the first to demonstrate that female rats are more sensitive to the 
impact of CRF on cocaine reinstatement compared to male rats (Buffalari et al., 2012). In our human laboratory 
studies, we found higher subjective stress response and greater HPA axis disruption in cocaine-dependent 
women compared to men (Brady et al., 2009). Of interest, high stress and craving following CRF administration 
was associated with higher relapse rates in the month following laboratory testing (Back et al., 2010).   
 
In this same study, the heart rate response following CRF was also more robust and prolonged in women 
(Brady et al., 2009), suggesting greater noradrenergic activity.  Interactions between the brain’s noradrenergic 
and CRF systems are critical to the stress response (Koob et al., 2014; McRae et al., 2017). The noradrenergic 
system is comprised of two main projections distributed throughout the brain: the dorsal noradrenergic bundle 
(DNB) originating in the locus coeruleus (LC) and the ventral noradrenergic bundle (VNB) in the brain stem. The 
noradrenergic receptor system is made up of alpha1, alpha2, and beta receptor subtypes (Berridge and 
Waterhouse, 2003). Alpha-2 adrenergic agonists, such as clonidine, guanficine and lofexidine, stimulate 


V20 7.25.23 
inhibitory presynaptic alpha-2 receptors and decrease norepinephrine (NE) cell firing and release centrally 
(Aghajanian, 1982).  Preclinical studies indicate significant sex differences in the LC-NE system, including 
increased numbers of LC neurons and differences in dendritic structure, so female rats receive more CRF-
containing afferents from limbic regions (Bangasser et al., 2016).  In addition, estrogen can increase NE in LC 
target regions by enhancing NE synthesis and reducing degradation (Bangasser et al., 2106). Finally, one study 
found that CRF was 10–30 times more potent in activating LC neurons in female versus male rats (Curtis et al., 
2006). 
A.4. Sex and gender differences in response to noradrenergic agents. Preclinical evidence suggests that 
increased NE activity is a mediator of stress-induced reinstatement. Yohimbine, an alpha-2 receptor antagonist 
that increases NE release, facilitates reinstatement of cocaine (Feltenstein and See, 2006; Lee et al., 2004), 
methamphetamine (Shepard et al., 2004), and alcohol (Le et al., 2005) seeking.   Our SCOR group was the first 
to demonstrate that female rats were more sensitive to the impact of yohimbine on cocaine-reinstatement than 
males, with females in proestrus demonstrating the greatest response to yohimbine  (Feltenstein et al., 2011).  
Our SCOR group also demonstrated gender specific sensitivity to noradrenergic dysregulation in cocaine 
dependence using a human laboratory paradigm. In a double-blind placebo-controlled cross-over study of 
yohimbine prior to cocaine cue exposure, women reported greater anxiety and craving with yohimbine compared 
to men (Moran-Santa Maria et al., 2014), suggesting that noradrenergic-mediated stress increased the salience 
of drug cues for women more than men.   
Of interest, alpha-2 agonists selectively block reinstatement of heroin, cocaine, alcohol and nicotine-
seeking in animal models (Erb et al., 2000; Shaham et al., 2000; Highfield et al., 2001; Yamada and Bruijnzeel, 
2011; Le et al., 2005).  Several human laboratory studies have also demonstrated that alpha-2 agonists decrease 
both stress and cue-induced craving in cocaine- and nicotine-dependent individuals (Jobes et al., 2011; Fox et 
al., 2012; Fox et al, 2014). One investigation of the impact of guanfacine on stress and cue-induced response in 
cocaine-dependent men and women found that guanfacine significantly attenuated cocaine and alcohol 
craving, anxiety, and negative emotion in women but not in men (Fox et al., 2014). A Cochrane review found 
that clonidine treatment for smoking cessation was more effective in women than in men (Gourlay et al., 
2004). In a meta-analysis (n = 813) of clonidine studies for smoking cessation, end-of-treatment quit rates in 
women were 70% for clonidine versus 18% for placebo, whereas men did not demonstrate a medication effect 
(Glassman et al., 1988). McKee and colleagues (2015) found that guanfacine significantly and equally reduced 
the number of cigarettes per day following a quit attempt for men and women over a 4-week treatment period.  
However, guanfacine decreased smoking lapse, cigarettes smoked, and tobacco craving following stress in 
women but not in men. Although preliminary, these findings suggest that interventions that decrease 
noradrenergic activity may be more efficacious in reducing substance use in women as compared to men due 
to sex differences in stress-related sensitization. 
A.5.  Opioids, HPA Axis and Noradrenergic Systems. In opioid dependence, stress system dysregulation is 
of major significance because of the complex relationships between stress-related neuropeptides (i.e. CRF), the 
endogenous opioids, and the LC-NE system. The LC–NE system is reciprocally regulated by endogenous 
opioids and CRF (Curtis et al., 2001; Kawara et al., 2000; Valentino and Van Bockstaele 2001; 2013). Preclinical 
studies demonstrate that chronic morphine sensitizes the LC-NE system to CRF expressed as increased 
sensitivity of the neurons to stress, providing a potential mechanism to link opioid use with stress-sensitive 
disorders (Xu et al., 2004). As detailed above, there is substantial pre-clinical evidence indicating sex differences 
in these systems, but these differences have not been specifically explored with regard to opioids.   
 
There is some lack of consistency in studies of HPA axis function in opioid dependence.  As expected 
because opioid receptors exert inhibitory control over CRF and HPA axis output, ACTH and cortisol are reduced 
during heroin exposure and early studies demonstrated normalization of HPA axis function during methadone 
maintenance (Kreek et al., 2002; Kreek et al., 1983). More recent studies have demonstrated some persistent 
alterations in HPA axis activity in methadone-maintained individuals, including increased sensitivity to high dose 
CRH administration (Schulger et al., 2003) and decreased cortisol and CRF levels (Zhang et al., 2009), 
suggesting suppressed HPA axis function. Although the impact of buprenorphine maintenance on HPA axis 
function has not been as thoroughly explored, one study using a metyrapone challenge suggested suppressed 
HPA axis function in individuals on buprenorphine maintenance (Kakko et al., 2008). It is clear, however, that 
opioid withdrawal engages CRF and other stress-systems, including noradrenergic pathways, and is associated 
with anxiety and dysphoria (Schulger et al., 2003). Several studies have demonstrated that increased cortisol 
during opioid withdrawal is positively correlated with opioid craving (Nava et al., 2008; Shi et al., 2009).    


V20 7.25.23 
A.6. Apha-2 Agonists in Opioid Dependence. Clonidine was the first alpha-2 agonist shown to ameliorate 
some signs and symptoms of opioid withdrawal (Gold et al., 1978) and is now used in opioid detoxification.   
Although clonidine is traditionally used only for opioid detoxification, Kowalczyk and colleagues (2015) conducted 
a randomized double-blind, placebo-controlled relapse prevention trial of adjunctive clonidine treatment in 118 
OUD men and women on buprenorphine. The rationale for the trial was based on preclinical reinstatement 
studies cited above (Erb et al., 2000; Shaham et al., 2000; Highfield et al., 2001).   To preserve consistency with 
the preclinical models,  a relapse prevention model requiring a period of abstinence before entering the 
medication treatment portion of the trial was used as preclinical data suggests that cessation of on-going drug 
use is mediated by different neural mechanisms than those involved in prevention of relapse (Shalev et al, 2002; 
Kalivas and Volkow, 2005).  Ecologic momentary assessment (EMA) was used during the 14-week trial to query 
participants about daily life stress and craving. The clonidine-treated group had a significantly longer duration of 
abstinence as compared to the placebo group. EMA assessment demonstrated that daily life stress was partly 
decoupled from opioid craving in the clonidine group, supporting the hypothesis that clonidine exerted its 
beneficial effects by muting the stress response. The number of women in the sample was not large enough to 
support gender-specific data analysis. Of interest, in studies using a preclinical model of polysubstance abuse, 
methadone blocked cocaine and heroin-induced reinstatement, but not stress-induced reinstatement (Leri et al., 
2004; Sorge et al., 2005).     
 
Lofexidine, also an alpha-2 agonist, has been licensed for opioid detoxification in England since 1992. 
Three studies and a Cochran review comparing the efficacy and tolerability of lofexidine to clonidine suggest 
comparable efficacy in reducing withdrawal, with a better risk-benefit profile for lofexidine including better 
tolerability and less hypotension (Kahn et al., 1997; Lin et al.,1997;  Carnwath and Hardman, 1998; Gowling et 
al, 2016).  In a study of 18 opioid-dependent individuals stabilized on naltrexone (NTX), treatment with lofexidine 
versus placebo was tested (Sinha et al., 2007).  During the 4-week treatment period, the lofexidine-NTX patients 
had higher abstinence rates and improved relapse outcomes as compared to the placebo–NTX group. Ten 
subjects participated in a human laboratory stress/drug cue exposure paradigm.  The lofexidine–NTX patients 
had significantly lower heart rate and attenuated stress and drug cue response as compared to the placebo–
NTX group. The sample size did not support a gender-specific analysis in this study.  As in the study by 
Kowalczyk and colleagues (2015), participants were stabilized on NTX before initiation of study medications,  
making this a relapse prevention study.  Following these two positive clinical studies and based on the preclinical 
data, we will use a relapse prevention model in this study requiring a period of abstinence before the medication 
treatment period.   
 
In sum, alterations in the stress response and noradrenergic system are important in pathophysiology of 
OUD. Alpha-2 agents, which decrease noradrenergic activity, may be helpful in decreasing the stress response 
in OUD individuals.  In cocaine and nicotine dependence, alpha-2 agents have a more robust impact in women 
as compared to men, however gender differences in OUD individuals have not been explored. The primary 
objective of this study is to explore gender differences in the impact of an alpha-2 agonist, lofexidine,  on the 
relationship between stress, craving and drug use in individuals with OUDs.   
A.7.  Conclusions.  OUDs are increasing at alarming rates in women. Stress and dysregulation in biologic stress 
response systems appear to play an important role in drug use and the connection between stress and drug use 
may be particularly important for women.  Alterations in CRF, the HPA axis and noradrenergic system are 
important in the pathophysiology of OUDs and there is evidence that agents that decrease noradrenergic activity 
may help to prevent relapse and stress reactivity in individuals with OUDs, but gender differences in these effects 
have not been systematically explored. The primary objective of this study is to explore gender differences in the 
impact of an alpha-2 agonist, lofexidine,  on the relationship between stress, craving and drug use in individuals 
with OUDs.   
 
B. INNOVATION 
The proposed study will test truly novel hypotheses using innovative methodology. Specifically, it will build on 
our previous SCOR work investigating sex and gender differences in the stress-relapse connection, while 
expanding the focus to opioid dependence, a problem of epidemic proportions in the United States. Several 
studies suggest alpha-2 agonists may be useful in reducing stress-induced craving and relapse in OUDs and 
studies in cocaine and nicotine dependence suggest that women may be more responsive to these agents as 
compared to men. However, to our knowledge, there are no previous or ongoing studies investigating gender 
differences in the impact of alpha-2 agonists in decreasing stress-induced craving or relapse in OUDs. In 
addition, we will use a novel alpha-2 agent, lofexidine. While lofexidine has been approved for use in England, 


V20 7.25.23 
it is now being evaluated by the FDA for use in the United States. Studies suggest that lofexidine is better 
tolerated than clonidine, the alpha-2 agent most commonly used in the United States for opioid detoxification 
(Gowing et al., 2009). We will utilize a novel dual-level approach by examining the impact of lofexidine on stress 
and drug cues presented in a laboratory paradigm and on ambient stress, craving and stress cues occurring 
over the course of a clinical trial. In the latter case, we will use innovative mobile technology to allow for 
assessment of craving, stress and stress-cue reactivity in the “day to day” natural environment before, during 
and after treatment in individuals with OUD. We will also assess medication compliance using an innovative 
video capture procedure.  These approaches represent a highly innovative “next step” in the development of 
personalized, gender-specific treatment for individuals with OUD. 
 
