Support Models for Addiction Related Treatment (SMART) Trial of Opioid Use Disorder OUD) in Pregnant Women
Phase: NA
Conditions: Opioid-use Disorder
Sponsor: Yale University

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Title: Support Models for Addiction Related Treatment (SMART) Trial of Opioid 
Use Disorder in Pregnant Women  
Protocol Number:  2000027031
National Clinical Trial (NCT) Identified Number:   NCT04240392
Principal Investigator: Ariadna Forray, MD
Funding: Patient Centered Outcomes Research Institute (PCORI)
Protocol Version: 13.0
Version Date: Feb 13, 2025
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Table of Contents
STATEMENT OF COMPLIANCE.......................................................................................................................................1
INVESTIGATOR’S SIGNATURE ........................................................................................................................................2
1
PROTOCOL SUMMARY......................................................................................................................................3
1.1
Synopsis..................................................................................................................................................3
1.2
Schema...................................................................................................................................................5
1.3
Schedule of Activities .............................................................................................................................6
2
INTRODUCTION.................................................................................................................................................7
2.1
Study Rationale ......................................................................................................................................7
2.2
Background ............................................................................................................................................8
2.3
Risk/Benefit Assessment......................................................................................................................11
2.3.1
Known Potential Risks ......................................................................................................11
2.3.2
Known Potential Benefits .................................................................................................11
2.3.3
Assessment of Potential Risks and Benefits ....................................................................12
3
OBJECTIVES AND ENDPOINTS .........................................................................................................................13
4
STUDY DESIGN ................................................................................................................................................16
4.1
Overall Design ......................................................................................................................................16
4.2
Scientific Rationale for Study Design....................................................................................................17
4.3
Justification for Intervention................................................................................................................18
4.4
End-of-Study Definition........................................................................................................................19
5
STUDY POPULATION .......................................................................................................................................20
5.1
Inclusion Criteria ..................................................................................................................................20
5.2
Exclusion Criteria..................................................................................................................................20
5.3
Lifestyle Considerations .......................................................................................................................21
5.4
Screen Failures .....................................................................................................................................21
5.5
Strategies for Recruitment and Retention ...........................................................................................21
6
STUDY INTERVENTION(S) OR EXPERIMENTAL MANIPULATION(S)..................................................................22
6.1
Study Intervention(s) or Experimental Manipulation(s) Administration..............................................22
6.1.1
Study Intervention or Experimental Manipulation Description .......................................22
6.1.2
Administration and/or Dosing ..........................................................................................23
6.2
Fidelity..................................................................................................................................................23
6.2.1
Interventionist Training and Tracking...............................................................................23
6.3
Measures to Minimize Bias: Randomization and Blinding ...................................................................24
6.4
Study Intervention/Experimental Manipulation Adherence................................................................24
6.5
Concomitant Therapy...........................................................................................................................25
6.5.1
Rescue Therapy ................................................................................................................25
7
STUDY INTERVENTION/EXPERIMENTAL MANIPULATION DISCONTINUATION AND PARTICIPANT 
DISCONTINUATION/WITHDRAWAL.............................................................................................................................26
7.1
Participant Discontinuation/Withdrawal from the Study ....................................................................26
7.2
Lost to Follow-Up .................................................................................................................................26
8
STUDY ASSESSMENTS AND PROCEDURES.......................................................................................................27
8.1
Endpoint and Other Non-Safety Assessments .....................................................................................27
8.1.1
Screening Procedures.......................................................................................................27
8.1.2
Standard of Care Prenatal Visit.........................................................................................28
8.1.3
Timeline Follow Back Visits...............................................................................................28
8.1.4
Week 26 Visit....................................................................................................................28
8.1.5
Week 34 Visit....................................................................................................................29
8.1.6
Birth
29
8.1.7
3 Months Post-Partum Visit..............................................................................................29
8.2
Safety Assessments..............................................................................................................................30
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8.3
Adverse Events and Serious Adverse Events........................................................................................30
8.3.1
Definition of Adverse Events ............................................................................................30
8.3.2
Definition of Serious Adverse Events................................................................................30
8.3.3
Classification of an Adverse Event....................................................................................30
8.3.4
Time Period and Frequency for Event Assessment and Follow-Up..................................31
8.3.5
Adverse Event Reporting ..................................................................................................32
8.3.6
Serious Adverse Event Reporting .....................................................................................32
8.3.7
Events of Special Interest .................................................................................................32
8.4
Unanticipated Problems.......................................................................................................................32
8.4.1
Definition of Unanticipated Problems..............................................................................32
8.4.2
Unanticipated Problems Reporting ..................................................................................33
9
STATISTICAL CONSIDERATIONS.......................................................................................................................33
9.1
Statistical Hypotheses ..........................................................................................................................33
9.2
Sample Size Determination..................................................................................................................34
9.3
Populations for Analyses......................................................................................................................34
9.4
Statistical Analyses...............................................................................................................................35
9.4.1
General Approach.............................................................................................................35
9.4.2
Analysis of the Primary Endpoint(s)..................................................................................35
9.4.3
Analysis of the Secondary Endpoint(s) .............................................................................35
9.4.4
Baseline Descriptive Statistics ..........................................................................................36
9.4.5
Planned Interim Analyses ................................................................................................36
9.4.6
Sub-Group Analyses..........................................................................................................36
9.4.7
Tabulation of Individual Participant Data.........................................................................36
9.4.8
Exploratory Analyses ........................................................................................................36
10
SUPPORTING DOCUMENTATION AND OPERATIONAL CONSIDERATIONS ......................................................37
10.1
Regulatory, Ethical, and Study Oversight Considerations ....................................................................37
10.1.1
Informed Consent Process................................................................................................37
10.1.2
Study Discontinuation and Closure...................................................................................37
10.1.3
Confidentiality and Privacy...............................................................................................37
10.1.4
Safety Oversight................................................................................................................38
10.1.5
Clinical Monitoring ...........................................................................................................38
10.1.6
Quality Assurance and Quality Control.............................................................................38
10.1.7
Data Handling and Record Keeping ..................................................................................39
10.1.8
Protocol Deviations ..........................................................................................................40
11
REFERENCES....................................................................................................................................................41
12        APPENDIX:
Study Personnel and Roles……………………………………………………………………………….50
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STATEMENT OF COMPLIANCE
This trial will be conducted in compliance with the protocol, International Council on Harmonization Good 
Clinical Practice (ICH GCP) and applicable state, local and federal regulatory requirements. Each engaged 
institution must have a current Federal-Wide Assurance (FWA) issued by the Office for Human Research 
Protections (OHRP) and must provide this protocol and the associated informed consent documents and 
recruitment materials for review and approval by an appropriate Institutional Review Board (IRB) or Ethics 
Committee (EC) registered with OHRP. Any amendments to the protocol or consent materials must also 
be approved before implementation. 
The protocol, informed consent form(s), recruitment materials, and all participant materials will be 
submitted to the IRB for review and approval. Approval of both the protocol and the consent form(s) 
must be obtained before any participant is consented. Any amendment to the protocol will require 
review and approval by the IRB before the changes are implemented to the study. All changes to the 
consent forms will be IRB approved; a determination will be made regarding whether a new consent 
needs to be obtained from participants who provided consent, using a previously approved consent 
form by the IRB of record.  
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INVESTIGATOR’S SIGNATURE
The signature below constitutes the approval of this protocol and provides the necessary assurances 
that this study will be conducted according to all stipulations of the protocol, including all statements 
regarding confidentiality, and according to local legal and regulatory requirements and applicable US 
federal regulations and ICH guidelines, as described in the Statement of Compliance above.
Principal Investigator:
Signed:
Date:
Name*:
Title*:
Investigator Contact Information
Affiliation*:
Address:
Telephone:
Email:
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1
PROTOCOL SUMMARY
1.1
SYNOPSIS 
Title:
Support Models for Addiction Related Treatment (SMART) Trial of 
Opioid Use Disorder in Pregnant Women  
Grant Number:
MAT-2018C2-12891
Study Description:
Between 1999 and 2014 the point prevalence of an Opioid Use 
Disorder (OUD) in pregnant women increased from 1.5 to 6.5 per 1000 
deliveries, which is in line with rates of opioid prescribing in the general 
population.(1) Unfortunately, providers of outpatient medication 
assisted treatment (MAT) are less likely to treat pregnant women 
compared to non-pregnant women (75% vs 91%).(2)  The provision of 
MAT in reproductive health settings may augment the capacity to treat 
pregnant women with an OUD and increase treatment rates, but the 
optimal models for care need to be determined. We propose a cluster 
randomized clinical trial to compare the effectiveness of two models of 
support for reproductive health clinicians to provide care for pregnant 
and postpartum women with an OUD: 1) a collaborative care (CC) 
approach based upon the Massachusetts Office-Based-Opioid 
Treatment (OBOT) Model,(3) that would provide onsite training, and 
support to providers and patients through the use of a care managers 
(CMs) vs 2) a telesupport approach modeled on the Project Extension 
for Community Healthcare Outcomes (ECHO), a remote education 
model that provides mentorship and guided practice and participation 
in a learning community, via video conferencing.(4)  
Objectives:
1) To determine differences in engagement and retention between 
participants who receive care from a center that uses a CC vs an 
ECHO support model. We hypothesize that the benefit from a CM 
and proactive monitoring approach will lead to greater treatment 
engagement and retention among patient participants.
H1: Participants with an OUD are more likely to be engaged in care 
if the center is randomized to the CC vs the ECHO model of 
support.
H2: Participants with an OUD treated in CC centers are more likely 
to be retained in MAT and/or non-pharmacological care for an 
OUD than those treated in a center randomized to the ECHO 
model of care.
2) To determine differences in patient-reported outcomes between the 
two treatment models. For this domain we will use the Patient 
Activation Measure (PAM) as the sentinel measure.
H3: Participants in the CC, compared to the ECHO condition, will 
have higher PAM scores at week-36 and 3-months post-
partum.  
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Endpoints:
Treatment Retention
Treatment Engagement
Patient Activation Measure (PAM)
Birth Outcomes
Study Population:
264 pregnant women with opioid use disorder
Phase or Stage:
Phase 3
Description of 
Sites/Facilities:
12 characteristically matched obstetrical centers in Connecticut and 
Massachusetts.  
Study 
Intervention/Experimental 
Manipulation:
Collaborative Opioid Prescribing Model (CC)
Project ECHO (Extension for Community Healthcare Outcomes)
Study Duration:
4 years
Participant Duration:
Approximately 44 weeks (8 weeks pregnant– 3 months post-partum) 
1.2
SCHEMA 
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Note: Randomization occurs at the level of 
the obstetrical practice.  Thus, all 
participants in a practice will receive OUD 
under the same model
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1.3
SCHEDULE OF ACTIVITIES 
Study  
Screening
Visit 13 (BLine)
Visit 23
Visit 33
Visit 43
Visit 53
26 Week Visit
Visit 63
Visit 73
Visit 83
36 Week Visit
Visit 93
Visit 103
Birth
Visit 113
3 Months post-
partum visit
Window
+/- 4 
weeks
+/- 
4weeks
+/- 4 weeks
Informed Consent
X
NIDA Quickscreen
X
Demographics
X
Concomitant Medication
X
X
X
X
X
X
X
X
X
Medical History
X
X
Pregnancy Questionnaire
X
Urine Drug Screening1
X------------------------------------------------------------------------------------X
DSM-5 OUD Checklist6
X
Contact Information 
X
Assigned OUD Treatment2
X------------------------------------------------------------------------------------X
Time Line Follow Back4
X
X
X
X
X
X
X
x
X
Post Traumatic Stress 
Disorrder Checklist for DSM- 
5 (PCL-5)
X
Fagerstrom Test for Nicotine 
Dependence (FTND)
X
X
X
X
HIV Risk -Taking Behavior 
Scale (HRBS)
X
Patient Activation Measure 
(PAM)
X
X
X
X
Shared-Decision Making 
Questionnaire-9 (SDM-Q-9)
X
X
X
X
Perceived efficacy in Patient-
Physician Interactions 
Questionnaire (PEPPI)
X
X
X
X
Kim Alliance Scale-
Communication subscale 
(KAS-CM)
X
X
X
X
PROMIS Emotional Short 
Form 4a
X
X
X
X
PROMIS Satisfactions with 
Roles and Activities Short 
form 8a
X
X
X
X
Satisfaction with Roles and 
Activities
X
X
X
X
Edinburgh Postnatal 
Depression Scale (EPDS)
X
X
X
X
Adverse Childhood 
Experience Questionnaire
X
Stigma Related Rejection 
Scale
X
X
Treatment Utilization Form
X
X
X
X
X
X
X
X
X
Substance Abuse Attitude 
Survey (Treatment 
Optimism)8
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1.
Standard of care urine drug screens will be tested for the presents of illicit and licit opiate drugs at every prenatal visit after consent.  
Results are recorded by the clinic staff and faxed to the Yale research assistant.  
2.
Participants will receive OUD treatment via the clinic assigned treatment method (either CC or ECHO) throughout the length of their 
participation. 
3.
Participant will enter the study at different point of pregnancy.  Therefore, it is likely that participants will complete varying numbers 
of visits between screening and the 26-week visit, and the 34-week visit and birth.  This is expected and is not considered a protocol 
deviation.   Visit 1 will follow immediately after the consenting process
4.
The Time Line Follow Back will be conducted monthly during the length of the study.  The number of TLFB assessments will vary 
depending on when the patient enters the study and when they give birth.  
5.
All participating centers will perform a drugs screen such as the NIDA Quick Screen or equivalent validated instrument as standard of 
care.  If it is positive the DSM-5 OUD checklist will be completed to determine study eligibility. 
6.       The DSM-5 OUD Checklist will be administered to any patients who have a positive NIDA Quick Screen as part of the standard of care.              
7.       Birth outcomes include: low birth weight, resuscitation at delivery, fetal demise, preterm birth, duration of hospitalization.  
       8.       The Substance Abuse Attitude Scale, the Physicians Worklife Survey and the Qualitative Interviews will be completed by physicians
                 And done prior to the first participant being enrolled at the site and after the last participant is enrolled at the site.                     
2
INTRODUCTION
2.1
STUDY RATIONALE 
In 2015, an estimated 3.8 million individuals in the US misused pain relievers and over 1.9 million 
suffered from an OUD.(5, 6) The lethality of opioid misuse is staggering in that more than 90 people in 
the US die each day from an opioid overdose for a total of 33,000 deaths in 2015.(7) Pregnant women 
have not been spared. About 5% of pregnant women report nonmedical use of opioids in the prior year 
and 1% report nonmedical use in the preceding month.(8) Similarly, an analysis of commercial insurance 
beneficiaries finds that 2.2% of pregnant women were dispensed opioids at least 3 times in 
pregnancy.(9) Not only is nonmedical use of opioids a problem in and of itself, it primes individuals to 
transition to illicit opioids such as heroin. National data from the Centers for Disease Control found a 
startling upsurge in the rates of an OUD among obstetrical inpatients, increasing 333% from 1.5 to 6.5 
cases per 1000 deliveries between 1999-2014. (1) Although data from Connecticut (CT) were not 
available for this analysis, the rate of change in Massachusetts (MA) was 6th out of the 30 states and the 
District of Columbia that contributed data.  
The potential consequences of maternal opioid misuse in pregnancy are documented extensively and 
include maternal and fetal effects. Neonatal opioid withdrawal syndrome (NOWS) has received 
widespread attention (10) as rates of maternal opioid use have risen. National estimates for NOWS 
show escalations from 3.4 to 5.8 per 1000 hospital births between 2009 and 2012. (11) In utero opioid 
exposure also increases the risk of premature rupture of membranes,(12) preterm birth,(12) small for 
gestational age delivery,(13) and still birth.(12)  On the maternal side, opioid use in pregnancy is 
associated with placental abruption, preterm labor, cardiac arrest and death.(12) Indeed, a recent 
analysis finds that the 300 percent increase in opioid use among pregnant women during the study 
period paralleled an upsurge in cardiac events, the leading cause of death in pregnancy.(14) The annual 
Physicians Worklife 
Survey(PWS)8
Birth Outcomes)7
X
Qualitative Interviews (sub 
group
X
X
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percent increment in risk of an acute heart attack or cardiac arrest between 2002 and 2014 was 13% for 
women who used opioids during pregnancy. (14) These data illustrate the need for treatment of an OUD 
in pregnancy. 
The context for women who misuse opioids in pregnancy needs to be considered.  For example, poverty, 
unstable housing, interpersonal violence and food insecurity occur frequently among women with an 
OUD; these factors can influence maternal, fetal and neonatal health.(15-18) General medical conditions 
can complicate pregnancy. About 60-70% of pregnant women who inject drugs and use opioids in 
pregnancy are positive for Hepatitis C (19, 20) and ~1% are HIV positive.(21) As well, co-use of 
substances that have deleterious effects on maternal and fetal outcomes,(22-26) particularly 
benzodiazepines, cocaine, nicotine and alcohol, are a problem.(27-29) A third component to morbidity 
derives from concurrent psychiatric illness confronting pregnant women with substance use disorders. 
Among women with non-medical prescription opioid use, more than 40% have a depressive or anxiety 
disorder.(30) 
2.2
BACKGROUND 
Treatment for pregnant women with an OUD includes medication and behavioral therapy/psychosocial 
support.(31-34) At minimum, psychosocial support should include an assessment of the mother’s needs 
and referral to psychosocial treatment services.(32) Medication assisted treatment (MAT) is a critical 
component of standard care for pregnant women with an OUD (35, 36) and is recommended by the 
American College of Obstetricians and Gynecologists (ACOG)(33) and other experts.(5, 37) It enhances 
adherence to prenatal care (38) and increases the likelihood that the mother will continue MAT after 
delivery, a period of high risk among perinatal women with OUD.(39) Initially MAT included methadone 
but now includes buprenorphine and naltrexone (not yet indicated for use in pregnancy), which can be 
prescribed in primary care settings.(40)  
 
