Optimizing Pregnancy and Treatment Interventions for Moms 2.0
Phase: NA
Conditions: Pregnancy, High Risk, Opioid-Related Disorders, Pregnancy Related
Sponsor: University of Utah

i 
  
 
 
 
 
 
 
 
 
 
 
 
 
Study Protocol 
 
Optimizing Treatment  
Interventions for Moms 2.0 
 
NCT03833245 
 
Document Date: 4/22/2020 
 
 
 
 

ii 
 
TABLE OF CONTENTS 
 
INTRODUCTION ............................................................................................................. 1 
 
Background and Significance to the Field .................................................................... 1 
OPIOID-RELATED ADVERSE EVENTS AMONG WOMEN PERSIST AS A SERIOUS PUBLIC 
HEALTH PROBLEM.................................................................................................................. 1 
OPIOID USE DISORDER DURING PREGNANCY IS A TREATABLE CHRONIC CONDITION 1 
 
OBJECTIVES.................................................................................................................. 5 
 
Primary Objectives ....................................................................................................... 5 
 
STUDY DESIGN ............................................................................................................. 6 
 
Overview of Study Design ............................................................................................ 6 
 
Duration of Study and Visit Schedule ........................................................................... 6 
 
OUTCOME MEASURES ................................................................................................. 7 
 
Primary Outcome Measure .......................................................................................... 7 
 
Secondary Outcome Measure(s) ................................................................................. 7 
 
Study Timeline ............................................................................................................. 7 
 
STUDY POPULATION .................................................................................................... 8 
 
Participant Inclusion Criteria ........................................................................................ 8 
 
Participant Exclusion Criteria ....................................................................................... 8 
 
Strategies for Recruitment and Retention .................................................................... 8 
 
SITES .............................................................................................................................10 
 
Number of Sites and Participant Flow .........................................................................10 
 
STUDY PROCEDURES .................................................................................................11 
 
Screening Visit ............................................................................................................11 
 
Informed Consent Procedures for Participants .....................................................11 
 
HIPAA Authorization and Medical Record Release Forms ..........................................11 
 
Baseline Visit ..............................................................................................................11 
 
Randomization ............................................................................................................12 
 
Treatment/Intervention ................................................................................................12 
 
Premature Withdrawal of Participants .........................................................................14 
 
Study Halting Rules ....................................................................................................14 
 
Follow-Up ...................................................................................................................14 
 
Blinding .......................................................................................................................14 
 
Type of Blinding ...................................................................................................14 
 
Maintenance of the Blind .....................................................................................14 

iii 
 
 
Breaking the Blind ................................................................................................14 
 
Participant Reimbursement .........................................................................................15 
 
STUDY ASSESSMENTS ...............................................................................................16 
 
General Measures ......................................................................................................17 
 
Inclusion/Exclusion ..............................................................................................17 
 
Locator Form .......................................................................................................17 
 
Demographics Form ............................................................................................17 
 
Study Completion Form .......................................................................................17 
 
Clinical and Safety Assessments ................................................................................18 
 
Adverse Events (AEs) and Serious Adverse Events (SAEs) ................................18 
 
Suicidal Behavior Evaluation ................................................................................18 
 
TRAINING REQUIREMENTS ........................................................................................19 
 
Overall ........................................................................................................................19 
 
STATISTICAL DESIGN AND ANALYSES .....................................................................20 
 
General Design ...........................................................................................................20 
 
Study Hypotheses ................................................................................................20 
 
Rationale for Sample Size and Statistical Power .........................................................20 
 
Projected Number of Sites ...................................................................................20 
 
Projected Number of Participants per Site ...........................................................20 
 
Statistical Methods for Primary and Secondary Outcomes ..........................................21 
 
REGULATORY COMPLIANCE, REPORTING AND MONITORING ..............................23 
 
Regulatory Compliance ...............................................................................................23 
 
Statement of Compliance ............................................................................................23 
 
Institutional Review Board Approval ............................................................................23 
 
Informed Consent .......................................................................................................23 
 
Quality Assurance Monitoring .....................................................................................24 
 
Participant and Data Confidentiality ............................................................................25 
 
Health Information Portability Accountability Act (HIPAA) ....................................25 
 
Investigator Assurances ..............................................................................................25 
 
Financial Disclosure/Conflict of Interest ...............................................................25 
 
Clinical Monitoring.......................................................................................................26 
 
Prisoner Certification ...................................................................................................26 
 
Regulatory Files ......................................................................................................26 
 
Records Retention and Requirements .....................................................................26 

iv 
 
 
Study Documentation ..............................................................................................27 
 
Protocol Deviations .................................................................................................27 
 
Adverse Events (AEs) ......................................................................................27 
 
DATA AND SAFETY MONITORING PLAN ...................................................................29 
 
DATA MANAGEMENT ..................................................................................................32 
 
Design and Development ............................................................................................32 
 
Site Responsibilities ....................................................................................................32 
 
Data Collection ...........................................................................................................32 
 
Data Editing ................................................................................................................32 
 
Data Transfer/Lock .....................................................................................................32 
 
Data Quality Assurance ..............................................................................................32 
 
APPENDIX A: ADVERSE EVENT REPORTING AND PROCEDURES .........................34 
 
REFERENCES ...............................................................................................................37 
 

1 
 
 
INTRODUCTION  
 
Background and Significance to the Field 
Opioid-Related Adverse Events among Women Persist as a Serious Public Health Problem  
The US opioid epidemic continues to result in serious health consequences for pregnant and 
postpartum women. In the US from 2007 to 2012, an average of 21,000 pregnant women each 
year reported past month opioid misuse. 1 Age adjusted rates for overdose among women in the 
US increased more than six-fold from 1.4 in 1999 to 8.5 in 2016.2 Examining Pennsylvania (PA) 
and Utah (UT; the states where recruitment will happen in this study), these states have some of 
the highest rates of overdose among women compared to other US states.2 Specifically, PA’s 
overdose rate among women surpassed the national average in 2016, and rates of overdose 
death in UT among women have ranged 2-9 times higher than the national rate between 2009 to 
2016.2 Both PA and Utah are among the states with the highest opioid prescribing to pregnant 
women, with Utah being the highest in the nation (41.6%).3 Prenatal opioid use disorder (OUD) 
in the US has brought serious health consequences for mother and infant—including preterm 
delivery, low birth weight, NAS, and poor breastfeeding, and includes substantial expenditures of 
health care resourcs.4-9 Chances for HIV (OR=20.3, 95% CI = 13.8–29.7) and HCV (OR=150.2. 
95% CI = 120.9–186.6) infection among women with OUD are markedly higher than for those 
without OUD.10 Pregnant women with OUD have high rates of psychiatric illnesses,11,12 such as 
depression and anxiety,12-16 and other substance use disorders (SUDs),14,16,17 with particularly 
high rates of smoking (>80%).10,14,17 Neonatal abstinence syndrome (NAS), an opioid withdrawal 
syndrome among neonates, has also increased substantially from 3.4/1000 births in 2009 to 
5.8/1000 births in 2012.18 Poly-substance use among pregnant women with OUD has also been 
associated with higher levels of needed medications to treat NAS19 and longer duration of NAS 
treatment.20 Smoking combined with opioid use during pregnancy has likewise been related to 
longer duration of NAS treatment,21,22 greater NAS severity,23,24 and higher levels of medication 
needed to treat NAS symptomology.21,25 Any prenatal opioid use also has been associated with 
birth defects, including neural tube defects,26,27 conoventricular septal defects, atrioventricular 
septal defects, hypoplastic left heart syndrome, and gastroschisis.27 Compared with women 
without any SUDs, children born to mothers with OUD or OUD plus other SUDs also have been 
documented to have lower cognitive functioning as they mature.28 Problems resulting from illicit 
and prescription OUD also result in significant social issues. Pregnant women with OUD have 
been observed to have financial and housing instability,16 challenges related to employment, and 
involvement with the legal system.29,30 These data call for rapid and targeted primary prevention 
activities aimed at assisting pregnant women with OUD to become linked to and retained in 
treatment in order to reduce harms to them (including overdose) and their offspring. This project 
will expand our preliminary research of a novel patient navigation (PN) intervention designed to 
link and retain pregnant women with OUD in treatment (including MAT) and improve the health 
and wellbeing of mother and infant. 31  
Opioid Use Disorder during Pregnancy is a Treatable Chronic Condition 
The National Institute on Drug Abuse defines addiction as a chronic disease that can be managed 
and treated successfully with appropriate care.32 OUD among pregnant women is no exception 
and is a serious chronic health condition characterized by needs for long-term treatment and 
retention efforts. Prescription opioid-related OUD treatment admissions among pregnant women 
increased in the US from 2% in 1992 to 28% in 2012.33 In the US, the majority of illicit and 
medication-related OUD treatment admissions among women in 2012 were for pregnant 
compared to non-pregnant women.1 It is unfortunate that approximately 34% of pregnant women 
who enroll do not complete OUD treatment, with the majority leaving against medical advice 
(58%), being terminated early by the facility (20%), being incarcerated (5%), or dying (1%).33 