C. APPROACH 
C.1. Preliminary Studies 
C.1.a. Capacity of Research Team. The proposed research requires experience in: 1.) recruitment, retention, 
and assessment of OUD individuals, 2.) human laboratory stress induction procedures, 3.) collection and 
interpretation of neuroendocrine and physiologic measurements, 4.) ambulatory assessments, and 5.) clinical 
trial conduct and follow-up of individuals with SUDs. As detailed below, the multidisciplinary research team has 
the requisite expertise to successfully conduct the proposed work and a proven track-record. The proposed 
project will be co-directed by Drs. Kathleen Brady and Connie Guille. Dr. Brady is a Distinguished University 
Professor with a 30-year history of successful conduct of clinical trials and human laboratory studies in individuals 
with SUDs. Dr. Connie Guille’s research focus is perinatal OUD, incuding the ultization of EMA to identify 
predictors of opioid use. Drs. Brady and Guille have been collaborators for the past decade. Dr. Kelly Barth is a 
board-certified Addiction Psychiatrist with specific interests in chronic pain management, the interface of pain 
and addictions, and gender differences in OUDs. Dr. Jenna McCauley is a licensed clinical psychologist with 
experience in assessment of early life trauma and opioid research, as well as clinical trial conduct and follow-up 
of individuals with SUDs.  Importantly, these investigators have been working closely together over the past 2 
years leading state-wide efforts to address the opioid epidemic in South Carolina.  As such, they are a cohesive 
team with a history of successful collaboration. 
C.1.b. Experience with Recruitment, Retention, and Assessment OUDs. Dr. Brady has been conducting 
clinical trials in close connection with local treatment programs over the past 20 years as part of the NIDA-funded 
clinical trials network (DA013727). The Charleston Center is a public treatment program located 1 block from the 
MUSC campus.  In 2017, Charleston Center treated 356 men and 224 women with primary OUDs.  In 2017, the 
MUSC addiction treatment service treated over 250 patients with OUDs, including approximately 100 individuals 
on buprenorphine, the target population for this proposal.  Dr. Brady and colleagues recruited 126 men and 
women with OUDs from these settings over a two-year period.  A subset of these individuals participated  in a 
human laboratory study similar to the proposed project (described below). In addition, this team is currently 
leading a multi-pronged statewide effort focused on the opioid epidemic which includes a component focused 
on providing buprenorphine and rapid access to treatment for OUD patients presenting in emergency rooms 
(ERs). In the MUSC ER, they have identified 56 individuals with OUD in the last 6 months and facilitated 
treatment at the Charleston Center and MUSC addiction treatment services.Shoreline Behavioral Health in 
Conway, SC  works closes with DAODAS to provide medication-assisted treatment to residents of Horry County. 
With these multiple recruitment sites, we anticipate no difficulties meeting recruitment goals for the proposed 
study.  
C.1.c. Stress Induction Procedures and Neuroendocrine/Physiologic Measurement. Dr. Brady has 
conducted a number of human laboratory studies involving stress induction and drug cue exposure in alcohol, 
cocaine and nicotine dependence (Brady et al., 2009; Moran et al., 2014; Hartwell et al., 2011; Brady et al., 
2006).  Of direct relevance, Drs. Brady and colleagues completed a pilot study involving a human laboratory 
stress task in 39 (N=19 women; 20 men) individuals with OUD.  Subjects were randomly assigned to either the 
Trier Social Stress Test (TSST; n=19) or no-stress control (no stress; n=20) followed by opioid cue exposure. 
Distress tolerance, Inventory of Drug Taking Situations and Time-line Follow-back were completed at baseline. 
Self-reported visual analog scale ratings of stress and craving, as well as heart rate and salivary cortisol were 
assessed immediately before and at multiple time points for 60 minutes following the TSST/drug cue exposure.  
Individuals were followed for one month after the  laboratory session to assess opioid use (Time-line Follow-
Back) and daily stress. Significant group (TSST vs. no stress) differences emerged in self-reported stress 
[F(1,35)=41.77, p<.001], anger [F(1,35)=13.00, p<.001], sadness [F(1,35)=4.78, p<.05], cortisol and heart rate 


V20 7.25.23 
(HR) [F(1,35)=5.28, p<.05], with the TSST group exhibiting more reactivity. Women demonstrated significantly 
greater self-reported stress [F(1,35)=11.24, p<.01], (Figure 1); however, they exhibited significantly less cortisol  
response following the TSST as compared to men. Data (Figure 2) are shown as log 10 transformed model-
based means and standard errors adjusted for baseline cortisol.   Of interest, women also exhibited a significantly 
protracted HR response following the TSST compared to men; it had not returned to baseline by the end of the 
1 hour follow-up period (Figure 3) suggesting greater 
noradrenergic stimulation in women.  This finding is similar 
to the gender-specific pattern of response seen in 
cocaine-dependent individuals in an earlier SCOR study 
(Brady et al., 2009). Women in this study reported 
significantly more daily hassles and used opioids on a 
higher percentage of days in the one-month follow-up 
period as compared to men (Table 1). In addition, lower 
distress tolerance, measured at baseline, was significantly 
associated with a higher   percentage of opioid use days 
for women (b=17.01, p=.013), but not for men. In 
summary, these data suggest  that OUD women 
demonstrate greater subjective and noradrenergic stress 
response than OUD men. The pattern of low cortisol and 
high subjective response to stress exhibited by women in 
this study has been associated with higher relapse in studies 
in cocaine dependence (Back et al., 2010).  Furthermore, women reported lower distress tolerance, higher 
experience of daily hassles and a robust relationship between low distress tolerance and drug use. Taken 
together, these preliminary findings suggest that 
an intervention targeting stress vulnerability, 
particularly through blockade of noradrenergic 
activation, may be particularly effective in relapse 
prevention for opioid-dependent women.   
C.1.d. 
Experience 
with 
Ambulatory 
Assessments. During the last funding period, the 
MUSC 
SCOR 
research 
group 
developed 
ambulatory assessment tools to assess stress 
reactivity and drug craving, collect data on drug use and withdrawal symptoms, validate abstinence, and 
measure/encourage medication adherence. The Cue Reactivity Ecological Momentary Assessment (CREMA) 
paradigm was modified to assess cue- and stress-related nicotine craving (Wray et al., 2015). Over 80% of 
CREMA sessions were successfully completed (Tomko et al., 2017), supporting the feasibility of remote 
collection of this type of data. We also capitalized on the capabilities of the REDCap data system to remotely 
collect self-report of drug use and video confirmation of medication adherence (Tomko et al., in press). In a 
smoking cessation trial, there was high compliance with video (73.8%) and self-report (74.8%) completion. All 
                         
                                Men (n=21)   Women (n=18)      Stats 
% days using  
30.4 
55.3 
p = 0.107 
Daily Hassles Score 
One Week 
46.3 
105.4 
p = 0.018 
One Month  
41.6 
87.5 
p = 0.058 
  
Figure 1: Stress Response 
Figure 2: Cortisol Response 
Figure 3: Heart Rate Response 
0
2
4
6
8
10
Baseline
Post
TSST
Cue +0
Cue +15 Cue +30 Cue +60
Female
Male
64
68
72
76
80
Female
Male
-1
-0.75
-0.5
-0.25
Baseline
Post
TSST
Cue +0 Cue +15 Cue +30 Cue +60
Female
Male
TABLE 1: MONTH AFTER TESTING  
Figure 3: Heart Rate Response 


V20 7.25.23 
participants agreed that the surveys and videos were easy to use, and the majority of participants preferred the 
REDCap assessments to traditional, paper measures. In an ongoing pharmacotherapy trial for cannabis use 
disorder (UG3DA04323), we have observed high compliance with video uploads for medication adherence, with 
a median of 80% of medication doses verified.  
C.2. Research Design and Methods. This project is a double-blind, placebo-controlled trial to assess gender 
differences in the impact of lofexidine, an alpha-2 agonist, on stress-related opioid craving in men and women 
with OUD on stable buprenorphine or methadone maintenance. Following this period, participants will be 
randomized to receive either lofexidine or placebo for a 5-week period during which cue reactivity ecological 
momentary assessment (CREMA) will be used to assess stress levels, craving and drug use and video 
confirmation of medication adherence will be employed. Naturalistically collected stress and drug cue reactivity 
data will be complemented by administration of a validated laboratory stress (the Trier Social Stress Task) and 
drug cue exposure procedure at the end of the 5-week treatment period while participants are still taking study 
medications. A schematic of study procedures is shown below. 
C.2.a. Participants. A total of 136 participants (68 men and 68 women) with OUD who have been on a stable dose 
of buprenorphine or methadone for at least 2 weeks, aged 18 to 65 years of age, will be recruited over a 54-
month period. Additional inclusion criteria are consent to random assignment, ability to read and provide informed 
consent and willingness to remain abstinent from illicit opioids during the 1-week baseline assessment period. 
Contingency management procedures (described below) will be used to facilitate the maintenance of abstinence 
during this period.  Exclusion criteria are women who are pregnant, nursing, or planning to become pregnant 
during the course of the study; having a history of or current major psychiatric or medical disorder; hypotension 
or QTc prolongation on EKG; and meeting criteria for moderate or severe use disorder for another substance 
with the exception of nicotine. A detailed list of inclusion/exclusion criteria can be found below.  
C.2.b. Recruitment. MUSC staff will recruit participants from the Charleston Center,, MUSC and community 
addiction treatment programs, Shoreline Behavioral Health, and through media advertisements As noted in 
C.1.b., we have a long and successful track record of recruiting from these programs for clinical trials, and the 
numbers of patients on buprenorphine or methadone maintenance at both sites are more than adequate for 
recruitment of the required four participants per month to meet the study timeline.   
 
C.2.c. Procedures 
C.2.c.1. Ensuring a Robust and Unbiased Approach: Rigor and Transparency. The proposed study will 
achieve robust and unbiased results via several design features including: explicit inclusion/exclusion criteria; 
randomization of treatment condition; placebo control; blinding; use of validated laboratory and interview/self-
report measures and methods; explicit hypotheses and planned statistical analyses; power estimates; 
management of retention/attrition and missing data; and careful consideration of potential confounds. All 
experimental details are reported in a detailed and fully transparent manner to support replication. 
C.2.c.2. Screening and Eligibility Assessment. Individuals interested in participating will be screened by an 
MUSC research study intake coordinator on site at the Charleston Center, MUSC/community treatment program, 
Shoreline Behavioral Health or over the phone  A quick screen, focused on inclusion/exclusion diagnoses, 
medical status, medication regimen, and ability/willingness to complete assessments and study procedures, will 
be used to initially determine study eligibility. Potential participants will be given a full description of study 
procedures and asked to read and sign an IRB-approved Informed Consent Form if they choose to participate. 
Inclusion/exclusion criteria are detailed below. 
Inclusion Criteria: 1.) Able to provide informed consent and function at an intellectual level sufficient to allow 
accurate completion of assessment instruments. 2.) Meet DSM-5 criteria for OUD (within the past three months); 
while individuals may also meet criteria for another substance use disorder, they must not meet criteria for 
moderate or severe use of any other substance (except tobacco or marijuana) within the last 60 days.  3.) On a 
Assessment
Informed consent
Inclusion/exclusion
Baseline measures
Days 1-7
CREMA evaluation for 
baseline  assessment
Contingency management to 
facilitate abstinence
Days 8-40
Lofexidine or placebo
CREMA evaluation
Video assessment  of 
medication adherence
Day 39/40
Laboratory evaluation of 
stress (TSST) and drug 
cue


V20 7.25.23 
stable dose of buprenorphine or methadone for 4 weeks.  4.) Age 18-60. 5.) Women of childbearing potential 
must agree to utilize an effective means of birth control. 6.) Must consent to random assignment. 
 
Exclusion Criteria: 1.) Women who are pregnant, nursing or of childbearing potential and not practicing an 
effective means of birth control. 2.) Evidence or history of major medical illnesses, including liver or renal 
diseases, abnormal vaginal bleeding, suspected or known malignancy, thrombophlebitis, deep vein thrombosis, 
pulmonary embolus, clotting or bleeding disorders, heart disease, insulin-dependent diabetes, history of stroke 
or other medical conditions that the investigator deems as contraindicated for the individual to be in the study. 
3.) History of or current psychotic disorder or bipolar I affective disorder. 4.) Current suicidal or homicidal risk. 
5.) Taking any medications known to act on the adrenergic system (B-blockers, alpha agonists or antagonsits). 
6.) Hypotensive individuals with a sitting blood pressure of < 90/50 mmHg  7). QTc interval of > 440 in males 
and > 460 in females as the combination of lofexidine and methadone may increase QTc interval. For males with 
a QTc of greater than >440, but less than 470 AND absence of any history of CV disease AND absence of family 
history of CV death, they are eligible for enrollment. For females with a QTc of greater than >460, but less than 
490 AND absence of any history of CV disease AND absence of family history of CV death, they are eligible for 
enrollment. 8.) Known allergy to lofexidine.   
C.2.c3. Screening and Diagnostic Instruments. Quick Screen: The instrument is designed to assess for 
substance dependence and obvious psychiatric, medical, and logistic exclusions. Mini-International 
Neuropsychiatric Interview (M.I.N.I) is a brief structured interview designed to assess DSM-5 diagnoses using 
a series of questions in dichotomous format (yes/no). The M.I.N.I. is similar in sensitivity, specificity, and inter-
rater reliability to other lengthier diagnostic interviews, such as the SCID-I/P (Sheehan & Lecrubier, 2003; 
Sheehan et al., 1998). The alcohol and drug use disorder modules will be used to thoroughly assess current and 
lifetime diagnostic status for abuse and dependence. It has excellent inter-rater and test-retest reliability (First et 
al., 2002). Menstrual History Diary will be used for female participants to estimate the timing of their cycle for 
the 90-days prior to study entry and track during study participation. Perceived Stress Scale (PSS) is a 10-item 
assessment of daily stress (Cohen et al., 1983) that has previously been used in substance use research (Fox 
et al., 2009; Hyman et al., 2007). Adverse Childhood Experiences (ACE) Questionnaire assesses childhood 
maltreatment and exposure to household dysfunction. It has been utilized to examine the relationship between 
adverse childhood experiences and health risk behavior in adulthood (Felitti et al., 1998).  The Life Stressor 
Checklist-Revised (LSC-R; Wolfe & Kimerling, 1997) will be used to assess for the number of exposures to 
various potentially traumatic life events including accidents, interpersonal violence, and death of a relative. 
Participants will answer yes or no for 30 potential life events.  In addition to providing data to assess the impact 
of daily stress and early childhood trauma on opioid use, utilization of the PSS and ACE will likely allow for 
potential cross-SCORE collaborations as these scales have been previously recommended as components of 
the core assessment battery utilized across centers. Coronavirus Impact Scale: 12 item questionnaire 
assesses life changes that have occurred as a result of the coronavirus (Stoddard & Kaufman, 2020). We will 
also ask how substance use has been impacted. 
 