Some women still wish to forgo MAT in pregnancy and prefer medically-assisted withdrawal. Concerns 
are the risk of NOWS and other neonatal complications,(41, 42) but equally important to consider are 
the high rates of relapse to substance misuse (17%-96%; average 48%),(42) and other complications 
among women who decline MAT.(38, 43-45) Women must be fully informed of the risks and benefits of 
MAT in order to make a decision. As well, women must be educated and engaged in making decisions 
regarding the type of MAT, if any, to accept.  For example, birth outcomes may be slightly improved 
under buprenorphine versus methadone treatment (36) although differences are small and reflect the 
characterstics of patients engaged in one or the other treatment.(46) 
The treatment of pregnant women with OUD entails greater complexity than typically found for non-
pregnant individuals with OUD. Pregnant women require regular prenatal care and for those receiving 
MAT, dosage adjustments.(5, 36, 40, 47) We note the high rates of infections above.  Unfortunately, 
access to care for pregnant women with an OUD can be challenging.(2, 17) One model,(48) applied to 
pregnant women with OUD,(49) describes difficulties with treatment access in the following domains: 
availability (wait lists, absence of specialized addiction programs, centers that will not enroll pregnant 
women);(2, 15) accessibility (limited transportation, competing time demands given child care, lack of 
family and friend support);(50) affordability (lack of insurance or other financial);(51) and acceptability 
(concerns over reports to child protective services,(52) stigma/shame related to the illness, provider 
attitudes toward illness and MAT).(50, 53) While addiction treatment admissions among pregnant 
women with OUD have increased (26, 54, 55) the use of MAT remains low, with one group finding a rate 
of 37% in 2010(26) and 46% in 2012.(55) The legitimate concerns many women have about the possible 
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effects of gestational medication use on their offspring may deter use of MAT.  However, under-
treatment is not limited to medication use since completion rates in specialty treatment programs 
during this critical reproductive time were only 66%, likely reflecting the barriers noted above.(26)
Given the scope of opioid crisis, the need for treatment outpaces the capacity to provide it.(56) 
Increasing the cadre of buprenorphine providers can help address this but there are barriers including: 
lack of patient and physician interest,(57-59) lack of expertise and education,(57, 58, 60, 61) limited 
physician time and resources, (57, 62, 63) stigma towards patients with OUD,(58, 61) concern about 
abuse or diversion,(56, 64) lack of institutional support,(56, 59, 62) cumbersome regulations,(60, 65) and 
insurance barriers (e.g. insufficient rates of reimbursement).(56, 57, 61, 63) Provider barriers may be 
particularly problematic for pregnant women with an OUD.(66) A possible solution is to combine 
addiction care (including MAT) with prenatal care.(50, 67-69) Some existing programs provide “women-
centered” care to patients with an OUD, including prenatal care, MAT, care coordination, behavioral 
health services, family planning and breastfeeding support.(18, 67, 70) Such programs are more likely 
than non-women-centered programs, to dose opiate agonist treatment (buprenorphine) to fit the 
physiology of pregnancy, enhance the utilization of long-acting contraception and have better rates of 
breastfeeding continuation.(67)  Despite the potential benefits of a program that provides conjoint 
prenatal and addiction care, there is a major gap in knowledge regarding the best models for 
supporting centers that would like to provide such women-centered care to women with an OUD 
treated in obstetrical settings. The models of care we propose to test address many of these concerns, 
although they differ in their potential to affect many of them: 1) we know that the cadre of physicians, 
including obstetricians, who are trained to provide MAT is insufficient; 2) we also know that among 
those who have been waivered to use MAT, many obstetrical providers do not provide MAT; 3) indeed, 
many obstetricians identify lack of support for their provision of addiction care, especially given the 
complex needs of this patient population (71) as the reason they do not provide MAT. There is a need to 
compare different types of support to obstetrical practices that would allow them to deliver addiction 
care, in a women-centered manner.
Comparative Results on Maternal and Fetal Outcomes and Patients’ Perception of Care (RQ-3):  If 
addiction treatment, including MAT, is provided through obstetrical practices, we need to do it with 
fidelity and in a way that meets patients’ needs. Only a few studies have assessed possible differences in 
maternal and fetal well-being for gravidas treated in programs that provided combined vs separate 
prenatal care and addiction treatment.(67)  Some cohort studies provided information on fetal 
outcomes in centers that provide combined care.(18, 20) We were unable to identify studies or trials 
that compared different models of combined prenatal and substance use care for pregnant women with 
OUD.  Gaps in this literature are many, some of which include: rates of engagement in addiction 
treatment; level of retention in prenatal care and addiction treatment; rates of adverse birth outcomes; 
utilization of MAT as part of addiction treatment; rates of continuing MAT during the postpartum 
period; treatment of concurrent substance misuse and psychiatric conditions. 
As well, but equally important is the lack of knowledge regarding women’s experiences when they 
receive treatment under different models of combined care.  Some of the domains of importance 
include patient’s engagement in care, knowledge of care, confidence in managing pregnancy and their 
addiction, alliance with their providers, emotional well-being, ability to fulfill important roles in life, and 
retain custody of their children if they wish to do so.  A trial of different models of care can provide 
information to fill in these important gaps.
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Primary Care Models of Addiction Treatment (RQ-5): A technical report by the Agency for Healthcare 
Policy and Research (AHRQ) (72) outlines 12 models of care to provide MAT for OUD. Although they 
include “Integrated Prenatal Care and Medication-Assisted Treatment” as a model, they acknowledge 
that it is an insufficiently tested model and few details of such a model are articulated. We focus on two 
of the other 11 models that could be used to integrate prenatal care and addiction treatment: 1) 
Collaborative Opioid Prescribing Model (CC) and 2) Project Extension for Community Healthcare 
Outcomes (ECHO).
Collaborative Opioid Prescribing Model (Massachusetts Model): This model is based upon CC, a system 
developed initially to enhance the capacity for treatment of depression in primary care settings.(73) The 
model has since been refined (74, 75) and tested for treatment of other disorders; it has been deployed 
in additional venues including obstetrical-gynecological settings.(76, 77) CC, as articulated by the 
University of Washington, includes several components: (1) patients are systematically evaluated 
(screened) for medical and behavioral health needs; (2) a care manager assists with assessment and 
enrolls patients in a registry that includes data on symptoms that are collected longitudinally; the care 
manager provides some proactive behavioral treatment and care coordination; 3) a psychiatrist reviews 
cases and assists the primary physician in providing stepped-care recommendations that are tailored to 
the particular patient’s needs.(78) Components of CC that have the greatest impact on successful 
outcomes include the use of standard screening among all patients in the system (e.g. clinic) and 
administration of psychological treatments.(79)  CC has been applied to the treatment of OUD in open 
trials of non-pregnant patients (80, 81) and pregnant women.(68) It increased treatment initiation, 
engagement and use of psychotherapy among non-pregnant patients.(82) To our knowledge, there are 
no controlled or efficacy trials using CC for treatment of OUD in pregnancy. However, the model was felt 
to be sufficiently strong for MA to promote a statewide program for Federally Qualified Health Centers 
(FQHCs) in order to enhance the capacity of primary care providers to use buprenorphine.(3) As 
implemented in 14  primary care centers, the “Massachusetts Model” is slightly different than CC for 
depression outlined above and includes: (1) patients are systematically (screened) for opioid use and an 
OUD by a care manager; (2) the care manager assists with assessment and enrolls patients into a registry 
that includes symptom data that are collected longitudinally; (3) the care manager provides education, 
some behavioral treatment and care coordination; (4) the care manager assists with induction 
(treatment initiation) and follow-up (urine toxicology screens; UDS).  In this way, the care manager 
assists the physician with time burdens and offers additional effort to tailor treatments and referrals to 
the needs of the patient. The Massachusetts Model does not include a psychiatrist.   
Project ECHO (Extension for Community Healthcare Outcomes):  This model was developed to build 
capacity to treat chronic, complex health conditions in rural and underserved communities that lack 
ready access to clinical specialists.(83, 84) Developed at the University of New Mexico Health Sciences 
Center to train primary care clinicians to treat patients with hepatitis C in rural communities (84, 85), it 
is now widely replicated across the country and around the world. Project ECHO uses a virtual hub-and-
spoke educational model that links primary care clinicians with specialists through a real-time learning 
model made possible by inexpensive videoconferencing technology.(84, 86) Unlike traditional 
telemedicine, the ECHO model results in “force multiplication,” (87) where a few specialists mentor 
many providers, who in turn provide enhanced care for large numbers of patients that would otherwise 
have limited access to specialty care. Project ECHO has been broadened to address many other 
conditions, such as HIV,(88, 89) mental illness,(90, 91) chronic pain,(92, 93) diabetes,(94) and OUD; it 
has been found to be an effective and potentially cost-saving model.(86) 
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In 2005, the Integrated Addictions and Psychiatry (IAP) ECHO clinic was developed to treat substance 
use and psychiatric disorders in New Mexico.(95) Supporting the availability of MAT with buprenorphine 
was a major focus of the IAP ECHO clinic. Support consists of video-conferencing and presentations of 
cases reviewed by the practitioners in a network of centers, “spokes,” that are curated by an expert in a 
“hub” (usually located in an academic medical center) who is available remotely. A typical ECHO session 
consists of 1) introductions of participants; 2) a brief didactic session, usually a 30-minute presentation 
on substance use or mental health; and 3) discussion of case presentations submitted by participants in 
advance. A community partner of ours would provide ECHO and would modify this by adding time 
during the first few months for education and training. The IAP program has contributed to training the 
largest number of buprenorphine-wavered physicians in rural areas of New Mexico, from <20 when the 
program started to 140 as of 2014.(95) The focus on OUD and buprenorphine training and support 
enhanced the capacity to treat OUD in New Mexico. While we know capacity to treat increased, there 
are no trials evaluating the efficacy of ECHO for the treatment of OUD in pregnancy compared to other 
methods. 
2.3
RISK/BENEFIT ASSESSMENT 
2.3.1
KNOWN POTENTIAL RISKS 
The research procedures in this study are associate with minimal risk to the participants.  
Stigma: The stigma associated with admitting use of substances in pregnancy is a problem and can deter 
women from seeing both prenatal care and treatment for an OUD. As well, practitioners may have 
negative attitudes towards patients with an OUD and be reluctant to offer them care. They may also be 
unwilling to manage women who require opioid agonist treatment and insist on abstinence, which may 
not be possible for some women. These issues will need to be addressed via broader education of a 
range of stakeholder groups. 
Legal Concerns:  Some states have mandatory reporting of substance use in pregnancy while others do 
not require notification unless the mother or baby tests positive for substances at delivery. Patients may 
not be willing to use prenatal care or participate because they may be concerned with potential legal 
consequences and involvement of Child Protective Services if they disclose opioid use.  Obstetrical 
programs may also have concerns about reporting requirements and the burden this places on 
practitioners.  This issue of reporting will need to be handled sensitively and in collaboration with 
patients so that women do not feel punished because they are trying to engage in treatment.  We will 
include training for sites in both conditions on non-judgmental ways to handle reporting requirements.  
We will also provide guidance on complying with the laws.  In qualitative work, we will explore the 
impact of reporting requirements on treatment and on participants’ willingness to receive treatment.
2.3.2
KNOWN POTENTIAL BENEFITS 
Impact on Health Decisions 
There is a dire need to establish care delivery systems that can address the opioid crisis in pregnant 
women. While there are several “ideal” models, a helpful model is one that could be implemented in 
obstetrical settings alongside prenatal care and would help pregnant women minimize their use of 
opioids and other substances.  Both models outlined above have strengths and weaknesses in this 
regard.  ECHO is scalable and as evidenced by the dramatic success in New Mexico, shows great promise 
to train obstetrical providers.  The development of a “learning community” through the group case 
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presentation process, is a very powerful way in which to share knowledge and enhance therapeutic 
confidence among providers.  This can go beyond clinical issues of medication initiation and titration to 
include ways to improve referral systems.  Depending upon the commitment of the practice and their 
willingness to share resources, multiple individuals can be trained, and this can include physicians and 
support staff.  The potential down-side of ECHO is the time-crunch physicians experience.  While each 
practice can dedicate staff duties as it would desire, there is no explicit CM role in the ECHO model.  In 
this sense, ECHO may have a greater impact in settings where some extender activities are already 
available (e.g. social worker services, recovery coaches, advanced practice nurses) although this is not 
clear. In addition to extender concerns, members of the team in the practice who plan to participate in 
ECHO (in this case physicians and nurses), must make time and be available to attend the ECHO sessions 
and to share case information with their colleagues.  Availability can be a challenge in busy obstetric 
settings not only because of issues of patient flow but because of obstetrical emergencies.
As noted, CC has the benefit of a CM. The CM is trained in supporting behavioral techniques such as 
recovery coaching. The down side of CC is that it is potentially more labor intensive--the CM must be 
willing to follow a group of patients rather closely and this can take time. CC can also be costlier than 
ECHO and ultimately practices must be willing to dedicate resources to the CM.  Medicare has made the 
costs of a CM billable and MA Medicaid has started to allow providers to bill for recovery coaching. 
Medicaid in CT does not allow practitioners to bill for these services but a study such as ours can inform 
policy makers. 
The qualitative work proposed in this application can be very helpful. Infrastructure burdens can be 
explored. We will also qualitatively and quantitatively measure physicians’ attitudes, perception of 
support, and perception of relationship with patients to enrich our understanding of clinicians’ needs. 
Such results of this study may be helpful to payers and providers. 
Impact on Questions that Affect Outcomes of Interest to Patients
Although the study compares delivery models for pregnant women with OUD, it is also poised to 
address many outcomes that are of interest to patients.  First and foremost, our primary aims were 
developed with our community partners who felt treatment availability, engagement and retention 
were critical.  Also, of interest to patients is their empowerment to make or share medical decision, 
including whether to elect MAT or not (see above).  The study would also address domains that are 
important to patient stakeholders including: 1) communication between providers and patients; 2) 
recovery-related outcomes (role satisfaction, confidence in managing addiction); 3) emotional well-
being; and 4) birth outcomes. 
2.3.3
ASSESSMENT OF POTENTIAL RISKS AND BENEFITS 
Potential Risks  
Patient participants may experience distress while completing standardized assessment surveys, with 
feelings of guilt about substance use during pregnancy; anxiety and worry of adverse outcomes for 
themselves and their infants; and fear of public disclosure and potential legal consequences. The 
research team includes 4 psychiatrists who will be available to provide support for women who 
experience any psychological distress. We will reinforce the notion that all of the usual care available on 
site will be available to all participants.  We will provide referrals as needed. 
There is risk associated with a breach of confidentiality, and the release of unwanted information to 
persons outside the research team.  There are also risks related to reporting requirements for substance 
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use in pregnancy (MA) or after delivery (all sites).  This risk is present whether or not a woman 
participates in the study.  We will follow usual clinic procedures for reporting. 
There is a risk of clinical worsening (e.g., suicidal ideation, out of control substance use) in either groups 
that is common in this population.  
Protection Against Risks 
To minimize risks associated with study participation, we will take the following steps:  First, designated 
staff person or care managers will tell potential participants that some assessment questions focus on 
sensitive topics and they can always choose not to answer a specific question.  If a participant is upset by 
survey content, or develops suicidal ideation, the care manager can locate appropriate clinic staff or 
study staff to assist with the situation.  We will train research staff to identify severe psychological 
distress and under those circumstances will inform a senior member of the research team to determine 
the safest course of action. We will also include a rescue protocol for worsening opioid or other 
substance use or suicidal ideation.  This may include inpatient or partial hospitalization. Study faculty are 
experienced in the management of such circumstances with patient safety of paramount importance.  
We will tell participants that their clinical data are confidential and protected under HIPAA.  We will link 
research data only by a participant ID number.  We will collect survey data by computer using REDCAP®, 
a secure, encrypted program that affords additional protection of confidentiality for study participants. 
To further protect pregnant women participating in this research, we will obtain a Federal Certificate of 
Confidentiality.   In addition, women will be told their decision to participate in the study is voluntary.  
They can choose not to participate or they can choose to withdraw from the study at any time, and it 
will not adversely affect their care at the clinic.
Benefits
It is critical to help pregnant women avoid use of illicit opioids as well as other substances that can 
negatively affect her health and contribute to adverse birth outcomes and longer-term problems with 
her offspring. This comparative effectiveness trial will compare models of care that may help pregnant 
women with OUD by providing onsite OBOT and counseling and it may help pregnant women for OUD in 
the future to tests these models of care. 
Use of Collaborative Care with the obligatory longitudinal symptom monitoring, the provision of 
supportive psychological and psychiatric treatment, and the option of MAT shows promise to: reduce 
the maternal and fetal consequences of non-prescribed or illicit opioid use, minimize co-use of 
additional harmful substances such as cocaine and benzodiazepines, and improve maternal functioning 
at delivery and 3-months post-delivery. The condition of telesupport and a learning community is also 
poised to enhance the likelihood of buprenorphine prescribing and the care of pregnant women with an 
OUD.  Patients, clinicians, payers and policy makers will benefit from a comparison of these two models.
3
OBJECTIVES AND ENDPOINTS 
Our primary aims are:
1)
To determine differences in engagement and retention in OUD treatment (MAT and/or non-
pharmacological care) between participants who receive care from a center that uses a CC vs an 
ECHO support model. We hypothesize that the benefit from a CM and proactive monitoring 
approach will lead to greater treatment engagement and retention among patient participants.
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H1a: Participants with an OUD are more likely to be engaged in OUD treatment if the center is 
randomized to the CC vs the ECHO model of support.
H1b: Participants with an OUD treated in CC centers are more likely to be retained OUD treatment 
than those treated in a center randomized to the ECHO model of care.
2)
To determine differences in patient-reported outcomes between the two treatment models. For this 
domain we will use the Patient Activation Measure (PAM) as the sentinel measure. Patients can be 
assigned to one of four PAM levels based upon their scores. Originally, we planned to operationalize 
this outcome as whether or not patients increased at least one PAM level. Operationalization of this 
outcome was changed to a continuous outcome (i.e. the PAM score) on 10.25.21 to increase power 
for this outcome and to follow what is more commonly reported in the literature. The dichotomous 
outcome will be a secondary outcome.  
H2: Participants in the CC, compared to the ECHO condition, will have higher PAM scores at week 36 