2 
 
Rates of relapse for mothers with OUD (in and outside of treatment) in the postpartum period who 
have achieved abstinence during pregnancy period have been noted to be as high as 80%.34,35 
Such relapse events following periods of abstinence are potentially fatal if individuals with 
decreased tolerance to opioids re-engage in opioid consumption with pre-abstinence quantities.36-
38  
Altogether, OUD is a serious chronic health condition, and pregnant women with OUD are at high 
risk for a number of comorbid medical, behavioral, and psychosocial problems that require 
concerted efforts—including linking and helping to retain women in OUD treatment as well as to 
other needed psychosocial resources and care. Fortunately, pregnancy has been observed to be 
an optimal time for behavior change among women.39-46 
Following the Chronic Care Model,47 the most effective models of care for chronic health 
conditions are designed to proactively engage patients, support clinical decisions based in 
evidence, employ information systems to guide practice, and promote patient self-management 
and uptake of community resources. 47-51 Models of care deployed in systems tooled to care for 
chronic health conditions have been demonstrated to significantly and clinically improve quality 
of care and patient outcomes.48-51 For pregnant women with OUD, some components of chronic 
condition models have been developed and tested. Yet, they have largely been developed and 
implemented in a fragmented fashion, resulting in limited outcomes. These components of care 
fall into two general areas: pharmacological and integrated/comprehensive care.  
Pharmacological treatment is successful but addresses only one aspect of the chronic 
condition. The dominant method of care for pregnant women with OUD is medication assisted 
treatment (MAT), specifically methadone and buprenorphine treatment.52 Opioid detoxification is 
not recommended during pregnancy given negative impacts on neonate birthweight and possible 
maternal withdrawal.53 Managing opioid withdrawal symptomology is significant for pregnant 
women in order to prevent subsequent opioid relapse. Preventing relapse is summarily important 
due to the serious health risks associated with illicit opioid use, such as infectious diseases 
transmission (HIV/HCV) and overdose.5,54 MAT is key in the care of pregnant women with OUD, 
but it must also be combined with additional behavioral health services that target psychosocial 
aspects of addiction.55,56 However, methadone and buprenorphine treatment studies rarely report 
improvements for outcomes such as engagement in mental healthcare, self-management, or 
social service resources. Superior models of care for opioid dependent pregnant women, 
therefore, ideally should be established upon principles of chronic disease management.57 It is 
important note that we recognize both methadone and buprenorphine therapies, as most 
medications, have strengths and limitations.52,58 The focus of this study will be to help patients 
engage in either form of MAT, following the woman’s preference, given benefits for mother and 
infant.  
Integrated and comprehensive care models are valuable but have limitations. To address 
the multiple and complex issues confronting pregnant women with OUD, integrated and 
comprehensive care models have been developed, tested, and have moved the field closer 
towards chronic condition management. Integrated care models for pregnant women with OUD 
are predominantly comprised of multidisciplinary teams providing care16,59 or outpatient SUD 
services delivered within hospitals/clinics where pregnant women receive healthcare services60-
62 (i.e., co-located behavioral health models). Results of these models have yielded health 
improvements for infants born to pregnant women with OUD.60-62 However, these models exclude 
important needs of pregnant women with OUD; such as mental health services, housing, food 
security, and poly-substance use. These models also lack methods for providers to promote self-
management and use of resources critical to mothers’ health and infant psychosocial 
development.  

3 
 
Given these limitations, comprehensive care models have been utilized among drug dependent 
women to provide a more complete spectrum of services in one location; including supported 
housing, counseling, pharmacotherapy, case management, physical/mental healthcare, and child 
and pediatric care.58,63-74 Comprehensive care models have demonstrated valuable results, 
especially for improved maternal and birth outcomes.64,72 These models have likewise shown less 
need for child protective services involvement, fewer child removals,69 and cost-effectiveness. 72 
However, most comprehensive care models delivered to pregnant women with OUD report few 
outcomes for services such as mental health, housing, and food security issues. A larger and 
more problematic limitation is these models require large amounts of space for in/outpatient 
services and high volumes of patients/revenue to support staffing expenditures. 71,72 Altogether, 
currently available integrated care models are limited for effective management of care for chronic 
disorders, such as addiction, which has serious and harmful consequences. Current 
comprehensive care models are arguably not easily implemented, scalable, or sustainable. We 
propose to build on these models to show our patient navigation (PN) intervention has the 
potential to substantially amplify outcomes for both mother and infant, including the breadth of 
outcomes for both populations in a likely scalable and sustainable model.  
Patient navigation for chronic health conditions. A highly promising option for chronic care 
management for linking and retaining pregnant women with OUD in treatment is the PN model. 
PN was first developed and implemented in 1990 by Dr. Harold Freeman.75 As a surgical 
oncologist, Freeman observed an unsettling 5-year survival rate of only 39% among low income 
and uninsured women presenting to the Harlem Hospital Center with later stages of breast 
cancer.75,76 Freeman initiated affordable breast screenings and the Hospital center began utilizing 
patient navigators. These low-cost services produced substantial improvements for early 
diagnosis and increased 5-year survival to 70%.75 Based on this success, PN has been tested 
and utilized for nearly 25 years for women with breast cancer.77 PN has evolved to address other 
conditions; such as HIV, palliative care, spinal disorders, behavioral/mental health disorders, and 
chronic diseases.75,78,79  
PN is distinct from other models such as care coordination or basic case management. The 
Agency for Healthcare Research and Quality distinguishes these models according to the core 
aims of each intervention.78 For example, care coordination is defined by different providers 
involved in the care of a patient.78 Each provider is dependent on the others to carry out their 
role.78 Case management is defined by the Case Management Society of America’s as, “...a 
collaborative process of assessment, planning, facilitation and advocacy for options and services 
to meet an individuals’ health needs through communication and available resources to promote 
quality cost-effective outcomes.” 78,80 PN is unique insofar as its focus is on reducing barriers and 
guiding patients through complex fragmented healthcare and social service systems.75,78 PN does 
not require a floor within a hospital to be allocated for in/outpatient services or require a substance 
abuse treatment program to be embedded within a healthcare setting. Importantly, PN is a model 
of care having a patient-centered philosophy that can be provided by non-professional (bachelors-
level) staff.  
Two themes unite and permeate PN models. First, PN breaks down barriers that prevent patients, 
typically 
the 
underserved, 
from 
accessing 
health, 
psychiatric, 
social, 
and 
family 
services.75,76,78,79,81,82 Barriers often include psychosocial issues such as fear/anxiety, 
communication, transportation, finances, the medical system, and lack of information.75,76,81 
Second, to understand the patient and address their barriers to care, patient navigators develop 
1-to-1 relationships to provide personalized support focusing on individual needs.75,76,78,81 Despite 
evidence of its strong effectiveness and support for dissemination, PN has only recently begun to 
be researched in relation to behavioral health problems.83-86 Lasser et al. showed that PN 
recipients made smoking cessation plans and engaged in treatment more than controls. Bradford 
et al.87 found PN recipients with HIV exhibited improved health results, enhanced HIV outcomes, 

4 
 
better physical and mental health, and more health insurance enrollment. Detailed within the 
preliminary studies section below, our team recently completed a proof-of-concept study where 
we tested feasibility as well as monitored the initial impact of a PN intervention for pregnant 
women with OUD receiving MAT in a prenatal care clinic (N=21). 31 Our findings included 
demonstrating clear intervention feasibility and promising initial results for women in a number of 
behavioral and physical health domains, including improvements for opioid/substance use, 
mental health, and prenatal care outcomes. 31  

5 
 
 
OBJECTIVES  
 
Primary Objectives 
Strong evidence supports PN as an evidence-based practice to address various health conditions 
among different populations and settings.79,81,85,88,89 Navigation’s strengths for populations with 
OUD encompass individual-level support, case coordination, and strength-based case 
management that include activities such as: (1) linking patients to OUD treatment, health care, 
and social services, (2) monitoring and encouraging adherence to treatment, (3) shepherding 
follow-through with commitments, and (4) ensuring treatment retention and outreach for women 
who disengage in care. Therefore, given poor neonatal outcomes; 4-7 complex physical, mental, 
and behavioral health comorbidities, 10-17 and social/legal problems for pregnant women with 
OUD,16,29,30 PN is a likely potent model of care that has excellent prospects for improving health 
and psychosocial outcomes. Accordingly, our Optimizing Pregnancy and Treatment Interventions 
for Moms 2.0 (OPTI-Mom 2.0) project will expand our proof-of-concept project and conduct a 
small-scale multisite randomized clinical trial. Specifically, this project will achieve three Specific 
Aims (Table 1). Accomplishing the following Aims establishes critical foundational data for a 
subsequent fully-powered multisite randomized trial.  
Table 1. OPTI-Mom 2.0 Specific Aims: 
 To enhance the PN intervention to prevent postnatal relapse 
 To expand protocols/procedures for multisite, randomized, health system-wide testing  
 To demonstrate the preliminary benefit of PN for facilitating: linkage to 
treatment/retention in behavioral/physical health care and psychosocial services 
 
 
 
 

6 
 
 
STUDY DESIGN  
 
Overview of Study Design  
Opioid dependent pregnant women who present at Magee-Womens Hospital of UPMC and the 
University of Utah Hospital ≤32 weeks of gestation will be approached for potential participation 
in our OPTI-Mom 2.0 study. Our prenatal intervention is designed to span between 8 and 14 
weeks and is dependent on gestational age at the time of enrollment. This allows study 
participants to receive the maximum amount of intervention sessions available prior to delivery. 
The following Approach Section describes preliminary data we have collected to support this 
proposal, project design, inclusion/exclusion criteria for participation, recruitment, intervention 
conditions, data collection/analysis, and timeline. 
 
Duration of Study and Visit Schedule 
This study will require 36 months to complete. Patient recruitment will last 15 months, intervention 
deliver will last 24 months, and assessments will last 30 months. As indicated, the prenatal portion 
of the study will include up to 10 sessions that span between 8 and 14 weeks. In addition, we will 
also provide 4 postnatal interventions that span 8 weeks. Each of these sessions lasts 1-1.5 
hours. All participants, in the treatment or control group, will be required to complete 4 
standardized assessments, which will occur at baseline, following the completion of the prenatal 
portion of the intervention, following the postnatal portion of the intervention at approximately 2 
months post delivery, and 6 months following delivery. See SOP for data collection.  

7 
 
 
OUTCOME MEASURES  
 
Primary Outcome Measure  
 
The primary outcomes in this study are (1) OUD and other SUD treatment linkage/retention, (2) 
opioid abstinence, (3) adherence to MAT, and (4) linkage/retention in psychosocial services. 
 
Secondary Outcome Measure(s)  
 
Secondary outcomes of this study involve capturing prenatal care, HIV/HCV risk behaviors, 
depression and anxiety, and child/mother indicators. 
 
Study Timeline 
Quarter 1 of the project will involve IRB application/completion, intervention 
augmentation/adaptation, protocol adaptation/expansion, and assessment battery completion. 
The first 2 quarters will also involve hiring/training personnel. Subsequently, patient recruitment 
will occur over 15 months, with intervention delivery and outcome assessments happening 
simultaneously. Intervention delivery and outcome assessments will extend 9 and 15 months 
beyond recruitment, respectively, in order to allow sufficient time to complete each. DSMB 
meetings will also happen semi-annually.  

8 
 
 
STUDY POPULATION  
This study will recruit adult women who are pregnant, with opioid use disorder, who are presenting 
at the Magee-Womens Hospital of UPMC or the University of Utah Health system for any care 
needs.  
 