Substance-Related Instruments. Time Line Follow-back (TLFB; Sobell & Sobell, 1992) is a calendar-based 
instrument designed to assess daily substance consumption. Opioid use will be recorded in times used per day 
as well as quantity, type of opioid and route of administration. Urine Drug Screening: Urine samples will be 
collected and analyzed for prescribed and illicit drugs at baseline and at each study visit. All urine specimens will 
be analyzed using drug test cups with temperature-controlled monitoring. Drug test cups with immunoassay drug 
screen cards will be used to identify the following substances: oxycodone, buprenorphine, methadone, tramadol, 
benzodiazepines, Opiate 300 group analytes (morphine, heroin, and codeine), THC, cocaine, amphetamine, 
methamphetamine, ethyl glucuronide, fentanyl, K2,  and MDMA. Other drugs may be detected by these analytes 
at high concentrations. For example, hydrocodone may be detected under the oxycodone test at high 
concentration levels. The cups also include adulterant testing for creatinine, nitrite, pH, bleach and specific 
gravity.   Saliva drug screening: Saliva drug screens will be obtained from Forensic Fluids and will test for THC, 
cocaine, opiates, benzodiazepines, methadone, oxycodone, buprenorphine,  and fentanyl. Patients will collect 
and store samples which will be returned to the clinic and sent to Forensic Fluids in batches. Samples will be 
de-identified. Inventory of Drug-Taking Situations (IDTS) (Annis et al., 1997) measures typical drug using 
situations based on Marlatt and Gordon’s (1985) eight category taxonomy. This instrument will be used at 
baseline and contains eight subscales mapping frequency of use in distinct types of situations including use 
during negative situations (unpleasant emotions) and positive situations (social situations).  Although initially 
developed for alcohol use, it has been modified for other SUDs and has demonstrated sensitivity to gender 


V20 7.25.23 
differences (Ross et al., 1994). Brief Pain Inventory (BPI) (Cleeland & Ryan, 1994). Assesses severity of pain 
and impact on functioning. This measure will be completed at screening and at the end of treatment. 
 
An EKG and physical exam including orthostatic hypotension testing will be conducted by a licensed medical 
provider. Serum will be collected for baseline labs and a UDS will be collected. If the participant is female, a 
pregnancy test will be done prior the urine drug screen. Females who are pregnant will not be allowed to 
participate. Participants at Shoreline will have labs drawn by Mako Medical Lab at the Shoreline site. 
 
C2.c4.. Remote screening visit:. Patients may also complete the initial visit remotely if warranted. In this case, 
subjects will be electronically consented using Doxy.me or RedCap or a combination. The informed consent will 
be emailed to the participant prior to the video call. The patient will have the opportunity to ask questions on the 
call and will electronically sign the document. A signed copy will be emailed to the participant. The M.I.N.I 
interview and medical history then be conducted, also via Doxy.me Patients will be advised to find a private 
location during these procedures to protect privacy and confidentiality. Patients will be sent survey links to 
complete self-report questionnaires.The blood draw, EKG and orthostatic BP will be done at Baseline. A physical 
exam may be done if it is warranted based on medical history. Urine drug screening and pregnancy testing will 
not be done until baseline for participants who screen remotely. 
 
 
C.2.c.5. Phase 1:  Baseline and Medication Trial 
a. Initial Study Visit.  Participants will be trained to use CREMA and the one-week naturalistic baseline data 
collection period will begin following screening procedures. If it is determined that patient is ineligible based on 
labwork, they will be excluded and baseline procedures will end.  
b.  Baseline Assessment (Study days 1-7). Throughout this study period, participants will come to the clinic 
for UDS collection.  To facilitate opioid abstinence during the baseline period, we will use a standard contingency-
management procedure. Participants will earn payments of $10 for the first negative UDS and $20 for the second.  
Two consecutive UDSs during the baseline week must be negative for illicit opioids in order for the subject to 
enter the medication treatment part of the trial.  During the baseline assessment period, participants will be asked 
to use CREMA (described below).  Subjects may have up to 10 days to provide the negative UDSs. 
c. CREMA Assessment. Cue Reactivity Ecological Momentary Assessment (CREMA; Warthen & Tiffany, 2009; 
Wray, Godleski, & Tiffany, 2011; Wray et al., 2015) can collect subjective ratings of stress, craving, etc.  either 
without provocation or using photos from the International Affective Picture System (IAPS; Lang, Bradley, & 
Cuthbert, 2008) presented on a mobile electronic device (iPhone). If an individual does not have an iPhone or 
does not wish to use his/her own for the study, a phone will be provided. Participants will be instructed to keep 
their phone with them at all times.Participants will complete a daily survey about substance use and stressful life 
events over the previous 24 hours. Auditory alarms will alert participants to complete one randomly scheduled 
session per day to rate stress, craving and mood. This visual analog scale is anchored with adjectival modifiers 
(“not at all, mildly, moderately, and extremely”). The scale includes items assessing anxiety, stress, irritability, 
and craving.  Participants will also be alerted to daily random CREMA sessions including IAPS pictures; session 
will randomly include neutral IAPS pictures or stressful IAPS pictures (described below).  Iindividuals be 
presented one of two types of picture cues that differ based on content: stress-related (i.e., a child in distress) or 
neutral (i.e., sunglasses). Each picture will appear only once during the study. Participants will be instructed to 
look at the photo carefully for 10 seconds. An alarm will sound at the end of the trial, and participants will complete 
a post-cue rating scale assessment, ratings of how carefully they looked at the photographs and their distraction 
level. Using this strategy, we can assess ambient emotional state and craving as well as “evoked” response to 
stressful cues.   To encourage CREMA session completions, participants will be compensated $10.00  for each 
day they complete all sessions. Previous studies employing this incentive strategy have reported 85-90% 
completion rates (Gass et al., 2011; Warthen et al., 2009), including in our previous SCOR work (Wray et al., 
2015).  
d. Lofexidine/Placebo Titration Procedures (Days 8-17). After two consecutive negative drugs screens have 
been obtained, participants will be randomly assigned to study medication (lofexidine or matching placebo). For 
the Shoreline site, medication will be dispensed by IDS and delivered to MUSC staff at that site. At the 
randomization visit, females will provide saliva samples for estradiol and progesterone testing. Trained study 
personnel will evaluate heart rate, orthostatic blood pressure, and pre-syncope and syncope signs and 
symptoms prior to the initiation of Lofexidine. Lofexidine will not be dispensed if the participant is found to have 


V20 7.25.23 
one of the following on physical exam: 1) clinically significant bradycardia as determined by study physician; 2) 
orthostatic hypotension defined as a systolic blood pressure decrease of at least 20mm Hg or a diastolic blood 
pressure decrease of at least 10mm Hg within three minutes of standing; 3) participant endorsement of pre-
syncope symptoms such as lightheadedness, muscular weakness, blurred vision, or feeling faint during the 
evaluation of orthostatic blood pressure; or 4) syncope (fainting) during the evaluation of orthostatic blood 
pressure. Participants with bradycardia, orthostatic hypotension, pre-syncope or syncope would be terminated 
from the study and study staff will facilitate appropriate follow-up medical care. To minimize risks of hypotension, 
lofexidine will be titrated over a 10-day period with 0.36 mg QDfor days 1 and 2; 0.36 mg BID for days 3 and 4; 
0.36 mg TID for days 5 and 6; 0.36 mg BID and 0.72 QD days 7 and 8; 0.37 QD and 0.72 BID for days 9 and 
10,  and 0.72 mg TID on day 11 and throughout the rest of the study (see Table 2). This is the dose recommended 
by the regulatory agencies in England and the titration schedule is consistent with lofexidine titration in 8 
published studies (Gish et al., 2010).  
Table 2 
Days 
AM Dose (mg) 
PM Dose (mg) 
QHS Dose (mg 
Days 1 and 2 
(Study days 8 and 9) 
 
 
0.36 
Days 3 and 4 
(Study days 10 and 
11) 
0.36 
 
0.36 
Days 5 and 6 
(Study days 12 and 
13) 
0.36 
0.36 
0.36 
Days 7 and 8 
(Study days 14 and 
15) 
0.36 
0.36 
0.72 
Days 9 and 10 
(Study days 16 and 
17) 
0.36 
0.72 
0.72 
Days 
11-40 
(Study days 18-40) 
0.72 
0.72 
0.72 
 
 
Trained study personnel will evaluate heart rate, orthostatic blood pressure, pre-syncope and syncope signs and 
symptoms at all study visits during the titration period. If the study participant does not have bradycardia, 
orthostatic hypotension, or pre-syncope or syncope signs or symptoms as defined above, the dose of Lofexidine 
will be increased according to the titration schedule (Table 2). If bradycardia, orthostatic hypotension, or 
signs/symptoms of pre-syncope or syncope are identified at any point, the dose of Lofexidine will be lowered to 
the prior tolerated Lofexidine dose and the participant will remain at that dose for the duration of the study. At 
the beginning of the study, participants will be given a rescue pack of 36 tablets in case visits are missed. This 
will cover 3 days at the full dose. 
The medical provider will inform the participant, verbally and with a take-home hand-out, of common side 
effects of lofexidine (dizziness, somnolence, dry mouth) and precautions to minimize risks associated with 
blood pressure (BP) decreases (hydration, standing up slowly). Participants will attend study visits three times 
a week during the induction period and throughout the study during which a UDS will be collected. The MUSC 
Investigational Drug Service will be responsible for randomization, will keep a record of the blind and will be 
available should unblinding be required. In the event that WorldMeds is unable to supply matching placebo. 
lofexidine tablets (supplied by US WorldMeds) will be encapsulated along with matching placebo capsules by 
Pitt Street Pharmacy, a specialty compounding pharmacy. Randomization will be stratified on 
presence/absence of other substance use as well as the presence/absence of significant childhood trauma 
(ACE>4). 
e. Medication maintenance and adherence monitoring (Days 18-40). Trained study personnel will evaluate 
heart rate, orthostatic blood pressure, pre-syncope and syncope signs and symptoms once per week following 
the Lofexidine titration. If bradycardia, orthostatic hypotension, or signs/symptoms of pre-syncope or syncope 
are identified at any point, the dose of Lofexidine will be lowered to the prior tolerated Lofexidine dose and the 
participant will remain at that dose for the duration of the study.Participants will record themselves taking their 
medications A survey link will be sent to the participant’s cell phone via app alert two to three times daily, 
depending on where they are in the medication schedule. Video capture will occur through the CREMA app. The 
research coordinator will review the subjects’ videos before each study visit.  As discussed, we have used this 


V20 7.25.23 
technology successfully for medication adherence monitoring. To encourage compliance, participants will 
receive $10 for each day that they complete their medication adherence videos.  
f. Intervention phase (Study Days 18-40). During the 5-week medication phase, study participants will come in 
three times per week for UDSs. Blood pressure and pulse will be assessed at each visit. If the SBP < 90 mmHg 
and > 20% below screening value and/or DBP is < 50 mmHg and >20% below screening value, or the individual 
is complaining of symptoms of hypotension, the medication dosage will be reduced.  If these symptoms do not 
resolve, the individual will be removed from the study and followed until vital signs normalize. EKG’s will be 
performed at Weeks 4 and 6 to monitor QT intervals.  A contingency-management procedure will be implemented 
to facilitate study visit adherence. The payments will start at $4 and increase by $4 for each consecutive visit.  
g. Virtual monitoring: In order to reduce face-to-face visits when necessary, remote monitoring may be done 
during the medication phase. At the randomization visit, patients will be given a wrist blood pressure cuff for at 
home monitoring, and they will be trained in testing orthostatic blood pressure. Patients will come to the clinic 
once a week for a UDS, to meet with staff/medical personnel and have ave orthostatic testing done, and receive 
medication refills. Two weekly visits will be conducted via Telehealth. Patients will be observed doing a saliva 
drug screen and doing orthostatic blood pressure testing. If patients are symptomatic or having difficulty with 
telehealth procedures, they may be asked to attend the clinic more frequently. Participants who are not 
comfortable with telehealth procedures may choose to attend clinic visits instead.  
C.2.c.5. Phase Two: Scripted Opioid 
Imagery 
and 
Laboratory 
Stress 
Induction Session (Days 39 and 40). At 
the end of the five-week period of 
lofexidine 
or 
placebo 
administration, 
participants will return to complete a 
scripted opioid imagery taksk and a 
laboratory stress task (Trier Social Stress 
Test, 
TSST). 
Tasks 
will 
be 
counterbalanced. Subjects will remain on 
study medications for the test days. 
Subjects who miss their scheduled visits 
may be re-scheduled for up to one week. 
a.Session Preparation. Participants will 
be instructed to arrive at 8:00am on the 
test days, and to avoid caffeinated 
beverages since caffeine can introduce 
variability in heart rate response. If the 
individual is nicotine-dependent, (s)he will 
be provided with a nicotine patch 
throughout their study visit. Upon arrival, 
the participant will be breathalyzed and 
will provide a urine sample to be tested for drugs of abuse. For women, a pregnancy test will be done prior to 
the urine drug screen, and saliva will be collected for estrogen and progesterone measurement.  
b.Progesterone and Estrogen.  As there is significant individual variability in progesterone and estrogen levels 
across the menstrual cycle, measurement of progesterone and estrogen at the time of testing in combination 
with the menstrual cycle history will allow us to approximate the menstrual cycle phase as well as to utilize all 
participants’ data with absolute progesterone and estrogen levels as continuous measures. 
c. Design timing. Subjects will first undergo a progressive relaxation task. Baseline assessments of subjective, 
hormonal (cortisol), and physiologic measures (blood pressure and heart rate) will be collected following 
relaxation, 5 minutes before the stressor or imagery; TSST takes 15 minutes, and the imagery takes 5 minutes. 
At the end of the stressor of drug cue, a salivary sample will be collected to assay cortisol and physiological 
(blood pressure and heart rate) and subjective measures (Mood Rating Scale, Opioid Craving Questionnaire, 
STAI) will be obtained. Measurements will also be obtained at 5- 30-, and 60-minutes post-task.  
d. Trier Social Stress Task (TSST) is a standardized psychological stress challenge which has been used 
extensively in research studies. A meta-analysis supports its utility for evoking a HPA axis stress response in a 
laboratory setting (Dickerson & Kemeny, 2004). It has induced a robust and reliable physiological stress 
Test Day 1 
TABLE 3: LAB TESTING TIMELINE 
8:15am 
UDS, Saliva 
8:35 am 
Relaxation 
8:55am 
Baseline 1  Subjective, physiologic, endocrine 
measurement 
9:00am - 9:15am 
TSST/Imagery 
9:15am 
Subjective, physiologic, endocrine measurement 
9:20am 
Subjective, physiologic, endocrine measurement 
9:45am 
Subjective, physiologic, endocrine measurement 
10:15am 
Subjective, physiologic, endocrine measurement 
 