and 3-months post-partum.  
Our secondary aims are: 
1)
To determine differences in engagement and retention in MAT between participants who receive 
care from a center that uses a CC vs an ECHO support model. We hypothesize that the benefit from 
a CM and proactive monitoring approach will lead to greater MAT engagement and retention among 
patient participants.
H1a: Participants with an OUD are more likely to be engaged in MAT if the center is randomized to 
the CC vs the ECHO model of support.
H1b: Participants with an OUD treated in CC centers are more likely to be retained in MAT for an OUD 
than those treated in a center randomized to the ECHO model of care.
2)
To determine differences in birth outcomes between participants who receive care from a center 
that uses a CC vs. and Echo support model.  For this domain we will examine birth weight.  
H2: Babies born to mothers treated in CC centers will have higher birth weights on average 
compared to babies born to mothers treated in ECHO centers. 
3)
To determine differences in obstetrical providers’ work satisfaction among the two treatment 
models according to the Physicians Worklife Survey.
H3:  Obstetrical providers randomized to the CC compared to the ECHO condition will score higher 
on subscales (autonomy, relationship with patients, patient care issues and relationship with staff) 
of the Physicians Worklife Survey.
Primary, secondary and exploratory outcomes are listed in the table below:
Outcome  
Type of 
Outcome 
Assessment Tool 
Assessment timepoints 
Sample 
size 
Treatment engagement
Primary
Medical records and 
study database
Prenatal treatment period 264
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Treatment retention
Primary
Medical records and 
study database
Birth and 3-months post-
partum
264
Patient Activation 
Primary
Patient Activation 
Measure
Baseline, 26 weeks ,36 
weeks and 3 months post-
partum
264
#/% initiated onto MAT
Secondary
Medical records and 
study database
Prenatal treatment period 264
#/% retained on MAT
Secondary
Medical records and 
study database
Birth
TBD
Birth weight
Secondary
Medical records and 
study database
Birth
264
Physician Work Satisfaction
Secondary
Physician Work Life 
Survey
Before first participant 
enrollment and after last 
participant enrollment
12
#/% increasing at least one 
PAM level
Secondary
Patient Activation 
Measure
Week 36 and 3-months 
post-partum
264
#/% offered MAT
Exploratory
Medical records and 
study database
Prenatal treatment period 264
#/% continuing MAT at 3 
months postpartum
Exploratory
Medical records and 
study database
3-months post-partum
TBD
#/% engaging in an opioid 
treatment program at 3 
months post delivery
Exploratory
Medical Records and 
study database
3-months post-partum
264
#/% abstinent from illicit 
opioids or misuse or 
prescription opioids
Exploratory
a. TLFB 
b. Urine Drug 
screens
a. monthly
b. each prenatal visit and 
birth and post birth
264
#/% with concurrent 
substance use 
Exploratory
a. TLFB 
b. Urine Drug 
screens
a. monthly
b. each prenatal visit and 
birth and post birth
264
Low birth weight
Exploratory
Medical records and 
study database
birth
264
Resuscitation at delivery
Exploratory
Medical records and 
study database
birth
264
Fetal demise
Exploratory
Medical records and 
study database
birth
264
Preterm birth
Exploratory
Medical records and 
study database
birth
264
Duration of hospitalization
Exploratory
Medical records and 
study database
Hospital discharge
264
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Shared Decision Making
Exploratory
SDM-Q-9
Baseline, 24 weeks and 36 
weeks
264
Patient-Physician Interaction
Exploratory
PEPPI-5
Baseline, 24 weeks, 36 
weeks and 3 months post-
partum
264
Clinician/Patient therapeutic 
relationship
Exploratory
Kim Alliance 
Communication 
(KAC)
Baseline, 24 weeks, 36 
weeks and 3 months post-
partum
264
Satisfaction with roles and 
activities
Exploratory
PROMIS Emotional 
Short Form 4a
Baseline, 24 weeks, 36 
weeks and 3 months post-
partum
264
Depression
Exploratory
EPDS
Baseline, 24 weeks, 36 
weeks and 3 months post-
partum
264
4
STUDY DESIGN
4.1
OVERALL DESIGN
Yale will lead this study to compare the effectiveness of two models of support for reproductive health 
clinicians who will provide prenatal and addiction care for pregnant and postpartum women with an 
opioid use disorder in obstetrical centers in Connecticut and Massachusetts.  The two models being 
compared are: 1) a collaborative care (CC) approach, based upon the Massachusetts Office-Based-
Opioid Treatment Model, that would provide onsite training, and support to providers through the use 
of a care managers; and 2) a tele-support approach modeled on the Project Extension for Community 
Healthcare Outcomes (ECHO), a remote education model that provides mentorship and guided practice 
and participation in a learning community via video conferencing.  Twelve obstetrical centers who 
currently do not have a system in place to treat pregnant women with OUD will be recruited and their 
characteristics matched.  The unit of randomization is the obstetrical center. We will randomly assign 
one center in each pair to either the CC or ECHO model, 6 sites to each model of support.  A statistician, 
blinded to the identities of the clinics, will assign a number to each clinic using a random number 
generator; within each matched pair, the clinic with the lower number will be assigned to CC and the 
other will be assigned to ECHO. Among the centers, we would recruit 264 women in total, 132 women 
from the CC sites and 132 from the ECHO sites, about 20 per site among the 12 sites. 
Although we will recruit centers that report caring for at least 40 women per year who have an OUD, we 
will need an accurate method for estimating the rate of opioid use in order to compute outcomes.  we 
will obtain the base rate of opioid and other illicit substance use in each practice by obtaining urine drug 
screens from all women attending the obstetrical practice for a prenatal visit in a one-week period. 
Urine collection will be anonymous and will use a small portion of the sample women typically provide 
at each prenatal visit.  Clinic staff will collect urine samples from their patients as normal.  A Yale 
research assistant will then test a small portion of the sample with an instant urine toxicology test.  
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Results will be entered anonymously into a REDCAP@yale database and assigned a random subject 
number.  Research assistants will have no contact with the patients themselves and no identifying 
information will be collected.  Results of the urine collections will be used to determine the prevalence 
of substance use at each study practice.  This procedure will be repeated annually during the study to 
ensure the accuracy of the estimate.
Recruitment of patient participants will be facilitated by universal screening by practice sites and referral 
to the study if appropriate.  Screening for opioid misuse will occur at prenatal visits as recommended by 
the American College of Obstetricians and Gynecologists.   Clinicians will follow up on affirmative 
answers and discuss study participation with them.  A designated staff person (DSP) will hand potentially 
eligible women a tablet that includes screening questions and a patient consent document.  After 
reviewing the consent form, and having any questions answered and signing the consent form, study 
participants will then complete a baseline assessment that includes demographic information and 
questions about pregnancy dates and a checklist that would indicate an opioid use disorder (OUD) (via a 
tablet computer).  After completion of these questions, the tablet and DSP will determine whether the 
woman remains eligible for participation and will be enrolled.  The participant will be assigned a study 
identification number.  She will then complete additional questions that are part of the baseline 
assessment for Visit 1 (see Table 1).  
Potentially eligible women will also be given the option of having a researcher contact them by phone 
and reviewing the consent via phone or Yale Zoom if that is their preference.  In this scenario, women 
will provide verbal consent to the DSP at the practice site if they are interested in being contacted by 
study staff, and the obstetrical provider will provide her name and contact information to research staff. 
Referred women will be contacted by phone or by a research assistant who will explain the entire 
protocol and all of its requirements at length. Additionally, women are encouraged to ask questions 
about any confusing points. Subjects are told that they may withdraw from the project at any time, 
without prejudice, and without any adverse effect on their medical care at their prenatal clinic.  Women 
who express interest in study participation will be emailed or texted a link of the study consent form 
using REDCap@yale.  Participants will be provided with time to review the content and the researcher 
will then review the eConsent form, and answer any remaining questions.  Once the participant has 
signed and submitted the eConsent form the research assistant will receive a REDCap notification of its 
submission and will review the form to confirm it is filled out correctly.  The research assistant will then 
open the corresponding ‘Person Obtaining Consent’ form as a survey and electronically sign it.   
Screening and baseline assessments as described above will then be emailed or texted to the 
participant.
After enrollment, a urine drug screen (UDS) will be obtained at each prenatal visit (the urine will be 
collected as part of the regular prenatal visit and tested for the presence of illicit and licit opiate drugs). 
Study sites will be asked to report results of UDS by completing a form that is entered into REDCap. 
Participants will also be contacted monthly by a Yale research assistant (who is blind to condition) to 
complete a Time Line Follow-Back (TLFB) and the Treatment Utilization Form that includes questions 
about the quantity and frequency of all substances used and treatment received.   Study participants will 
complete additional self-report questionnaires at the following assessment points: enrollment, 26 weeks 
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and 36 weeks (+/- 4 weeks), and at 3M post-partum.  Data will be collected using a tablet provided by 
the DSP.  In addition, maternal/infant medical record data will be extracted by the DSP and provided to 
the Yale and UMass data collection teams. These data will include maternal, fetal and neonatal 
outcomes.  
In addition to the above recruitment strategies, we will also ask women who participate in the study if 
they know any other women who might be interested in participating.  We will explain to the participant 
that if they know any other pregnant women who may have an opioid use disorder (i.e. known or 
suspected use of illicit opiods or known to be on MAT) that they can let the women know abut the 
Project Smart Study and give our contact information.  We will give our business cards to any women 
who think they might know someone who would be interested and they will need to contact us directly.  
Due to the sensitive nature of the study, we will not collect any contact information about the otential 
participant; she will need to contact us cfrom the information on the business card and thus show her 
interest in the study.  
Participants who recommend someone who consents and is eligible for the study will be compensated 
with a $25 Amazon gift card for the referral.
A subset of patient participants in the trial will be given the opportunity to participate in a separate 
qualitative interview. These interviews will collect data on patent level of satisfaction with MAT 
experiences at the clinics.  
The experiences of physicians involved in the project will also be assessed.  At least one provider from 
each practice (minimum of 12) will also be invited to participate in qualitative interviews to assess their 
perceptions of the implementation of MAT within their practice including barriers and facilitators to 
implementation.  All providers who participated will be asked to complete brief forms asking about 
workload and clinical support.
4.2
SCIENTIFIC RATIONALE FOR STUDY DESIGN
Given the scope of opioid crisis, the need for treatment outpaces the capacity to provide it.(56) 
Increasing the cadre of buprenorphine providers can help address this but there are barriers including: 
lack of patient and physician interest,(57-59) lack of expertise and education,(57, 58, 60, 61) limited 
physician time and resources, (57, 62, 63) stigma towards patients with OUD,(58, 61) concern about 
abuse or diversion,(96, 97) lack of institutional support,(59, 62, 96) cumbersome regulations,(60, 65) and 
insurance barriers (e.g. insufficient rates of reimbursement).(57, 61, 63, 96) Provider barriers may be 
particularly problematic for pregnant women with an OUD.(2) A possible solution is to combine 
addiction care (including MAT) with prenatal care.(50, 67-69) Some existing programs provide “women-
centered” care to patients with an OUD, including prenatal care, MAT, care coordination, behavioral 
health services, family planning and breastfeeding support. (18, 67, 70) Such programs are more likely 
than non-women-centered programs, to dose opiate agonist treatment (buprenorphine) to fit the 
physiology of pregnancy, enhance the utilization of long-acting contraception and have better rates of 
breastfeeding continuation.(67)  Despite the potential benefits of a program that provides conjoint 
prenatal and addiction care, there is a major gap in knowledge regarding the best models for 
supporting centers that would like to provide such women-centered care to women with an OUD 
treated in obstetrical settings. The models of care we propose to test address many of these concerns, 
although they differ in their potential to affect many of them: 1) we know that the cadre of physicians, 
including obstetricians, who are trained to provide MAT is insufficient; 2) we also know that among 
those who have been waivered to use MAT, many obstetrical providers do not provide MAT; 3) indeed, 
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many obstetricians identify lack of support for their provision of addiction care, especially given the 
complex needs of this patient population (Society of Maternal Fetal Medicine Workshop Report, 
forthcoming, 2018) as the reason they do not provide MAT. There is a need to compare different types 
of support to obstetrical practices that would allow them to deliver addiction care, in a women-centered 
manner.
Comparative Results on Maternal and Fetal Outcomes and Patients’ Perception of Care (RQ-3):  If 
addiction treatment, including MAT, is provided through obstetrical practices, it needs to be done with 
fidelity and in a way that meets patients’ needs. Only a few studies have assessed possible differences in 
maternal and fetal well-being for gravidas treated in programs that provided combined vs separate 
prenatal care and addiction treatment.(67)  Some cohort studies provided information on fetal 
outcomes in centers that provide combined care.(18, 20) We were unable to identify studies or trials 
that compared different models of combined prenatal and substance use care for pregnant women with 
OUD.  Gaps in this literature are many, some of which include: rates of engagement in addiction 
treatment; level of retention in prenatal care and addiction treatment; rates of adverse birth outcomes; 
utilization of MAT as part of addiction treatment; rates of continuing MAT during the postpartum 
period; treatment of concurrent substance misuse and psychiatric conditions. 
As well, but equally important is the lack of knowledge regarding women’s experiences when they 
receive treatment under different models of combined care.  Some of the domains of importance 
include patient’s engagement in care, knowledge of care, confidence in managing pregnancy and their 
addiction, alliance with their providers, emotional well-being, ability to fulfill important roles in life and 
retain custody of their children if they wish to do so.  A trial of different models of care can provide 
information to fill in these important gaps.
4.3
JUSTIFICATION FOR INTERVENTION
Collaborative Opioid Prescribing Model (Massachusetts Model): 
This model is based upon CC, a system developed initially to enhance the capacity for treatment of 
depression in primary care settings.(73) The model has since been refined (74, 75) and tested for 
treatment of other disorders; it has been deployed in additional venues including obstetrical-
gynecological settings.(76, 77) CC, as articulated by the University of Washington, includes several 
components: (1) patients are systematically evaluated 
(screened) for medical and behavioral health needs; (2) a CM 
assists with assessment and enrolls patients in a registry that 
includes data on symptoms that are collected longitudinally; 
the CM provides some proactive behavioral treatment and 
care coordination; 3) a psychiatrist reviews cases and assists 
the primary physician in providing stepped-care 
recommendations that are tailored to the particular 
patient’s needs.(78) Components of CC that have the 
greatest impact on successful outcomes include the use of 
standard screening among all patients in the system (e.g. clinic) and administration of psychological 
treatments.(79)  CC has been applied to the treatment of OUD in open trials of non-pregnant 
patients(80, 81) and pregnant women.(68) It increased treatment initiation, engagement and use of 
psychotherapy among non-pregnant patients.(82) To our knowledge, there are no controlled or efficacy 
trials using CC for treatment of OUD in pregnancy. However, the model was felt to be sufficiently strong 
for MA to promote a statewide program for Federally Qualified Health Centers (FQHCs) in order to 
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enhance the capacity of primary care providers to use buprenorphine. (3) As implemented in 14 centers 
with primary care patients, the “Massachusetts Model” is slightly different than CC for depression 
outlined above and includes: (1) patients are systematically (screened) for opioid use and an OUD by a 
CM; (2) the CM assists with assessment and enrolls patients into a registry that includes symptom data 
that are collected longitudinally; (3) the CM provides education, some behavioral treatment and care 
coordination; (4) the CM assists with induction (treatment initiation) and follow-up (urine toxicology 
screens; UDS).  In this way, the CM assists the physician with time burdens and offers additional effort 
to tailor treatments and referrals to the needs of the patient. The Massachusetts Model does not 
include a psychiatrist.   
Project ECHO (Extension for Community Healthcare Outcomes):  
This model was developed to build capacity to treat chronic, complex health conditions in rural and 
underserved communities that lack ready access to clinical specialists.(83, 84) Developed at the 
University of New Mexico Health Sciences Center to train primary care clinicians to treat patients with 
hepatitis C in rural communities(84, 85), it is now widely replicated across the country and around the 
world. Project ECHO uses a virtual hub-and-spoke educational model that links primary care clinicians 
with specialists through a real-time learning model made possible by inexpensive videoconferencing 
technology.(84, 86) Unlike traditional telemedicine, the ECHO model results in “force 
multiplication,”(87) where a few specialists mentor many providers, who in turn provide enhanced care 
for large numbers of patients that would otherwise have limited access to specialty care. Project ECHO 
has been broadened to address many other conditions, such as HIV,(88, 89) mental illness,(90, 91) 
chronic pain,(92, 93) diabetes,(94) and OUD; it has been found to be an effective and potentially cost-
saving model.(86) 
In 2005, the Integrated Addictions and Psychiatry (IAP) ECHO clinic was developed to treat substance 
use and psychiatric disorders in New Mexico.(95) Supporting the availability of MAT with buprenorphine 
was a major focus of the IAP ECHO clinic. Support consists of video-conferencing and presentations of 
cases reviewed by the practitioners in a network of centers, “spokes,” that is curated by an expert in a 
“hub” (usually located in an academic medical center) who is available remotely. A typical ECHO session 
consists of 1) introductions of participants; 2) a brief didactic session, usually a 30-minute presentation 
on substance use or mental health; and 3) discussion of case presentations submitted by participants in 
advance. A community partner of ours would provide ECHO and would modify this by adding time 
during the first few months for education and training. The IAP program has contributed to training the 
largest number of buprenorphine-wavered physicians in rural areas of New Mexico, from <20 when the 
program started to 140 as of 2014.(95) The focus on OUD and buprenorphine training and support has 
enhanced the capacity to treat OUD in New Mexico. While we know capacity to treat has increased, 
there are no trials evaluating the efficacy of ECHO for the treatment of OUD in pregnancy compared to 
other methods. 
4.4
END-OF-STUDY DEFINITION
The end of the study is defined as completion of the 3-month post-partum visit shown in the Schedule of 
Activities (SoA), Section 1.3.
5
STUDY POPULATION
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In this study design both the clinician and the patient- participant are contributing data toward the study 
aims.  Physicians and patient – participants will both provide informed consent as appropriate.   
Physician – participants will need to be a member of a practice or clinic that was included in the clinical 
trial which has a CM, DSP or obstetrician, who will be providing care and be willing to provide informed 
consent.
5.1
INCLUSION CRITERIA
In order to be eligible to participate in this study, a participant must meet all of the following criteria:
1.
Provision of signed and dated informed consent form
2.
Females ≥ 18 years old 
3.
Documented pregnancy in the medical record of less than 34 weeks gestation
4.
Delivery date no later than July 1, 2024
5.
Willingness to adhere to the study schedule 
6.
Confirmed opioid use disorder by the DSM-5 Opioid Use Disorder questionnaire 
7.
Ability to communicate in English
In order for providers who are not principal investigators to participate they must meet the following 
criteria:
1.
Provision of verbal consent
2.
Willingness to adhere to the study schedule based upon site randomization
3.
Speak English
5.2
EXCLUSION CRITERIA
 