Participant Inclusion Criteria  
This study will recruit women for participation meeting the following inclusion criteria: 
• 
Adult (≥18 years) 
• 
English speaking  
• 
Pregnant women (pregnancy status verified by gestational age >6 weeks from last 
menstrual period confirmed by ultrasound)  
• 
OUD verified by examination of medical records for an OUD diagnosis and the DSM 
Checklist (modified from the DSM-IV to confirm current diagnosis for substance use 
disorders) 
• 
Plan to carry their babies to delivery verified by patient self report 
 
Participant Exclusion Criteria  
All women meeting any of the exclusion criteria at baseline will be excluded from study 
participation: 
 
• 
Experienced a psychotic or a manic episode in the last 30 days documented in their 
medical record or self report 
• 
Beyond the 32nd week of gestation  
• 
Cannot provide collateral contact information of 2 persons 
• 
Cannot provide a reliable phone number  
• 
Plan to move from the area within study recruitment to 6 months after their delivery  
• 
Inability or unwillingness of subject to give written informed consent. 
• 
Other factors that would cause harm or increased risk to the participant or close contacts, 
or preclude the participant’s full adherence with or completion of the study 
• 
Has been on buprenorphine or methadone for >6 weeks. 
 
Strategies for Recruitment and Retention  
Two hospitals will be utilized as locations for identifying, recruiting, and engaging with potential 
project participants. The following methods will be used to recruit women into this study.  
 
• 
Behavioral health staff at both performance sites will be trained in referring possible 
patients to our study. Behavioral health staff will be trained in the inclusion and exclusion 
criteria for this study. OPTI-Mom research staff will reach out to hospital staff each month 
to ensure they are familiar with study and encourage them to referral patients. When they 
encounter patients who they believe will be eligible for this study, they will relay to patients 
that they might be eligible for study participation (see Study Information Form). If the 
participant expresses interest in learning more about the study opportunity, the behavioral 
health staff member will facilitate contact with the study staff either by directly connecting 
the patient to the staff in person or via phone. If time does not allow for directly connecting 
the patient to the study staff, the patient will be provided with a study advertisement 

9 
 
handout and/or the behavioral health staff person will relay patient contact information to 
the study staff.  
• 
Patients will be contacted through the University of Pittsburgh Pitt+Me research registry. 
Patients with ICD9/10 codes for pregnancy and OUD or opioid overdose will be identified 
in this registry. Potential participants in the Pitt+Me system have already acknowledged 
interest possibly participating in research. All participants are UPMC patients. Once 
contacted by Pitt+Me, these patients contact study staff who will screen for possible 
inclusion in the study. 
• 
Study staff at both performance sites will also be trained to identify potentially eligible 
patients using patient medical records systems to locate women with OUD and who are 
pregnant (See Magee EMR review 1-2 and Utah EMR review). Once identified in the 
medical record systems, patients will be mailed a letter informing them they are eligible 
for a research study. Letters will be mailed to participants as much as weekly. Letters will 
not disclose how patients are possibly eligible in order to protect privacy. Patients will be 
invited to contact study stuff to learn more about the study. Patients will also be informed 
in the letter that research staff will contact them after a week of not hearing back from 
them. After a week, research staff will reach out to potential patients.  
• 
Study flyers will also be posted within the hospitals and clinics bulletin boards, waiting 
rooms of the performance sites and local outreach sites and facilities (see Advertisement). 
These flyers will contain general study information and study staff contact information.  
 
Study staff who contact patients will do so from the University of Utah SUPeRAD clinic, staff 
research office space in Research park, staff office space from Magee Womens Research 
Institute or an appropriate and private location. Calls will be made from study use only cell phones 
or from office phones. Voicemail and other messaging is all password protected. If patients 
provide an email address, study staff may also contact them via this method. All computers and 
university related email accounts used to contact potential participants will be password protected.  
 
Both sites will capture the number of eligible patients approached, number of patients 
approached, number of patients who chose to screen and those who did not. Reason for not 
screening will be captured. We will also capture the reason for why patients who were screened 
as ineligible were not eligible. Finally, we also capture the number of patients who chose to 
provide informed consent and those that did not. We will likewise capture the reasons patients 
may given for not providing informed consent and enrolling in the project. All these records will be 
captured using REDCap.  
 
In order to ensure adequate follow up with participants; contact and locator information will be 
used to engage patients through multiple mediums, including phone, text, email, social media, 
and mail. See SOP for Continued Engagement.  

10 
 
 
SITES 
 
Number of Sites and Participant Flow 
Two sites will be used for participant recruitment in this study. A total of 122 women will be 
recruited for participation in this study. We anticipate an even distribution of 61 women recruited 
at each site. For the 61 women recruited and randomized to the PN condition, we expect 
approximately 30 will be recruited at the University of Utah and 31 at the University of Pittsburgh. 
Based on estimates of a recruitment window of 15 months and active intervention delivery across 
24 months, we will recruit approximately 5 patients per month between both sites. In terms of 
monthly patient caseload during the 6 busiest months of the study, each site will have 
approximately 9 to 12 active (pre and postnatal) participants at one time.  

11 
 
 
STUDY PROCEDURES  
 
Screening Visit 
Once patients have been identified and have expressed interest in learning more about this 
possible study opportunity, staff will receive permission to screen these patients using the 
inclusion and exclusion criteria. Permission for screening will be obtained using an oral screening 
consent form (see SOP for Screening, Consent, Locator, Initiation, Assessment and Blinding). 
Those who screen positive will then be provided with the full consent documents for study 
enrollment.  
 
Informed Consent Procedures for Participants  
Study procedures and the potential risks and benefits of participating in the trial will be explained 
to participants (see SOP for Screening, Consent, Locator, Initiation, Assessment and Blinding). 
We also will obtain permission to audio record intervention sessions for intervention fidelity 
monitoring purposes. Given the multi-site nature of the trial, it is possible that ancillary studies will 
be proposed before or after the study begins recruitment. For this reason, during the informed 
consent process, we also will seek permission to contact the participant in the future about other 
study opportunities. Staff will be available to answer questions about the consent form while 
participants are reviewing it. Prior to signing the consent form, the participant must pass a brief 
consent comprehension tool to illustrate comprehension of the study activities. After successful 
completion of the tool and signing the consent form, participants will be given a copy to keep for 
their records. The informed consent process will take approximately 20 minutes to complete. 
 
Participants who pass the screen and consent will complete a locator information form which will 
be used to contact them to remind them of follow-up visits and to locate participants who cannot 
be found. Trained study staff members will work with the participant to complete this form. When 
completing this form, participants will be required to provide their names, addresses, and 
telephone numbers as well as contact information for at least 2 other persons. Locator information 
will be updated at the follow-up visits and at any other time during the study, as needed. The 
locator information form will take approximately 5-10 minutes to complete. Patients not able to 
provide at least 2 collateral contacts will not be allowed to participate in the study. Participants 
will be directed to inform their 2 collateral contacts that they are in the study. The participant will 
also be informed that she may disclose any level of detail about her involvement with the study to 
her locator contact she wishes. By sharing this information, should the study contact the collateral, 
these individuals will know the participant is already in the study.  Locator information will be 
reverified at each follow up visit.  
 
HIPAA Authorization and Medical Record Release Forms 
As part of the enrollment process, we will obtain written permission from the patient to access 
their University of Utah and University of Pittsburgh medical records. We will likewise obtain 
permission from participants to access services records from community agencies where they 
may obtain health and social services.  
 
Baseline Visit  
After patients complete the locator information form, they will complete a baseline assessment. 
The study staff member administering the assessment will have completed all required CITI 
training modules. Drs. Cochran and Krans will also train the study staff in survey administration 
methods, specifically with how to appropriately ask sensitive questions and to respond to 
responses from patients regarding sensitive topics (including reporting information to study PIs 

12 
 
by the participant regarding intention to harm self or others). Training will include Drs. Cochran 
and Krans going over the survey with the research assistant, modeling appropriate 
administration, practicing administration, and supervised administration for the first 3 subjects 
enrolled in the study. The study baseline assessment will happen at the SUPeRAD clinic, 
research offices, Magee Womens Research Institute, or other appropriate and private locations. 
Assessments will be completed using REDCap surveying technology. Survey responses will be 
reviewed by study staff to ensure completeness. Completed surveys will be immediately saved 
online. The baseline assessment will take approximately 30-45 minutes.  
 
Randomization  
Following the baseline assessment, participants will be randomized on a 1:1 basis to PN or 
standard care (i.e., short-term case management + referral). The study statistician will create a 
randomization list to assign patients to treatment or control conditions. The statistician will also 
review the randomization data on a regular basis to ensure that the scheme is being implemented 
according to plan. If a participant drops out of the study at any point after randomization, the 
randomization slot will not be re-allocated to a new patient due to the intent-to-treat nature of the 
study. 
 
Treatment/Intervention  
Standard care. The standard care condition at Magee and the University of Utah hospitals 
includes brief case management and referral. The brief case management involves the participant 
speaking to a hospital social worker who conducts a patient needs assessment in the areas of 
behavioral health and social services. All patients will be referred to MAT and any identified 
behavioral health or social service needs. For MAT, Magee-Womens Hospital offers resources 
for onsite induction to methadone or buprenorphine (mono-product), with continued methadone 
maintenance only provided by community partners and continued buprenorphine offered by an 
internal Magee clinic or community partners. University of Utah patients are offered 
buprenorphine induction and maintenance (buprenorphine-naloxone product) at a local University 
of Utah outpatient clinic or from community partners. Methadone services for University of Utah 
patients are only provided by community partners. Staff social workers at Magee and the 
University of Utah will be provided with information on the study each quarter during the study 
recruitment phase and be instructed to closely follow and not deviate from their hospital standard 
care protocol. These quarterly meetings/trainings will be delivered in order to prevent threats to 
internal validity and biasing study outcomes.  
Patient navigation (PN). Details of the navigation can be found in the PN Intervention Manual. 
The PN intervention will be delivered by the study navigator. Table 4 contains details of the PN 
intervention. The PN intervention will initiate following participant recruitment. It is important to 
note that in Table 2, PN sessions do not strictly coincide with specific weeks of pregnancy since 
the women can be recruited up to ≤32 weeks of gestation. The prenatal portion of the intervention 
includes up to 10 sessions delivered prior to delivery. The postnatal portion of the intervention will 
be delivered as 4 sessions over 8 weeks. Women who complete the intervention before delivery 
will receive regular calls/texts until delivery wherein the navigator will encourage and reinforce 
abstinence and treatment retention (see SOP for continued engagement). All contact will be 
reported by staff in a participant contact log developed for the study that will be used to quantify 
level of patient contact.  
Our PN model is based on the work of Parker37 and the recently completed Project HOPE study 
(Hospital Visit as Opportunity for Prevention and Engagement for HIV-Infected Drug Users).38,110 
The study navigators will receive a two day training in motivational interviewing tailored to the 
study intervention manual and must demonstrate motivational interviewing proficiency assessed 
by trainers. The navigators will also receive a one-day training in the intervention protocol by study 

