Clinical trial NCT02941692
Conditions: Substance Misuse Interpersonal Conflict Neuroendocrine Reactivity
Sponsor: Medical University of South Carolina
Start date: 2014-06-01; Completion date: 2017-03-01
Enrollment: 66 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
Oxytocin is a promising new medication found to have positive effects on prosocial behavior, reduce negative affect such as fear and anxiety, and reduce stress-induced addictive behaviors. This study aims to investigate the extent to which a 40 IU dose of intranasal oxytocin improves couples' conflict resolution skills and subjective, physiological, and neuroendocrine responses to conflict. Conflict resolution discussions will take place in the laboratory and will be videotaped.

Detailed description:
Substance use disorders (SUD) are characterized by dysregulation of the hypothalamic-pituitary axis (HPA). The neuropeptide oxytocin, commonly administered as an intranasal spray, is a drug that has prominent anxiolytic and prosocial effects on human behaviors. While the mechanisms of action facilitating the behavioral effects of oxytocin in humans is complex and many questions about this process remain, there is a consensus in the existing literature that oxytocin modulates HPA axis reactivity to stressful social stimuli. Preliminary studies suggest that oxytocin is known to reduce couple conflict among normative couples. A more developed line of research indicates that oxytocin mitigates addictive behaviors in the context of various drugs of abuse. Given the high prevalence and severity of dyadic conflict among couples where one or both partner has substance abuse, and given the salience of dyadic conflict as a precipitant to substance use behaviors, it is critical to investigate the therapeutic effects of oxytocin among couples with substance use problems. Namely, oxytocin holds promise as a potential augmenter for conjoint couples therapies, particularly those targeting the reduction of substance use problems. However, only two studies have examined the effects of oxytocin on couples' communication behaviors. Those two studies found that couples' communication skills improved following the administration of oxytocin. It is important to extend this line of research to examine conflict resolution skills among couples with substance use problems. To date, no studies have examined the effects of oxytocin on subjective, physiological, or neuroendocrine reactivity to dyadic conflict. The present study aims to fill that gap in the literature.

Arms: arm 1: Participants randomized to this condition will receive 40 IU dose of intranasal oxytocin. arm 2: Participants randomized to this condition will receive a matching dose of intranasal saline spray as placebo.
Interventions: intervention 1: Oxytocin intervention 2: Placebo
Intervention descriptions: intervention 1: None intervention 2: Placebo for Oxytocin

Protocol documents:
Prot_SAP_000.pdf: 
 
 
Flanagan, Julianne C. v.7/23/15 
1 
 
 
 
 
 
 
PI Name:  Julianne C. Flanagan, Ph.D. 
 
Study Title:   The Effects of Oxytocin on Couples’ Conflict-Resolution Interactions  
 
TABLE OF CONTENTS  
 
1. Specific Aims 
2. Background and Significance 
3. Preliminary Studies 
4. Research Design and Methods 
5. Protection of Human Subjects 
6. References/Literature citations 
 
 
1. SPECIFIC AIMS_________________________________________________________________ 
 
Dyadic conflict is highly prevalent among individuals with substance use disorders. Dyadic 
conflict is known to precipitate and exacerbate negative health correlates such as addiction, 
depression, PTSD, and intimate partner violence. Most notably, dyadic conflict is a salient proximal 
trigger for substance use behaviors and substance use problems. Researchers have demonstrated that 
behavioral interventions for couples yield positive mental health and substance abuse outcomes. 
Indeed, conjoint couples therapies are increasingly becoming known for their capacity to effectively 
treat addiction (1, 2). However, an important limitation remains in the literature on couples therapy 
interventions. Whereas the augmenting effects of numerous pharmacological agents have been 
investigated in the context of individual behavioral interventions, and the existing literature 
overwhelmingly demonstrates that the most positive mental health outcomes are derived from the use 
of both pharmacological and behavioral interventions concurrently, studies investigating 
pharmacological augmenters for couples interventions are scant.  
Oxytocin is a neuropeptide known to have prominent anxiolytic and prosocial effects. Among 
both animals and humans, oxytocin is known to mitigate the effects of social stress on addictive 
behaviors. Among normative couples, preliminary data suggests that oxytocin promotes more positive 
conflict resolution skills. Taken together, this literature suggests that oxytocin holds promise as a tool to 
modulate the effects of dyadic conflict on addictive behaviors. If evidence supporting this notion 
emerged, these data would support the investigation of oxytocin as a potential augmenter to couples 
therapies for substance abuse problems. However, the first step toward evaluating oxytocin in this role, 
and the primary objective of the proposed study, is to examine the extent to which oxytocin improves 
conflict resolution skills among couples with substance abuse. Our secondary objective is to examine 
the extent to which oxytocin mitigates couples’ subjective, physiological, and neuroendocrine reactivity 
to dyadic conflict. Thirty-six couples (n=72) consisting of at least one partner with recent substance 
abuse will participate in the study. The study will consist of one 4-hour laboratory visit. Couples will 
complete a thorough psychosocial assessment interview and two 10-minute videotaped conflict 
resolution tasks using a well-established paradigm. Participants will be randomly assigned to self-
administer either a 40 IU dose of intranasal oxytocin or placebo. We will implement a double-blind 
design. We will examine standardized, repeated dependent measures of change in each partner’s 
conflict resolution skills, subjective, physiological, and neuroendocrine responses to the conflict 
resolution task. The following specific aims are proposed: 
 
Specific Aim 1: Examine the effects of oxytocin on couples’ conflict resolution skills. 
Medical University of South Carolina 
Protocol 


 
 
Flanagan, Julianne C. v.7/23/15 
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Couples will complete a psychosocial assessment and two 10-minute videotaped conflict resolution 
tasks. 45 minutes prior to the second conflict resolution task, a 40-IU dose of intranasal oxytocin or 
saline spray will be administered to both partners. Conflict resolution skills will be coded according to a 
well-established system and compared from Task 1 to Task 2. 
 
Specific Aim 2: Examine the effects of oxytocin on couples’ subjective, physiological, and 
neuroendocrine reactivity to the conflict resolution task. 
Subjective (craving, distress, feelings toward partner), physiological (heart rate, skin conductance, skin 
temperature), and neuroendocrine (salivary cortisol, Dehydroepiandrosterone) measures will be 
assessed at baseline and at 6 other time points throughout the laboratory portion of the study for both 
partners.   
 
2. BACKGROUND AND SIGNIFICANCE___________________________________________ 
 
A. Overview 
 
Substance use disorders (SUD) are characterized by dysregulation of the hypothalamic-pituitary 
axis (HPA). The neuropeptide oxytocin, commonly administered as an intranasal spray, is a drug that 
has prominent anxiolytic and prosocial effects on human behaviors (3-6). While the mechanisms of 
action facilitating the behavioral effects of oxytocin in humans is complex and many questions about 
this process remain, there is a consensus in the existing literature that oxytocin modulates HPA axis 
reactivity to stressful social stimuli (7-9). Preliminary studies suggest that oxytocin is known to reduce 
couple conflict among normative couples (10, 11). A more developed line of research indicates that 
oxytocin mitigates addictive behaviors in the context of various drugs of abuse (12-14). Given the high 
prevalence and severity of dyadic conflict among couples where one or both partner has substance 
abuse, and given the salience of dyadic conflict as a precipitant to substance use behaviors (15-17), it 
is critical to investigate the therapeutic effects of oxytocin among couples with substance use problems. 
Namely, oxytocin holds promise as a potential augmenter for conjoint couples therapies, particularly 
those targeting the reduction of substance use problems. However, only two studies have examined the 
effects of oxytocin on couples’ communication behaviors. Those two studies found that couples’ 
communication skills improved following the administration of oxytocin. It is important to extend this line 
of research to examine conflict resolution skills among couples with substance use problems. To date, 
no studies have examined the effects of oxytocin on subjective, physiological, or neuroendocrine 
reactivity to dyadic conflict. The present study aims to fill that gap in the literature. 
 