A patient participant who meets any of the following criteria will be excluded from participation in this 
study:
1.
Experiencing cognitive or emotional impairment that precludes them from providing informed 
consent 
2.
Current hospitalization, incarceration, or institutionalization (if women present for care after 
institutionalization, they will be eligible to participate), or a court case pending such that 
incarceration during the study treatment period would be likely
3.
Have plans to move from the area in which they are currently seeking their obstetrical care within 
the study period (which will be 44 weeks at most)
Providers will be excluded who:
1.
 Have no exposure to one of the two models of support that are being compared
2.
Are a temporary worker (e.g. student or per diem for a short period of time, although long-term 
per diems will be allowed)
3.
Are not willing to undergo training for buprenorphine administration
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5.3
LIFESTYLE CONSIDERATIONS
During this study, participants are asked to:

Come to visits as scheduled

Continue or begin any behavioral or medication assisted OUD treatment (MAT).
o
Note the MAT status of patients can vary:  women may choose to receive 
buprenorphine, they may receive methadone from anther provider, or they may choose 
to receive no MAT.  We would also allow women to change their decisions about MAT; 
we would like to respect their choice and they may decide later to engage in MAT.  We 
will also include women who are on methadone since they may prefer to switch to 
buprenorphine or no MAT.
5.4
SCREEN FAILURES
Screen failures are defined as participants who consent to participate in this study but are not 
subsequently entered in the study due to not meeting one or more eligibility criteria. Screen failures 
may be rescreened if their status changes at any point during their prenatal care.   Rescreened 
participants will be assigned the same participant number as for the initial screening.
5.5
STRATEGIES FOR RECRUITMENT AND RETENTION
Participants will be enrolled at 12 obstetrical centers that are matched on demographics of patient 
population. Within each pair of centers, each will be randomly assigned to the CC or ECHO condition. We 
will enroll 264 women in total, half in each treatment condition.  
Recruitment was impacted by the Covid-19 Pandemic, and we re-evaluated our recruitment plan based 
upon our first 16 months of recruitment (10.25.21).  We reduced our anticipated to sample size to 264 
participants in in total or 132 in each treatment group with an average of 20 participants per site, 
allowing for 10% attrition. For the engagement outcome, we anticipated screening 360 eligible patients. 
Women will be enrolled at each site by a designated staff person (DSP), most likely a nurse (at the CC 
practices it will be the CM). We will be placing recruitment flyers and posters in the two clinic sites 
advertising the study.  We will have a social media page that describes the project.  A QR Code on the 
flyers and poster will direct potential participants to the social media page.  There the woman can 
read about the study or choose to watch a short video describing the study. As recommended by 
ACOG,(33) the DSP will administer their standard opioid screening to all pregnant women at all sites. 
Women with a positive screen will be invited to participate. DSPs will then obtain written consent from 
patients who agree to participate in the trial or remote consenting will be done as described earlier.  The 
DSM-5 checklist will be completed for the diagnosis of OUD.  Women who meet criteria for OUD will be 
deemed eligible to participate in the trial. To minimize attrition, the DSP will then: 1) explain the 
importance of follow-ups, 2) rapidly schedule first visit with a provider associated with the study after 
confirmation of eligibility and consent, 3) collect at least 3 verified locators, 4) call women to remind 
them of their appointments, and will have contact with a significant other who can provide collateral 
information and maintain subject involvement. Investigators will monitor participants who drop out and 
explore with the staff reasons for the dropouts.
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In addition to patient participants in the trial, qualitative interviews will be conducted with a subset of 
patient participants and physicians involved in the project.  Patient participants will be contacted, 
consented and enrolled in this portion of the project by computer randomization.   
Physicians will provide verbal consent form prior to participation.   
Incentives:
Patients enrolled at both the CC and ECHO sites will be compensated up to $310.  This would include $5 
for Screening, $50 for Baseline, $15 for the initial phone interview, $5 for each following Timeline 
Follow-back phone interview, $25 for 26-week follow-up, $25 for 36-week follow-up and $50 for 3-
Month post-partum follow-up. 
Patients who enroll in the qualitative portion of the study would be paid up to an additional $50 for each 
interview (at 6 months of pregnancy and 3 months post-partum).   Participants who are not randomized 
to be offered the qualitative interviews will be compensated up to $210.
 