 
 
Test  Day 2 
815am 
UDS, Saliva 
8:35am 
Relaxation  
8:55am 
Baseline 1: Subjective, physiologic, endocrine 
measurement 
9:00am 
Opioid imagery/TSST 
9:05am 
Subjective, physiologic, endocrine measurement 
9:10am 
Subjective, physiologic, endocrine measurement 
9:35am 
Subjective, physiologic, endocrine measurement 
10:05 am 
Subjective, physiologic, endocrine measurement 


V20 7.25.23 
response in cocaine, alcohol, and cannabis-dependent individuals in our previous studies (McRae et al., 2006; 
McRae-Clark et al., 2011; Waldrop et al., 2010). At test initiation, the participant is told that (s)he will give a 
speech and perform an arithmetic task. The topic of the speech will be why (s)he should be hired for a particular 
job (the individual’s “dream job”). The participant will deliver the speech as though speaking to a group of 
potential employers. The experimenter then tells the participant that (s)he has 5 minutes to prepare the speech 
and starts the countdown clock (placed in view of the individual). The experimenter leaves the room and five 
minutes later, three individuals unfamiliar to the participant (the audience) enter the room; the individual is 
instructed by one audience member to stand and begin his/her prepared speech (without notes). The speech 
will be delivered for 5 minutes. If the individual pauses, (s)he will be instructed to continue. At the end of the 
speech task, the individual will be instructed to serially subtract 13 from 1,022 as quickly and accurately as 
possible. The mental math recitation will continue for 5 minutes, at the end of which time, the spokesperson will 
instruct the individual to stop and be seated, and the audience leaves the room. 
e. Opioid imagery script.  We are using a scripted imagery paradigm developed by Sinha and Tuit (2012). A 
script will be developed based on staff interviews with subjects about a time they craved and used opioids. The 
5-minute script will be audio-recorded and played back to the subject during the task. Subjects will be asked to 
listen and imagine the task as if they are there.   
f. Assessments.  Self-Report Measures. Mood Rating Scale:  As described above and used with the CREMA 
sessions, to allow for cross-task comparisons. State-Trait Inventory (STAI): The STAI is a 20-item self-report 
scale (Spielberger, 1983) employing a Likert-scale format with four responses per item (1-4). Ten of the STAI 
items measure feelings of stress and anxiety, while the remaining ten items measure feelings of relaxation. The 
STAI has good psychometric properties. Opioid craving will also be measured using a Likert scale format.  We 
have had good success with this in prior studies in OUDs (Back et al., 2014) Physiological Measures. Heart rate 
and blood pressure will be measured using an intermittently inflatable cuff as indices of physiological arousal 
during the test session. Hormonal Measures. Cortisol: Cortisol will be measured in unstimulated passive saliva 
using the Salimetrics expanded range, high sensitivity salivary cortisol enzyme immunoassay kit. This kit has a 
lower sensitivity level of <0.003 µg/dL. The correlation between salivary and serum cortisol has been shown to 
be high (r=0.91, p<0.0001). Cortisol is commonly measured as an indication of stress response in human 
laboratory studies.  
Modifications may be made to lab day procedures if necessary for patient and staff safety, ie fewer confederates, 
remote procedures. 
 
g. Discharge. Following assessments, participants will be given instructions to taper their lofexidine over the 
next five days.  A member of the research staff will be available to discuss management of any craving or urges 
to use any substance if craving remains elevated at the end of study procedures.   
C.2.c.6. Follow-up Assessment (Days 41-47). During a one-week follow-up period, lofexidine will be tapered... 
They will  come to the two times during the taper for BP monitoring (0.72 BID for two days, 0.36 mg BID for 2 
days, 0.36 QD for 1 day).  After five days, participants will return to the clinic and return clinic-provided phones, 
complete a questionnaire regarding their experience with the CREMA and REDCap surveys, and be provided 
referrals to treatment if interested.  
Participant Compensation: Participants will be compensated $40 for completing the screening visit, and an 
additional $20 for completing the screening the first time they are scheduled.  They will receive $20 for the 
CREMA training and a $25 bonus if they come to their first baseline visit as scheduled..They will receive $10.00 
for each day that all CREMA sessions are completed. During the opioid abstinence period, participants can earn 
a total of $30 for completing drug testing (2 negative UDS compenstated at $10 and $20). During the medication 
period, subjects can receive up to  $10 for each day they complete medication videos and $364 
($4+$8+$12+$16+$20+$24+$28+$32+$36+$40+$44+$48+ $52) for completing study visits with UDS. 
Participants will be compensated $10 for each blood pressure check during the tapering phase. Participants will 
also be compensated $50 for completion of each human laboratory session, a $50 bonus for completing both as 
scheduled,and $100 for the follow-up. follow-up visit, for a total potential compensation of $819 per participant 
plus earnings from CREMA and medication videos. Participants will be asked to complete a W-9. This document 
may be completed in person or via Doxy.me. 
Confidentiality: Confidentiality of all research data will be maintained by keeping all data in a locked file, limiting 
access to the computer database to only study personnel, and by using patient code numbers as opposed to 
names on all paperwork.   


V20 7.25.23 
 
C.2.d. Statistical Analysis and Data Management 
Data Management and Reduction: All paper-based assessments (other than laboratory reports) will be entered 
into REDCap, a secure, web-based application designed exclusively to support data capture for research 
studies. REDCap provides an intuitive interface for data entry (with data validation), audit trails for tracking data 
manipulation, and automated export procedures for data downloading to statistical packages such as SPSS and 
SAS. Quarterly database management and data integrity audits will be conducted and reports submitted. 
Statistics and Data Analysis (complete statistical/data analysis plan in Biostatistics Resource Core): 
Aim 1: Using a human laboratory paradigm, determine the impact of lofexidine on stress and drug cue-
induced craving in women and men with OUDs:  The primary study outcome of interest in Aim 1 is the 
differential craving, stress and anxiety response to a human laboratory paradigms containing both a stressor 
(TSST) and an opioid specific cue between participants randomized to lofexidine and placebo in addition to 
buprenorphine/methadone maintenance.  Hypothesis 1: Lofexidine will attenuate drug craving and subjective 
stress response to a stress task in opioid-dependent individuals compared to individuals receiving placebo. 
Hypothesis 2:  Lofexidine will attenuate drug craving and subjective stress response to a drug-related cue in 
opioid-dependent individuals. Hypothesis 3: The ameliorative effects of lofexidine on stress and cue-reactivity 
will be more pronounced in females than male subjects. To assess the hypothesis that lofexidine will attenuate 
drug craving and subjective stress response to the stressor and the opioid-related cue task, multilevel 
longitudinal GLMMs will be developed using all post-stressor and post-cue data.  Initial models will control for 
study design aspects such as order (stressor or cue first), treatment assignment, and baseline craving and stress 
(task level).  Covariate adjusted models will additionally include baseline characteristics determined to be 
correlated with study outcomes or those determined to be significant effect modifiers.  To examine the differential 
effects of lofexidine on stress and cue-reactivity across female and male subjects, the models will have additional 
parameters added to include an indicator of participant gender and the interaction between gender and 
randomized treatment assignment.  Relevant interactions will be assessed in all models.  Least square means 
and associated standard errors will be assessed to compare craving and subjective stress response between 
treatment assignments at all time points.   
Aim 2: To evaluate the impact of lofexidine on opioid craving and subjective experience of daily stressors 
in men and women with OUDs:  The primary measures of interest for Aim 2 are craving and stress ratings in 
response to stress-related cues using Cue Reactivity Ecological Momentary Assessment (CREMA) as well as 
subjective experiences of daily life stressors  Hypothesis 1: Lofexidine will decrease craving and decrease the 
subjective experience of daily stressors in opioid-dependent men and women.  Exploratory Hypothesis 2: 
Lofexidine will be more efficacious in decreasing stress-related craving in opioid-dependent women as compared 
to men.  To assess this hypothesis a multilevel generalized linear mixed effects models with repeated measures 
(GLMMs) will be developed using CREMA session response data from the 5-week period during study 
medication administration.  Pre-cue stress and craving rating will be centered and used as a time varying 
covariate in all analysis.  Additionally, CREMA cue response data during the 7 day baseline assessment period 
will be used as a time naïve covariate in all analyses.  Least squares means and associated standard errors will 
be used for post-hoc comparisons of craving and stress response between women and men over time.    Models 
developed to address hypothesis 2 will be utilized to examine the impact of gender on opioid use and stress-
related craving during study treatment. All other relevant interactions will be assessed in all models.   
Exploratory Aim 3:  To evaluate the impact of lofexidine on illicit drug use in men and women with OUDs:  
Daily use data will be collected through morning reports via EMA and verified by urine drug screens (3 times 
weekly).  Hypothesis 1: Lofexidine will increase the number of consecutive days abstinent as compared to 
placebo.  Hypothesis 2: Lofexidine will be more efficacious in increasing consecutive days abstinent in women 
as compared to men.  Time to relapse will be calculated as the days between the start of study medication 
(following titration; day 14) and the first day of lapse to opioid use or the laboratory stress induction day (day 40).  
Additionally, daily use data will be examined to determine the maximum number of consecutive days abstinent 
during follow up.  Kaplan-Meier estimates and log-rank tests will be used to assess initial relationships between 
study treatment assignment and relapse while Cox proportional hazards models will be developed to assess the 
differential time to return to use across gender (using and appropriate interaction term).  A significant interaction 
indicates that treatment may impact return to use time differently in women and men.  Proportionality of hazards 
will be assessed using log-log plots and log-time interactions. 


V20 7.25.23 
Power and Sample Size (complete sample size justification available in Biostatistics Resource Core): 
The current study is powered on the primary Aims 1 and 2.  In the proposed study, response to a laboratory 
stressor, CREMA cue response and daily use data will be tested using GLMMs (assuming a Gaussian 
distribution) and the study will be powered to sufficiently address the least of the study treatment effect sizes 
determined to be clinically meaningful for the study hypothesis.  Aim 1: Sinha and colleagues (Sinha, et al 2007), 
in a small pilot sample, demonstrated that lofexidine in combination with naltrexone attenuated craving and anger 
in response to laboratory drug and stress cues as compared to naltrexone alone.  Results indicate a larger 
change in opioid craving scores in response to drug-related and stress cues occurs in placebo participants than 
lofexidine treated participants [Drug related cue response Δ=2.2; SDP=2.6; between group Cohen’s d=0.85, 
p<0.05 and stress cues response Δ=2.1; SDP=2.4; between group Cohen’s d=0.88, p<0.05].  Moreover, Fox and 
colleagues (2014)  conducted a trial of guanfacine in cocaine-dependent individuals and noted stress and craving 
response to stress and drug-related imagery.  They noted significant gender differences across treatment 
assignment for craving and stress response to drug-related imagery [Craving Δ=3.0; SDP=3.8; Treatment x Sex 
Intx Cohen’s d=0.79, p<0.05; Negative Emotion Δ=3.0; SDP=2.9; Treatment x Sex Intx Cohen’s d=1.0, p<0.05].  
Sample sizes in both the Sinha and Fox studies were somewhat small. Smaller but still clinically relevant effect 
sizes in an adequately powered study are anticipated.  Therefore, a 20% reduction in craving and stress 
response from the previous studies is anticipated in the current design (Cohen’s d=0.64 for the sex x treatment 
interaction on craving response). Aim 2:  Kowalczyk and colleagues (2015), showed that daily life craving reports 
as measured by EMA were significantly reduced in opioid using participants randomized to clonidine as 
compared to placebo [6.3% (95% CI=5.6-7.1) vs. 11.8% (10.9-13.0); between group Cohen’s d=1.6].  To assess 
the least of the differences anticipated in project 2, a sample size of 39 participants randomized to each female 
and males across active lofexidine and placebo groups would provide 80% power with a type 1 error rate of 5% 
to detect the treatment x sex interaction in craving and stress response to laboratory drug based cues (total 
n=156; 78 per group). We anticipate 25% attrition between randomization and the end of the 5-week active 
treatment period.  Thus, inflating the necessary sample size to 68 participants randomized per treatment group 
with a total of n=136 randomized participants will provide adequate power.   
C.2.e. Operational Plan and Research Timetable. Funding for five years is requested. The first three months 
will be spent hiring and training personnel and preparing for study initiation. We have established standard 
operating procedures, so we anticipate rapid study start-up. 54 months will be needed for participant recruitment 
and data collection. The final three months will be used for participant follow-up, data analysis and manuscript 
preparation. 
D. Conclusions 
The prevalence of OUDs in the US is alarming and women appear to be at particular risk for overdose death.  In 
spite of this, little is known about gender-specific treatment for opioid dependence.  Evidence from a  number of 
sources demonstrate  that drug-dependent women show a greater response to stress-inducing stimuli and 
greater noradrenergic sensitivity as compared to men. Moreover, several studies suggest that alpha-2 agonists, 
which decrease noradrenergic activity,  may be useful in stress-induced craving and relapse in OUDs and studies 
in cocaine and nicotine dependence suggest that women are more responsive to these agents compared to 
men. In addition, we have promising preliminary data suggesting that interventions targeting stress vulnerability 
may be particularly effective in relapse prevention for opioid-dependent women. However, to our knowledge, 
there are no previous or ongoing studies investigating gender differences in the impact of alpha-2 agonists in 
decreasing stress-induced craving or relapse in OUDs. We have assembled a multidisciplinary team which 
includes experienced senior investigators as well as promising and productive junior investigators who will 
solidify their interest and increase their expertise in sex- and gender-based research through working on this 
important project.  This project will provide important information about a novel treatment strategy which may 
demonstrate preferential efficacy in the treatment of women with OUD.    
 