B. The Effects of Oxytocin on Addictive Behaviors in the Context of Social Stress 
 
Social stress, both generally and specifically in relation to dyadic conflict, is known to exacerbate 
addictive behaviors. One well-developed body of literature evidencing this connection demonstrates a 
strong temporal association between verbal and physical intimate partner violence and substance use 
behaviors (15, 18-21). Studies examining the effects of social stress on subjective, physiological, and 
neuroendocrine reactivity among substance-dependent individuals suggests that social stress 
exacerbates craving, use, and relapse (22, 23). More recently, many studies have examined the 
potential for oxytocin to reduce stress reactivity in the context of addiction. Research in both animal and 
human studies has shown that oxytocin reduces addictive behaviors (i.e. withdrawal, craving, 
substance self-administration) and subjective, physiological, and neuroendocrine stress reactivity (12, 
14, 24, 25). However, this literature has not been extended to examine whether oxytocin mitigates 
substance use behaviors and stress reactivity in response to dyadic conflict among substance-abusing 
couples. 
 
C. The Effects of Oxytocin on Prosocial Behavior 


 
 
Flanagan, Julianne C. v.7/23/15 
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Oxytocin has well-established and prominent effects on prosocial human behavior (5). It promotes 
feelings of warmth, trust, and safety and promotes social bonding (5, 26). Some research asserts that 
these effects are due to oxytocin’s influence on humans’ capacity to read and respond to social cues 
and to better retain positive social memories. While some researchers caution that amplifying one’s 
capacity to interpret social cues may not always be adaptive(27), and that one’s social context and 
history may play an influential role in the response to oxytocin, the consensus in the existing studies on 
humans is that oxytocin’s positive therapeutic effects are promising. Despite the abundant literature that 
has documented the prosocial effects of oxytocin in animals and humans, only one study to date has 
investigated the effects of oxytocin on human couples interactions. Ditzen and colleagues (28) found 
that among normative couples, oxytocin increased positive communication and decreased cortisol 
levels in response to a conflict resolution task. Notably, and consistent with other literature citing gender 
differences in response to oxytocin (citations), this study also found that female partners had reduced 
ANS activity in response to dyadic conflict while male partners showed increases ANS activity in 
response to dyadic conflict. While, as mentioned above, some researchers caution about the 
consistency of positive effects of oxytocin, it is important to note that in this study, the increase in ANS 
activity was associated with more positive conflict resolution behaviors. Thus, an increase in 
physiological reactivity in the context of oxytocin and dyadic conflict may indicate a positive, rather than 
negative response.  
In addition to the scarcity of literature investigating the effects of oxytocin on dyadic conflict, this 
literature is limited by the investigation of normative couples only. Given the prominence and 
effectiveness of couples therapies to treat substance abuse problems (1, 2), a natural extension of the 
existing literature is to examine the therapeutic effects of oxytocin on couples with substance abuse 
problems. Namely, we aim to investigate the effects of oxytocin on substance-abusing couples’ conflict 
resolution skills and their subjective, physiological, and neuroendocrine responses to dyadic conflict. 
 
  
D. Conclusion 
 
In summary, dyadic conflict is a salient predictor of addictive behaviors. Along these lines, several 
evidence-based behavioral interventions for couples aimed at treating substance abuse problems have 
been developed: By effectively reducing couple conflict and improving conflict resolution skills, the 
chances of positive treatment outcomes for substance abuse problems are greatly increased and more 
effectively sustained.  
Abundant literature also indicates that oxytocin has positive influences on humans’ prosocial and 
addictive behaviors. Despite this literature, only one study has investigated the effects of oxytocin on 
couples’ conflict resolution skills, and this study was conducted among normative, rather than 
substance-abusing couples. Thus, we aim to investigate the extent to which oxytocin improves dyadic 
conflict resolution skills and mitigates negative subjective, physiological, and neuroendocrine responses 
to dyadic conflict. Findings from this study may support the evaluation of oxytocin as an augmenter to 
behavioral couples interventions targeting substance abuse. 
 
  
 
3. PRELIMINARY STUDIES__________________________________________________________ 
 
 
Studies conducted by Dr. Flanagan and her collaborators that demonstrate their collective 
experience in conducting intervention development research are outlined below. These studies also 
demonstrate the need to investigate oxytocin as a pharmacological augmenter to behavioral couples 
interventions. 
 
 Dr. Flanagan has experience in the collection of dyadic data and the precautions necessary 
when assessing men, women, and couples with acute and complex mental health problems, substance 


 
 
Flanagan, Julianne C. v.7/23/15 
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abuse problems, interpersonal violence, and criminal justice system involvement. She also has 
extensive clinical experience in facilitating psychotherapy groups for men and women from several 
specialized clinical populations. Dr. Flanagan oversaw the day to day implementation of three NIH-
funded clinical trials during her pregraduate work. Each of these studies aimed to assess the efficacy of 
alcohol interventions on the reduction of violence among individuals court mandated to batterer 
intervention treatment or in partial hospital substance abuse treatment. Dr. Flanagan conducted 
recruitment, assessment, and retention of participants as well as dissemination of data in presentation 
and peer review publications (29, 30).  
 
Dr. Flanagan’s program of research has focused extensively on the conduct of studies focused 
on improving women’s health. Namely, the reduction of interpersonal violence, substance use, and 
mental health problems. Dr. Flanagan carried out anNIAAA-funded National Research Service Award 
titled “Risk Factors for Intimate Partner Violence During Pregnancy”. During this time, Dr. Flanagan 
collaborated with a university-affiliated health clinic to recruit 180 pregnant women and conducted 
follow-up assessments with more than two thirds of this sample. Several studies have been published 
from this data (8, 31, 32). Dr. Flanagan is also trained on the laboratory procedures for collecting 
observational problem solving data from couples and employing the coding system outlined below (33). 
 
Currently, Dr. Flanagan is collaborating with Dr. Back in the conduct of her NIDA-funded clinical 
trial investigating Concurrent Treatment with Prolonged Exposure (COPE) among Iraq and Afghanistan 
combat Veterans. Dr. Flanagan functions as a member of the study treatment team and will gain first-
hand experince in the execution of a large scale clinical trial focusing on treating Veterans in the 
Charleston community. To date, we have found that approximately one third (37.7%) of the participants 
in the COPE study have reported aggression during the thirty days prior to baseline assessment, and 
approximately half (53.2%) have reported aggression during their lifetime. Drs. Flanagan and Back are 
in the process of presenting these findings, including an assessment of the differences in mental health, 
substance use, and combat exposure, between individuals who enter treatment with a recent history of 
aggression compared to those who do not. Dr. Flanagan has published two other manuscripts 
regarding the use of aggression among Veterans (6, 34). 
 
Finally, Dr. Flanagan has collected focus group data from 20 substance-abusing male Veterans 
and 14 civilian women partnered with Veterans to inform the development of potential treatments for 
couples struggling with substance abuse problems. These data suggest that anger and distrust are two 
primary obstacles to better relational health among these couples and aprticipants have requested 
interventions to faciltiate improved management of these challenging emotions. Recently, Dr. Flanagan 
has been collaborating with Dr. Back and other colleagues to develop her expertise in the use of 
laboratory-based stress induction paradigms. Dr. Flanagan has co-authored two manuscripts under 
review focusing the use of a social stress paradigm to examine subjective, physiological, and 
neuroendocrine reactivity among individuals dependent on prescription opioids. Dr. Flanagan has also 
led the analyses of these data to examine the influence of interpersonal trauma on stress reactivity in 
this sample. Finally, Dr. Flanagan is in the preliminary stages of a collaboration with other members of 
the CND to examine the interactive effects of oxytocin and childhood adversity on stress reactivity 
among cocaine-dependent individuals.  
 