6
STUDY INTERVENTION(S) OR EXPERIMENTAL MANIPULATION(S)
6.1
STUDY INTERVENTION(S) OR EXPERIMENTAL MANIPULATION(S) ADMINISTRATION
6.1.1
STUDY INTERVENTION OR EXPERIMENTAL MANIPULATION DESCRIPTION
The sites randomized to CC will have 4-6 on-site support visits at the outset of the study.  These visits will 
occur during the first 3 months of the project.  During these visits, study staff will again review 
buprenorphine induction procedures (heretofore referred to as “initiation” rather than “induction”) and 
dosing of buprenorphine as well as therapeutic behavioral treatments.  We will provide the center with 
forms and educational materials to help dosing during initiation procedures. At the same time, we will set 
up visits for the CM to meet with a recovery coach trainer provided by our community partner, CCAR.  
We will review data collection materials and methods.
The CC team includes the nursing CM and obstetrical provider. The CM responsibilities include: 1) 
screening patients for an OUD; 2) entering CC participants into the patient registry; 3) providing 
education to participants about OUD (and psychiatric disorders such as depression if needed); 4) 
assistance in initiation procedures for patients who would like to receive buprenorphine;(3) 5) informing 
the obstetrical provider of a positive UDS and need to consider an increase in buprenorphine; if the 
patient is on methadone, the outside treatment program obtains a UDS and will make appropriate 
adjustments but the CM can provide support and will collect UDS as project data; 6) if the patient is not 
receiving MAT, a discussion about starting MAT or psychological treatment; 7) following a safety transfer 
protocol, a manual SOP provided to the sites by the Yale research team at the study start-up meeting; if 
the patient has 3 consecutive urines that are positive for illicit substances and the dose of buprenorphine 
is maximized (24 mgs/day), or if there is definitive evidence of diversion, or the participant is receiving 
any form of MAT and has dangerous level of cocaine, opioid or methamphetamine use), or is suicidal; 8) 
recovery coaching. For research purposes, the CM will confirm informed consent, collect and enter 
results of the UDS into a database. At enrollment and at 26 and 36 weeks’ gestation and 3 months 
postpartum she will ask participants to complete an assessment battery of self-reported measures. 
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The Weitzman Institute (WI), a community partner and provider for the ECHO condition, is a research and 
innovation center embedded within one of the largest FQHCs in the country, Community Health Center, 
Inc.(CHC). It is focused on improving care for medically underserved and special populations. Since 2013, 
CHCI/WI has provided education and technical assistance through its established video conference and 
online learning platforms to over 800 primary care providers and over 200 care team members who treat 
patients with chronic pain and opioid addiction in 28 states plus Washington DC and Puerto Rico. CHC/WI 
partners with national experts in pain care, substance abuse disorder, and MAT to create and deliver a 
robust training program for clinicians across the country through Project ECHO ®.  The WI will work with 
our study team (Drs. Fiellin, Callaghan, Lipkind, Yonkers, Byatt and Forray) to develop and staff the 
sessions. Data collection will mirror the CC condition and conducted by a person designated by the 
practice, designated study person (DSP).
6.1.2
ADMINISTRATION AND/OR DOSING
CC- Obstetricians, who are X-waivered will see all participants; initially they will discuss preferences for 
addiction treatment (buprenorphine, methadone or no MAT) with the participant. For gravidas who elect 
treatment with buprenorphine, obstetricians will adjust the dose of buprenorphine until patients are 
stabilized.  They will see stabilized buprenorphine, methadone and no MAT participants as needed for 
OUD care (typically every 1-2 weeks for those who are prescribed buprenorphine; other women it may be 
more or less frequently), and typical prenatal care. The obstetrician may benefit from ongoing support 
via e-mail and video conference available at no cost from the SAMHSA-funded Prescriber Clinical Support 
System for MAT (PCSS-MAT).  Practices may elect to have more than one obstetrician or APRN complete 
the X-waiver process so that they can provide back-up care during the absences of the primary study 
obstetrician.
The care team (CM, obstetrician) will meet at least monthly but more frequently if the case load is in 
need of more frequent meetings, and will review the CC participants’ scores, UDS and needs. The 
obstetrician can refer a participant to psychological or psychiatric treatment offsite and/or could be 
contacted by the CM for support, recovery coaching and to troubleshoot issues with attendance or other 
issues. 
ECHO- The practice members who participate in ECHO will include obstetricians and nurses as well as 
other members of the care team who wish to join. ECHO sessions are recorded and available 
asynchronously for review if providers are unavailable. Providers participating in Project ECHO sessions 
are given access to a password-protected website containing the recorded sessions, a discussion board, 
and resource library. CME credits are available for each session and are provided through the American 
Academy of Family Physicians (AAFP) and can motivate providers to attend. 
A DSP will obtain consent, check the UDS and enter results of the UDS into a database.  At enrollment, 26 
and 34 weeks’ gestation and at 3-month postpartum visit, this person will give participants a tablet with 
an assessment battery of self-reported measures. 
Thus, essential differences between models are: 1) CC has designated roles for the CM (a participant 
registry and psychotherapeutic support via recovery coaching); 2) ECHO has ongoing support from a 
learning community tailored to the needs of the practices.
6.2
FIDELITY
6.2.1
INTERVENTIONIST TRAINING AND TRACKING
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After clinical sites have been finalized, they will be randomized to a condition and start-up meeting for 
sites in each condition will be scheduled. Prior to the meeting we will ask physicians (who have not 
completed the waiver-2000 process) at each site to complete 4 hours of on-line training for the waiver-
2000 process (Drug Addiction Treatment Act of 2000 (DATA 2000) buprenorphine waiver trainings).  The 
additional 4 hours will be completed at the start up meeting. At the meeting, we will provide education 
about OUD, especially in pregnancy. We will review the study protocol, discuss site concerns and 
challenges and plans for either the on-site visits or ECHO sessions.  
The WI will train faculty to the ECHO model and deliver the sessions in Year 1 of the project.  The sessions 
will occur more frequently during this time (2-4 times per month) since this is the time when the most 
intensive education is needed.  After that, they will receive monthly sessions during Years 2.  In addition 
to ECHO, providers in this condition will have access to the educational materials that the CC condition 
has.  We will inform them of the PCSS-MAT that offers support to clinicians who prescribe 
buprenorphine. While the roles in the ECHO condition are not prescribed as they are in CC, the practice 
may decide to have a specific nurse in charge of many of the tasks of the CM, but this is not obligatory 
and we will not be providing the onsite training.  We recognize that sites will vary in terms of the 
availability and proximity of psychiatric and psychological services.  To help neutralize differences we will 
include educational material that discusses supportive counseling and motivational interviewing for 
substance use disorders.  We will present this material to the learning community as an educational 
component prior to discussion of cases during ECHO sessions.  As well, part of the ECHO curriculum will 
discuss building a referral network and enhancing referral to counseling and the use of motivational 
interviewing. 
6.3
MEASURES TO MINIMIZE BIAS: RANDOMIZATION AND BLINDING
Matching of Clinics- Participating clinics will be matched as closely as possible based on state, size and 
academic vs. non-academic / community hospital to lessen site interactions with the data.    
Randomization of Clinics- Within each matched pair, one clinic will be randomly assigned to the CC 
condition and one will be assigned to the ECHO condition. Randomization will occur by assigning a number 
to each clinic using a random number generator; within each matched pair, the clinic with the lower 
number will be assigned to CC and the other will be assigned to ECHO. 
Blinding of Research Staff- The statistician will be blinded to the identities of the clinics when assigning 
treatment allocation during randomization. Research staff who will contact the participants to conduct 
the monthly TLFB will be blinded to the treatment condition.  In addition, the research staff who extract 
the maternal and infant outcome data  
6.4
STUDY INTERVENTION/EXPERIMENTAL MANIPULATION ADHERENCE
Our primary outcomes are percent of pregnant women who are i) successfully engaged at least one visit 
per month for 3 months) and ii) retained on MAT and/or non-pharmacological care (for the purposes of 
this protocol, these visits will be with billable opioid use treatment providers)at delivery and through 3 
months postpartum . The percent will be determined via annual baseline assessments of women who 
would be eligible according to an estimation of the number of women in the practice who have urine 
tests positive for opioids (see section D.5.d.).  We define unsuccessful retention according to a 
modification of Wilder, et al. (2015),(98) as women who enrolled in pharmacological or behavioral 
treatment for opioid misuse who stopped treatment with no plan for ongoing therapy or medication for 
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two months (e.g. discharge, relapse and left treatment, lost to follow up with no discharge plan) during 
pregnancy, and the 3 months post-delivery. We add percent engagement as our outcome because a site 
may look successful in retention if they only engage a very motivated subset of eligible women in 
treatment yet are able to retain them. This would miss a proportion of women who may have complex 
illness and are more difficult to both engage and retain in treatment. We adopt a broader outcome that 
includes therapy rather than just initiation and continuation of MAT with input from our community 
partners who felt that allowing women to select either MAT and/or psychotherapy respects patient 
choices. We include percent retained because engagement is not sufficient to consider a treatment as 
successful. Exploratory analyses will compare the number of women engaged and retained in 
treatment.  We include visits with the care manager as indicative of receiving behavioral therapy in the 
CC condition only if there is a specific focus on addiction treatment (e.g. recovery counseling) since that 
condition by default has on-site treatment available. For analysis, we would use two intervals: in 
pregnancy and then after delivery.  Pregnancy and postpartum are very different time intervals and it is 
useful to differentiate them.  We would then measure overall retention during the entire study period.  
6.5
CONCOMITANT THERAPY
Medication assisted treatment (MAT) is a critical component of standard care for pregnant women with 
an OUD (35, 36) and is recommended by the American College of Obstetricians and Gynecologists 
(ACOG)(33) and other experts.(5, 37) It enhances adherence to prenatal care (38) and increases the 
likelihood that the mother will continue MAT after delivery, a period of high risk among perinatal 
women with OUD.(39) Initially MAT included methadone but now includes buprenorphine and 
naltrexone (not yet indicated for use in pregnancy), which can be prescribed in primary care 
settings.(40)  
MAT status of patients can vary:  women may choose to receive buprenorphine, they may receive 
methadone from anther provider, or they may choose to receive no MAT.  We would also allow women 
to change their decisions about MAT; we would like to respect their choice and they may decide later to 
engage in MAT.  We will also include women who are on methadone since they may prefer to switch to 
buprenorphine or no MAT. 
Outside behavioral therapy- Patients can be receiving behavioral therapy at the onset of the study or 
choose to begin therapy while on the study.  Concomitant therapy will be recorded in the eCRFs.  
6.5.1
RESCUE THERAPY
All practices will have a rescue protocol.  This includes guidance on substance use and on suicidal plan 
endorsement.
Rescue Protocol for Substance Use
1) Consider increasing buprenorphine dose beyond 24 mg per day for the following reason:
a. Temporary elevation during third trimester to address physiologic changes in 
metabolism, if patient has been on 24mg per day prior to pregnancy and shows signs 
of withdrawal in the third trimester.  
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2) If 3 consecutive urines are positive for illicit opioids (or at least one urine positive for illicit 
opioids and one or more missed appointments at which additional urines would have been 
collected), and buprenorphine is maximized, consider transfer to a structured treatment 
program 
a.
Structured treatment programs can include:
i.
 methadone program or any outpatient opioid treatment program with methadone 
or buprenorphine along with multidisciplinary services and more supervision of 
medication prescriptions
ii.
inpatient substance use treatment
iii.
intensive outpatient treatment
b.
Alternatively, consider increasing adjuvant treatments such as groups, counseling, Peer 
Support, or Recovery Coaches.
3)
Consider a transfer of care to methadone if there is definitive evidence of diversion -for example as 
evidenced by 3 consecutive urine drug tests negative for buprenorphine 
Rescue Protocol for Suicidal Ideation
1)
If a participant endorses greater than “0” on the Edinburgh Postnatal Depression Rating Scale 
question # 10, the tablet will be programmed to have a hard stop.  The participant will be 
instructed to show the scale to their nurse or doctor so that sites can employ their usual 
procedures to further assess suicide plans or intent and manage the patient (eg. assessment by 
a behavioral health care provider or referral to the emergency department)
2)
Study personnel will work with sites that do not have a pre-existing suicide protocol to develop 
such a plan
7
STUDY INTERVENTION/EXPERIMENTAL MANIPULATION DISCONTINUATION AND 
PARTICIPANT DISCONTINUATION/WITHDRAWAL
7.1
PARTICIPANT DISCONTINUATION/WITHDRAWAL FROM THE STUDY
Participants are free to withdraw from participation in the study at any time upon request.
An investigator may discontinue a participant from the study for the following reasons:
 

Lost-to-follow up; unable to contact subject 

Any event or medical condition or situation occurs such that continued collection of follow-up 
study data would not be in the best interest of the participant or might require an additional 
treatment that would confound the interpretation of the study

The participant meets an exclusion criterion (either newly developed or not previously 
recognized) that precludes further study participation
The reason for participant discontinuation or withdrawal from the study will be recorded in the CRF. 
7.2
LOST TO FOLLOW-UP
A participant will be considered lost to follow-up if he or she fails to return for at least three visits 
scheduled visits and study staff are unable to contact the participant after at least 3 attempts. 
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The following actions must be taken if a participant fails to return to the clinic for a required study visit:

The site will attempt to contact the participant, reschedule the missed visit within three weeks, 
counsel the participant on the importance of maintaining the assigned visit schedule and ascertain 
if the participant wishes to and/or should continue in the study

Before a participant is deemed lost to follow-up, the investigator or designee will make every 
effort to regain contact with the participant including email, text and telephone contact 
(depending upon patient preference).  If a participant does not respond to email, we will attempt  
3 telephone calls and, if necessary, a certified letter to the participant’s last known mailing address 
or local equivalent methods). If the participant responds but does not respond again, this will 
reset the attempts to contact unless she has asked us not to contact her. These contact attempts 
will be documented in the participant’s medical record or study file. 

Should the participant continue to be unreachable, he or she will be considered to have 
withdrawn from the study with a primary reason of lost to follow-up
8
STUDY ASSESSMENTS AND PROCEDURES
8.1
ENDPOINT AND OTHER NON-SAFETY ASSESSMENTS
8.1.1
SCREENING & BASELINE PROCEDURES

Substance Misuse Screen – All patients seen at the participating clinical are asked substance 
misuse screening questions as part of their standard or care.  Patients who answer affirmatively 
will be approached for consent.  