13 
 
investigators. Navigators will complete 3-5 practice sessions, which will be audio recorded and 
assessed using intervention checklists. Feedback from practice sessions will be shared with 
navigators in directly and in group discussions. Intervention fidelity checking will also occur 
throughout the study with navigators audio recording all PN sessions, which will be selected at 
random for fidelity assessments and feedback by the study coordinator and project investigators.  
The primary goal of the current PN intervention is linking patients before and after delivery to 
treatment/psychosocial care and clinical support for participants’ retention in those services. All 
PN patients will be referred to MAT by the study navigator (see standard care description above 
for site differences for MAT resources). It is through the navigator linking and helping to retain 
participants to OUD, other SUD, medical, mental health, social, and family services that will 
stimulate positive short- and long-term outcomes for mother and infant. While Magee and the 
University of Utah hospitals facilitate initiation into MAT, a major challenge for women is linking to 
services for ongoing MAT and subsequently being retained in care. Patients will be encouraged 
to work with their providers to choose the form of medication, buprenorphine or methadone, which 
will best meet their needs. The navigator will support and encourage the patient to follow through 
with this treatment. The PN intervention will also target better compliance with pre/postnatal 
maternal healthcare, more effective transition of newborns into pediatric care, and relapse 
prevention (i.e., Aim 2). The PN intervention specifically encompasses two complementary and 
necessary services: strengths-based case management (SBCM) and 1-to-1 clinical support (see 
Table 2). PN sessions will last 1-1.5 hours. Furthermore, given the challenges keeping this 
population engaged in care, the intervention emphasizes community outreach. For example, the 
navigator can visit the neighborhoods to meet participants’ social and family networks to 
empathically encourage and support engagement with health, social services systems, and 
recovery support (i.e., narcotics anonymous, alcoholics anonymous) if patients become 
disengaged in care or follow up.  
SBCM is an evidenced-based component of the PN model that has been demonstrated to help 
individuals with substance use disorders and chronic health conditions engage in needed care. 
34,35 The navigator will apply the specialized skills of SBCM to link patients to ongoing MAT 
services and guide participants to active engagement in health and social services. SBCM gives 
patients responsibility for, and ownership of, their recovery.35 SBCM has been shown to have a 
variety of positive effects, particularly treatment retention111,112 and linkage with community 
services.113 SBCM utilizes patients’ strengths for goal setting and developing a working alliance35 
between providers and patients. The specific elements the navigator will focus on include: helping 
patients obtain and complete paperwork; accessing and engaging in drug/mental health 
counseling/treatment/mutual support, social services uptake, MAT linkage/retention, and 
engagement in pre/post-natal care and pediatric/developmental care for newborns. It is important 
to note that participants and the navigator will collaborate to identify already existing health and 
community services that participants will subsequently engage in with the navigator’s assistance. 
One-to-one clinical support is a paramount PN component for identifying, establishing, and 
retaining health behavior improvement goals. One-to-one clinical support is designed to 
motivate and assist patients recognize and overcome internal/external barriers to care, 
including: emotional support, decision support, lifestyle change support, monitoring outcomes of 
screening/diagnostics, health behavior, and HIV/HCV prevention education.37 HIV/HCV 
prevention messaging will address needle sharing and unsafe sex. Patients will receive support 
and verbal reinforcement for completion of paperwork, engaging in drug/mental health 
treatment, social services uptake, agonist adherence, and engaging in pediatric/developmental 
care for their infants. One-to-one clinical support will be delivered using motivational 
interviewing skills.114 Motivational interviewing is an evidence-based approach for promoting 
health behavior change in healthcare settings.114,115 The navigator will collaborate with 
participants to resolve ambivalence toward change by guiding them to establish their own goals 

14 
 
and strategies, giving them ownership in outcomes, helping build self-efficacy, and increasing 
the likelihood of achieving abstinence and MAT retention goals. We have also aligned PN 
session objectives to support and assist women to prepare for, discuss, and successfully 
complete specific maternal milestones. 
 
Premature Withdrawal of Participants  
All participants will be followed for the duration of the study unless they withdraw consent, are no 
longer pregnant due to spontaneous abortion (miscarriage) or termination that was unplanned at 
the time of enrollment, die, or the investigator or sponsor decides to discontinue their enrollment 
for any reason. Reasons for the investigator or sponsor terminating a participant from the study 
may include, but are not limited to, the participant becoming a threat to self or others, lack of 
funding, DSMB early termination of the study for safety or effectiveness determination.  
 
Study Halting Rules 
The study will be halted based on lack of funding.  
 
Follow-Up  
Participants will be assessed at baseline, following the completion of the prenatal portion of the 
intervention, following the postnatal portion of the intervention at approximately 2 months post 
delivery, and 6 months following delivery. See SOP for data collection. Appointments for follow 
up sessions will be made with participants by study staff. At the follow up visits, the first step in 
the assessment will be to confirm participant contact information and to ensure locator 
information has not changed. Following contact information verification, patients complete a 
survey assessment similar that completed at the baseline assessment. The study follow up 
assessments will happen at the SUPeRAD clinic, research offices, Magee Womens Research 
Institute, or other appropriate and private locations using REDCap surveying technology. Survey 
responses will be reviewed by study staff to ensure completeness. Completed surveys will be 
immediately saved online. The follow up assessments assessment will take approximately 30-
45 minutes at each visit—see urine drug screen SOP.  
 
Blinding  
 
Type of Blinding  
This study is a single blinded randomized clinical trial.  
 
Maintenance of the Blind  
The individuals blinded to the study condition will be those conducting the study assessments. 
The baseline assessment will be blinded given that the randomization will not be revealed until 
after the assessment is completed. The follow up assessments will be conducted by a blinded 
research assistant.  
 
Breaking the Blind  
As the research assistant is the only blinded party, there is no scenario in which the blind will 
need to be broken.  Investigators providing clinical management and decision-making are 
informed of each participants randomization result.  
 
 

15 
 
 
Participant Reimbursement  
Women will receive $30 for enrolling in the study and completing the baseline assessment, $40 
for completion of the second assessment, $50 for the third assessment, and $75 for the final 
assessment. Patients that complete all 4 assessments will be given a completion bonus of $50. 
Patients will also be provided with a $10 compensation for each navigator session they attend to 
cover costs associated with transportation and/or parking. Participant compensation 
administration will be carried out by the study project coordinator or research assistants.  
 
 

16 
 
 
STUDY ASSESSMENTS  
A full and complete list of all assessments used in the study is to be included in the following 
sections.  
Outcom
e 
Domain 
Name 
Source 
Screen 
Base 
PreNat 
2mo 
6mo 
1/2ary 
Engage 
Treatment 
Services Review 
Self-
Report 
  
x 
x 
x 
x 
1/2ary 
SUD 
Timeline Follow 
Back 
Self-
Report 
  
x 
x 
x 
x 
1ary 
Engage 
Substance use 
treatment visits 
Medical 
record 
  
x 
x 
x 
x 
1ary 
Engage 
Psychiatric care 
visits 
Medical 
record 
  
x 
x 
x 
x 
1ary 
SUD 
Urine toxicology 
NA 
x 
x 
x 
x 
x 
1ary 
Engage 
Social service 
visits 
Agency 
record 
  
x 
x 
x 
x 
2ary 
HIV/HCV 
risk 
Risk Behavior 
Assessment 
Self-
Report 
  
x 
x 
x 
x 
2ary 
Social 
Maternal Social 
Support Index 
Self-
Report 
  
x 
x 
x 
x 
2ary 
Social 
Parenting Stress 
Index-Short 
Form 
Self-
Report 
  
x 
x 
x 
x 
2ary 
Social 
Maternal 
Attachment 
Inventory 
Self-
Report 
  
x 
x 
x 
x 
2ary 
Engage 
Adequacy of 
Prenatal Care 
Utilization 
Medical 
record 
  
  
  
x 
  
2ary 
Engage 
Pre/post 
maternal care 
visits 
Medical 
record 
  
x 
x 
x 
x 
2ary 
Engage 
Pediatric visits 
Medical 
record 
  
x 
x 
x 
x 
2ary 
SUD 
Neonatal 
abstinence 
syndrome 
Medical 
record 
  
  
  
x 
  
2ary 
Engage 
Pre/post 
maternal care 
visits 
Medical 
record 
  
x 
x 
x 
x 
2ary 
Engage 
Pediatric visits 
Medical 
record 
  
  
  
x 
x 
Covar 
SUD 
Drug Abuse 
Severity Test 10 
Self-
Report 
  
x 
x 
x 
x 
Covar 
SUD 
Alcohol Use 
Disorder 
Self-
Report 
  
x 
x 
x 
x 

17 
 
Identification 
Test 
Covar 
SUD 
Fagerstrom Test 
for Nicotine 
Dependence 
Self-
Report 
  
x 
x 
x 
x 
Covar 
Health 
Short Form 36  
Self-
Report 
  
x 
x 
x 
x 
Covar 
Psych 
Patient Health 
Questionnaire 
Self-
Report 
  
x 
x 
x 
x 
Covar 
Social 
Addiction 
Severity Index 
(employment) 
Self-
Report 
  
x 
x 
x 
x 
Covar 
SUD 
DSM 5 Checklist 
Self-
Report 
x 
x 
x 
x 
x 
 
 
General Measures  
 
Inclusion/Exclusion 
This form lists each inclusion and exclusion criterion to document eligibility. Eligibility is assessed 
continually as appropriate. Only participants who continue to meet study eligibility criteria are 
allowed to continue with the screening process, consent and randomization. 
 
Locator Form 
A locator form is used to obtain information to assist in finding participants during treatment and 
at follow-up. This form collects the participant’s current address, email address, and phone 
numbers. In order to facilitate locating participants if direct contact efforts are unsuccessful, 
addresses and phone numbers of family/friends who may know how to reach the participant are 
collected, as well as additional participant information such as social security number and other 
information to aid in searches of public records. This information will be collected at screening 
and will be updated at each visit. No information from this form is used in data analyses. 
 