In addition, Dr. Candice Monson is serving as a co-mentor and co-invetigator on the proposed 
project. Dr. Monson is Professor and Director of Clinical Training at Ryerson University. Dr. Monson 
previously served as Deputy Director of the Women’s Health Sciences Division at the National Center 
for PTSD in Boston as has an extensive research track record including serving as PI on several VA 
and NIH funded treatment development research studies focusing on designing couples therapies. Dr. 
Monson’s combination of expertise in couples therapy treatment development, women’s health, and 
Veterans health is an ideal compliment to Dr. Flanagan’s mentorship team. 


 
 
Flanagan, Julianne C. v.7/23/15 
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4. RESEARCH DESIGN AND METHODS (including data analysis) ________________________ 
 
A. Overview 
The primary objective of this study is to examine the extent to which oxytocin improves couples’ 
conflict resolution skills and mitigates their subjective, physiological, and neuroendocrine responses to 
this common stressor. Couples in which one or both partners have a recent history of substance abuse 
will be recruited. The present study will take place over one visit. In addition to a thorough psychosocial 
evaluation conducted by a trained clinician, couples will complete two laboratory conflict resolution 
tasks. Prior to the start of the second conflict resolution task, both partners will be administered a 40 IU 
dose of intranasal oxytocin. The flow chart below illustrates each element of the study: 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
B. Subjects 
 
Thirty-six couples (N=72 indivdiduals total) will be recruited to participate in the proposed study. 
Respondents will be screened by phone and provided all pertinent information about the study. 
Inclusion criteria are: 1) 18-65 years of age, 2) both partners are willing to participate, and 3) at least 
one partner has engaged in hazardous drinking (i.e. 4 or more drinks for women, 6 or more for men) or 
illicit drug use during the past 60 days. Exclusion criteria are: 1) pregnancy for women, 2) current 
psychotic or bipolar disorders, 3) active suicidal or homicidal ideation and intent, 4) subjects who would 
Phone Screen: Initial eligibility established 
Confirm eligibility; Baseline assessment including informed consent 
and psychosocial interview 
Observational conflict resolution task #1 
 
40 IU dose of intranasal oxytocin or placebo administered to both 
partners 
Observational conflict resolution task #2 
 


 
 
Flanagan, Julianne C. v.7/23/15 
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present a serious suicide risk, such as those with severe depression, or who are likely to require 
hospitalization during the course of the study, 5) severe, unilateral intimate partner violence in the past 
year, 6) BMI greater than 39. If both partners meet criteria for participation and independently provide 
informed consent, they will be scheduled to complete a baseline assessment. Participants will also be 
scheduled at the same time of day to control for diurnal variations in neuroendocrine function. 
 
 
C. Recruitment and Eligibility Screening  
 
Participants will be recruited through the use of flyers posted in MUSC treament clinics. 
Recruitment ads will also be placed in local newspapers and on Craigslist. These strategies have been 
sucessful in the PI’s mentor’s ongoing and past research endeavors and among other researchers 
within the Department of Psychiatry and the Clinical Neurosciences Division at MUSC. Respondents 
will contact research staff via phone to be screened for inclusion and exclusion criteria. The PI and 
research staff will conduct eligibility screening by phone. Respondents will be provided a brief 
description of the study including study scope and time commitment, and various methods of data 
collection including observational, physiological, and interview and self-report methods. Respondents 
will also be informed that none of their study data, including reports of sensitive nature such as IPV and 
UDS results will be shared with any third party including one’s partner. Initial screening questions can 
be found in the appendix section of this protocol. If respondents are eligible, they will be provided 
information about the purpose, nature, and duration of the study and asked if they would like to be 
scheduled to attend a baseline interview session with their partner. Participants will be provided with a 
full description of study procedures, given the opportunity to ask any questions they may have, and will 
be asked to read and sign an IRB-approved consent form before any study procedures take place. All 
participants will be consented in a private room apart from their partner to ensure confidentiality and 
safety of research participants.  
 
D. Assessment Measures. Table 1 presents the assessment instruments included in the study. 
 
Table 1. ASSESSMENT MEASURES 
Construct 
Measure  
Laboratory 
Task 
Assessments 
• Substance craving (3 items) 
• Emotional distress (1 item) 
• Feelings toward partner (11 items) 
• Constructive discussion (1 item)  
Physical Health 
Screening 
• Health Screening Interview 
Dyadic 
Functioning 
• Dyadic Adjustment Scale; DAS (35)  
• Conflict Tactics Scale-2; CTS-2 (36) 
• Reasons for Violence Scale (29)  
• Infidelity assessment (37) 
• TLFB for partner violence (38) 
• Self-Report of Aggression & Social Behavior Measure (39, 40) 


 
 
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Substance 
Abuse 
• Alcohol Use Disorders Test; AUDIT(41) 
• Drug Abuse Screening Test; DAST(42) 
• Fagerstrom Nicotine Dependence Test (43) 
• Time Line Followback; TLFB (38, 44)  
• Inventory of Drug-Taking Situations; IDTS (45) 
• Urine Drug Screen  
• Breathalyzer  
• Pregnancy test for women 
Mental Health  
• Mini International Neuropsychiatric Interview (MINI; 46) 
• Traumatic Life Events Questionnaire (47) 
• Patient Health Questionnaire; PHQ-9 (48) 
• Perceived Stress Scale -4; PSS-4 (49) 
• Interpersonal Sensitivity Measure; IPSM (50) 
• PTSD Checklist, Civilian Version; PCL-C(51) 
Coping Factors 
• Coping Strategies; Brief COPE (52) 
• Cognitive Emotion Regulation Questionnaire; CERQ-Short (53)  
Demographics 
• Age, gender, ethnicity, education, income, relationship information, military 
service 
 
Laboratory Conflict Resolution Task 
 
Couples will be asked to participate in two 10-minute video recorded problem-solving tasks 
while physiological measures are recorded for both partners. Using the procedure employed by 
McNulty and colleagues (33, 54), each partner will identify a topic of relationship difficulty, and a coin 
flip will determine the topic of the discussion. The couple will be asked to work towards a resolution or 
agreement on that topic. The conflict resolution skills of each partner will be estimated by coding each 
speaking turn using the Rapid Marital Interaction Coding Scheme (RMICS; 55). Each participant’s 
speaking turn is coded as being characterized by one of the following domains: psychological abuse, 
distress-maintaining attributions, dysphoric affect, withdrawal, relationship-enhancing attributions, 
acceptance, self-disclosure, humor, constructive problem discussion, other. An additional option is to 
calculate a total proportion of negative behavior and a total proportion of positive behavior exhibited by 
each participant by dividing the number of codes for a participant in a given conversation by the total 
number of speaking turns for that participant in that conversation.  
 
Coding will be conducted by Dr. Richard Heyman’s team at The RMICS Coding Center within 
the Translational Couples Research Laboratory at New York University. Dr. Heyman’s team provides 
fee-based coding, 25% reliability checking, reliability estimates at both system and code level, and 
SPSS output of the data. The RMICS is a widely used coding system providing dyadic coding services 
to investigators nationwide. Dr. Heyman’s team will be provided access to the secure network server 
used to store video coding materials in Dr. Back’s laboratory. 
 