PROTECTION OF HUMAN SUBJECTS 
1. RISKS TO THE SUBJECTS 
a. Human Subjects Involvement and Characteristics136 
Admission into the study is open to men and women and to all racial and ethnic groups, age 18-60. individuals 
with opioid use disorders (68 men and 68 women) will be recruited primarily through local substance use 
treatment facilities. Inclusion/exclusion criteria that apply to all participants are listed below: 
 


V20 7.25.23 
General Inclusion / Exclusion Criteria 
Inclusion Criteria 
1. Able to provide informed consent and function at an intellectual level sufficient to allow accurate completion 
of all assessment instruments.  
2. Meet DSM-5 criteria for opioid use disorder (within the past three months). While individuals may also meet 
criteria for mild use disorders of other substances, they must identify opioids as their primary substance of 
abuse and must not meet criteria for any other moderate or severe substance use disorder (except tobacco, 
caffeine, or marijuana) within the last 60 days.  
3. On a stable dose of daily buprenorphine or methadone for at least 2 weeks. 
4. Age 18-65.  
5. Women of childbearing potential must agree to use an effective means of birth control. 
6. Consent to remain abstinent from opioids during the 1-week baseline assessment period. 
7. Must consent to random assignment. 
 
 
 
Exclusion Criteria 
1. Women who are pregnant, nursing or of childbearing potential and not practicing an effective means of birth 
control.  
2. Evidence or history of major medical illnesses, including liver diseases, abnormal vaginal bleeding, suspected 
or known malignancy, thrombophlebitis, deep vein thrombosis, pulmonary embolus, clotting or bleeding 
disorders, heart disease, insulin-dependent diabetes, history of stroke or other medical conditions that the 
investigator deems as contraindicated for the individual to be in the study.  
3. History of or current psychotic disorder or bipolar I affective disorder. 
4. Current suicidal or homicidal ideation/risk. 
5. Taking medications known to act on adrenergic systems (B-blockers; alpha agonists or antagonists) 
6. Hypotensive individuals with a sitting blood pressure of < 90/50 
7. QTc interval of >440 in males and > 460 in females as the combination of lofexidine plus methadone may 
increase the QTc interval.  For males with a QTc of greater than >440, but less than 470 AND absence of 
any history of CV disease AND absence of family history of CV death, they are eligible for enrollment. For 
females with a QTc of greater than >460, but less than 490 AND absence of any history of CV disease AND 
absence of family history of CV death, they are eligible for enrollment. 
8. Known allergy to lofexidine 
9. Unable to comply with study procedures or pose threat to study staff. 
 
b. Sources of Materials 
Research material obtained from individual participants includes questionnaires and interviews with study 
personnel, ambulatory assessment data, and blood, saliva and urine samples. To ensure confidentiality, all 
participant data will be letter/number coded, and only the investigators will have access to the master lists of 
codes. The research material will be obtained specifically for research purposes.  Written research material 
obtained will be stored in the Addiction Sciences Division or at Shoreline Behavioral Health, in an office that is 
locked when not in use. Saliva samples will be stored and processed in the Medical University of South Carolina 
Research Nexus Laboratory. MUSC staff at Shoreline will collect saliva samples, freeze and store them on site, 
and then send to MUSC for processing. 
 
c. Potential Risks 
1. Risks due to lofexidine:  A Cochrane review provides a comprehensive overview of adverse events associated 
with lofexidine and other alpha-adrenergic agents (Gowing et al., 2009).  Adverse events associated with 
lofexidine are primarily related to its alpha-adrenergic agonist effects.  Hypotension has been reported (Yu et al., 
2008; Gowing et al., 2009; Khan et al., 1997), but generally this was mild and studies comparing lofexidine with 
other alpha-agonists found that hypotension was seen less frequently with lofexidine.  Rebound increase in blood 
pressure after lofexidine discontinuation has also been reported (Yu et al., 2008), but was not severe enough to 
require intervention.   Sedation, dizziness and dry mouth have also been reported with lofexidine at higher rates 
than placebo, but lower when compared to other alpha-agonists (Khan et al., 1997; Gowing et al., 2009 ). A case 
report (Schmitter et al., 2004) and a dose escalation study (Schmitter et al., 2009) report QTc interval 
prolongation in individuals with lofexidine added to methadone, but there have been no reports of QTc 
prolongation with lofexidine monotherapy.    
 


V20 7.25.23 
2. Risks due to study procedures: Participants will be asked not to use illicit opioids for 7 days, however all will 
be stabilized on buprenorphine or methadone so there should be no risk of opioid withdrawal symptoms. 
 
3. Potential risks of rating scales and questionnaires: These are all non-invasive, should add no risk, and have 
been used without difficulty or any adverse events in our previous studies. The only minor inconvenience could 
be the time taken to complete them. Some participants may feel uncomfortable disclosing personal thoughts and 
feelings.  
 
4. Risks of stress induction procedures: There is a small risk of increased stress or opioid craving as a result of 
the CREMA procedures; however, it will likely not differ substantially from the reactivity elicited by stimuli 
commonly encountered in the day-to-day environment of study participants. Participants that report sustained 
significant stress or craving after the laboratory session will be provided a debriefing to address symptoms. 
 
5. Risks of loss of confidentiality: Careful efforts aimed at maintaining confidentiality have been effective in 
previous research, and only participants’ code numbers will be recorded on the forms themselves to protect 
confidentiality. Phones provided by study staff to participants will be password protected to limit access to study 
assessments and pictures; participants utilizing their own phones will be asked to password protect their device 
for the duration of the study.  
 
2. ADEQUACY OF PROTECTION AGAINSTS RISKS  
a. Recruitment and Informed Consent 
Potential study participants will primarily be recruited through local treatment settings. Medical records will not 
be reviewed to identify potential study participants.  The study PI, a Co-I, or other qualified study staff will obtain 
informed consent. The informed consent form includes a detailed description of the study procedures, along with 
statements regarding participants’ rights to withdraw from the procedure at any time without consequences. The 
informed consent form will be explained to participants in easy-to-understand language, and subjects will be 
instructed to read the form carefully prior to signing it.  Consent will be documented by the signature of the 
participant on the informed consent agreement, accompanied by the signature of the individual obtaining the 
consent. 
 
b. Protections Against Risks 
All study participants will be closely monitored for psychiatric and medical stability. All sessions will be conducted 
under the supervision of experienced personnel. If crisis intervention is necessary, senior staff will be available 
to evaluate the subject and provide an intervention or referral. If hospitalization is indicated, the patient will be 
hospitalized through the Center for Drug and Alcohol Programs at MUSC or an appropriate referral will be made. 
All participants will be fully informed that they may withdraw from the study at any time without penalty.  
 
Lofexidine will be titrated over ten days when it is initiated.  Participants will be seen by a medical provider on 
three times a week uring dosage escalation and orthostatic hypotension testing will be done.  The medical 
provider will inform the participant, verbally and with a hand-out to take home, concerning common side effects 
of lofexidine (dizziness, somnolence, dry mouth) and precautions to minimize risks associated with blood 
pressure decreases (hydration, standing up slowly). The target dose of lofexidine is 2.16 mg per day, but if 
hypotension or other troublesome side effects develop, the medical provider may slow the titration for that 
individual.  At the end of the study, medications will be tapered over a five-day period.  Participants will be seen 
every other day during medication taper and blood pressure will be monitored.   
 
To ensure confidentiality, all participant data will be coded by letters and/or numbers, and only the investigators 
will have access to the master lists of codes.  All participant records will be kept in a locked cabinet in an office 
that will be locked at times when not in use. Participants who screen remotely and have virtual medication 
monitoring visits will be instructed to find a private location to conduc these visits. The research staff understands 
the importance of maintaining confidentiality, and this method of maintaining confidentiality has been used for 
several years by our research group and has been effective. All electronic databases are stored on HIPAA-
compliant servers with restricted access. All co-investigators and study personnel have completed (or will 
complete upon hiring) training in Good Clinical Practices as mandated by NIH and the MUSC IRB. 
 
 


V20 7.25.23 
Participants will be taught about potential side effects of lofexidine, and will be closely followed by psychiatrists, 
a PharmD, and other members of the research team. Pregnancy tests will be performed prior to lofexidine 
administration. Adverse events will be monitored throughout the study. A member of the research staff will be 
available to discuss management of any craving urges if craving remains elevated at the end of any study 
procedures. 
 
3. DATA SAFETY AND MONITORING PLAN 
 This section is based on the recommendations in NIDA’s “Guidelines for Developing a Data and Safety 
Monitoring Plan” (www.drugabuse.gov/funding/dsmbsop.html). A detailed DSMP will be developed and 
approved by NIH program staff prior to study initiation.  
 
1. Summary of the Protocol.   
This application proposes to investigate the effects of lofexidine on stress-induced craving and relapse.  The 
primary outcome of interest is stress reactivity. Inclusion/exclusion criteria are outlined above.  Power 
calculations and sample sizes are in the Data Analysis Plan section above.  
 
2. Trial Management.   
The study will be managed from the Addiction Sciences Division within the Department of Psychiatry and 
Behavioral Sciences at the Medical University of South Carolina.  The target population is described above in 
the inclusion/exclusion criteria. 
 
3. Data Management and Analysis. 
Data will be entered by research assistants directly into a computer using standard database software using 
REDCap.  The data analysis plan is outlined in the Data Analysis Plan section.  
 
4. Quality Assurance. 
Quarterly data audits will be conducted.  Confidentiality protections are outlined above. 
 
5. Regulatory Issues. 
Potential conflicts of interest will be reported using the upcoming NIH rules for disclosure.  Adverse Events 
(AEs)/Serious Adverse Events (SAEs) occurring during the course of the project will be collected, documented, 
and reported in accordance with protocol and IRB reporting requirements.  All research staff involved with 
adverse event reporting will receive general and protocol specific AE/SAE training including identification, 
assessment and evaluation, and documentation and reporting.  A research assistant will identify any potential 
adverse events during the course of the study from participant self-report and administration of the visit 
assessments and procedures. The research assistant will provide information to a study physician, who will be 
responsible for AE/SAE assessment and evaluation including a determination of seriousness and study 
relatedness. Any significant actions taken by the local IRB and protocol changes will be relayed to ORWH/NIDA.   
 
6. Definition of AE and SAE. 
An Adverse Event (AE) is defined as any untoward medical occurrence in a study subject administered a 
pharmaceutical product that does not necessarily have a causal relationship with this treatment (ICH GCP).  Any 
unwanted change, physically, psychologically or behaviorally, that occurs in a study participant during the course 
of the trial is an adverse event.  A Serious Adverse Event (SAE) is defined as an adverse event that has one of 
the following outcomes: 
• 
Results in death, 
• 
Is life-threatening, 
• 
Requires inpatient hospitalization or prolongation of existing hospitalization, 
• 
Results in persistent or significant disability/incapacity, 
• 
Is a congenital anomaly/birth defect OR 
• 
Requires intervention to prevent one of the above outcomes. 
 
7. Documentation and Reporting. 


V20 7.25.23 
AEs/SAEs are documented and reported as per protocol and IRB requirements.  Research staff will identify 
adverse events and obtain all available information to assess severity, seriousness, study relatedness, 
expectedness, outcome and the need for change or discontinuation in the study intervention.  Adverse events 
are generally documented on AE Logs and AE Case Report Forms (CRFs).  Additional relevant AE information 
if available should be documented in a progress note in the research record as appropriate to allow monitoring 
and evaluating of the AE.  If the AE meets the definition for serious, appropriate SAE protocol specific reporting 
forms are completed and disseminated to the appropriate persons and within the designated timeframes as 
indicated above.  For each AE/SAE recorded, the research staff will follow the AE/SAE until resolution, 
stabilization or until the participant is no longer in the study as stated in the protocol. When a reportable SAE is 
identified, the research staff will notify the MUSC Institutional Review Board (IRB) within 24 hours and complete 
the AE report form in conjunction with the PI.  The MUSC IRB meets monthly and is located at 165 Cannon 
Street, Rm. 501, Charleston, SC  29425.  Communication with the IRB is through email, memos, official IRB 
forms, and online reporting. A report will also be sent to the NIH program officer assigned to the project. 
 
If complete information is not available when the initial 24-hour SAE report is disseminated, follow-up information 
will be gathered to enable a complete assessment and outcome of the event.  This information may include 
hospital discharge records, autopsy reports, clinic records, etc.  The research staff will attach copies of source 
documents to the SAE report for review by the PI and for forwarding to the NIH program officer as appropriate 
within 2 weeks of the initial SAE report.  In addition, the PI will provide a signed, dated SAE summary report, 
which will be sent to the ORWH/NIDA Medical Safety Officer within two weeks of the initial SAE report. 
 