Demographics Form 
The Demographics form collects information about demographic characteristics of the participant, 
including date of birth, ethnicity, race, education, employment status, and marital status. This form 
is completed at screening. 
 
Study Completion Form 
This form tracks the participant’s status in the study. It is completed at the final postnatal visit or 
once the 6-month follow-up visit window lapses for participants who do not complete this final 
follow-up. This form is used in data analyses to address variables such as treatment retention 
and completion. This form also provides a location for the site PI attestation of review of all study 
data. 
 
 

18 
 
 
Clinical and Safety Assessments  
 
Adverse Events (AEs) and Serious Adverse Events (SAEs) 
At each visit the study navigator assesses for AEs and SAEs by asking the study participant, 
“How have you been feeling since your last visit?” AEs and SAEs may also be spontaneously 
reported to study staff at any visit following consent. AEs and SAEs suggesting medical or 
psychiatric deterioration will be brought to the attention of a study clinician for further evaluation 
and management. Visits will emphasize overdose risk and risk-management. Any reported 
overdose is recorded as an AE or SAE, or in a separate form. AE and SAE reporting is according 
to the reporting definitions and procedures outlined in the protocol and in accordance with 
applicable regulatory requirements.  
For the purpose of this study, the following AEs do not require reporting in the data system but is 
captured in the source documentation as medically indicated: 
Grade 1 (mild) unrelated adverse events. This would typically include mild physical events such 
as headache, cold, etc., that were considered not reasonably associated with the study 
intervention. 
 
 
Suicidal Behavior Evaluation 
Within the Patient Health Questionnaire is embedded a validated single item suicide screening 
tool. This item is assessed at each visit. If the participant screens positive for depression, the 
navigator will ensure the participant contacts the Resolve Crisis Center to arrange for follow up 
(1-888-796-8226) within the University of Pittsburgh or the Crisis and Interventional and Hospital 
Diversion Crisis Line within the University of Utah (1-801-587-3000). If the participant screens 
positive for suicidality, the navigator will immediately follow the study Suicide Management Plan 
(see REDCap form). Similarly, if the participant appears to be intoxicated or reports experiencing 
symptoms of opioid withdrawal, the navigator will immediately notify the site study physician who 
can further assess and direct steps for possible additional care depending on participant need. 
 
 
   

19 
 
 
TRAINING REQUIREMENTS  
 
Overall 
A Training Plan will be developed to incorporate general training, study-specific training, 
mechanisms for competency assessment as well as a detailed description of training, supervision, 
and fidelity monitoring procedures. The Investigative Team is responsible for the development of 
a comprehensive Training Plan, instructional material, and delivery of the training. 
 
Training will include Human Subjects Protection (HSP) and Good Clinical Practice (GCP) as well 
as protocol-specific training on assessments, medication management for pharmacological 
studies, study interventions, safety and safety event reporting, study visits and procedures, data 
management, quality assurance, laboratory procedures, etc. The University of Utah site is 
primarily responsible for development and delivery of study-specific training related to the study 
intervention(s) and procedures. The University of Utah site also is responsible for training related 
to data management, the electronic data capture system, and good data management practices.  
 
Study staff is required to complete institutionally required training per their research site, 
Institutional Review Board(s), and authorities with regulatory oversight. Tracking of training 
completion for individual staff as prescribed for assigned study role(s) will be documented, 
endorsed by the site Principal Investigator and the project coordinator. As changes occur in the 
prescribed training, the Training Plan and training documentation tracking forms will be amended 
to reflect these adjustments. 
 

20 
 
 
STATISTICAL DESIGN AND ANALYSES  
 
General Design  
This study design for this project is a small scale, multisite, phase 2, single blinded, randomized 
clinical trial. Randomization will be stratified by hospital site and performed in blocks of 6 to 
ensure an even distribution of Magee and University of Utah participants in PN and standard 
care groups. 
 
Study Hypotheses  
H1: PN recipients will have superior linkage and retention in: (a) OUD and other SUD treatment, 
(b) psychosocial services, and (c) pre/postnatal care compared to standard care.  
 
H2: A larger portion of PN patients will be (a) MAT adherent and (b) drug abstinent compared to 
standard care. 
 
H3: Higher levels of engagement/retention in care will positively moderate improvements in: (a) 
abstinence, (b) HIV/HCV risk behaviors, (c) depression/anxiety, and (d) child/mother outcomes 
(e.g., health care, NAS, stress). 
 
Rationale for Sample Size and Statistical Power  
 
Projected Number of Sites  
Two hospitals will be utilized as locations for identifying, recruiting, and engaging with potential 
project participants. Both hospital locations are major centers of activities for women’s health 
within their respective health care systems. Both study hospitals are destination service centers 
for pregnant women to receive testing, care, and for eventual delivery. Specifically, Magee-
Womens Hospital of UMPC is a hub for women’s health care in Allegheny County as well as 
western PA. This hospital provides a number of health care services to pregnant women, including 
emergency department, obstetrics/gynecology, midwifery, and fertility services. The University of 
Utah is likewise a hub for care in Salt Lake City and the state of UT. This hospital is an urban 
level-1 trauma center with a number of services available for pregnant women, which include 
obstetrics/gynecology, midwifery, and fertility services. 
 
Projected Number of Participants per Site 
Given this study is designed as a pilot study testing an expanded intervention and 
protocols/procedures, sample size is not based on a power estimate. Rather, our sample size is 
based on our estimates of how many patients can be screened and consented within the study 
timeframe, an appropriate method for pilot studies.90 Based on the above detailed counts of MAT 
inductions among pregnant women from Magee-Womens Hospital from 2013 and 2017, we 
anticipate an average of 141 potential women recruits each year. Further, based on the above 
described numbers of total pregnant women with OUD/overdose (i.e., poisoning) from the 
University of Utah from 2015-2017, we anticipate an average of 58 potential recruits each year. 
Therefore, if we screen and recruit patients across 15 months, and if 70% are eligible and 
interested, and of those, 70% provide informed consent; we will recruit a total of 122 patients in 
this study who will be randomized to the PN (n=61) or standard care conditions (n=61). 
Importantly, working to recruit, randomize, provide PN/standard care, and retain 122 pregnant 
women with OUD during the study timeframe will allow us sufficient time to learn to implement 
and manage this study across 2 sites in preparation for a subsequent fully-powered trial. 

21 
 
While definitive estimation and hypothesis testing are not the aim of this pilot study, the target 
sample sizes will allow estimation of odds ratios via 95% confidence intervals comparing outcome 
rates in the treatment and control arms, while accounting for within site clustering, with lower 
bounds differing from the odds ratio estimate by a factor of 1/3 to 1/2 and upper bounds differing 
from the odds ratio estimate by a factor of 2 to 3 for a broad range of overall rates, true odds 
ratios, and magnitude of site-to-site effects. In particular, the pilot study will allow detection of 
strong signals of preliminary benefit, and provide suggestions of benefit for more subtle signals.  
Of the 122 women recruited to participate in this project, based on our preliminary information 
about patient flow at each site, we expect that 61 will be recruited at each site. For the 61 women 
recruited and randomized to the PN condition, we expect an equal recruitment distribution at each 
site.  Based on estimates of a recruitment window of 15 months and active intervention delivery 
across 24 months, we will recruit approximately 5 participants between both sites. In terms of 
monthly caseload during the 6 busiest months of the study, each site will have approximately 9 to 
12 active (pre and postnatal) participants at one time. 
 
DSMB recommendation on November 1, 2019 was to evenly distribute recruitment goals for both 
sites. This is due to more outside agencies in Pennsylvania that are offering prenatal care and 
services for women with substance use disorders.  
 
Statistical Methods for Primary and Secondary Outcomes  
We will employ descriptive statistics to calculate measures of central tendency, frequencies, and 
proportions for patient demographics and substance use, health, social, and mother/child 
indicators. T-tests and χ2 tests will be used to assess mean and proportion differences between 
outcome variables by study group at each time point. Specifically, we will examine unadjusted 
differences between PN and standard care patients for linkage/retention in: (a) OUD and other 
SUD counseling, (b) psychosocial services, and (c) pre/postnatal care compared to standard care. 
We will also examine unadjusted differences between groups for MAT adherence, opioid and 
non-opioid drug abstinence, HIV/HCV risk behaviors, depression/anxiety, and child/mother 
outcomes (e.g., NAS, parental stress, attachment, and maternal social support). 
We will also develop a series of multilevel models to examine treatment, time, and covariate 
effects associated with our primary and secondary study outcomes (Equation 191,92). The 
multilevel framework allows for a flexible treatment of time where change as a putative outcome 
may be nonlinear, accelerates, or decelerates at different rates across time. The framework is 
also forgiving of unequal numbers of observations and unequal spacing of observations across 
participants (i.e., missing data patterns). Models will be constructed using a model-building 
sequence proposed by Singer and Willett,93 in which: (a) empirical growth plots will be examined 
visually, (b) an unconditional model will be fit, (c) an unconditional linear growth model will be fit, 
(d) unconditional non-linear models (e.g., a piecewise model) will be fit, (e) the models’ fit in the 
prior steps will be compared using the Akaike Information Criterion to determine the best growth 
model, and (f) time-invariant (e.g., baseline mental health diagnoses) and time-varying (e.g., drug 
use) predictors will be added to the models. We will examine the association of these predictors 
with the study outcomes across time. We will also test higher levels of service linkage/retention 
as moderators for improvements in (a) abstinence, (b) HIV/HCV risk behaviors, (c) 
depression/anxiety, and (d) child/mother outcomes. 
Included below is the equation for a random-coefficient multilevel growth model. The 𝑌𝑌 in the 
equation represents a binary opioid abstinence outcome, for example, for the 𝑖𝑖 th participants at 
time t. The symbol “~” indicates that the binary response with linear predictor given by the right 
hand side in the context of a logistic mixed effects model, with random effects for site, and 
potentially time within site. The primary variable types are represented in the equation: (a) time is 

22 
 
a variable representing time that may require multiple time variables in the event of nonlinear 
change (e.g. quadratic), (b) time-varying is any variable measured at each time point, and (c) 
invariant is a variable measured at the person-level. The model below can easily be extended to 
a third level if it is determined that there is variability in coefficients across centers.  
 