Data Collection Procedures 
The extant couples literature emphasizes the utility of collecting physiological data in addition to 
self-report and observational data to examine dyadic synchronicity in physiological responses, gender 
differences in physiological arousal during the problem solving task, and to relate physiological data to 
self-report ratings of mental health, dyadic functioning, and substance abuse (56). Physiological 
measures to be collected in this study include skin conductance, skin temperature, heart rate, salivary 
cortisol and dehydroepiandrosterone (DHEA). All physiological measures will be collected using the 
ProComp Infiniti biofeedback acquisition tool (Thought Technology, Ltd.). Heart rate and skin 
conductance will be collected using electrodes on the participant’s right clavicle and on their ankle. Skin 
temperature will be measured using a self-adhering sensor placed on the participant’s index finger of 
the non-dominant hand. Cortisol and DHEA will be measured via participants’ saliva samples. 
Participants will be asked to avoid drinking coffee and smoking in the hours prior to their appointment to 


 
 
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avoid interference with physiological measures. Participants will also be assessed at the same time of 
day to control for diurnal variations in neuroendocrine function.  
 Following informed consent, couples will complete self-report and interview measures in 
separate rooms. When finished, couples will be escorted into a room together asked to relax for a 15 
minute period in this room to acclimate to their surroundings. Following this relaxation period, finger 
sensors will be placed and baseline measures of all physiological data will be collected. DHEA and 
cortisol will be collected at 8 time points in all: baseline, immediately following the first conflict-resolution 
task, 15 minutes after the first conflict resolution task, immediately prior to the second conflict resolution 
task, immediately after the second conflict resolution task, and 15, 30, and 60 minutes after the conflict 
resolution task. Skin temperature, skin conductance, and heart rate will be measured continuously from 
baseline through the end of the laboratory task. Subjective measures will be administered at baseline, 
immediately before and after both conflict resolution tasks.  Following completion of the first conflict 
resolution task and its associated post-test measurements, couples will self-administer either oxytocin 
or placebo spray and 45 minutes later will begin the second conflict resolution task. A timeline for 
completion of the laboratory taskis outlined below: 
 
Laboratory Task Timeline 
TIME 
PROCEDURE 
MEASUREMENT 
8:00am 
Informed consent and questionnaires at 
Charleston Center 
Informed consent; pregnancy test; 
breathalyzer; UDS; Interview and self-
report assessment measures 
9:00am 
Couple escored to CTRC; Relaxation 
period begins 
 
9:20am 
Finger sensors placed; Begin baseline 
measurement 
Neuroendocrine:Salivary cortisol; DHEA  
Physiological: Skin temperature; skin 
conductance; heart rate 
Subjective: craving; distress; mood; 
feelings toward partner 
9:30am 
Begin conflict resolution task #1 
 
9:40am 
End conflict resolution task #1 
 
Neuroendocrine:Salivary cortisol; DHEA  
Physiological: Skin temperature; skin 
conductance; heart rate 
Subjective: craving; distress; mood; 
relationship satisfaction; aggression 
9:50am 
Oxytocin or placebo self-administered 
 
10:30am 
Finger sensors replaced; Begin second 
baseline measurement 
Neuroendocrine:Salivary cortisol; DHEA  
Physiological: Skin temperature; skin 
conductance; heart rate 
Subjective: craving; distress; mood; 
feelings toward partner 
10:40am 
Begin conflict resolution task #2 
 
10:50am 
End conflict resolution task #2 
Neuroendocrine:Salivary cortisol; DHEA  
Physiological: Skin temperature; skin 
conductance; heart rate 
Subjective: craving; distress; mood; 
feelings toward partner 
11:05am 
15-minute post task assessment 
Neuroendocrine:Salivary cortisol; DHEA  
Physiological: Skin temperature; skin 
conductance; heart rate 
Subjective: craving; distress; mood; 
feelings toward partner 


 
 
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11:20am 
30-minute post task assessment 
Neuroendocrine:Salivary cortisol; DHEA  
Physiological: Skin temperature; skin 
conductance; heart rate 
Subjective: craving; distress; mood; 
feelings toward partner 
11:50am 
60-minute post task assessment 
Neuroendocrine:Salivary cortisol; DHEA  
Physiological: Skin temperature; skin 
conductance; heart rate 
Subjective: craving; distress; mood; 
feelings toward partner 
 
Oxytocin administration and Neuroendocrine Assays 
 
A 40-IU dose of intranasal oxytocin will be self-administered. Dr. Brady will provide prescriptions for 
oxytocin for research participants assigned to the oxytocin condition to research pharmacy services on 
the MUSC campus, who will compound the oxytocin doses and inform investigators as to the proper 
number of nasal sprays necessary to achieve the intended dose.  
 
Unstimulated salivary samples will be collected at the previously  noted time points by CTRC 
medical staff to measure cortisol and DHEA. Passive drool will be collected in polypropolene vials and 
iced immediately. Samples will be aliquoted into 1.81.8 nunc tubes and frozen at -70°C until assayed. 
Samples will be assayed twice using a high sensitivity salivary cortisol enzyme immunoassay system 
with an intra-assay precision (coefficient of variation, CV) of 3.35% - 3.65% with a sensitivity of <0.003 
ug/dL (Salimetrics LLC).  Samples will be analyzed using a PowerWave HT Microplate 
Spectrophotometer in conjunction with a Precision Series Automated Liquid Handling System (BioTek 
Instruments, Inc.).  
 
E. Compensation 
 
Participants will be remunerated for their time in cash. Each participant will be paid $100 upon 
completion of the study. In the event that participants complete only part of the study, they will be 
remunerated $15 for completing self-report and interview measures, $15 for the first conflict resolution 
task, and $70 for taking the oxytocin dose and completing the second conflict resolution task. 
 
F. Maximizing Engagement and Retention 
 
The proposed study targets a population facing considerable challenges that may influence the 
research team’s ability to recruit participants through the duration of the study. The PI will recruit 
adequate research staff to assist in the recruitment, assessment, and scheduling appointments. All 
study staff will be trained in available techniques that the PI and Dr. Back have used in previous 
studies to minimize participant burden and facilitate participants’ access to study staff and their 
attendance at study appointments. Study staff will provide appointment reminder cards, will call or text 
the day prior to each appointment to remind participants of study appointments, and will contact 
participants immediately by phone and/or email if appointments are missed.  
 
G. Data Analysis 
 
General. Data analysis will be conducted using SPSS v. 21 and MplusTM software version 5.2 or 
higher (57). All analyses will be tested using significance level <0.05. Preliminary analyses will include 
determining the characteristics of the sample including demographic variables and descriptive statistics 
for all variables of interest included in the study. Reliability of assessment measures will be calculated 
prior to beginning main study analyses. We will also compare individuals who were eligible but declined 


 
 
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participation following screening and/or informed consent with those who chose to participate. We will 
also compare participants who withdrew or dropped out of the study following baseline assessment with 
study completers on demographic variables and main variables of interest. Subsequent analyses will be 
theory-driven and informed by the primary research questions of this study. Bivariate associations 
between variables will be examined via correlation. Demographic variables with significant bivariate 
associations with main outcome variables will be employed as covariates in subsequent analyses. The 
PI will conduct these preliminary analyses in consultation with Dr. Back and biostatistics consultation 
provided through SCTR at MUSC.   
 
Missing Data. Given the multi-modal assessment strategy employed in the proposed study, it is 
expected that only a small proportion of missing data will appear. However, in the event that more than 
10% of data on a key varible is missing, we will attempt to reduce bias and maximise statistical power 
by choosing and employing a method for imputing data. This method will be chosen in collaboration 
with Dr. Back and biostatistics consultation available through SCTR resources. 
 
Preliminary Analysis. All study variables will be examined to assess normality, distributions, 
and outliers. Non-normal data will be transformed using log-10 or natural log transformation in an 
attempt to achieve greater normality of distributions. If appropriate normality cannot be achieved on key 
variables of interest, non-parametric statistical analyses will be employed.  
 
Longitudinal Analysis. Linear regression analyses, structural equation modeling, and 
hierarchical linear modeling (HLM) will be employed to test study hypotheses. These approaches, HLM 
in particular, are ideally suited to analyze non-independent data reported by dyads (58). Multilevel 
models will be estimated, where the statistical non-independence of each partner’s data is controlled by 
estimating each partner’s parameters simultaneously through a procedure described in greater detail by 
Raudenbush and colleagues (59).  
 
 
Hypothesis 1: Couples will demonstrate improved conflict resolution skills from the first observational 
conflict resolution task to the second following the administration of oxytocin. 
 
Hypothesis 2: Couples will demonstrate lessened subjective, physiological, and neuroendocrine 
reactivity to the second conflict resolution task following the administration nof oxytocin.  
 