We will report adverse events to the Medical University of South Carolina (MUSC) Institutional Review Board 
(IRB) online as soon as possible, but no later than 10 working days after the investigator first learns of the event.  
The MUSC IRB AE reporting requirements are as follows:  All deaths that occur during the study or 30 days post 
termination from the study are required to be reported as adverse events even if they are expected or unrelated.  
Other adverse events are reportable to the MUSC IRB if the AE is unexpected AND related or possibly related 
AND serious or more prevalent than expected.  All three criteria must be met for an AE to be reported to the 
MUSC IRB.  The IRB definition of unexpected is that the AE is not identified in nature, severity or frequency in 
the current protocol, informed consent, investigator brochure or with other current risk information.  The definition 
of related is that there is a reasonable possibility that the adverse event may have been caused by the drug, 
device or intervention.  Reportable AEs are reviewed by the IRB Chair and reported to the IRB Board at the next 
meeting. 
8. Trial Safety. 
The potential risks and benefits and methods to minimize these risks are outlined above. The research staff will 
report any unexpected AEs or any scores of “severe” on the side-effect symptom rating form or any FDA-defined 
serious AEs to the PI within 24 hrs so that the PI can decide on the appropriate action.  All unexpected AEs will 
be monitored while they are active to determine if treatment is needed.  Study procedures will follow the FDA’s 
Good Clinical Practice Guidelines (www.fda.gov/oc/gcp). Any outside requests for information or any breaches 
in confidentiality will be reported to Dr. Brady.  
 
9. Trial Efficacy. 
An interim analysis is not planned at this time; however, an analysis will be performed if requested by ORWH/ 
NIDA or the DSMB. 
 
10. DSM Plan Administration. 
Drs. Brady and Guille will be responsible for monitoring the study, and will participate in weekly study meetings. 
A DSM report will be filed with the IRB and ORWH/NIDA on a yearly basis, unless greater than expected 
problems occur.  The report will include participant characteristics, retention and disposition of study participants, 
quality assurance issues and reports of AEs, significant/unexpected AEs and serious AEs.  Outcomes will be 
reported at the end of the trial. 
 
11. DSM Board.   
A Data Safety and Monitoring Board will be formed to monitor both the rate and severity of adverse events.  This 
panel will include 3 clinicians with expertise in substance use disorders and a statistician.   


V20 7.25.23 
12.  Risk Benefit Ratio. 
The assessments and questionnaires are non-invasive and have inherently minimal risks.  Potential risks of 
concern are loss of confidentiality and adverse events to lofexidine and stress induction procedures. As 
discussed above, our research team will attempt to minimize these risks.  Knowledge gained by the proposed 
study would help fill an important void in development of a potential gender-specific treatment for opioid use 
disorders. 
 
 
. 
4. POTENTIAL BENEFITS OF THE PROPOSED RESEARCH TO THE SUBJECT AND OTHERS 
Possible risks to study participants include adverse reactions to lofexidine administration or stress 
induction procedures. Potential benefits include detailed assessment of substance use and referral for 
treatment. Participants in the lofexidine condition may experience a reduction in stress-related drug 
craving. The minimal risks are reasonable in relation to the potential benefits to be gained from the 
study. 
 
5. IMPORTANCE OF THE KNOWLEDGE TO BE GAINED 
This study may provide important information that can improve treatment for future patients with opioid and other 
drug use disorders. The moderate risks of the investigation are considered reasonable in relation to the expected 
knowledge to be gained.   
 
6. CLINICALTRIALS.GOV REQUIREMENTS 
In accordance with Public Law 110-85, this project will be registered at the ClinicalTrials.gov Protocol 
Registration System Information Website prior to study initiation. 
 
 
 
 


Page 1 of 12                                                                                                     Version Date 4.27.22 
IRB Number: Pro00081381 
Date Approved 5/2/2022 
Medical University of South Carolina 
 
CONSENT TO BE A RESEARCH SUBJECT 
 
Impact of lofexidine on stress, craving and opioid use 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
A. PURPOSE AND BACKGROUND: 
 
You are being asked to volunteer for a research study. The research is sponsored by the National Institute on Drug 
Abuse. The purpose of this study is to determine if the medication lofexidine, taken together with buprenorphine or 
methadone, is more effective at reducing opiate craving, use and stress response than buprenorphine or methadone 
alone, and to see if this effect is different for men and women. Lofexidine is FDA approved to treat opioid withdrawal. 
This study also involves a cue presentation app known as “CREMA” (Cue Reactivity Ecologic Momentary 
Assessment) which delivers pictures and surveys to you on an iPhone during your everyday routine (more information 
below). You are being asked to participate in this study because you are between the ages of 18 and 65, have opioid 
use disorder, and are currently prescribed buprenorphine or methadone. The investigators in charge of this study are 
Kathleen Brady, M.D., Ph.D., and Connie Guille, M.D. The study is being conducted at the MUSC Addiction Sciences 
Division and Shoreline Behavioral Health and will involve 136 volunteers. 
 
B. PROCEDURES: 
Screening: If you agree to be in this study, you will first be evaluated and the results of the evaluation must meet 
Concise Summary 
You are being asked to volunteer for a research study. Research studies are voluntary and include 
only people who choose to take part.  The purpose of this study is to see if the medication 
lofexidine, taken together with buprenorphine or methadone, is more effective at reducing opioid 
craving, opioid use and/or stress response compared to buprenorphine or methadone alone, We 
are also looking to see if these effects are different for men and women. Lofexidine is FDA 
approved to treat physical symptoms of opioid withdrawal. In this study, we are looking to see if 
it also reduces stress response, opioid craving and opioid use. 
 
Participants will complete a screening visit to determine study eligibility. During the first week, 
participants will be asked to abstain from opioid use other than buprenorphine or methadone. 
Participants will come to the clinic that week for urine drug testing. After 2 tests are negative, 
participants will be randomly assigned to take either lofexidine or placebo (inactive medication) 
two to three times a day for about 5 weeks. During this time, participants will upload videos of 
themselves taking their medication. They will come to the clinic 3 times a week for urine drug 
screens and to have their vital signs measured. They will also participate in “CREMA” sessions 
(Cue Reactivity Ecologic Momentary Assessment).  Twice a day these sessions will ask about 
substance use, craving and stress.  An additional session each day will include looking at stressful 
or neutral pictures and rating stress and craving.  At the end of five weeks, participants will return 
to the clinic on two consecutive days to participate in a stress task and an opioid related imagery 
task. For the next five days, participants will taper their medication dose. During this time they 
will continue to come to clinic to have their vital signs measured and complete a follow-up visit. 
 
There may be no direct benefit to you for participating in this study.  Study medication risks are 
detailed below; the most common side effects are low blood pressure, tiredness, dizziness and dry 
mouth. 
 
If you are interested in learning more about this study, please continue to read below. 
 
 


Page 2 of 12                                                                                                     Version Date 4.27.22 
IRB Number: Pro00081381 
Date Approved 5/2/2022 
entrance requirements. This first evaluation will include psychiatric interviews, an assessment of your alcohol and 
drug use, and a physical exam including an EKG. During the physical exam you will have blood drawn (about 2 
teaspoons) to assess your general health. You will also be asked to provide a urine sample to test for drugs of abuse. 
If you are female and of child-bearing potential, you will have a pregnancy test prior to urine drug screening. If you 
are pregnant, you will not be allowed to participate. You will be asked to fill out several forms dealing with how often 
and why you use opiates, your mood symptoms, pain, stressful events, and the impact Covid-19 has had in your life.  
Remote screening: The initial visit may also be done remotely. In that case, the consent will be emailed to you prior to 
the screening appointment. You will be asked to find a private location to have a video call with study staff. On the 
call, study staff will obtain informed consent and do the initial interview. You will also speak with study medical staff 
to review your medical history.  If you are eligible, you will be sent survey links to complete questionnaires. You will 
have an EKG and blood draw at your baseline visit. If you complete screening remotely, you will not provide urine 
for pregnancy and/or drug screening until the baseline visit. You may be asked to meet with medical staff for a physical 
exam if they think it is necessary based on your history. If you meet all entrance requirements, you will be trained on 
how to use CREMA on an iPhone.  If necessary, you will be scheduled to return to complete urine samples over the 
next week. Two consecutive urine samples must be negative for opioids other than buprenorphine or methadone in 
order to continue to the next phase of the study. 
 
CREMA: Cue Reactivity Ecologic Momentary Assessment (CREMA) is an app that allows you to complete study 
procedures without having to come in to the lab and provides information about your response to different types of 
cues in a real-world setting. You will complete three CREMA sessions a day during the study. In one session that will 
occur at the same time each day, you will be asked about substance use and stress over the previous 24 hours. One 
session will occur randomly and you will be asked about your current stress, craving and mood. During one session 
you will be shown either neutral pictures or stressful pictures and asked to rate levels of stress, craving, and mood.    
 
Medication phase: After completing the baseline week assessments and testing negative for opioids (other than 
buprenorphine or methadone) at two visits, you will receive study medication, either lofexidine or placebo (a capsule 
that does not contain any active medication). Neither you nor the study staff will know which medication you are 
taking as both lofexidine and placebo will be given as capsules identical in appearance. You will be randomly assigned 
to receive either lofexidine or placebo. This means that you have a 50/50 chance (like flipping a coin) of being in either 
group. Neither the researchers nor you will make the choice regarding your group assignment. The medication will be 
started at a low dose and increased according to the following schedule: 0.36 mg on the first two evenings, 0.36 mg in 
the morning and evening on days 3 and 4; 0.36 mg in the morning, afternoon, and at bedtime on days 5 and 6; 0.36 
mg in the morning and afternoon and 0.72 mg at bedtime on days 7 and 8; 0.36 mg in the morning and 0.72 mg in the 
afternoon and at bedtime on days 9 and 10, and 0.72 mg in the morning, afternoon and at bedtime on Day 11 and 
throughout the rest of the study.    
Days 
AM Dose (mg) 
Afternoon 
Dose (mg) 
PM Dose (mg 
Days 1 and 2 
 
 
0.36 (2 pills) 
Days 3 and 4 
0.36 (2 pills) 
 
0.36 (2 pills) 
Days 5 and 6 
0.36 (2 pills) 
0.36 (2 pills) 
0.36 (2 pills) 
Days 7 and 8 
0.36 (2 pills) 
0.36 (2 pills) 
0.72 (4 pills) 
Days 9 and 10 
0.36 (2 pills) 
0.72 (4 pills) 
0.72 (4 pills) 
Days 11-33 
0.72 (4 pills) 
0.72 (4 pills) 
0.72 (4 pills) 
 
You will be required to take your medication two times daily during titration, and three times daily for the remainder 
of the medication phase.  You are asked to take your medication each morning, afternoon, and evening. Doses must 
be 6 hours apart. To assist in monitoring your medication dosing the CREMA app will send you reminders with a link 
to upload a video of yourself taking the medication.  You will be trained on how to do this 


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IRB Number: Pro00081381 
Date Approved 5/2/2022 
at your randomization visit.  If you do not have an iPhone or do not wish to use your own, we will provide one to you 
for the duration of the study. Study phones will be de-activated at the end of the study, and lost or stolen phones will 
be reported to the federal funding agency.  
You will have study visits three times a week for five weeks.  At these visits, your blood pressure and pulse will be 
measured, and your urine will be tested for drugs of abuse. At one of these visits, you will have an interview with a 
staff member to discuss a time you were craving opioids. At Weeks 4 and 6 you will have an EKG performed. 
Remote monitoring: If it is necessary to limit clinic visits, medication monitoring may be done remotely.  For remote 
monitoring, you will have one clinic visit a week and two virtual visits. At your first medication visit, you will 
receive a blood pressure cuff that fits on your wrist and you will be trained on how to measure orthostatic blood 
pressure. This process involves lying down for 3-5 minutes, then taking your blood pressure. Next you will sit up for 
30 seconds, then stand up and measure your blood pressure again. You will have video calls with staff twice a week 
to complete these procedures. Once you are on a stable dose, you will only need to do regular blood pressure checks 
on these calls. You will also be provided with saliva drug screens that can be done at home, and you will do these on 
the video calls as well. The saliva drug screen involves collecting saliva with a swab kit that will be provided to you.  
Stress task: After five weeks of study medication, you will return to the clinic on two consecutive days to complete a 
stress task and an opioid imagery task. You will be asked to arrive at 8:00 am each day and to avoid caffeinated 
beverages. If you smoke cigarettes, you may be provided with a nicotine patch. Your urine will be tested for drugs of 
abuse. If you are female, you will provide a saliva sample so we can measure your hormone levels, and your urine 
will be tested for pregnancy prior to your drug screen. Approximately thirty minutes after you arrive, a blood 
pressure cuff will be placed on your arm. Throughout the procedures, you will provide saliva samples for hormone 
measurement, rate your mood and level of opiate craving, and your heart rate and blood pressure will be measured. 
Stress task: You will complete a progressive relaxation task, and then you will be asked to deliver a speech and 
perform a math problem out loud in front of a group of strangers.   
 Opioid imagery task: You will complete a progressive relaxation task, and then you will listen to a recording based 
on your interview about craving opioids. 
You will be randomly assigned to complete either the stress or opioid imagery task first. 
Medication taper and follow-up: After the second visit, you will reduce your study medication dose over the next 
week. You will be asked to come into the clinic after each dose reduction to have your blood pressure and pulse 
measured. This will total two visits. After your final dose reduction, you will come to the clinic to provide a urine 
drug screen, have vital signs collected, and complete surveys about the study and a questionnaire about pain. 
Participation in this study is totally voluntary, and you may choose not to participate. You may also withdraw your 
consent and discontinue participation at any time. Discontinuation will in no way jeopardize your ability to receive 
treatment at this Institution now or in the future. You may be withdrawn from the study without your consent if the 
researchers believe it is in your best interest. 
 