Equation 1. 
Level 1:  
Yti ~ β0i + β1itimeti + β2itime-varyingti + β3itimetitime-varyingti 
Level 2:  
β0i = γ00 + γ01invarianti + u0i  
 
 
β1i = γ10 + γ11invarianti + u1i  
 

23 
 
 
REGULATORY COMPLIANCE, REPORTING and MONITORING 
 
Regulatory Compliance  
This study will be conducted in accordance with the current version of the protocol, in full 
conformity with the ethical principles outlined in the Declaration of Helsinki, the Regulations for 
the Protection of Human Subjects codified in the International Council for Harmonization Good 
Clinical Practice (GCP) Guidelines, and all other applicable regulatory requirements. An 
Operations Manual will be provided as a reference guide and study quality assurance tool. 
 
Statement of Compliance  
This trial will be conducted in compliance with the appropriate protocol, current Good Clinical 
Practice (GCP), the principles of the Declaration of Helsinki, and all other applicable regulatory 
requirements. Participating sites must obtain written approval of the study protocol, consent form, 
other supporting documents, and any advertising for participant recruitment from the Institutional 
Review Board (IRB) of record in order to participate in the study. Prior to study initiation, the 
protocol and the informed consent documents will be reviewed and approved by an appropriate 
IRB. Any amendments to the protocol or consent materials must be approved before they are 
implemented. Unanticipated problems involving risk to study participants will be promptly reported 
to and reviewed by the IRB of record, according to its usual procedures. 
 
Institutional Review Board Approval  
Prior to initiating the study, site investigators will obtain written IRB approval to conduct the study 
at their respective site. If changes to the study protocol become necessary, protocol amendments 
will be submitted in writing by the investigators for IRB approval prior to implementation. In 
addition, IRBs will approve all consent forms, recruitment materials, and any materials given to 
the participant, and any changes made to these documents throughout study implementation. For 
changes to the consent form, a decision will be made regarding whether previously consented 
participants need to be re-consented. IRB continuing review will be performed annually, or at a 
greater frequency contingent upon the complexity and risk of the study. Each site principal 
investigator is responsible for maintaining copies of all current IRB approval notices, IRB-
approved consent documents, and approval for all protocol modifications. These materials must 
be received by the investigator prior to the initiation of research activities at the site, and must be 
available at any time for audit. 
 
The University of Utah will be the IRB of record for the protocol, and will provide study oversight 
in accordance with 45 CFR 46. Participating institutions have agreed to rely on the University of 
Utah and have entered into reliance/authorization agreements for the study protocol.  
 
Informed Consent  
The informed consent process is a means of providing study information to each prospective 
participant and allows for an informed decision about participation in the study. Informed consent 
continues throughout the individual’s study participation. The informed consent form will include 
all of the required elements of informed consent, and may contain additional relevant consent 
elements. Each study site must have the study informed consent approved by their IRB(s). To 
confirm that each consent form contains the required elements of informed consent as delineated 
in 21 CFR 50.25(a) and CFR 46.116(a), as well as pertinent additional elements detailed in 21 
CFR 50.25(b) and 45 CFR 46.116(b), a copy of the IRB-approved consent, along with the IRB 
study approval, must be sent to the University of Utah prior to site initiation and with each 
subsequent consent revision. Every study participant is required to sign a valid, IRB-approved 
current version of the study informed consent form prior to the initiation of any study related 

24 
 
procedures. The site must maintain the original signed informed consent for every participant in 
a locked, secure location that is in compliance with all applicable IRB and institutional policies and 
that is accessible for QA review. Every study participant will be given a copy of the signed consent 
form.  
 
Prior to informed consent, research staff will explain the study to the potential participant and 
provide a copy of the consent to read. All participants will receive a verbal explanation in terms 
suited to their comprehension of the purposes, procedures, and potential risks of the study and 
their rights as research participants. Extensive discussion of risks and possible benefits will be 
provided to the participants. Participants will have the opportunity to carefully review the written 
consent form and ask questions prior to signing. The participants should have the opportunity to 
discuss the study with their family and close friends or think about it prior to agreeing to participate. 
If the participant is interested in participating in the study, a staff member will review each section 
of the IRB-approved informed consent form in detail and answer any questions the participant 
may pose. The participant will consent by signing and dating the consent document. The person 
obtaining consent and a witness, if required by the local IRB(s), will also sign and date the consent 
document.  
 
The informed consent form must be updated or revised whenever important new safety 
information is available, or whenever the protocol is amended in a way that may affect participants’ 
participation in the trial. A copy of the informed consent will be given to a prospective participant 
to review during the consent process and to keep for reference. The rights and welfare of the 
participants will be protected by emphasizing to them that the quality of their medical care will not 
be adversely affected if they decline to participate in this study. The participant will be informed 
that their participation is voluntary and they may withdraw from the study at any time, for any 
reason without penalty. Individuals who refuse to participate or who withdraw from the study will 
be treated without prejudice. Study sites will be responsible for maintaining signed consent forms 
as source documents for quality assurance review and regulatory compliance. 
 
The study does not preempt any applicable federal, state, or local laws which require additional 
information to be disclosed in order for informed consent to be legally effective. It is in 
conformance with 42 CFR 2.52, which allows for research-related provisions with regard to the 
disclosure of substance use disorder patient identifying information in the absence of the informed 
consent process and HIPAA authorization. 
On 4/2/2020 the University of Utah IRB, the IRB of record, approved the use of eConsent 
technology via REDCap in response to the COVID-19 pandemic as a supplement to in-person 
consent. For each site, the REDCap project includes a downloadable consent, each page of the 
IRB stamped consent, the consent comprehension tool, the option to authorize or decline audio 
recording of PN sessions, the option to decline or consent to enrollment prior to electronically sign 
and dating, and the ability to download a copy of their signed consent. The signed consent is 
available for review and download by the lead and enrolling site.  Research staff delegated to 
obtain informed consent will continue to follow the procedures outlined above virtually.  In person 
consent is not restricted with this amendment, however, it is dependent on local guidelines and 
regulations.  
 
Quality Assurance Monitoring  
In accordance with federal regulations, the study sponsor is responsible for ensuring proper 
monitoring of an investigation, and ensuring that the investigation is conducted in accordance with 
the protocol. As this study does not have a sponsor assigned monitor, the investigator has 

25 
 
delegated this responsibility to the lead site who will oversee aspects of site conformity to make 
certain the site staff is operating within the confines of the protocol, and in accordance with GCP. 
This includes but is not limited to protocol compliance, documentation review, and ensuring the 
informed consent process is being correctly followed and documented. Non-conformity with 
protocol and federal regulations can be reported as a protocol deviation and submitted to the IRB 
for further review. 
 
Participant and Data Confidentiality  
Confidentiality will be maintained in accordance with all applicable federal regulations and/or 
state/Commonwealth law and regulations. By signing the protocol signature page, the investigator 
affirms that information furnished to the investigator will be maintained in confidence and such 
information will be divulged to the IRB/Privacy Board, Ethical Review Committee, or similar expert 
committee; affiliated institution; and employees only under an appropriate understanding of 
confidentiality with such board or committee, affiliated institution and employees.  
 
To further protect the privacy of study participants, the lead investigator will obtain a federal 
Certificate of Confidentiality (CoC) from NIH, which protects identifiable research information from 
forced disclosure, and will distribute it to all sites when received. This protects participants against 
disclosure of sensitive information (e.g., drug use). The CoC allows the investigator and others 
who have access to research records to permanently refuse to disclose identifying information on 
research participation in any civil, criminal, administrative, legislative, or other proceeding, 
whether at the federal, state, or local level, excepting certain circumstances. 
 
By protecting researchers and institutions from being compelled to disclose information that would 
identify research participants, the Certificates of Confidentiality help achieve the research 
objectives and promote participation in studies by helping assure confidentiality and privacy to 
participants. The NIH office that issues the CoC will be advised of changes in the CoC application 
information. Participating sites will be notified if CoC revision is necessary. Participant records will 
be held confidential by the use of study codes for identifying participants on CRFs, secure storage 
of any documents that have participant identifiers, and secure computing procedures for entering 
and transferring electronic data. 
 
Per Section 2012 of the 21st Century Cures Act all ongoing or new research funded by CDC as 
of December 13, 2016 that is collecting or using identifiable, sensitive information is 
automatically covered by a CoC. 
 
 
Health Information Portability Accountability Act (HIPAA)   
Study sites will be required to obtain authorization from participants for use of protected health 
information. Sites will be responsible for communicating with the IRBs or Privacy Boards of record 
and obtaining the appropriate approvals or waivers to be in regulatory compliance. Releases of 
participant identifying information that are permitted by the HIPAA regulations, but which are 
prohibited by other applicable federal regulations and/or state/Commonwealth law and regulation, 
are prohibited. 
 
Investigator Assurances  
 
Financial Disclosure/Conflict of Interest  
All investigators will comply with the requirements of 42 CFR Part 50, Subpart F to ensure that 
the design, conduct, and reporting of the research will not be biased by any conflicting financial 

26 
 
interest. Everyone with decision-making responsibilities regarding the protocol will confirm 
annually that they have met their institutional financial disclosure requirements. 
 
Clinical Monitoring 
Investigators will conduct periodic review to examine whether study procedures are conducted 
appropriately and that study data are generated, documented and reported in compliance with 
the protocol, GCP, and applicable regulations. Reviews will occur at mutually agreed upon times, 
regulatory documents, case report forms (CRFs), informed consent forms and corresponding 
source documents for each participant. Reviews will verify that study procedures are properly 
followed, site personnel are trained and able to conduct the protocol appropriately, whether 
submitted data are accurate and in agreement with source documentation and review 
regulatory/essential documents such as correspondence with the IRB. Reports will be prepared 
following the visit and forwarded to the principal investigator and site principal investigators. 
Reviewers will have the opportunity and ability to view any study-associated document or file. If 
the review of study documentation indicates that additional training of site study personnel is 
needed, the reviewer will undertake or arrange for that training. 
 