 
First, average levels of each of the outcome variables will be estimated through the use of a level-1 
equation of a multilvel model. This approach will allow us to examine the average estimates of change 
in each of the outcome variables over the multiple time points assessed.Chi-square analyses and effect 
sizes will also be estimated to examine the between-subjects variance in each variable of interest. Chi-
square analyses will indicate whether changes on each variable differed significantly across either or 
both partners. We will also examine the within-subject relationships between mental health and 
substance abuse variables over time for both partners.  
 
 
H. 
Strengths of the Research Design 
Expertise of Research Team. The PI, her mentor, co-mentor, and consulting staff at MUSC 
were assembled for the specific purpose of the proposed study. Each investigator taking part in this 
project has expertise in the treatment of PTSD, SUDs, and interpersonal violence. Dr. Flanagan also 
has expertise in the assessment and treatment of couples and the administration of behavioral 
interventions for couples in a variety of treatment settings. 


 
 
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Use of multi-modal, longitudinal assessments. The combined use of self-report, interview, 
observational, physiological, and dyadic data will provide rich and highly informative data. The repeated 
measures design of this study (assessing the same constructs over multiple assessment time points) 
will allow the research team maximize construct validity and evaluate a wide range of potential outcome 
variables in order to derive the most information possible from these data. 
Assessment of novel treatment approach. Oxytocin has demonstrated tremendous promise 
in the fields of addiction. The present study is one of the first to investigate the effects of oxytocin on 
couples conflict resolution skills. It is the first to examine its effect on dyadic conflict resolution among 
couples with substance abuse problems, and the first to examine its effects on subjective, 
physiological, and neuroendocrine correlates dyadic conflict.  
 
I. 
Limitations of study design 
Use of retrospective self-report data. Recall bias may be a factor that limits the validity and  
generalizability of the proposed study. The use of multi-model assessment approaches may minimize 
the limitations incurred by this design element.  
 
Absence of control group. A more rigorous design may include a control group receiving 
placebo with which to compare a treatment group. However, the goal of this preliminary study is to 
evaluate the feasibility and preliminary efficacy of oxytocin on the above mentioned factors and to 
provide information that will facilitate its revision and improvement.  
 
J. 
Project timeline 
During the first 3 months of this project, 2-3 couples will be recruited to pilot the study 
procedures. Also during this time, the study database will be created and data entry will be ongoing. 
Following the completion of this pilot phase, recruitment and assessment of couples will continue. 
Data cleaning and maintenance will also begin in month 4 and will continue through the duration of the 
study. Dissemination of data including presentation of preliminary pilot data at national conferences 
will begin in the second year of the project.  
 
  
 
K. 
Study personnel 
Principal Investigator: Julianne C. Flanagan, Ph.D. is an Assistant Professor within the  
Department of Psychiatry and the Division of Clinical Neurosciences at MUSC. Dr. Flanagan is a 
clinical psychologist with 10 years of specialized training in the treatment of trauma, substance abuse, 
and interpersonal violence. Dr. Flanagan received her Ph.D. from the University of Tennessee, 
completed her internship at the VAMC Puget Sound, Seattle, and a postdoctoral fellowship in the NIDA-
funded T32 training program within the Department of Psychiatry at Yale University School of Medicine.  
She was the PI of a NIAAA-funded NRSA entitled Risk Factors for Intimate Partner Violence During 
Pregnancy. She is currently serving as Co-Investigator on a NIDA-funded study aimed at evaluating the 
efficacy of an integrated treatment for PTSD and substance abuse among OIF/OEF Veterans (PI; 
Back). She also has extensive experience working with diverse and vulnerable populations (e.g., 
pregnant women, incarcerated and court-mandated individuals, individuals with substance use 
disorders). Across various studies, she has taken a lead role in developing and implementing 
recruitment protocols; hiring, training and supervising research staff; designing and maintaining 
stringent human subjects protection plans; conducting statistical analyses; and preparing data for 
conference presentation and submission to peer-reviewed journals. She has expertise in mental health 
treatment, including dyadic interventions among civilian and military populations to address PTSD and 
co-occurring problems such as substance abuse and interpersonal violence.  
Co-Investigator: Sudie E. Back, Ph.D. is an Associate Professor in the Department of Psychiatry 
at the Medical University of South Carolina (MUSC), and a clinical psychologist specializing in 
substance use disorders (SUDs) and the integrative treatment of co-occurring PTSD. She is a Staff 


 
 
Flanagan, Julianne C. v.7/23/15 
12 
 
Psychologist at the Charleston VAMC’s Substance Abuse Treatment Clinic (SATC). Dr. Back has been 
involved in the treatment of comorbid SUD/PTSD patients for the past 15 years. She served as a 
therapist on the original Stage Ia, NIDA-funded trial of COPE, was a Co-I on the RCT of COPE in 
Australia, a Therapist Trainer on a NIDA-funded study (PI: Hien) comparing COPE with relapse 
prevention among civilians with SUDs and PTSD, and was a therapist trainer for a STRONG STAR 
study (PI: Roache) examining the pharmacologic treatment of co-occurring alcohol dependence and 
PTSD in OEF/OIF Veterans. She is first author on the COPE manual, which is currently in press with 
Oxford University Press. She is the past PI of a 4-year NIDA-funded National Research Service Award 
that investigated cocaine dependence and PTSD. In addition, Dr. Back was involved with the Clinical 
Trials Network (CTN) and served as a therapist and a therapist trainer. She will serve as PI on this 
study. She will work closely with Dr. Flanagan to ensure that the project is successfully implemented. 
Co-Investigator: Kathleen Brady, M.D., Ph.D. is a Professor in the Department of Psychiatry at 
the MUSC and a staff psychiatrist at the Ralph H. Johnston VAMC in Charleston. She is a board-
certified psychiatrist specializing in addiction psychiatry who has been actively involved in clinical 
research in the drug abuse area for the past 18 years. Dr. Brady received her Ph.D. in Pharmacology 
from Virginia Commonwealth University and her M.D. degree from the Medical University of South 
Carolina (MUSC), where she completed a residency in psychiatry and completed an Addiction 
Psychiatry fellowship. As a Professor of Psychiatry at MUSC, Dr. Brady is Director of the Clinical 
Neuroscience Division, Director of the Women’s Research Center, Director of the General Clinical 
Research Center (GCRC), and Associate Dean for Clinical and Translational Research. She has also 
served as the PI for the Southeastern Node of the NIDA Clinical Trials Network (CTN) since 2000. She 
will assist with implementation of the project and dissemination activities and will provide oxytocin 
prescriptions to research pharmacy services in this study.  
Co-Investigator: Dr. Margaret Moran-Santa Maria, Ph.D. is an Assistant Professor in the 
Department of Psychiatry at the Medical University of South Carolina.  She has 17 years of preclinical 
research experience and training in rodent models of stress including addiction.  She has seven years 
of clinical research experience and training in substance use disorders and trauma, including extensive 
experience administering oxytocin in human trials.  She has extensive experience with recruiting, 
retaining, assessing, and evaluating outcomes substance-dependent individuals and healthy resilient 
controls. She has collaborated with Drs. Back and Flanagan on multiple projects and publications that 
are directly related to this project. Dr. Moran-Santa Maria will be a Co-I on the study. 
Study Physician: Bryan K. Tolliver, M.D., Ph.D. is an Assistant Professor in the Department of 
Psychiatry at MUSC and a licensed addictions psychiatrist with extensive experience working with 
adults who have experienced significant life stressors and substance use disorders. 
Consultant: Michael E. Saladin, Ph.D. is a clinical psychologist and Professor in the Department of 
Health Sciences and Research at MUSC. Dr. Flanagan seeks to advance her training under the 
proposed award by collecting physiological data such as skin conductance and heart rate of Veterans 
and their intimate partners during an observational problem-solving task. Dr. Flanagan is particularly 
interested in examining the synchronicity of intimate partners’ physiological responses during an 
observational problem solving task. He has both clinical and research expertise in examining and 
treating PTSD and substance abuse, as well as in implementing laboratory-based, experimental 
psychopathology protocols that involve the measurement of physiological responses to stress cues. 
Additionally, as Co-PI on a clinical research component of the SCOR P50 (Brady PI), he has over 12 
years of experience examining gender differences in reactivity to both substance and stress cues/tasks. 
Dr. Saladin’s role in this study is to assist the PI by providing consultation related to the collection and 
analysis of physiological data. He will guide Dr. Flanagan through the setup of the necessary data 
collection equipment and computer software, provide feedback regarding the design of her data 
collection protocol, and provide consultation regarding appropriate methods to reduce and analyze the 
data. Finally, I will be available to consult with Dr. Flanagan during the project period and will assist with 
the implementation of her training plan as needed.  