Demographics- Consented patients will have demographic data collected including information 
about pregnancy dates, medications and complications. 

Concomitant Therapy- Participants will be asked about any medications or other therapy they 
have received since their last visit.  This information will be recorded in the eCRF.  

Medical History- Participants will be asked about their medical history.  Medical history will also 
be collected through review of the patient’s medical record if available.  

Pregnancy Questionnaire- The following information will be collected about the patient’s 
current pregnancy; dates, medications and complications

Urine Drug Screening- Urine collected at pre-natal visit will be tested for illicit drugs and licit 
opioids  

DSM-5 OUD Checklist- Patient’s will complete the DSM-5 OUD checklist to confirm OUD.   

Contact Information-  At least 3 verified locators will be collected for each participant.  If 
available, one of these contacts will be a significant other who can provide collateral 
information and maintain subject involvement

Self-Assessments Including:
o
Patient Activation Measure (PAM)
o
Post Traumatic Stress Disorder Checklist for DSM-5 (PCL-5)
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o
Fagerstrom Test For Nicotine Dependence (FTND)
o
HIV Risk Taking Behavior Scale (HRBS)
o
Shared-Decision Making Questionnaire-9 (SDM-Q-9)
o
Perceived efficacy in Patient-Physician Interactions Questionnaire (PEPPI)
o
Kim Alliance Scale-Communication subscale (KAS-CM)
o
PROMIS Emotional Short Form
o
Satisfaction with Roles and Activities
o
Edinburgh Postnatal Depression Scale (EPDS)
o
Stigma Related Rejection Scale
o
Adverse Childhood Experience Questionnaire
8.1.2
STANDARD OF CARE PRENATAL VISIT

Assigned OUD Treatment- Physicians and clinical staff will follow the treatment plan for their 
assigned group (CC or ECHO) at each patient visit.  

Urine Drug Screening- Urine collected at pre-natal visit will be tested for illicit drugs and licit 
opioids.
8.1.3
TIMELINE FOLLOW BACK VISITS

Timeline Follow Back- Participants will also be contacted monthly by a research assistant (who is 
blind to condition) to complete a Time Line Follow-Back (TLFB) about the quantity and 
frequency of all substances used and treatment received.  

Treatment Utilization Form- Participants will be asked about any medications or other therapy 
they have received since their last visit.  
8.1.4
WEEK 26 VISIT

Self-Assessments Including:
o
Patient Activation Measure (PAM)
o
Fagerstrom Test For Nicotine Dependence (FTND)
o
Shared-Decision Making Questionnaire-9 (SDM-Q-9)
o
Perceived efficacy in Patient-Physician Interactions Questionnaire (PEPPI)
o
Kim Alliance Scale-Communication subscale (KAS-CM)
o
PROMIS Emotional Short Form
o
Satisfaction with Roles and Activities
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o
Edinburgh Postnatal Depression Scale (EPDS)

Qualitative Interviews (sub group)
8.1.5
WEEK 36 VISIT

Self-Assessments Including:
o
Patient Activation Measure (PAM)
o
Fagerstrom Test For Nicotine Dependence (FTND)
o
Shared-Decision Making Questionnaire-9 (SDM-Q-9
o
Perceived efficacy in Patient-Physician Interactions Questionnaire (PEPPI
o
Kim Alliance Scale-Communication subscale (KAS-CM)
o
PROMIS Emotional Short Form
o
Satisfaction with Roles and Activities
o
Edinburgh Postnatal Depression Scale (EPDS)
8.1.6
BIRTH

Birth Outcomes- Birth outcomes will be collected through review of the patient’s medical record 
including low birth weight, resuscitation at delivery, fetal demise, preterm birth, duration of 
hospitalization.  
8.1.7
3 MONTHS POST-PARTUM VISIT 

Self-Assessments Including:
o
Patient Activation Measure (PAM)
o
Fagerstrom Test For Nicotine Dependence (FTND)
o
Shared-Decision Making Questionnaire-9 (SDM-Q-9
o
Perceived efficacy in Patient-Physician Interactions Questionnaire (PEPPI)
o
Kim Alliance Scale-Communication subscale (KAS-CM)
o
PROMIS Emotional Short Form
o
Satisfaction with Roles and Activities
o
Edinburgh Postnatal Depression Scale (EPDS)
o
Stigma Related Rejection Scale

Qualitative Interviews (sub group)