Prisoner Certification 
As per 45 CFR 46 Subpart C, there are additional protections pertaining to prisoners as study 
participants. A prisoner is defined as any individual involuntarily confined or detained in a penal 
institution. The term is intended to encompass individuals sentenced to such an institution under 
a criminal or civil statute, individuals detained in other facilities by virtue of statutes or commitment 
procedures which provide alternatives to criminal prosecution or incarceration in a penal 
institution, and individuals detained pending arraignment, trial, or sentencing. 
If a participant in the study becomes a prisoner during the course of the study, and the relevant 
research proposal was not reviewed and approved by the IRB in accordance with the 
requirements for research involving prisoners under Subpart C of 45 CFR 46, the investigator 
must promptly notify the IRB. All research interactions and interventions with, and obtaining 
identifiable private information about, the now-incarcerated participant must be suspended 
immediately. The lone exception to this regulation is if the investigator asserts that it is in the best 
interests of the prisoner-participant to remain in the study while incarcerated. The investigator 
must promptly notify the IRB of this occurrence. 
 
Regulatory Files  
The regulatory files should contain all required regulatory documents, study-specific documents, 
and all important communications. Regulatory files will be checked at each participating site for 
regulatory document compliance prior to study initiation, throughout the study, as well as at study 
closure. 
 
Records Retention and Requirements  
Research records for all study participants (e.g., case report forms, source documents, signed 
consent forms, audio and video recordings, and regulatory files) are to be maintained by the 
investigators in a secure location for a minimum of 3 years after the study is completed and closed. 
These records are also to be maintained in compliance with IRB, state and federal requirements, 
whichever is longest. The sponsor and Principal Investigator must be notified in writing and 
acknowledgment must be received by the site prior to the destruction or relocation of research 
records. 
 

27 
 
 
Study Documentation  
Each participating site will maintain appropriate study documentation (including medical and 
research records) for this trial, in compliance with regulatory and institutional requirements for the 
protection of confidentiality of participants. Study documentation includes all case report forms, 
workbooks, source documents, monitoring logs and appointment schedules, sponsor-investigator 
correspondence, and signed protocol and amendments, Ethics Review Committee or Institutional 
Review Board correspondence and approved consent form and signed participant consent forms. 
As part of participating in a CDC study, each site will permit authorized representatives from CDC 
and regulatory agencies to examine (and when permitted by law, to copy) clinical records for the 
purposes of quality assurance reviews, audits, and evaluation of the study safety, progress, and 
data validity.  
 
Source documents include all recordings of observations or notations of clinical activities and all 
reports and records necessary for the evaluation and reconstruction of the clinical research study. 
Whenever possible, the original recording of an observation should be retained as the source 
document; however, a photocopy is acceptable provided that it is a clear, legible, and exact 
duplication of the original document. 
 
Protocol Deviations  
Any departure from procedures and requirements outlined in the protocol will be classified as 
either a major or minor protocol deviation. The difference between a major and minor protocol 
deviation has to do with the seriousness of the event and the corrective action required. A minor 
protocol deviation is considered an action (or inaction) that by itself is not likely to affect the 
scientific soundness of the investigation or seriously affect the safety, rights, or welfare of a study 
participant. Major protocol deviations are departures that may compromise the participant safety, 
participant rights, inclusion/exclusion criteria or the integrity of study data and could be cause for 
corrective actions if not rectified or prevented from re-occurrence. Sites will be responsible for 
developing corrective action plans for both major and minor deviations as appropriate. Corrective 
action plans will be reviewed/approved by the PI with overall approval by the IRB of record. All 
protocol deviations will be monitored at each site for (1) significance, (2) frequency, and (3) impact 
on the study objectives, to ensure that site performance does not compromise the integrity of the 
trial. All protocol deviations will be recorded, reviewed by the PI, and saved in the study electronic 
files. Additionally, each site is responsible for reviewing the IRB of record’s definition of a protocol 
deviation or violation and understanding which events need to be reported. Sites must recognize 
that the IRB definition of a reportable event may differ and act accordingly in following all reporting 
requirements for both entities. 
 
Adverse Events (AEs)  
Specific adverse events that will be collected in this study are described in further detail in 
Appendix A. 
Two study clinicians are have been appointed in this project, who will review or provide 
consultation for each Serious Adverse Event (SAE) as needed at each site. These reviews will 
include an assessment of the possible relatedness of the event to the study intervention or other 
study procedures. Study clinicians will also provide advice for decisions to exclude, refer, or 
withdraw participants as required.  
Each of the sites has established practices for managing medical and psychiatric emergencies, 
and the study staff will continue to utilize these procedures. Treatment providers at each site will 

28 
 
be responsible for monitoring participants for possible clinical deterioration or other problems, and 
for implementing appropriate courses of action. 

29 
 
 
DATA AND SAFETY MONITORING PLAN  
1.0 
OVERSIGHT OF CLINICAL RESPONSIBILITIES 
A. Site Principal Investigator 
Each participating site’s Principal Investigator (PI) is responsible for study oversight, including 
ensuring human research subject protection by designating appropriately qualified, trained 
research staff and medical clinicians to assess, report, and monitor adverse events. All adverse 
events (AEs) occurring during the course of the clinical trial will be collected, documented, and 
reported by the investigator or sub-investigators according to the Protocol, see Appendix. The 
occurrence of AEs and serious adverse events (SAEs) will be assessed at each clinic visit during 
the study. Serious adverse events will be followed until resolved or considered stable. Reportable 
AEs are required to be entered into the data system within 7 days of the site staff becoming aware 
of the event. Reportable SAEs (including death and life-threatening events) are required to be 
entered into data system within 24 hours of site's knowledge of the event).  
B. Medical Monitor 
The site study clinician is responsible for reviewing all adverse events and serious adverse events 
reported. All SAEs will be reviewed at the time they are reported data capture program. The site 
clinician will also indicate concurrence or not with the details of the report provided by the site PI. 
Where further information is needed, the study clinician will discuss the event with the site staff.  
All AEs are reviewed on a regular basis to observe trends or unusual events. 
C. Data and Safety Monitoring  
The study Data and Safety Monitoring Plan will involve monthly meetings held to discuss subject 
health and general research issues. Any serious and unexpected adverse changes in a subject's 
clinical status that are associated with the research intervention will be immediately brought to 
the attention of the PI and University of Pittsburgh site PI. A description of any such events will 
be conveyed to the IRB. Meetings will include, but not be limited to, reviewing the following data 
for patients: 
• 
Level of depression 
• 
Attendance prenatal care 
• 
Adherance to MAT  
• 
Food/housing insecurity 
• 
Issues with interpersonal violence 
• 
Illicit drug use 
The DSMP will also involve the PI, site PI, and coinvestigators evaluating the progress of the 
research study, including assessments of data quality and timeliness and participant recruitment, 
accrual, and retention. Clinical outcomes and adverse event data will be used to determine 
whether there is any change in the anticipated benefit-to-risk ratio for study participants and 
whether the study should continue as originally designed, should be changed, or should be 
terminated. The PI, site PI, and coinvestigators will also assess external factors or relevant 
information (e.g., pertinent scientific literature) that may have an impact on the safety of study 
participants or the ethics of the research study and review study procedures designed to protect 
the privacy of the research subjects and confidentiality of their research data.  
We will also recruit two Data Safety Monitoring Board members, one from the University of Utah 
and one from University of Pittsburgh, who will review information generated by the DSMP 

30 
 
semiannually and who can provide safety recommendations to the study team. The DSMB 
affiliated with this trial will be responsible for conducting periodic reviews of accumulating safety, 
trial performance, and outcome data. Reports will be generated and presented for DSMB 
meetings. The DSMB will receive listings of AEs and summary reports of all SAEs at a frequency 
requested by the DSMB, but at least annually. Furthermore, the DSMB will be informed of 
expedited reports of SAEs. The DSMB will make recommendations as to whether there is 
sufficient support for continuation of the trial, evidence that study procedures should be changed, 
or evidence that the trial (or a specific site) should be halted for reasons relating to safety of the 
study participants or inadequate trial performance (e.g., poor recruitment). Following each DSMB 
meeting, outcomes will communicated, based on DSMB recommendations, in writing to the study 
PI. This communication summarizing study safety information will be submitted to participating 
IRBs. 
D. Quality Assurance (QA) Monitoring 
The monitoring of the study site(s) will be conducted on a semi-annual basis. The purpose of 
these visits is to assess compliance with the protocol, GCP requirements, and other applicable 
regulatory requirements, as well as to document the integrity of the trial progress. The 
investigative site will provide direct access to all trial related sites (e.g., pharmacy, research 
office), source data/documentation, and reports for the purpose of monitoring and auditing, as 
well as inspection by local and regulatory authorities. Areas of particular concern will be the review 
of inclusion/exclusion criteria, participant Informed Consent Forms, protocol adherence, safety 
monitoring, IRB reviews and approvals, regulatory documents, participant records, and PI 
supervision and involvement in the trial. The reviewer will interact with the site staff to identify 
issues and re-train the site as needed to enhance research quality. 
QA Site Visit Reports will be prepared by the reviewer following each site visit.  These reports will 
be sent to the site PI and study PI.  
E. Database Protection 
The database will be secured with password protection. The manager will receive only coded 
information that is entered into the database under those identification numbers. Electronic 
communication with outside collaborators will involve only unidentifiable information. 
F. Management of Risks to Participants 
Confidentiality 
Confidentiality of participant records will be secured by the use of study codes for identifying 
participants on CRFs, and secure storage of any documents that have participant identifiers on 
site, as well as secure computing procedures for entering and transferring electronic data. The 
documents or logs linking the study codes with the study participant on site will be kept locked 
separately from the study files and the medical records. No identifying information will be 
disclosed in reports, publications or presentations. 
Information That Meets Reporting Requirements 
The consent form will specifically state the types of information that are required for reporting and 
that the information will be reported as required. These include suspected or known sexual or 
physical abuse of a child or elders, or threatened violence to self and/or others. 
 

31 
 
Participant Protection 
AEs and concomitant medications will be assessed and documented at clinic visits.    Individuals 
who experience an AE that compromises safe participation in the study will be discontinued from 
further intervention and provided referrals for other treatment or to specialized care. Study 
personnel will request that the participant complete an end visit to assure safety and to document 
outcomes. 
 
Longterm Data Storage and Sharing 
Data for this project be will stored on University of Utah cloud computing servers and/or archives 
for long term-storage. Electronic access to these data are password protected, encrypted, and 
HIPAA compliant. Physical access will be protected by storage in locked cabinets inside locked 
facilities. Data will be de-identified before sharing with other investigators on a need to know basis, 
and on the agreement that once the data analysis is complete, the data will be returned or 
destroyed. Data will only be shared with investigators with appropriate data sharing agreements 
and/or Institutional Review Board for Human subjects approvals, as required. 