 
 
Flanagan, Julianne C. v.7/23/15 
13 
 
Consultant: Peter Tuerk, Ph.D. is an Assistant Professor in the Department of Psychiatry and 
Behavioral Science at MUSC and Associate Director of the PCT at the Ralph H. Johnson VAMC, where 
he specializes in treating OEF/OIF Veterans. He also serves as Director of Research Training (DRT) for 
the APA-accredited psychology internship. Dr. Tuerk specializes in exposure therapy for PTSD and 
currently works with Dr. Edna Foa (founder of PE) as a trainer of PE therapy for the national VA PE 
dissemination effort. In that role, he works closely with Dr. Foa in providing clinical supervision and 
instruction to VA therapists across the country. Dr. Tuerk also has expertise in the area of physiological 
data collection. For the proposed project, Dr. Tuerk will assist the PI in the collection and analysis of 
dyadic physiological data.  
Study Prescriber: Anjinetta Johnson, P.A. is a physician assistant who has worked with our group 
on a variety of past studies. Ms. Johnson will contribute to screening participants for eligibility, 
conducting clinical interviews, history and physical exams and venipuncture when necessary. She will 
also be able to write prescriptions for study medications. 
Research Assistant: Alexandra Snead, B.A. is currently a first year graduate student at the Citadel 
working towards her Masters degree in psychology. Ms. Snead will be responsible for data entry and 
will participate in participant recruitment and assessment activities.  
 
 
6. PROTECTION OF HUMAN SUBJECTS________________________________________________ 
 
Risks to the subjects.  The PI and co-investigators located at MUSC have completed the mandatory 
University of Miami CITI Human Subjects Research Education Course online. All research activities will 
reviewed by MUSC’s IRB on a yearly basis. The research staff will ensure that all information needed 
for the continuing review is at the IRB in accordance with IRB requirements. 
 
Human Subjects Involvement and Characteristics. A total of 30 couples (60 individuals) who meet 
inclusion criteria will be enrolled in the proposed study over a 2 year period. Women and men of all 
racial and ethnic groups are eligible for participation in the proposed study. Charleston’s population is 
64% Caucasian, 34% African American and 2% identifying a racial background other than those 
previously listed. Therefore we anticipate a similar racial spectrum for the proposed study. Individuals 
under the age of 18 will not be included in the study. Inclusion criteria dictate that all participants must 
be 18-65 years of age, both partners must be willing to participate, at least one partner in the couple 
must endorse substance abuse in the past 60 days. Exclusion criteria include pregnancy for women, 
current psychotic or bipolar disorders, active suicidal or homicidal ideation and intent, subjects who 
would present a serious suicide risk, such as those with severe depression, or who are likely to require 
hospitalization during the course of the study, severe unilateral IPV in the past year, or BMI greater 
than 39. If both partners meet criteria for participation and independently provide informed consent, 
they will be scheduled to complete a baseline assessment. 
 
Targeted/Planned Enrollment Table 
 
Total Planned Enrollment: 40 
 
 
TARGETED/PLANNED ENROLLMENT: Number of Subjects 
Ethnic Category 
Sex/Gender 
Females 
Males 
Total 
Hispanic or Latino 
   0 
    0 
      0 
Not Hispanic or Latino 
   36 
    36 
      72 
Ethnic Category: Total of All Subjects* 
72 


 
 
Flanagan, Julianne C. v.7/23/15 
14 
 
Racial Categories 
 
American Indian/Alaska Native 
0 
0 
0 
Asian 
0 
0 
0 
Native Hawaiian or Other Pacific Islander 
0 
0 
0 
Black or African American 
24 
24 
48 
White 
12 
12 
24 
Racial Categories: Total of All Subjects* 
36 
36 
72 
 
*The “Ethnic Category: Total of All Subjects” must be equal to the”Racial Categories: Total of All 
Subjects”.  
 
 
Sources of Materials. All data collection described in this protocol is collected specifically for the 
purposes of the proposed research project. All data will be collected on the MUSC campus. Self-report, 
observational, physiological, and interview data will be collected. Data will be used to evaluate the 
efficacy of oxytocin to improve conflict resolution skills among couples with recent substance abuse. 
Observational problem-solving tasks will be recorded for data analytic purposes and will be kept on the 
secure, password protected CND network. Participants will also provide breathalyzer and UDS samples 
analyses prior to the beginning of each interview and group treatment session. To maintain standards 
of confidentiality set forth by the American Psychological Association, all digital and paper data 
collected will be numerically coded, kept in locked filing cabinets and password-protected computers 
within MUSC’s encrypted data server. No parties shall have access to these data aside from the PI and 
necessary research staff. A master list of participant names, ID number, and contact information will be 
kept in a location separate from study materials within MUSC’s encrypted data server. Video recorded 
problem solving tasks will be kept in the same manner as the other PHI collected in this study: secured 
on the password protected CND server. 
 
Potential Risks. Research participation may result in psychological distress as a result of the conflict 
resolution task, from disclosing personal or sensitive information about their health, their history, or their 
relationship within the self-report or interview portions of data collection. Loss of confidentiality is a risk 
of participation. Risks associated with intranasal oxytocin have been noted among women given 
intravenous, rather than intranasal, oxytocin for its FDA-approved purpose, to induce labor. These risks 
include seizures, mental disturbances, nausea, vomiting, irregular heartbeat, high blood pressure, and 
unexpected bleeding or contraction of the uterus and have been observed in a small number of women. 
However, preliminary studies conducted by the PI, Dr. Back, and senior researchers in our department 
and others conducting clinical trials in this area indicate that risks of intranasal oxytocin administration 
at the planned dose of 40 IU is minimal and manageable through the proposed human subjects 
protection methods described below. All possible efforts to minimize participant burden and distress will 
be made. All possible efforts will also be made to protect the confidentiality of participants’ data, except 
in the event of imminent risk to self or others, or in the event of disclosure of child or elder abuse. In the 
event that confidentiality must be broken to protect the safety of participants or others, only the data 
essential to make an adequate report to authorities will be disclosed. All participants will review the 
IRB-approved informed consent document with research staff in a private room separate from their 
partner. Through this process, research staff will inform all research participants of the risks of 
participation, including emotional distress. In the event that a participant experiences substantial 
distress or reports risk of harm to oneself or others, they will be asked to complete a safety plan and if 
necessary, call 911. The Mobile Crisis Unit of Charleston County and urgent care services on the 
MUSC campus are additional resources available to study staff and research participants. Drs. 
Flanagan and Back are licensed clinical psychologists equipped to help participants effectively manage 
their distress and to evaluate conditions in which participants may need additional assistance. In the 
event that a participant becomes distressed during or following an assessment, the PI will also contact 
the participant the following day to ensure they have received resources necessary, and to assess their 


 
 
Flanagan, Julianne C. v.7/23/15 
15 
 
safety and welfare. In the event that any adverse event occurs resulting from study participation, that 
event will be reported in writing to the MUSC IRB and NIH within 24 hours. In past and ongoing studies 
conducted at MUSC, these resources have been sufficient to manage problems or distress related to 
participation in studies on similar topics.   
 