At 3 months post-partum interviews will be conducted on approximately 20-30 randomly 
selected patients.  Questions on the interview will be regarding the patients’ knowledge 
and experience with Child Protective Services (DCF).  Consent for interviews will be 
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obtained using a verbal consent which will be read to providers prior to beginning the 
audiorecording.  Verbal consent will be used in lieu of written consent as a signed 
consent would be the only PHI linking the patient to the transcript.  Interviews will be 
audiorecorded  and identified by a subject number only.  Interviews will be transcribed 
and any identifying information pertaining to the patient or the clinic at which they 
receive obstetrical care will be removed.  Upon completion of transcription, 
audiorecordings will be destroyed.  All notes, audio recordings and transcriptions will be 
stored in YaleBox, a password protected, secure cloud storage system.  Only members of 
the study team will have access to this system.  Compensation for interviews will be a 
$50 Amazon egift card.
RE AND POST SUBJECT ENROLLMENT
Physicians will complete the Substance Abuse Attitudes Survey, the Physicians WorkLife Survey and the 
optional Qualitative Interview prior to first participant enrollment at the site and after the last 
participant enrollment at the site.
Physicians will also be given the opportunity to participate in a voluntary interview regarding policies and 
procedures of DCF reporting issues at their clinics.  Interviews will be conducted once sites are trained on 
the study.
Interviews will be audiorecorded  and identified by a subject number only.  Interviews will be 
transcribed and any identifying information pertaining to the provider or the clinic will be 
removed.  Upon completion of transcription, audiorecordings will be destroyed.  All notes, audio 
recordings and transcriptions will be stored in YaleBox, a password protected, secure cloud 
storage system.  Only members of the study team will have access to this system.
Interviews will be conducted on approximately 10 to 15 randomly selected providers.  Consent 
for interviews will be obtained using a verbal consent which will be read to providers prior to 
beginning the audiorecording.  Verbal consent will be used in lieu of written consent as a signed 
consent would be the only PHI linking the provider to the transcript.  
Compensation for interviews will be a $50 Amazon egift card.
8.2
SAFETY ASSESSMENTS
Assessment of Adverse Events- Participants will be asked about any events that meet the definition of 
an AE listed below at each study contact.  This information will be recorded in the eCRF.
8.3
ADVERSE EVENTS AND SERIOUS ADVERSE EVENTS
8.3.1
DEFINITION OF ADVERSE EVENTS
This protocol uses the definition of adverse event from 21 CFR 312.32 (a): any untoward medical 
occurrence whether or not it is considered related to participation in the study.
8.3.2
DEFINITION OF SERIOUS ADVERSE EVENTS
A serious adverse event is any adverse event that results in one of the following:
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1. Results in death
2. Is immediately life-threatening
3. Requires in-patient hospitalization (other than for expected delivery or other anticipated 
obstetrical procedures unrelated to participation) or prolongation of existing hospitalization 
(other than for anticipated obstetrical reasons, e.g., cesarean section).
4. Results in persistent or significant disability or incapacity
5. Results in a congenital abnormality or birth defect
6. Is an important medical event that may jeopardize the subject or may require medical 
intervention to prevent one of the outcomes listed above
As with AEs, SAEs do not have to be related to participant in the study.  For example, if the participant is 
in a car accident and is hospitalize, that is considered an SAE and should be recorded.  It is important to 
note, that not all SAEs need to be report to IRBs.  Please see details below.
8.3.3
CLASSIFICATION OF AN ADVERSE EVENT
8.3.3.1
SEVERITY OF EVENT
Adverse events will be graded according to the following guidelines. 
•
Mild – Events require minimal or no treatment and do not interfere with the participant’s daily 
activities. 
•
Moderate – Events result in a low level of inconvenience or concern with the therapeutic 
measures. Moderate events may cause some interference with functioning.
•
Severe – Events interrupt a participant’s usual daily activity and may require systemic drug 
therapy or other treatment. Severe events are usually potentially life-threatening or 
incapacitating.  Of note, the term “severe” does not necessarily equate to “serious”.
8.3.3.2
RELATIONSHIP TO STUDY INTERVENTION/EXPERIMENTAL MANIPULATION
All adverse events (AEs) will have their relationship to study procedures, including the intervention, 
assessed by an appropriately-trained clinician based on temporal relationship and his/her clinical 
judgment. The degree of certainty about causality will be graded using the categories below. 
•
Related – The AE is known to occur with the study procedures, there is a reasonable possibility 
that the study procedures caused the AE, or there is a temporal relationship between the study 
procedures and the event. Reasonable possibility means that there is evidence to suggest a causal 
relationship between the study procedures and the AE.
•
Not Related – There is not a reasonable possibility that the study procedures caused the event, 
there is no temporal relationship between the study procedures and event onset, or an alternate 
etiology has been established.
8.3.3.3
EXPECTEDNESS 
Given the population of study participants the following AE are expected and will not recorded as part of 
the study.  Examples of this include hospitalization for delivery with or without complications.  Deliveries 
are expected events and adverse birth complications are not uncommon in this population.  This relates 
to the substances that are misused and not to the randomization of support systems.  
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Women on medication for OUD commonly deliver babies that are small for gestational age or early and 
this can be due to the medication, the earlier misuse of an opioid or use/misuse of other substances.  
Provision of medication for an OUD is recommended treatment outside of the study.  
Other common and expectable events include delivery of infants who require admission to a neonatal 
intensive care or step-down unit.  Again, this is a common event among women who use substances, 
including opioids and medication for OUD.  
Women may live in poverty or confront violence.  Sadly, this is not uncommon in this population so events 
such as assault, even if it culminates in hospitalization, would not be considered a severe AE related to 
the study conditions.  
Women with OUD commonly have comorbid problems with conditions such as depression and post-
traumatic stress disorder.  The presence of these conditions or symptoms of these conditions would not 
be attributable to this trial given that they are common outside of the trial and nothing in the trial 
promotes the onset or maintenance of these problems.
An example of an event related to the trial would be that the participant is upset by the questions that 
are asked of the participant.  In this instance, every attempt will be made to discuss this with the patient 
and provide care and treatment for their distress related to this.
Another example of an event related to the trial would be a breach of confidentiality.  Although we will 
add measures to minimize this risk, should it occur we will take corrective measures with the study team 
member who is responsible and/or modify systems to decrease the likelihood of a breach.
8.3.4
TIME PERIOD AND FREQUENCY FOR EVENT ASSESSMENT AND FOLLOW-UP
The occurrence of an adverse event (AE) or serious adverse event (SAE) may come to the attention of 
study personnel during study visits and interviews of a study participant presenting for medical care, or 
upon review by a study monitor.
All AEs, not otherwise precluded per the protocol, will be captured on the appropriate case report form 
(CRF). Information to be collected includes event description, time of onset, clinician’s assessment of 
severity, relationship to study procedures (assessed only by those with the training and authority to make 
a diagnosis), and time of resolution/stabilization of the event. All AEs occurring while on study will be 
documented appropriately regardless of relationship. All AEs will be followed to adequate resolution.
Any medical or psychiatric condition that is present at the time that the participant is screened will be 
considered as baseline and not reported as an AE. However, if the study participant’s condition 
deteriorates at any time during the study, it will be recorded as an AE. 
At each study visit, the investigator will inquire about the occurrence of AE/SAEs since the last visit.  
8.3.5
ADVERSE EVENT REPORTING 
AEs will be recorded as part of the participants study record and entered into the data capture system.  
They will be reported to the Data and Safety Monitoring Board (DSMB)
8.3.6
SERIOUS ADVERSE EVENT REPORTING 
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All SAEs will be reported to Dr. Forray (at Yale) or Drs. Yonkers or Byatt (at UMass) for evaluation.  Local 
IRBs will be notified by the site investigator according to local policy. They will be reported to the Data 
and Safety Monitoring Board (DSMB)
8.3.7
EVENTS OF SPECIAL INTEREST 
N/A
8.4
UNANTICIPATED PROBLEMS
8.4.1
DEFINITION OF UNANTICIPATED PROBLEMS
This protocol uses the definition of Unanticipated Problems as defined by the Office for Human Research 
Protections (OHRP).  OHRP considers unanticipated problems involving risks to participants or others to 
include, in general, any incident, experience, or outcome that meets all of the following criteria:
•
Unexpected in terms of nature, severity, or frequency given (a) the research procedures that are 
described in the protocol-related documents, such as the Institutional Review Board (IRB)-
approved research protocol and informed consent document; and (b) the characteristics of the 
participant population being studied;
•
Related or possibly related to participation in the research (“possibly related” means there is a 
reasonable possibility that the incident, experience, or outcome may have been caused by the 
procedures involved in the research); and
•
Suggests that the research places participants or others at a greater risk of harm (including 
physical, psychological, economic, or social harm) than was previously known or recognized.]
8.4.2
 UNANTICIPATED PROBLEMS REPORTING 
The investigator will report unanticipated problems (UPs) to the reviewing Institutional Review Board 
(IRB) according to local policy and to Drs. Yonkers, Forray and Byatt. The UP report will include the 
following information:
•
Protocol identifying information: protocol title and number, PI’s name, and the IRB project 
number
•
A detailed description of the event, incident, experience, or outcome 
•
An explanation of the basis for determining that the event, incident, experience, or outcome 
represents an UP
•
A description of any changes to the protocol or other corrective actions that have been taken or 
are proposed in response to the UP
To satisfy the requirement for prompt reporting, UPs will be reported to Drs. Yonkers, Forray and Byatt 
within 24 hours of becoming aware of the event.  This will be compiled and provided to the DSMB at 
regularly scheduled meetings or within 24 hours if they are serious AEs.
9
STATISTICAL CONSIDERATIONS 
9.1
STATISTICAL HYPOTHESES
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Primary Hypotheses:
H1: Participants with an OUD are more likely to be engaged in MAT and/or non-pharmacological 
care for an OUD if the center is randomized to the CC vs the ECHO model of support.
H2: Participants with an OUD treated in CC centers are more likely to be retained in MAT and/or 
non-pharmacological care for an OUD than those treated in a center randomized to the ECHO 
model of care.
H3: Participants in the CC, compared to the ECHO condition, will have higher PAM scores at week 
36  and 3-months post-partum.  
Secondary Hypotheses:
H1: Participants with an OUD are more likely to be engaged in MAT if the center is randomized to 
the CC vs the ECHO model of support.
H2: Participants with an OUD treated in CC centers are more likely to be retained in MAT for an 
OUD than those treated in a center randomized to the ECHO model of care.
H3: Babies born to mothers treated in CC centers will have higher birth weights on average 
compared to babies born to mothers treated in ECHO centers. 
H4:  Obstetrical providers randomized to the CC compared to the ECHO condition will score higher 
on subscales (autonomy, relationship with patients, patient care issues and relationship with 
staff) of the Physicians Worklife Survey.
H5: Participants in the CC, compared to the ECHO condition, are more likely to increase at least one 
PAM level from baseline to week 36  and 3-months post-partum.  
9.2
SAMPLE SIZE DETERMINATION
We plan to recruit a sample of 6 matched pair clusters (total of 12 clusters), with 6 clusters per condition 
and 20 patients per cluster for a total of 264 patients. Hypothesizing that CC will perform better than 
ECHO, this sample size achieves 80% power to detect a clinically meaningful minimum difference of 0.20 
between the CC proportion (0.94) and the ECHO proportion (0.74).
To estimate the sample size needed to test differences between models of care in the proportion of 
women retained in treatment at delivery using a permutation test, we used the method of Hayes and 
Bennett (1999) for matched-pair cluster randomized trials. Our null hypothesis is pECHO = pCC   and the 
alternate hypothesis is pECHO ≠ pCC, where p is the proportion of women retained in treatment at 
delivery, setting a two-sided type 1 error rate of 0.05.  We based the estimate of the proportion in the 
CC on a study by our co-investigator in which 94% of patients treated under a CC model continued MAT 
until delivery. 
We could not find empirical data for an estimate of the coefficient of variation, so we followed the 
approach of Hayes and Bennett (1999). We generated 10,000 data sets with 6 clusters each, with true 
proportions assumed uniformly distributed between 0.72 and 0.99 to allow for a relatively wide range of 
plausible retention proportion values. In each of the simulated data sets coefficient of variation values 
were calculated based on formula (9) in the manuscript. This follows the conservative approach 
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suggested on p.322 of the paper (i.e. to use the coefficient of variation between clusters within each 
group as an upper limit for the coefficient of variation in matched pairs designs). After examining the 
distribution of the resulting coefficient of variation we selected 0.10 as the value for our subsequent 
power calculations since more than 90% of the data sets had values under that threshold. 
In an ongoing study of mothers with depression randomized to cognitive behavioral therapy with or 
without a community ambassador, 37% of 103 participants increased by at least one PAM level.(M. 
Smith, 2019, personal communication) Using this proportion for the CC group, 40 participants per site 
will provide 80% power to detect a 15% difference in the proportion of women who increase at least 
one PAM level between CC and ECHO.  These estimates assume a two-sided test, with a significance 
level of 0.05 and an estimated within-pair coefficient of variation between clusters (CV) of 0.10.
For minimum detectable effect sizes for secondary outcomes at 80% power (assuming two-sided alpha = 
0.05,  6 CC sites, 6 Echo sites, 40 participants per group, CV=0.1) we generated the table below.
We were not able to assess power for the remaining secondary outcomes: physician work-life survey and 
engagement with MAT given the limited prior research on these topics.   
9.3
POPULATIONS FOR ANALYSES
Primary analyses will use an intention-to-treat analysis population. If missing data are a significant issue, 
we will use sensitivity analyses and/or multiple imputation methods, depending upon the nature of the 
missing data. Datasets for sensitivity analyses include per-protocol, complete cases, missing imputed as 
positive outcome (e.g. retained in treatment) and/or missing imputed as negative outcome (e.g. not 
retained in treatment). Multiply imputed data sets will be based upon multiple imputation methods that 
are appropriate for clustered data and the quantity, type (missing completely at random, missing at 
random, not missing at random), and pattern (monotone, or non-monotone) of missing data. Our safety 
analysis data sets will include all enrolled patients.
9.4
STATISTICAL ANALYSES
9.4.1
GENERAL APPROACH
We will follow CONSORT guidelines, modified for cluster randomized trials, for reporting the trial 
(www.consort-statement.org)(IR-5). Plans for data analysis will follow the major aims articulated above 
(IR-1) and the matched-pain cluster-randomized study design. We will examine the distribution of variables 
through descriptive statistics and graphical tools to verify that model assumptions are met to assess 
relationships between variables. Data analyses will use the intent-to-treat principle and we will attempt to 
follow all participants regardless of their retention to treatment. Dropouts (MD-3) and completers will be 
compared on baseline characteristics. Missingness (MD-2,4) will be examined for quantity, type (missing 
completely at random versus missing at random or not missing at random), and pattern (monotone, or 
non-monotone).  If missing data are a significant issue, we will use sensitivity analyses (MD-4) and multiple 
Table 2
Continuous Outcomes
Mean (std. dev.) in 
Collaborative Care Group
Minimum detectable  
difference
Effect size
(Cohen’s d)
Birth weight
3137 (629)
597
0.95
Dichotomous Outcomes
Proportion for 
Collaborative Care Group
Minimum detectable  
difference
Effect size
(Risk Ratio ECHO:CC)
Retained on MAT
0.89
0.20
0.78
PAM- increased 1 level*
0.37
0.20
0.46 
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imputation methods that are appropriate for clustered data to fill in missing values in order to minimize 
bias, maximize available information and get accurate estimates of uncertainty.  The possible impact of 
missing data on interpretation will be discussed in reports.
9.4.2
ANALYSIS OF THE PRIMARY ENDPOINT(S)
We updated our analysis plan on 1.30.24 since two sites recruited only one participant. We wanted to 
make use of the data from their matched pairs rather than having to drop 4 sites from our analyses. 
Thus, to increase the efficiency of our matched pair design and maximize data utilization from all sites 
we will not account for the matching of clusters in our analyses. 
We will test differences between treatment groups in the proportion of participants who are engaged 
and retained in treatment using generalized linear mixed models (GLMM). GLMM models will include a 
random effect for site to account for potential positive correlations among observations within sites and 
will evaluate the fixed effect for the interventions. For the PAM outcome, we plan to conduct linear 
mixed models, where the response variable will be the PAM score at the week-36 assessment and at 3-
months post-partum. Models will include a random effect for site and will evaluate fixed effects for the 
interventions and baseline PAM scores. If assumptions of normality are violated, we will consider 
transformations or alternative distributions to determine the model with the best fit. Due to the small 
number of samples, we will use small sample corrections in our mixed models. For continuous outcomes 
we will use Satterthwaite's degrees of freedom approximation given the small number of clusters and 
high variability in size of clusters in our study. For binary outcomes we will use restricted pseudo-
likelihood with between-within correction to the degrees-of-freedom.  
9.4.3
ANALYSIS OF THE SECONDARY ENDPOINT(S)
To tests differences in secondary patient outcomes between care models groups, we will use GLMM as 
described above.  
Our co-Investigator, Dr. Kaufman will collect and analyze qualitative data. Qualitative interviews will be 
will be audio recorded, transcribed, and independently coded by two trained masters level researchers 
who will be supervised by Dr. Kaufman. All transcripts will be de-identified. The team will develop codes 
to be used in the content analysis(102, 103) and utilize these codes to identify themes related to 
deployment of the two models. Themes will be examined both within and across informant groups. The 
team will use NVivo (104) to analyze data. Subsequent to the initial training, two staff will independently 
code each transcript and meet together with Dr. Kaufman to compare codes, discuss and work towards 
consensus in order to build a common understanding and use of codes.(105) Dr. Kaufman will review 
interrater reliability on a regular basis in order to prevent coder drift and will retrain staff as needed. The 
collection of data from multiple informants, iterative process of data collection and analysis and use of 
two researchers to code transcripts, increases creditability, transferability, dependability, and 
confirmability of the findings.(105, 106) 
9.4.4
BASELINE DESCRIPTIVE STATISTICS
Differences between care models in baseline demographic and clinical characteristics will be assessed  
using chi-square tests for categorical variables and t-tests for continuous variables, or their non-
parametric counterparts if the assumption of normality is not met. 
9.4.5
PLANNED INTERIM ANALYSES 
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N/A
9.4.6
SUB-GROUP ANALYSES
To evaluate heterogeneity of effects we will report estimates of proportion and means  together with 95% 
confidence intervals for each site. Due to feasibility constraints (only 12 sites) and lack of effect size 
estimates, we will not be able to perform a rigorous statistical evaluation of the effects of site level factors. 
However, we will present descriptive analyses of the sites that might be useful in guiding future use of the 
proposed models. 
In addition, we will provide descriptive and exploratory analyses to evaluate heterogeneity of treatment 
effects on subject-level outcomes due to individual-level covariates including age, race/ethnicity, parity, 
illicit substances vs non-medical use of opioid prescriptions and concurrent substance use. We will use 
mixed effects statistical models to account for potential positive correlations among observations within 
sites (by including random site effects) and fixed effects of the intervention and potential covariates at 
the individual level. Interactions between treatment and potential moderating factors will be considered.  
Generalized linear mixed models will be used for categorical outcomes and linear mixed models for 
continuous outcomes. 
9.4.7
TABULATION OF INDIVIDUAL PARTICIPANT DATA
Data will be analyzed at the site not individual level.
9.4.8
EXPLORATORY ANALYSES
Exploratory analyses will compare care models for eligible women (gravidas with an OUD, not in 
treatment when presenting for prenatal care) on the following outcomes: 1) #/% offered MAT including 
buprenorphine, specifically; and 2) rates of abstinence from illicit opioids or misuse of prescription 
opioids. (107)  Additionally, for all pregnant women treated with MAT: 3) #/% continuing MAT at 3 
months postpartum; 4) #/% engaging in an opioid treatment program at 3 months post-delivery.  We 
will also explore differences between care models in: 5) #/% with concurrent substance use according to 
the Time Line Follow-Back (TLFB) (107) and urine tests; 6) fetal and neonatal outcomes (low birth 
weight, resuscitation at delivery, fetal demise, preterm birth, duration of hospitalization).
Exploratory analyses will also compare models in terms of participant reported differences in: 1) the 
Shared-Decision Making Questionnaire-9 (SDM-Q-9) (108); 2) Perceived efficacy in Patient-Physician 
Interactions Questionnaire (PEPPI) (109); 3) Kim Alliance Scale-Communication subscale (KAS-CM) (110); 
4) PROMIS Emotional Short Form(111)  and Satisfaction with Roles and Activities(111); and 5) Edinburgh 
Postnatal Depression Scale (EPDS)(112, 113) . 
We will explore racial and ethnic differences on patient measures and possible differences in outcomes 
among those who were users of illicit street opioids vs misusers of prescription opioids. 
10
SUPPORTING DOCUMENTATION AND OPERATIONAL CONSIDERATIONS
10.1 REGULATORY, ETHICAL, AND STUDY OVERSIGHT CONSIDERATIONS
10.1.1 INFORMED CONSENT PROCESS
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10.1.1.1 CONSENT/ASSENT 
AND 
OTHER 
INFORMATIONAL 
DOCUMENTS 
PROVIDED 
TO 
PARTICIPANTS
Consent forms describing in detail the study intervention, study procedures, and risks will be given to the 
participant and written documentation of informed consent will be completed prior to any research 
procedures taking place. 
10.1.1.2 CONSENT PROCEDURES AND DOCUMENTATION
The DSP at each site will confirm informed consent.  Participants will be allowed as much time a necessary 
to read, understand and ask questions about the study and research procedures.  Consent will take place 
in a private room.    
10.1.2 STUDY DISCONTINUATION AND CLOSURE
This study may be temporarily suspended or prematurely terminated if there is sufficient reasonable 
cause. Written notification, documenting the reason for study suspension or termination, will be provided 
by the suspending or terminating party to study participants, investigator, funding agency, and regulatory 
authorities. Study participants will be contacted, as applicable, and be informed of changes to study visit 
schedule.
Circumstances that may warrant termination or suspension include, but are not limited to:

Determination of unexpected, significant, or unacceptable risk to participants

Demonstration of efficacy that would warrant stopping   

Insufficient compliance of study staff to the protocol (i.e., significant protocol violations)