32 
 
 
DATA MANAGEMENT  
 
Design and Development  
The University of Utah site will be responsible for development of electronic case report forms 
(eCRFs), development and validation of the clinical study database, ensuring data integrity, and 
training site and participating staff at both sites on applicable data management procedures. This 
will also include the University of Utah site working to: 1) develop a data management plan and 
will conduct data management activities in accordance with that plan, 2) provide final guided 
source documents and eCRFs for the collection of all data required by the study, 3) develop data 
dictionaries for each eCRF that will comprehensively define each data element, 4) conduct 
ongoing data monitoring activities on study data from all participating sites, 5) monitor any 
preliminary analysis data cleaning activities as needed, and 6) rigorously monitor final study data 
cleaning. The remainder of this section provides an overview of the data management plan 
associated with this protocol. 
 
Site Responsibilities  
The University of Utah will provide study leadership for data management, analysis, and reporting. 
The University of Utah will train staff at the University of Pittsburgh in data collection requirements, 
procedures, and security. Both sites will ensure before participant and other study data is 
uploaded to the data capture program, patient reported responses to interview questions are 
complete and accurate. Site audits will involve the University of Utah project coordinator reviewing 
uploaded study data to ensure completeness and accuracy of data. A trained University of Utah 
research staff member in day to day study operations will perform data reviews to ensure 
uploaded data from sites are complete and accurate.  
 
Data Collection  
The data collection process consists of direct data entry at the study sites into the data capture 
program. In the event that the data capture program is not available, the University of Utah site 
will make available a final set of guided source documents and completion instructions. Data entry 
into the data capture program should be completed according to the instructions provided and 
project specific training. The investigator is responsible for maintaining accurate, complete and 
up-to-date records, and for ensuring the completion of the eCRFs for each research participant.  
 
Data Editing  
Completed data will be entered into the data capture program. If incomplete or inaccurate data 
are found, a query will be generated to the sites for a response. Sites will resolve data 
inconsistencies and errors and enter all corrections and changes into the data capture program. 
 
Data Transfer/Lock  
The University of Utah study statistician and statistical program will conduct final data quality 
assurance checks and “lock” the study database from further modification.  
 
Data Quality Assurance  
To address the issue of data entry quality, the University of Utah will follow a standard data 
monitoring plan. An acceptable quality level prior to study lock or closeout will be established as 
a part of the data management plan. The management plan will entail the project coordinator 
generating regular data quality summaries during the course of the protocol. This will specifically 
involve building composite indicators and running descriptive statistics each month during 
participant recruitment and follow up.  

33 
 
PROTOCOL SIGNATURE PAGE  
 
 
 
 
 
 
      
 
 
 
 
Printed Name 
 
Signature 
 
Date 
ACKNOWLEDGEMENT BY INVESTIGATOR: 
• 
I am in receipt of version X of the protocol and agree to conduct this clinical study in 
accordance with the design and provisions specified therein. 
• 
I agree to follow the protocol as written except in cases where necessary to protect the 
safety, rights, or welfare of a participant, an alteration is required, and the sponsor and IRB 
have been notified prior to the action. 
• 
I will ensure that the requirements relating to obtaining informed consent and institutional 
review board (IRB) review and approval in 45 CFR 46 are met. 
• 
I agree to personally conduct or supervise this investigation at this site and to ensure that 
all site staff assisting in the conduct of this study are adequately and appropriately trained 
to implement this version of the protocol and that they are qualified to meet the 
responsibilities to which they have been assigned. 
• 
I agree to comply with all the applicable federal, state, and local regulations regarding the 
obligations of clinical investigators as required by the Department of Health and Human 
Services (DHHS), the state, and the IRB. 
 
SITE’S PRINCIPAL INVESTIGATOR 
      
 
 
 
 
Printed Name 
 
Signature 
 
Date 
 
Clinical Site Name  
 
      
 
 
 

34 
 
 
APPENDIX A: ADVERSE EVENT REPORTING AND 
PROCEDURES  
Each participating site’s Principal Investigator is responsible for study oversight, including 
ensuring human research subject protection by designating appropriately qualified and trained 
study personnel to assess, report, and monitor adverse events. See AE form in the electronic 
data capture program. 
 
Definition of Adverse Events and Serious Adverse Events 
 
An adverse event (AE) is any unexpected medical occurrence in humans, whether or not 
considered study intervention related which occurs during the conduct of a clinical trial. Changes 
from baseline in clinical status; i.e., death, miscarriage, pre-term birth, overdose, relapse, child 
protective services involvement including child removal; that are considered clinically significant 
by the study medical clinician are considered AEs.  
 
Suspected adverse reaction is any adverse event for which there is a reasonable possibility that 
the study intervention caused the adverse event. A reasonable possibility implies that there is 
evidence that the study intervention caused the event. 
 
Adverse reaction is any adverse event caused by the study intervention. 
 
An adverse event, suspected adverse reaction, or adverse reaction is considered “serious” 
(i.e., a serious adverse event, serious suspected adverse reaction or serious adverse reaction) if, 
in the view of either the study medical clinician or sponsor, it: 
 
1) 
Results in death: A death occurring during the study or which comes to the attention of 
the study staff during the protocol-defined follow-up period, whether or not considered 
caused by the study intervention, must be reported. 
2) 
Is life-threatening: Life-threatening means that the study participant was, in the opinion 
of the medical clinician or sponsor, at immediate risk of death from the reaction as it 
occurred and required immediate intervention.  
3) 
Requires inpatient hospitalization or prolongation of existing hospitalization.  
4) 
Results in persistent or significant incapacity or substantial disruption of the ability to 
conduct normal life functions.  
5) 
Is a congenital abnormality or birth defect. 
6) 
Is an important medical event that may not result in one of the above outcomes, but may 
jeopardize the health of the study participant or require medical or surgical intervention 
to prevent one of the outcomes listed in the above definition of serious event.   
Definition of Expectedness 
Any adverse event is considered “unexpected” if it is not listed in the protocol, consent, or is not 
listed at the specificity or severity that has been observed.  
 
 
 

35 
 
Medical and Psychiatric History 
A thorough medical and psychiatric history during the baseline phase should record any chronic, 
acute, or intermittent preexisting or current illnesses, diseases, symptoms, or concerning signs of 
the participant, to avoid reporting pre-existing conditions as new AEs and to assist in the 
assessment of worsening in intensity or severity of these conditions that would indicate an AE. 
Stable chronic conditions, such as arthritis, which are present prior to clinical trial entry and do 
not worsen are not considered AEs.  
 
Site’s Role in Eliciting and Reporting Adverse Events 
Appropriately qualified and trained personnel will elicit participant reporting of AEs and SAEs at 
each study visit designated to collect AEs. Adverse events (medical and/or psychiatric) 
assessment will initiate with participant consent and follow-up will continue through the final 
assessment. Study personnel will obtain as much information as possible about the reported 
AE/SAE to complete the AE/SAE forms and will consult as warranted.  
 
Standard reporting, within 7 days of the site becoming aware of the event, is required for 
reportable AEs. Expedited reporting (within 24 hours of their occurrence and/or site's knowledge 
of the event) is required for reportable SAEs (including death and life-threatening events). Local 
sites are responsible for reporting SAEs to the IRB of record, per the IRB or record’s guidelines. 
 
Sites are required to enter reportable AEs and SAEs in data capture program. The AE form is 
used to capture reportable AEs and SAEs (as defined in the protocol) and will be reviewed by the 
study PI upon submission. Additional information may need to be gathered to evaluate SAEs and 
to complete the appropriate CRFs and the summary. This process may include obtaining hospital 
discharge reports, medical records, autopsy records or any other type records or information 
necessary to provide a complete and clear picture of the serious event and events preceding and 
following the event. If the SAE is not resolved or stable at the time of the initial report or if new 
information becomes available after the initial report, follow-up information must be submitted as 
soon as possible. 
 
Reportable adverse events will be followed until resolution, stabilization or study end. Any serious 
adverse reactions will be followed until resolution or stabilization even beyond the end of the 
study.  
 
Site’s Role in Assessing Severity and Causality of Adverse Events 
Appropriately qualified and trained study personnel will conduct an initial assessment of 
seriousness, severity, and causality when eliciting participant reporting of adverse events. A study 
medical clinician will review reportable AEs for seriousness, severity, and causality on at least a 
weekly basis.  
 
 
 

36 
 
Guidelines for Assessing Severity 
The severity of an adverse event refers to the intensity of the event: 
 
Grade 1 
Mild 
Transient or mild discomfort (typically < 48 hours), no or 
minimal medical intervention/therapy required, 
hospitalization not necessary (non-prescription or single-use 
prescription therapy may be employed to relieve symptoms, 
e.g., aspirin for simple headache, acetaminophen for post-
surgical pain) 
Grade 2 
Moderate 
Mild to moderate limitation in activity some assistance may 
be needed; no or minimal intervention/therapy required, 
hospitalization possible. 
Grade 3 
Severe 
Marked limitation in activity, some assistance usually 
required; medical intervention/ therapy required, 
hospitalization possible. 
 
Guidelines for Determining Causality 
The study medical clinician will use the following question when assessing causality of an adverse 
event to study medication/intervention where an affirmative answer designates the event as a 
suspected adverse reaction: 
 
Is there a reasonable possibility that the study intervention caused the event?  
 
Reporting to the Data and Safety Monitoring Board 
The DSMB will receive listing of AEs and summary reports of all SAEs at a frequency requested 
by the DSMB, but at least annually. Furthermore, the DSMB will be informed of expedited reports 
of SAEs.  
 
Participant Withdrawal 
The study medical clinician must apply his/her clinical judgment to determine whether or not an 
adverse event is of sufficient severity to require that the participant be withdrawn from further 
study intervention. The study medical clinician should consult with the lead investigator as 
needed. If necessary, a study medical clinician may suspend any trial interventions and institute 
the necessary medical therapy to protect a participant from any immediate danger. A participant 
may also voluntarily withdraw from treatment due to what he/she perceives as an intolerable 
adverse event or for any other reason. If voluntary withdrawal is requested, the participant will be 
asked to complete an end-of-study visit to assure safety and will be given recommendations for 
medical care and/or referrals to treatment, as necessary. 

37 
 
 
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