Safety and Monitoring Plan.  Every possible effort will be made to protect the safety and 
confidentiality of research participants. In the event that any participant in this study reports or 
demonstrates the need for more substantial mental health, substance abuse, or other intervention 
including hospitalization, referral for treatment will be made by the research staff. Participants who 
report suicidality will be closely monitored by the research staff, will be engaged in safety planning, and 
if necessary, will be referred for psychiatric treatment/hospitalization. The PI and her mentor are 
licensed clinical psychologists and are equipped to monitor study participants for improvements and 
deterioration in mental health/substance use symptoms. Drs. Flanagan and Back have extensive 
experience working with acute populations and populations at-risk for severe mental health problems 
and substance abuse problems.   
 
The PI, in collaboration with her team of co-investigators, will follow MUSC’s well-established 
protocol for referring participants for emergency hospitalization, crisis management, management of 
suicidal/homicidal ideation, and acutely severely mentally ill individuals. In the event that research staff 
establishes the need for any of these services, research staff will page the on-call psychiatrist to consult 
about the participant’s presentation and treatment needs. Research staff will also have the option to 
escort the participant to the psychiatric walk-in clinic or hospital emergency room.  
 
Suicide Risk Reduction Plan. A specific protocol to address suicidal ideation among study 
participants has been developed. All investigators are highly trained doctoral-level psychologists or 
medical doctors with extensive experience in assessing and managing suicidality and self-harm 
behaviors, particularly among Veterans and their families. The baseline assessment includes specific 
assessments (on the PHQ-9) of suicidal ideation. Research assistants hired to conduct recruitment and 
have contact with study participants will be trained in the assessment of suicide risk and the protocol in 
place to facilitate access to care for those in need. Participants who report acute suicidal ideation, 
intent, and plan will be excluded from further participation in the study and will be immediately referred 
for psychiatric evaluation/care at one of the 24 hour care clinics on the MUSC campus or in the VAMC 
psychiatric emergency room. If research staff other than the PI conduct an assessment where acute 
suicidal ideation/intent is identified, the PI will contact that participant for further assessment of mental 
health treatment needs.  
 
B. ADEQUACY OF PROTECTION AGAINST RISKS  
 
Recruitment and Informed Consent 
 
Initial respondents will contact research staff by phone to be screened for eligibility. This brief 
screening measure contains questions directly pertaining to the study’s inclusion and exclusion criteria. 
Participants who meet eligibility criteria and are interested in participating will be scheduled with 
research staff for an in-person assessment session with their partner. In a private room apart from their 
partner, potential subjects will be provided with a full description of the nature and requirements of 
study participation, and asked to read and sign an IRB-approved consent form. 
 
Informed consent will be collected by the PI and trained research assistants. Dr.  Flanagan is a 
licensed clinical psychologist with extensive experience working with couples. Dr. Flanagan will train 
research staff in the study protocol, and the essential elements of ethical conduct of research so that 
each member of the research staff is well-equipped to provide participants with adequate information 
prior to their agreeing to participate in the study. 
 
Informed consent will be collected in a private room, separately for each member of the dyad. 
Research staff will provide information related to any questions participants may have. Participants will 


 
 
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16 
 
also be informed that they are not required to make an immediate decision about whether or not they 
choose to participate on that day. Although participants will complete the informed consent procedure 
apart from their partner to ensure each partner’s safety, confidentiality, and to minimize the potential for 
coercion by partners, all participants will have the opportunity to privately discuss their decision to 
participate with their partner prior to beginning any study procedures. 
 
Protection against Risk 
All research personnel will attend a required in-service training conducted by the PI, where the 
screening, informed consent, and assessment protocols will be described. The study protocol and 
safety plan will be printed and kept in a central location within the research space for easy access for all 
research staff. Protocols for the management of any participant or study-related emergency will be 
established and research staff will be trained on these protocols. Drs. Flanagan will be aware of the 
scheduling of all participant assessments. Dr. Flanagan will conduct many assessments. All participant 
assessments will be scheduled during normal working hours in the Charleston Center on MUSC 
campus in order to ensure the presence of clinical staff and to ensure the safety of participants and 
research staff.  
To protect participant confidentiality, all data will be stored in locked filing cabinets within a 
locked office and on MUSC’s encrypted computers and data servers. All participants will be assigned a 
numberical study identifier to minimize the potential to link identifying information with study data. One 
master list of study participants will be kept separate from all other study data. Access to data will be 
restricted to research staff. Data will be maintained in a manner consistent with IRB-approved protocol. 
Only deidentified data will be used to present findings in presentations or publications. All research staff 
have or will complete the University of Miami CITI training course in the responsible conduct of 
research.  
Drs. Flanagan and Back are clinical psychologists with extensive experience working in 
research and clinical settings with high-risk populations. They are intimately familiar with the safety 
needs of Veterans and their families and methods for optimizing participant safety. Drs. Flanagan and 
Back have received specialty training to safely manage crises and are equipped to train research staff 
to effectively do the same. Drs. Flanagan and Back will oversee the training of research staff in IPV 
safety planning. Dr. Flanagan has run more than one hundred couples through experimental protocols 
and recently published a first-authored manuscript describing the best practices for maintaining the 
highest level of participant safety in research including an IPV component (60), which directly impacted 
the methodology chosen in the proposed study. Both investigators are practicing clinicians and will be 
available to manage safety issues presented by research participants. In order to further ensure 
participant safety and minimize risk outside of working hours, each participant will be provided with a 
list of referral information to 24-hour acute care facilities, community counseling and mental health 
centers, suicide prevention hotlines and crisis management facilities, and substance abuse programs at 
the VA and in the surrounding community. Participants in the proposed study may experience 
emotional distress during the course of the treatment as they discuss problematic issues in their lives 
and relationships. However, based on the research team’s past experience and available literature the 
risks involved in the proposed project are minimal and manageable (60, 61). In the event that a 
participant is excluded from the study due to reports by one or both partners of safety concerns or 
coercion, research staff will immediately provide the participant with community resources and invite 
them to complete a safety plan. In the event that a participant arrives to an assessment session 
intoxicated, the study visit will be rescheduled and safe transportation home will be arranged for that 
participant. Dr. Flanagan will also call that participant the following day to follow-up, provide any 
necessary resources, referrals, or support, and encourage that participant to continue participation in 
treatment. Participants will be informed during the informed consent procedure that the fact of their 
participation and their responses are completely confidential and will not be shared with their partner, 
their health care providers, or any other third party. They will also be informed of the standard 
limitations of confidentiality set forth by the American Psychological Association such as imminent risk 


 
 
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of harm to self or others, or child or elder abuse. Participants will be informed that they can decide not 
to answer any questions and, should they become distressed or are uncomfortable with continuing to 
participate, they may discontinue participation at any time without penalty. The compensation schedule 
will be stated verbally and in writing in the initial study description and the informed consent procedure. 
The participant’s copy of the consent form will provide contact phone numbers and email for each 
member of the research team should a participant have any questions, comments, or concerns about 
their participation. Participants will have the opportunity to have a copy of the consent form mailed to 
them at any time.  
 
Potential benefits of the proposed research to the subjects and others  
Benefits of participation in the proposed study include a thorough psychological and substance 
use assessment, referral and access to appropriate treatment services and community resources if 
desired, and remuneration for one’s time and effort. While these benefits may be considered minimal, 
we believe that they outweigh the minimal risk and burden incurred by participants. Participation in the 
proposed study may facilitate improvement in relationship functioning and access to treatment services 
for some participants. Participants will also be participating in a study that has the potential to guide and 
provide treatment for similar members of the community. 
 