C. DURATION: 
Participation in this study involves up to 23 visits over a period of approximately two months. The initial screening 
visit will take about 3 hours and the CREMA training visit will take about 30 minutes.  The weekly visits, medication 
tapering visits and follow-up visits will take approximately 30 minutes. The visit with the opioid interview will take 


Page 4 of 12                                                                                                     Version Date 4.27.22 
IRB Number: Pro00081381 
Date Approved 5/2/2022 
about an hour and a half. The stress/imagery visits will take approximately 3 hours.   You will spend approximately 
20 minutes a day completing the CREMA sessions at home. 
 
D. RISKS/DISCOMFORTS: 
Participation in this study may involve risks. 
 
Medication: Side effects that were reported by more than 10% of patients treated with lofexidine, and more often than 
placebo, include trouble sleeping, low blood pressure when standing up, slow heart rate, low blood pressure, dizziness, 
drowsiness, sedation and dry mouth.  Rebound high blood pressure has also been observed when people abruptly stop 
taking lofexidine, however your dose will be tapered off gradually to prevent this increase, and your blood pressure 
and pulse will be monitored regularly throughout the study.  
 
Opioid abstinence: You will be asked to abstain from opioids other than buprenorphine or methadone for 7 days, 
however 
you 
should 
not 
experience 
withdrawal 
symptoms 
since 
you 
are already stabilized 
on 
buprenorphine/methadone. 
 
Treatment assignment: You will be assigned to treatment by chance. The treatment you receive may prove to be less 
effective or to have more side effects than the other study treatment or other available treatment. You may be in the 
group that receives placebo and does not receive active medication. 
 
Stress task: Participation in the speech and math task may cause some anxiety and feelings of stress. Some of the 
CREMA sessions may also cause anxiety, but should be no more stressful than events encountered in everyday life.  
 
Scripted opioid imagery: The interview and scripted imagery task may produce some craving for opioids or other 
discomfort. However, this discomfort is usually brief and you will be in the safety of an opioid-free laboratory 
environment. A member of the research team will be available to discuss your cravings with you prior to leaving the 
research facility. 
 
Blood draw: The risks of drawing blood include temporary discomfort from the needle stick, bruising, and infection. 
Fainting could occur. 
 
Interviews: The interviews and questionnaires that you will receive during the course of the study involve no specific 
risks or discomforts beyond those of a standard clinical interview situation, such as feeling upset at the review of your 
psychiatric status, boredom, or fatigue. If a question makes you feel uncomfortable you may refuse to answer it. 
 
Urine drug screening: If you are a female of childbearing potential, you will receive a pregnancy test, and if pregnant, 
you will not be allowed to participate in the study. If you are capable of becoming pregnant, you must be using a 
medically approved method of birth control (such as contraceptive pills, diaphragms, or other forms of barrier 
contraceptives) and you must continue to do so during the course of the study. Should you become pregnant during 
the study you must immediately contact your study doctor and discontinue treatment since the risk to your baby due 
to lofexidine is unknown. 
 
Your urine will be screened for the presence of opioids and other potentially abused or illegal drugs. These results will 
not be part of your medical record but will be kept in research records maintained by the investigator. Every effort will 
be made to protect the confidential nature of this information. However, there may be circumstances under which the 
investigator may release this information. If you are pregnant or become pregnant and test positive for illegal drugs, 
the SC Department of Social Services (DSS) may be notified. You could be at risk of going to jail or losing custody 
of your children. 


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Unknown Risks: The experimental treatments may have unknown side effects. The researchers will let you know if 
they learn anything that might make you change your mind about participating in the study. 
 
Confidentiality: There is a risk of a loss of confidentiality as a result of participation in this study. Information about 
you, as well as your image will be kept in password-protected databases and computers and will only be accessible 
by the principal investigator and the research staff. Video clips will only be viewed by approved research staff. 
Those video clips will be deleted when the study has ended and data analysis is complete. In order to ensure 
confidentiality, all participant information (questionnaires and identifying information) will be identified only by 
your initials and/or a code number and kept under lock and key and in password-protected databases.  
 
E. MEDICAL RECORDS AND CERTIFICATE OF CONFIDENTIALITY:  
This research is covered by a Certificate of Confidentiality from the Federal government. This means that the 
researchers may not disclose information or biospecimens that may identify you, even by a court subpoena, in any 
federal, state, or local civil, criminal, administrative, legislative, or other proceedings, nor can the information or 
biospecimens be used as evidence, unless you have consented to this disclosure. Information or biospecimens 
protected by this Certificate cannot be disclosed to anyone else who is not connected with the research except if you 
have consented to the disclosure, including for your medical treatment; or if it is used for other scientific research, as 
allowed by federal regulations protecting research subjects. 
 
A Certificate of Confidentiality does not prevent you from voluntarily releasing information about yourself or your 
involvement in this research. If you are an MUSC patient you have an MUSC medical record. If you have never 
been an MUSC patient, a MUSC medical record will be created for the purposes of this study. All information 
within your medical record can be viewed by individuals authorized to access the record. We will make every effort 
to keep confidential all research information in the medical record that identify you to the extent allowed by law; 
however, there is the possibility that your research information will be disclosed. 
 
The Certificate of Confidentiality will not be used to prevent disclosure as required by federal, state, or local law. 
Examples of required disclosure include: child abuse and neglect, or harm to self or others 
Finally, a Certificate may not be used to withhold information from the Federal government needed for auditing or 
evaluating Federally funded projects or information needed by the FDA. 
 
 
F. BENEFITS: 
You may receive a medication that may be effective in reducing your opioid use. Of course, this cannot be guaranteed 
or promised, and you may experience no direct benefit. The results of this study may also benefit other patients who 
might later be treated with the same medicine.  
 
G. COSTS: 
If you choose to use your own smartphone to upload your daily medication videos, any cellular data and usage 
rates assessed by your carrier will apply. 
 
H. PAYMENT TO PARTICIPANTS: 
In return for your time and effort, you will receive $40 for completing the screening visit ($20 for the interview and 
$20 for the physical), plus an additional $20 for completing the visit the first time you’re scheduled. You will receive 
a $25 bonus for attending the baseline visit as scheduled. You will receive $20 for downloading the app and being 
trained on CREMA, $50 for the opioid imagery visit, $50 for the stress task visit, a $50 bonus for completing both 
visits as scheduled, and $100 for the follow-up visit. During the week of baseline, you will receive $30 for negative 


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urine drug screens ($10 for the first and $20 for the second). You will receive $10 for each day that you complete all 
CREMA sessions.  During the medication phase, you will receive $10 for each day you complete all medication video 
uploads. You may earn up to $364 for completing study visits during the medication phase (schedule below). You will 
receive $10 for each blood pressure check during the medication tapering phase for a total of $20. The total possible 
compensation for study visits is $769. The completing CREMA sessions will depend on how many days are completed. 
Payments will be made using a pre-paid debit card called a ClinCard. It works like a bank debit card and you may use 
the card to purchase goods or services everywhere Debit MasterCard is accepted. You will be given a ClinCard at the 
beginning of the study.  Each time you receive payment for participation in this study, the money will be added to the 
card, as outlined in the payment schedule below.  Details of the debit card system are explained on an additional sheet. 
If you screen remotely and are not eligible, a ClinCard will be mailed to you. 
Study Visits 
Screening 
$40 
Screening attendance bonus 
$20  
Crema training  
$20 
Baseline attendance bonus 
$25 
Baseline week urine drug screens (Days 1-7) 
$10 + $20 = $30 
Scripted Imagery/TSST(Day 39) 
$50 
Stress task visit /Scripted Imagery (Day 40) 
$50 
Task completion bonus 
$50 
Tapering blood pressure checks 
$10 x 2 = $20 
Follow-up 
$100 
Total 
$405 
 
Weekly Medication Visits 
Week 1- Visits 1, 2 and 3 
$4 + $8 + $12 = $24 
Week 2 – Visits 4, 5, and 6 
$16 + $20 + $24 = $60 
Week 3- Visits 7,8, and 9 
$28 + $32 + $36 = $96 
Week 4- Visits 10, 11 and 12 
$40 + $44 + $48 = $132 
Week 5- Visit 13 
$52  
Total 
$364 
 
At - home tasks 
Crema sessions 
$10 per day  
Medication videos 
$10 per day 
 
 
Payments that you receive from MUSC for participating in a research study are considered taxable income per IRS 
regulations.  Payment types may include, but are not limited to: checks, cash, gift certificates/cards, personal property, 
and other items of value.  If the total amount of payment you receive from MUSC reaches or exceeds $600.00 in a 
calendar year, you will be issued a Form 1099. 
 
I. RECRUITMENT OF SUBJECTS: 
You are invited to participate in the recruitment of other subjects for this study. If you choose to participate, we 
will provide you with coupons that you may give to other people (e.g., peers, acquaintances) who you think would 
be eligible and interested in this study. You may choose to tell people to whom you give these coupons to call the 
study office if they are interested in participating in the study. These individuals will not be identified unless they 


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contact the study office themselves. If any of your coupons result in successful study recruitment, you will receive 
$20 for each one. Participation in the recruitment process is completely voluntary, and if you elect not to 
participate your participation in this study will not be affected in any way. 
 
J. ALTERNATIVES: 
There are alternative treatments for opioid use. These include special counseling and other  
therapies (such as twelve step groups and classes on relapse prevention) aimed at decreasing  
drug use. You may also choose not to participate. 
 
K. DATA SHARING: 
Information about you (including your identifiable private information and/or any identifiable biospecimens) may have 
all of your identifiers removed and used for future research studies or distributed to other researchers for future research 
without additional informed consent from you or your legally authorized representative. 
 
L. DISCLOSURE OF RESULTS: 
Results of the research will not be shared with you. However, any clinically relevant information that is discovered 
will be discussed with you. 
 
M. AUTHORIZATION TO USE AND DISCLOSE (RELEASE) MEDICAL INFORMATION: 
As part of this research study, your study doctor and his/her research team will keep records of your participation in 
this study. The health information MUSC may use or disclose (release) for this research study includes information in 
your medical record, results of physical exams, medical history, lab tests or certain health information indicating or 
relating to your condition.  
 
Your study doctor and his/her research team will use and disclose (release) your health information to conduct this 
study. The health information listed above may be used by and/or disclosed (released) to the following, as applicable: 
 
• The sponsor of the study including its agents such as data repositories or contract research 
organizations monitoring the study; 
• Other institutions and investigators participating in the study; 
• Other investigators in the Addiction Science Division conducting similar research; 
• Shoreline staff; 
• Pitt St. Pharmacy pharmacists and technicians; 
• Data Safety Monitoring Boards; 
• Accrediting agencies; 
• Clinical staff not involved in the study whom may become involved if it is relevant; 
• Parents of minor children if less than 16 years old.  Parents of children 16 years old or older require 
authorization from the child; or 
• Health insurer or payer in order to secure payment for covered treatment; 
• Federal and state agencies and MUSC committees having authority over the study such as: 
 
• The Institutional Review Board (IRB) overseeing this study; Committees with quality 
improvement responsibilities; Office of Human Research Protections; Food and Drug 


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Administration;  National Institutes of Health or Other governmental offices, such as a 
public health agency or as required by law. 
 
Those persons who receive your health information may not be required by Federal privacy laws (such as the Privacy 
Rule) to protect it and may share your information with others without your permission, if permitted by laws governing 
them.   You do not have to sign this consent form.  If you choose not to sign, it will not affect your treatment, payment 
or enrollment in any health plan or affect your eligibility for benefits.  However, you will not be allowed to be a 
participant in this research study. 
 
You will be given a copy of this consent form.  Your authorization will expire at the conclusion of this study or, if you 
are participating in a study designed for the development of a drug or device, your authorization will remain in effect 
until the drug or device is approved by the FDA or until the company’s application to study the drug/device is 
withdrawn.   You have the right to withdraw your agreement at any time.  You can do this by giving written notice to 
your study doctor.  If you withdraw your agreement, you will not be allowed to continue participation in this research 
study.  However, the information that has already been collected will still be used and released as described above.  
You have the right to review your health information that is created during your participation in this study.  After the 
study is completed, you may request this information. 
 
Your health information will be used or disclosed when required by law.  Your health information may be shared with 
a public health authority that is authorized by law to collect or receive such information for the purpose of preventing 
or controlling disease, injury or disability and for conducting public health surveillance, investigations or interventions.  
No publication or public presentation about the research study will reveal your identity without another signed 
authorization from you.   
 
If you have questions or concerns about this Authorization or your privacy rights, please contact MUSC’s Privacy 
Officer at (843) 792-8740.   
 
Regulations require that you be given a copy of the MUSC Notice of Privacy Practices (NPP) describing the practices 
of MUSC regarding your health information. One can be found at the end of this form. 
 
N. FUTURE CONTACT: The researcher in charge of this study might like to contact you in the future about other 
research opportunities. Please initial by your choice below for paper consents,or scroll down to the bottom of the 
screen and select your choice electronically. 
 