Data that are not sufficiently complete and/or evaluable

Determination that the primary endpoint has been met

Determination of futility
The study may resume once concerns about safety, protocol compliance, and data quality are addressed, 
and satisfy the funding agency, sponsor, IRB, or other relevant regulatory or oversight bodies. 
10.1.3 CONFIDENTIALITY AND PRIVACY 
Participant confidentiality and privacy is strictly held in trust by the participating investigators, their staff, 
the safety and oversight monitor(s), and the sponsor(s) and funding agency. This confidentiality is 
extended to the data being collected as part of this study. Data that could be used to identify a specific 
study participant will be held in strict confidence within the research team. No personally-identifiable 
information from the study will be released to any unauthorized third party without prior written approval 
of the sponsor/funding agency. 
All research activities will be conducted in as private a setting as possible.
The study participant’s contact information will be securely stored at each clinical site for internal use 
during the study. At the end of the study, all records will continue to be kept in a secure location for as 
long a period as dictated by the reviewing IRB, Institutional policies, or sponsor/funding agency 
requirements.
Study participant research data, which are for purposes of statistical analysis and scientific reporting, will 
be transmitted to and stored at Yale University. Individual participants and their research data will be 
identified by a unique study identification number whenever possible. The study data entry and study 
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management systems used by clinical sites and by Yale’s research staff will be secured and password 
protected. At the end of the study, all study databases will be de-identified and archived at the Yale.
Certificate of Confidentiality 
To further protect the privacy of study participants, the Secretary, Health and Human Services (HHS), has 
issued a Certificate of Confidentiality (CoC) to all researchers engaged in biomedical, behavioral, clinical 
or other human subjects research funded wholly or in part by the federal government.  We will apply for 
a CoC given the nature of our population.
Safety Oversight
Because of the vulnerable population involved we feel this study will require a DSMB.  We will recruit 4 
members, including at least 2 individuals with clinical experience with the population and a statistician.  
None of the individuals will have a conflict of interest and we will ask them to commit to participate as a 
member for the duration of the project.  We will draft a template for a charter that includes an overview 
of the study, the responsibilities of DSMB members, confidentiality requirements, review of safety data, 
DSMB meetings, DSMB reports and policies including reporting policies, i.e. minutes to IRBs, all sites, 
PCORI.  We will ask the DSMB to modify as needed and accept the final charter. The DSMB will meet at 
least every 6 months but may conduct additional meetings if needed. The members will have access to 
de-identified data if needed. The DSMB will generate reports and send them to IRBs and sites but will only 
include de-identified or summarized data. The meetings will include an open period, closed period and 
executive committee period.   We will include the type of adverse events and serious adverse events but 
we will invite DSMB members to ask about other elements they feel are appropriate.  
10.1.4 CLINICAL MONITORING
N/A
10.1.5 QUALITY ASSURANCE AND QUALITY CONTROL
Should independent monitoring become necessary, the PI will provide direct access to all trial related 
sites, source data/documents, and reports for the purpose of monitoring and auditing by the 
sponsor/funding agency, and inspection by local and regulatory authorities.]
Each site will perform internal quality management based on the SOPs to be provided by the Yale research staff 
regarding data and biological specimen collection, documentation and completion. All sites will follow a 
common quality management plan under the supervision of the site investigator and the research team 
at Yale.
Quality control (QC) procedures will be implemented as follows:
Informed consent --- The research team at Yale in conjunction with the site investigators will review both 
the documentation of the consenting process as well as a percentage of the completed consent 
documents.  This review will evaluate compliance with GCP, accuracy, and completeness.  Feedback will 
be provided to the study team to ensure proper consenting procedures are followed. 
Source documents and the electronic data --- We will monitor data quality by random inspection of 
the completed forms (e.g. TLFB and others) by the Yale project manager. Problems will be discussed 
by the site investigators.   If necessary, we will re-train data collectors.
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The data manager will update data files monthly so that she can correct errors and so that we can 
monitor consequential differences between models. Data cleaning, which is conducted on a quarterly 
basis while the study is ongoing to prevent missing data, will include checking for accuracy of key 
variables such as age, race, verification of missing data and non-response codes; examination of 
outliers; checks within and across files for logical inconsistencies. We will code all data by subject 
number only and will be locked in research offices.  Access to REDCAP is password-protected. We will 
keep data confidential and will not release protected health information to the public. Data will be 
available to research staff, DSMB, the local IRB and government agencies as required. After study 
completion, we may provide data to other researchers after a written request and after any possible 
identifying information is purged. We will follow all disclosure rules pertaining to HIPAA in the 
exchange of any study data with other researchers. We will not identify subjects by name in any report 
of the study and a request will be made to NICHD/NIDA for a Certificate of Confidentiality.
Intervention Fidelity — Consistent delivery of the study interventions will be monitored throughout the 
intervention phase of the study by the Weitzman Institute (for ECHO) and by Dr. Ian Bennet for the CC 
condition. Procedures for ensuring fidelity of intervention delivery are described in Section 6.2.1, 
Interventionist Training and Tracking. 
10.1.6 DATA HANDLING AND RECORD KEEPING 
10.1.6.1 DATA COLLECTION AND MANAGEMENT RESPONSIBILITIES 
Data collection will be the responsibility of the clinical trial staff at the site under the supervision of the 
site investigator and the research team at Yale. The investigator will be responsible for ensuring the 
accuracy, completeness, legibility, and timeliness of the data reported.
All source documents will be completed in a neat, legible manner to ensure accurate interpretation of 
data.  
Hardcopies of the study visit worksheets will be provided for use as source document worksheets for 
recording data for each participant consented/enrolled in the study when applicable.  Data recorded in 
the electronic case report form (eCRF) derived from source documents will be consistent with the data 
recorded on the source documents. 
Clinical data will be collected using REDCAP>, a 21 CFR Part 11-compliant data capture system provided 
by Yale. The data system includes password protection and internal quality checks, such as automatic 
range checks, to identify data that appear inconsistent, incomplete, or inaccurate. Clinical data will be 
entered directly from the source documents or in some cases directly by the participant.
10.1.6.2 STUDY RECORDS RETENTION 
Study documents will be retained for a minimum of 3 years. These documents should be retained for a 
longer period, however, if required by local regulations. No records will be destroyed without the written 
consent of Dr. Yonkers. It is the responsibility of Dr. Yonkers to inform the investigators when these 
documents no longer need to be retained.
10.1.7 PROTOCOL DEVIATIONS  
This protocol defines a protocol deviation as any noncompliance with the clinical trial protocol.  The 
noncompliance may be either on the part of the participant, the investigator, or the study site staff. As a 
result of deviations, corrective actions will be developed by the site and implemented promptly. 
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These practices are consistent with ICH GCP: 
•
Section 4.5 Compliance with Protocol, subsections 4.5.1, 4.5.2, and 4.5.3 
•
Section 5.1 Quality Assurance and Quality Control, subsection 5.1.1 
•
Section 5.20 Noncompliance, subsections 5.20.1, and 5.20.2. 
It will be the responsibility of the site investigator to use continuous vigilance to identify and report 
deviations. The site investigator will be responsible for knowing and adhering to the reviewing IRB 
reporting requirements. 
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APPENDIX: STUDY PERSONNEL AND ROLES
Kimberly Ann Yonkers, M.D., Co-Principal Investigator
Dr. Kimberly Yonkers is a Professor in the Departments of Psychiatry and Obstetrics, Gynecology and 
Reproductive Sciences at the Yale School of Medicine. She is Chief of the Psychological Medicine 
Service and Director of Research for the Yale New Haven Hospital (YNHH) Division of Psychiatry Dr. 
Yonkers also has a history of continuous NIH funding for the past 20 years with an emphasis on 
treatment of substance use disorders. As co-Principal Investigator of this proposed project, Dr. Yonkers 
and Dr. Forray will oversee the overall conduct of the project. Dr. Yonkers will work on administrative 
components of the project, ensuring that human subjects approvals are completed, data collection 
forms and systems are designed comprehensively and with good functionality and that the budgets and 
contracts are accurately managed. She will also participate with other members of the team in 
designing the educational material for both sites. She will work with PCORI, the SAC and the PSG in 
making modifications to the final protocol.  In terms of data collection and management systems, she 
will oversee the Project Manager and statisticians to design, test and implement the forms and 
databases that are needed for the extensive data collection.  Dr. Yonkers will work with Dr. Forray and 
others in developing a publication plan and will work with the team to develop and submit 
manuscripts. 
Ariadna Forray, M.D., Co-Principal Investigator
Dr. Forray is a reproductive psychiatrist and Associate Professor in the Department of Psychiatry. She is 
Co-Director of the Center for Wellness of Women and Mothers, a reproductive psychiatry research 
program. Dr. Forray has a background in women’s mental health and addiction. As a principal 
investigator and co-investigator on several NIH-funded grants, she has developed and implemented 
addiction treatment interventions, successfully recruited pregnant women with substance use disorders 
for participation in clinical research and collaborated with researchers and clinicians across disciplines. 
As co-Principal Investigator of this proposed project, Dr. Yonkers and Dr. Forray will oversee the overall 
conduct of the project. Dr. Forray will be responsible for the field aspects of the study.  With the other 
investigators, she will finalize the educational material for both groups, and will work to assemble the 
SAC and PSG and ensure that their input is integrated into the protocol.  She will oversee and provide 
onsite supervision and training of sites in Connecticut.  She will also work with the sites and the Project 
Manager to ensure that CT sites have the supplies and resources to conduct their tasks related to the 
trial, in addition to working with the Project Manager to plan and conduct staff meetings.
Nancy Byatt, D.O., MS, MBA, FACLP, UMass Site PI
Dr. Byatt is a perinatal and consultation-liaison psychiatrist, Associate Professor of Psychiatry, Ob/Gyn, 
and Quantitative Health Sciences, and expert in addressing perinatal mental health and substance use 
disorders in obstetric settings. She is the Medical Director of the population-based program, the 
Massachusetts Psychiatry Access Program for Moms (MCPAP for Moms), that aims to address perinatal 
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depression throughout the state of MA by building the capacity of front line Ob/Gyn providers to 
address perinatal mental health and substance use disorders. Her program of research - developing and 
evaluating innovative interventions to improve mental health outcomes for perinatal women mental 
health and substance use disorders - is completely aligned with the objectives of this application. She is 
currently testing and intervention, the PRogram In Support of Moms (PRISM).  It is a cluster randomized 
control trial (RCT) that compares a set of 6 Massachusetts practices using MCPAP for Moms telephone 
support to a set of 6 practices using MCPAP for Moms telephone support plus a stepped care approach.
Dr. Byatt will have ultimate managerial and administrative oversight for the Massachusetts sites 
and be the identified liaison with the Dr. Yonkers and the primary Yale study team. She will work in 
partnership with the PIs (Yonkers and Forray) and her Co-Is (Ms. Allen, Dr. Callaghan, Dr. Mittal, Dr. 
Lipkin, Dr. Fiellin) as well as the Study Advisory Group and the Patient Stakeholder Group in all aspects 
of the study. She will help ensure the integrity of the research, including developing materials for the IRB 
and working with UMMS and site-specific IRBs, and developing and executing participant recruitment 
strategies. She will help ensure data security and quality. She will participate on collaborative work with 
PCORI staff, patient stakeholders and the research group on the design, analyses and dissemination of 
study results, and will be involved all manuscript preparations. She will work closely with the study team 
and stakeholders on dissemination materials. She will participate in monthly conference calls with 
collaborators and provide progress updates. 
David Fiellin, M.D., Co-Investigator
Dr. Fiellin is an Addiction Medicine trained internist at Yale, who served as national Director of 
Buprenorphine Education for the American Society of Addiction Medicine, was the first Medical 
Director of the SAMHSA-funded Physician Clinical Support System for Buprenorphine (PCSS-B), and 
currently serves as a special advisor to the Provider Clinical Support System for Medication Assisted 
Treatment (PCSS-MAT). He will provide the in-person Drug Addiction Treatment Act of 2000 (DATA 
2000) buprenorphine waiver trainings.  He will also help develop the educational materials on OUD and 
MAT for the CC and ECHO conditions.
Katherine Callaghan, M.D., Co-Investigator 
Dr. Callaghan is an Assistant Professor at University of Massachusetts Medical School.  She is an 
Obstetrician-Gynecologist who was the founder of the Karen W Green Clinic for Pregnancy and 
Recovery.  This program is embedded in the Community Women’s Care program and provides both 
targeted obstetrical care and recovery services to pregnant and postpartum women in Central 
Massachusetts. The most recent year had 100 pregnant women with OUD.  Dr. Callaghan was also the 
PI for a 3-year SAMHA grant awarded to Massachusetts Department of Public Health’s Bureau of 
Substance Addiction Services in order to expand access to MAT for OUDs (MomsDoCare).  
Heather Lipkind, M.D., Co-Investigator
Dr. Lipkind is an obstetrician/gynecologist at Yale with a background in perinatal epidemiology. She has 
collaborated with Drs. Yonkers and Forray work on examining the association of psychiatric conditions 
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and pregnancy outcomes.  She will provide support on the use of buprenorphine in pregnancy for 
practices in CT.  She will also work with Dr. Yonkers on data collection systems, and help develop the 
educational materials for the CC and ECHO conditions. She will work with the team in writing up results 
of findings.
Leena P. Mittal, M.D., FACLP, Co-Investigator
Dr. Mittal is Director of the Division of Women’s Mental Health at the Brigham and Women’s Hospital.  
Dr Mittal is an Instructor of Psychiatry at Harvard Medical School.  She completed medical school at the 
University of Maryland School of Medicine and completed residency at the Harvard Longwood 
Psychiatry Residency Training Program.  She also completed a Psychosomatic Medicine fellowship at 
Brigham and Women’s Hospital.  Dr Mittal is board certified in Psychiatry, Psychosomatic Medicine and 
Addiction Medicine.  Dr Mittal is a Fellow of the Academy of Consultation Liaison Psychiatry.  She has 
developed an expertise in the treatment of perinatal mental health and substance use disorders and 
has developed a hospital based program for the integrated treatment of opioid use disorder with 
buprenorphine during pregnancy with prenatal care.  Dr Mittal has published a case series on 
collaborative care of opioid use disorders in pregnancy.  Additionally, Dr Mittal is responsible for 
expansion of a large statewide perinatal mental health consultation service to include capacity to 
provide consultations regarding Substance Use Disorders for obstetric, psychiatric and primary care 
providers.  
Joy Kaufman, Ph.D., Qualitative Analyst
Dr. Kaufman is a Professor of Psychiatry; Director of Program and Service System Evaluation at The 
Consultation Center; Director of Evaluation Research in the Division of Prevention and Community 
Research; and Director of Psychology Training at The Consultation Center.  Dr. Kaufman’s area of 
expertise is program evaluations, needs assessments, and qualitative and quantitative evaluations of 
service delivery systems.  Accordingly, her role on this project will be to conduct, code, and analyze the 
qualitative interviews administered to the providers and subjects at the 12 sites.  She will conduct 
interviews with providers and patients in years 1-3.
 
Ralitza Gueorguieva, Ph.D., Biostatistician 
Dr. Gueorguieva is a Research Scientist in the Department of Epidemiology and Public Health at the 
Yale School of Medicine. Dr. Gueorguieva has extensive experience in the analysis of clustered and 
longitudinal data and has worked with Drs. Yonkers and Forray on various other projects. The goal of 
the proposal is to compare two conditions and is a cluster randomized trial. As such, the design of the 
study and the structure of data to be collected require that sophisticated statistical models are used for 
proper inference.  
Kate Gilstad-Hayden, MS, Data Programmer/Manager 
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Ms. Gilstad-Hayden is an experienced data manager and statistician who has worked with the PIs of this 
application on previous projects.  She is experienced managing large, complicated datasets, overseeing 
randomization of study subjects, and analyzing clinical and therapeutic outcomes.  Ms. Gilstad-Hayden 
will be responsible for all data programming related to this project which will include programming data 
screens and tables for the study and checking the system to ensure functionality.  She will regularly 
monitor the integrity of the data and supervise the Research Associate with regards to data entry and 
cleaning. Lastly, she will work closely with Dr. Gueorguieva to clean and convert the raw data into final 
data sets which will be analyzed. Her effort has been adjusted to coincide with the work load.
Karen Hunkele, Project Coordinator
Ms. Hunkele is a Research Associate in the Department of Psychiatry at the Yale University School of 
Medicine. The role on this project will be to serve as Project Coordinator, to supervise the Research 
Assistant, and to assist Dr. Yonkers and Dr. Forray in overseeing all aspects of data collection, 
coordination with other sites, recruitment of study subjects, and data entry and management. Ms. 
Hunkele has a 20-year history of overseeing research projects, including multi-center projects, at Yale 
School of Medicine.
Protocol Contributions
Drs. Yonkers and Forray conceived the study and are the grant holders. They are responsible for the 
study design and implementation.
Drs. Byatt, Callahan, Fiellin, Lipkind, Mittal, and Ms. Hunkele contributed to the study design and are 
assisted with implementation. Dr. Gueorguieva and Ms. Gilstad-Hayden provided statistical expertise, 
and Ms. Gilstad-Hayden is conducting the primary statistical analysis. Dr. Kaufman provided the 
qualitative interview design and will be responsible for the qualitative analysis. All personnel listed 
above contributed to refinement of the study protocol and approved the final version,
 
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