Importance of the knowledge to be gained 
 
The proposed study presents the potential for important knowledge to be gained. Preclinical and 
preliminary human data suggest that oxytocin has great potential to influence treatment in the field of 
addictions. Individuals with addictions experience considerable mental health and relational challenges, 
yet research investigating pharmacological augmentations to improve conjoint therapies to treat these 
issues is scant. The present study is the first study to our knowledge to investigate the utility of oxytocin 
to improve conflict resolution skills and mitigate subjective, physiological, and neuroendocrine reactivity 
to this common stressor. The use of oxytocin as an augmenter to behavioral interventions, particularly 
those that employ conjoint dyadic modalities, present the potential for a highly efficient and cost-
effective way to meet the treatment needs of couples across settings nationwide.  
 
Risk to Benefit Ratio 
 
The experienced research staff conducting this study will make every possible effort to maintain 
the safety of our research participants, to minimize the risks and burden they incur as a result of 
participation, and to maximize potential benefits. The knowledge we may gain from the proposed study 
will address a crucial need for studies to develop and evaluate treatments to improve the health of 
couples. In the event that new information regarding the risk to benefit ratio becomes available during 
the course of the study, research participants will be notified. Further, the PI and her mentor will consult 
with our research team and DSMB to make any necessary study modifications. 
 
Data and Safety 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).  
 
 Summary of the Protocol. The proposed study aims to develop and conduct initial feasibility 
and efficacy testing of oxytocin for the improvement of couples’ conflict resolution skills. The primary 
outcome in this study includes an improvement in conflict resolution skills and a reduction in subjective, 
physiological, and neuroendocrine reactivity to dyadic conflict.  
Trial Management. The study will be managed from the Division of Clinical Neuroscience within 
the Department of Psychiatry and Behavioral Sciences at the Medical University of South Carolina.  
 
Data Management and Analysis. A data analytic plan is outlined in the Data Analysis section. 
Because this study is a preliminary test of a new medication, we are interested in examining a broad 
range of outcome variables. The main outcome variables include the frequency and severity of negative 
conflict resolution skills and the frequency and intensity of positive conflict resolution skills as well as 


 
 
Flanagan, Julianne C. v.7/23/15 
18 
 
subjective, physiological, and neuroendocrine reactivity to dyadic conflict. Outcome data will be 
analyzed using regression analyses, structural equation modeling, and hierarchical linear modeling. 
The alpha level for statistical significance will be set at .05.  
Quality Assurance. Data quality will be monitored by random inspection of completed 
assessment forms by research staff.  Any problems with the assessment process, data collection, or 
data entry will be discussed with the PI and Dr. Back.  
Regulatory Issues. All Adverse Events (AEs) that meet criteria for reportable AEs will be 
reported to the MUSC IRB and NIH within 10 working days. AEs are reportable if the AE is unexpected 
AND related or possibly related AND serious or more prevalent than expected. 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.  Serious AEs (SAEs) will be reported within 24-hours. Follow-up of all unexpected and 
serious AEs will also be reported to these agencies. All AEs are reviewed weekly by the PI, and 
annually by the Data Safety Monitoring Board (DSMB) and IRB. Any significant actions taken by the 
local IRB and protocol changes will be reported to NIDA. AEs and SAEs occurring during the course of 
study will be collected, documented, and reported in accordance with protocol and IRB reporting 
requirements. All research staff involved with adverse event reporting will receive training including 
identification, evaluation, and documentation and reporting. All research staff will identify any potential 
AEs during the course of the study from self-report data and administration of assessments and 
interviews. This information will be provided to the PI and Co-Investigators, who will be responsible for 
AE/SAE assessment and evaluation including a determination of seriousness and study relatedness. 
Definition of AE and SAE 
Anticipated Risk - Mild to moderate discomfort when completing the laboratory assessment is 
anticipated and is not considered an adverse event for this study.  Potential for relapse of alcohol and 
or drug use is anticipated and relapse is not considered an adverse event for this study. Potential for 
inpatient detoxification following a relapse is not unexpected among some subjects, particularly 
subjects with a prior history of medically supervised detoxification, and is not considered an adverse 
event for this study.  
 Adverse Event- An untoward medical event among randomized subjects occurring during a 
clinical study that can represent a new symptom experienced by a study subject or an exacerbation or 
worsening of an existing condition.  
 Serious Adverse Event- Any untoward medical event or adverse drug experience occurring at 
any dose that results in any of the following outcomes: 
 
1) Death. 
2) A life threatening event. 
3) Requires or prolongs inpatient hospitalization  
4) Persistent or significant disability/incapacity. 
5) A congenital anomaly or birth defect.  
 
Important medical events that may not result in death, be life-threatening or require 
hospitalization may be considered a serious adverse experience when, based upon appropriate 
medical judgment, they may jeopardize the subject and may require medical or surgical intervention to 
prevent one of the outcomes listed in this definition. 
 
Documentation and Reporting: 
 
Any clinical study event that is judged to be an AE will be recorded on the AE Form during the 
course of the study.  The PI ensures this information is captured during every study subject visit.  If the 
AE is not serious, the information is recorded, managed medically as appropriate, and the event is 
followed until resolution. AEs are reportable if the AE is unexpected AND related or possibly related 


 
 
Flanagan, Julianne C. v.7/23/15 
19 
 
AND serious or more prevalent than expected. All three criteria must be met for an AE to be a 
reportable AE. 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. SAEs are also recorded on the AE Form, 
managed medically as appropriate, and the event is followed until resolution.  In addition, the PI 
reviews all completed AE forms for determination of SAE that require reports to the Sponsor. The PI 
informs the Sponsor immediately of knowledge of a SAE.  As additional information becomes available 
on the SAE, it will be forwarded to the Sponsor.  All SAE reports shall be sent to the IRB and NIH within 
24 hours of learning of event occurrence. 
 
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. Additional relevant AE information if available will 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 subject is no longer in the study as stated in the protocol. 
When a reportable SAE is identified, the research assistant will initiate an SAE form, and the 
following individuals will be notified within 24 hours of the site’s initial notification of the SAE:   
 
 i. Study Co-Investigators.    
 
 ii. The MUSC institutional review board (IRB).  Committee meets monthly.  Communication 
with the IRB is through email, memos, official IRB forms, and online reporting. 
 
iii. The NIH program officer. 
 
iv. The data safety monitoring board members. 
 
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. In addition, the PI will provide a signed, dated 
SAE summary report, which will be sent to the NICHD Medical Safety Officer within two weeks of the 
initial SAE report. 
 
 
 
Study Safety. The potential risks and benefits and methods to minimize these risks are outlined 
above. Protocols for reported AEs and SAEs are outlined above. All unexpected AE and SAEs will be 
monitored until resolved. A detailed summary of all AEs will be prepared weekly by the research staff. 
At the weekly team meetings (or before if urgent), the research staff will report any premonitory 
symptoms of clinical deterioration.    
 
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 the PI. All 
requests by subject’s physicians and other medical providers will be referred directly to PI. 
 
 DSM Plan Administration. The PI will be responsible for monitoring the study. The PI and 
statistician will examine the outcomes database for missing data, unexpected distributions or 
responses, and outliers. A DSM report will be filed with the IRB on a yearly basis, unless greater than 
expected problems occur. The report will include subject characteristics, retention and disposition of 


 
 
Flanagan, Julianne C. v.7/23/15 
20 
 
study subjects, quality assurance issues and reports of AEs, significant/unexpected AEs and serious 
AEs. We will report results at the end of the trial. 
 
DSM Board. We will create a DSMB to monitor the overall participant safety, the rate and 
severity of adverse events, and the validity and integrity of the data. The panel includes 2 researchers 
with experience in treating patients with SUDs and PTSD (Kathleen Brady, M.D., Ph.D.; Therese 
Killeen, Ph.D) and a statistician (Dr. Amy Wahlquist). The DSMB will also include Dr. Erin McClure, 
Ph.D., an additional investigator in the field of addictions and oxytocin. The board may be called at any 
point if needed for unexpected AEs, etc. Modification will be made in the procedures and/or the protocol 
if necessary based on the recommendations of the board. Confidentiality will be maintained during all 
phases of the study. 
 
 
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