____Yes, I agree to be contacted 
 
_____No, I do not agree to be contacted 
 
O. SIGNIFICANT NEW FINDINGS: If there are significant new finding during the course of the study, you will 
be notified. 
 
P. CLINCIALTRIALS.GOV A description of this clinical trial will be available on http://www.ClinicalTrials.gov, 
as required by U.S. Law. This Web site will not include information that can identify you. At most, the Web site will 
include a summary of the results. You can search this Web site at any time. 
 
Results of this research will be used for the purposes described in this study. This information may be published, but 
you will not be identified. Information that is obtained concerning this research that can be identified with you will 


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remain confidential to the extent possible within State and Federal law. The sponsor and the Food and Drug 
Administration (FDA) will receive copies of the research records. The investigators associated with this study, 
employees of the sponsor, the FDA, and the MUSC Institutional Review Board for Human Research will have access 
to identifying information. All records in South Carolina are subject to subpoena by a court of law. 
 
In the event of a study related injury, you should immediately go to the emergency room of the Medical University 
Hospital, or in case of an emergency go to the nearest hospital, and tell the physician on call that you are in a research 
study. They will call your study doctor who will make arrangements for your treatment. If the study sponsor does not 
pay for your treatment, the Medical University Hospital and the physicians who render treatment to you will bill your 
insurance company. If your insurance company denies coverage or insurance is not available, you will be responsible 
for payment for all services rendered to you. 
 
Your participation in this study is voluntary. You may refuse to take part in or stop taking part in this study at any 
time. You should call the investigator in charge of this study if you decide to do this. The data collected on you to this 
point remains part of the study database and may not be removed. Your decision not to take part in the study will not 
affect your current or future medical care or any benefits to which you are entitled. 
 
The investigators and/or the sponsor may stop your participation in this study at any time if they decide it is in your 
best interest. They may also do this if you do not follow the investigator’s instructions. 
 
 
 
 
Volunteers Statement 
I have been given a chance to ask questions about this research study. These questions have been answered to my 
satisfaction. If I have any more questions about my participation in this study or study related injury, I may contact 
Dr. Brady at (843) 792-5205 or Dr. Connie Guille at (843) 792-6489. I may contact the Medical University of SC 
Patient and Family Care Liaison (843) 792-5555 concerning medical treatment. 
If I have any questions, problems, or concerns, desire further information or wish to offer input, I may contact the 
Medical University of SC Institutional Review Board for Human Research IRB  
Manager or the Office of Research Integrity Director at (843) 792-4148. This includes any questions about my rights 
as a research subject in this study. 
I agree to participate in this study. I have been given a copy of this form for my own records.  Please sign below for 
paper consents or scroll to the bottom of the screen to provide an electronic signature. 
 
 
 
 
___________________________________         ___________________________      
Signature of Person Obtaining Consent 
      Date 
 
 
                                                                                    _______________________________    
  
 
Signature of Participant                              Date         *Name of Participant 
 
 


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Date Approved 5/2/2022 
 
 
 
 
NOTICE OF PRIVACY PRACTICES 
MUSC Organized Health Care Arrangement (OHCA) 
 
 
 
 
THIS NOTICE DESCRIBES HOW MEDICAL INFORMATION ABOUT YOU MAY BE USED AND DISCLOSED AND HOW YOU 
CAN GET ACCESSS TO THIS INFORMATION. PLEASE REVIEW IT CAREFULLY. 
The Medical University of South Carolina and its affiliates (including but not limited to the Medical University Hospital Authority, MUSC 
Physicians, MUSC Physicians Primary Care, MUSC Health Partners, MUSC Health Alliance, MUSC Strategic Ventures, LLC, and MUSC Strategic 
Ventures (MSV) Health, Inc.) participate in a clinically integrated health care setting. As a result of this clinical integration, these organizations 
function as an Organized Health Care Arrangement (OHCA) as defined by the Health Insurance Portability and Accountability Act (HIPAA). For 
purposes of this notice, the members of the MUSC OHCA are collectively referred to in this document as “MUSC.” We collect, receive, or share 
this information about your past, present or future health condition to provide health care to you, to receive payment for this health care, or 
to operate the hospital and/or clinics.  
OUR PLEDGE REGARDING YOUR HEALTH INFORMATION  
MUSC is committed to protecting the privacy of health information we create and obtain about you. This Notice tells you about the ways in which 
we may use and disclose health information about you. It also describes your rights and certain obligations we have regarding the use and disclosure 
of your health information. We are required by law to: (i) make sure your health information is protected; (ii) give you this Notice describing our 
legal duties and privacy practices with respect to your health information; and (iii) follow the terms of the Notice that is currently in effect.  
HOW WE MAY USE AND RELEASE YOUR PROTECTED HEALTH INFORMATION (PHI) –  
A. The following uses do NOT require your authorization, except where required by SC law:  
1. For treatment. Your PHI may be discussed by caregivers to determine your plan of care. For example, the physicians, nurses, medical students 
and other health care personnel may share PHI in order to coordinate the services you may need.  
2. To obtain payment. We may use and disclose PHI to obtain payment for our services from you, an insurance company or a third party. For 
example, we may use the information to send a claim to your insurance company.  
3. For health care operations. We may use and disclose PHI for hospital and/or clinic operations. For example, we may use the information to 
review our treatment and services and to evaluate the performance of our staff in caring for you.  
4. Business Associates. Your medical information could be disclosed to people or companies outside our Health System who provide services. These 
companies typically are required to sign special confidentiality agreements before accessing your information. They are also subject to fines by the 
federal government if they use/disclosure your information in a way that is not allowed by law.  
5. For public health activities. We report to public health authorities, as required by law, information regarding births, deaths, various diseases, 
reactions to medications and medical products.  
6. Victims of abuse, neglect, domestic violence. Your PHI may be released, as required by law, to the South Carolina Department of Social Services 
when cases of abuse and neglect are suspected.  
7. Health oversight activities. We will release information for federal or state audits, civil, administrative or criminal investigations, inspections, 
licensure or disciplinary actions, as required by law.  
8. Judicial and administrative proceedings. Your PHI may be released in response to a subpoena or court order.  
9. Law enforcement or national security purposes. Your PHI may be released as part of an investigation by law enforcement or for continuum of 
care when in the custody of law enforcement.  
10. Military and Veterans. If you are a member of the U.S. or foreign armed forces, we may release your medical information as required by 
military command authorities.  
11. Uses and disclosures about patients who have died. We may provide medical information to coroners, medical examiners and funeral directors 
so they may carry out their duties.  
12. For purposes of organ donation. As required by law, we will notify organ procurement organizations to assist them in organ, eye or tissue 
donation and transplants.  
13. Research. We may use and disclosure your medical information for research purposes. Most research projects are subject to Institutional Review 
Board (IRB) approval. The law allows some research to be done using your medical information without requiring your written approval.  
14. To avoid harm. In order to avoid a serious threat to the health or safety of a person or the public, we may release limited information to law 
enforcement personnel or persons able to prevent or lessen such harm.  
THIS NOTICE DESCRIBES HOW MEDICAL INFORMATION ABOUT YOU MAY BE USED AND 
DISCLOSED AND HOW YOU CAN GET ACCESSS TO THIS INFORMATION.  PLEASE REVIEW 
IT CAREFULLY.


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15. For workers compensation purposes. We may release your PHI to comply with workers compensation laws.  
16. Marketing. We may send you information on the latest treatment, support groups, reunions, and other resources affecting your health.  
17. Fundraising activities. We may use your PHI to communicate with you to raise funds to support health care services and educational programs 
we provide to the community. You have the right to opt out of receiving fundraising communications with each solicitation.  
18. Appointment reminders and health-related benefits and services. We may contact you with a reminder that you have an appointment.  
19. Disaster Relief Efforts. We may disclose your medical information to an entity assisting in disaster relief efforts so that your family can be 
notified about your condition.  
Note: incidental uses and disclosures of PHI sometimes occur and are not considered to be a violation of your rights. Incidental uses or 
disclosures are by-products of otherwise permitted uses or disclosures which are limited in nature and cannot be reasonably prevented.  
B. You may object to the following uses of PHI:  
1. Inpatient hospital directories. Unless you tell us not to, we may include your name, location, general condition and religious affiliation in our 
patient directory so your family, friends and clergy can visit you and know how you are doing. 2. Information shared with family, friends or 
others. Unless you tell us not to, we may release your PHI to a family member, friend, or other person involved with your care or the payment for 
your care.  
3. Health plan. You have the right to request that we not disclose certain PHI to your health plan for health services or items when you pay for those 
services or items in full.  
C. Your prior written authorization is required (to release your PHI) in the following situations:  
You may revoke your authorization by submitting a written notice to the privacy contact identified below. If we have a written authorization to 
release your PHI, it may occur before we receive your revocation.  
1. Any uses or disclosures beyond treatment, payment or healthcare operations and not specified in parts A & B above.  
2. Mental Health Records unless permitted under an exception in section A.  
3. Substance Use Disorder Treatment records unless permitted under an exception in section A.  
4. Any circumstance where we seek to sell your information.  
WHAT RIGHTS YOU HAVE REGARDING YOUR PHI  
Although your health record is the physical property of MUSC, the information belongs to you, and you have the following rights with respect to 
your PHI:  
A. The Right to Request Limits on How We Use and Release Your PHI. You have the right to ask that we limit how we use and release your PHI. 
We will consider your request, but we are not always legally required to accept it. If we accept your request, we will put any limits in writing and 
abide by them except in emergency situations. Your request must be in writing and state (1) the information you want to limit; (2) whether you want 
to limit our use, disclosure or both; (3) to whom you want the limits to apply, for example, disclosures to your spouse; and (4) an expiration date.  
B. The Right to Choose How We Communicate PHI with You. You have the right to request that we communicate with you about PHI and/or 
appointment reminders in a certain way or at a certain location (for example, sending information to your work address rather than your home 
address). You must make your request in writing and specify how and where you wish to be contacted. We will accommodate reasonable requests.  
C. The Right to See and Get Copies of Your PHI. You have the right to inspect and/or receive a copy (an electronic or paper copy) of your medical 
and billing records or any other of our records used to make decisions about your care. You must submit your request in writing. If you request a 
copy of this information, we may charge a cost-based fee. MUSC will act on a request for access or provide a copy usually within 30 days of receipt 
of the request. We may deny your request in limited circumstances. If you are denied access to your records, you may request that the denial be 
reviewed by a licensed health care professional. Additionally, we may use and disclose information through our secure patient portal which may 
allow you to view and communicate with certain health care providers in a secure manner. For more information see our 
https://mychart.musc.edu/mychart/  
D. The Right to Get a List of Instances of When and to Whom We Have Disclosed Your PHI. This list may not include uses such as those made 
for treatment, payment, or health care operations, directly to you, to your family, or in our facility directory as described above in this Notice of 
Privacy Practices. This list also may not include uses for which a signed authorization has been received or disclosures made more than six years 
prior to the date of your request.  
E. The Right to Amend Your PHI. If you believe there is a mistake in your PHI or that a piece of important information is missing, you have the 
right to request that we amend the existing information or add the missing information. You must provide the request and your reason for the request 
in writing. We may deny your request in writing if the PHI is correct and complete or if it originated in another facility’s record. Notification will be 
provided within 60 days.  
F. The Right to Receive a Paper or Electronic Copy of This Notice: You may ask us to give you a copy of this Notice at any time. For the above 
requests (and to receive forms) please contact: Health Information Services (Medical Records), Attention: Release of Information / 169 Ashley 
Avenue / MSC 349 / Charleston, SC 29425. The phone number is (843) 792-3881.  
G. The Right to Revoke an Authorization. If you choose to sign an authorization to release your PHI, you can later revoke that authorization in 
writing. This revocation will stop any future release of your health information except as allowed or required by law.  
H. The Right to be Notified of a Breach. If there is a breach of your unsecured PHI, we will notify you of the breach in writing.  
HEALTH INFORMATION EXCHANGES  
MUSC, along with other health care providers, belongs to health information exchanges. These information exchanges are used in the diagnosis and 
treatment of patients. As a member of these exchanges, MUSC shares certain patient health information with other health care providers. Should you 
require treatment at another location that is a part of one of these exchanges, that provider may gather historical health information to assist with your 
treatment. You have the option of saying that this cannot be done. If you choose not to take part in these alliances, please contact the MUSC Privacy 
Office at 792-4037.  
HOW TO COMPLAIN ABOUT OUR PRIVACY PRACTICES  


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If you think your privacy rights may have been violated, or you disagree with a decision we made about access to your PHI, you may file a complaint 
with the office listed in the next section of this Notice. Please be assured that you will not be penalized and there will be no retaliation for 
voicing a concern or filing a complaint. We are committed to the delivery of quality health care in a confidential and private environment.  
PERSON TO CONTACT FOR INFORMATION ABOUT THIS NOTICE OR TO COMPLAIN ABOUT OUR PRIVACY PRACTICES  
If you have any questions about this Notice or any complaints about our privacy practices please call the Privacy Officer (843) 792-4037, the Privacy 
Hotline (800) 296-0269, or contact in writing: HIPAA Privacy Officer / 169 Ashley Avenue / MSC 332 / Charleston SC 29425. You also may send a 
written complaint to the U.S. Dept. of Health and Human Services, Office for Civil Rights. The address will be provided at your request or by 
visiting www.hhs.gov/ocr/privacy/hipaa/complaints/.  
CHANGES TO THIS NOTICE  
We reserve the right to change the terms of this Notice at any time. The changes will apply to all existing PHI we have about you.. This Notice will 
always contain the effective date and may be reviewed at http://academicdepartments.musc.edu/musc/about/compliance/privacy.html  
EFFECTIVE DATE OF THIS NOTICE  
This Notice went into effect on April 14, 2003 and was last revised on August 2018.