Pharmacologically-based Strategies for Opioid Substitution Therapy During Pregnancy
Phase: PHASE2
Conditions: Opiate Addiction, Pregnancy
Sponsor: Steve N. Caritis, MD

1 
 
5-24-2021 
 
 
Pharmacologically-based Strategies for Opioid Substitution Therapy During 
Pregnancy 
PRO18070495 / STUDY19100128 
NCT03831113 
Protocol version 1.8 
 
 
 
The Eunice Kennedy Shriver National Institute of Child Health and Human Development 
(NICHD) 
 
 
 
 
 
 
 
Principal Investigator: 
Steve N. Caritis, MD 
Magee-Womens Hospital 
300 Halket Street Room 2229 
Pittsburgh, PA 15213 
 
 

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Specific Aim 4 
Specific Aim 4 compares dose reduction strategies for Suboxone or Subutex in 
pregnancy that are based on the pharmacodynamic and pharmacokinetic 
characteristics of BUP. 
a) Primary Research Questions 
1. Is adherence during dose reduction influenced by the magnitude or frequency of a 
given dose reduction? 
2. Is adherence during dose reduction influenced by dosing frequency? 
3. Does mu receptor sensitivity change during dose reduction? 
 
b) Eligibility Criteria 
Inclusion Criteria – must meet all of the following: 
1. On a stable BID, TID or QID dosing regimen of BUP for at least 2 weeks as part of an 
established medication- assisted treatment (MAT) program. 
2. Willingness to undergo supervised dose reduction 
3. Subjects on BID, TID or QID dosing, willing to be assigned to the Magnitude, 
Frequency, or Dosing group, depending on their current dosing 
4. Single gestation between 14-30 weeks at the initiation of dose reduction 
5. On a BUP dose between 6- 24 mg daily (lower doses will not provide sufficient data 
points) 
6. Willingness to have urine samples tested for drugs of abuse and blood samples 
tested for BUP+M concentrations during the Medical Supervised Withdrawal (MSW) 
clinic appointments 
7. Willingness to attend weekly or biweekly MSW clinic appointments and to have daily 
contact via text messaging to complete daily logs of sleep quality, withdrawal 
symptoms and symptoms of craving. Subjects may consent to receiving daily text 
messages with a link to a REDCap where they can complete the daily questionnaires 
electronically. Alternatively, they may complete hard copies of the questionnaires and 
return them during their weekly clinic visits. 
8. Willingness to attend psychosocial support meetings, as needed. 
 
Exclusion criteria – cannot meet any of the following: 
1. Current use of cocaine, heroin, benzodiazepines, barbiturates, phencyclidine (PCP), 
or opioids other than BUP 
2. Currently taking more than two mental health medications 

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3. Active moderately severe depression (PHQ-9 score ≥15 or suicidal ideation) 
4. Current incarceration 
5. Lack of a phone or transportation to and from clinic. 
6. Major fetal malformation 
7. Mother with significant vaginal bleeding or serious medical or obstetrical complication 
that could adversely affect study 
8. Planned delivery at another institution 
9. HIV or AIDS 
10. Diagnosis of schizoaffective disorder or psychosis 
c) Pre-Study Screening 
The following information will be obtained for consented patients 1-2 weeks prior to 
initiation of the dose reduction: 
1. Demographic information: age, race, weight, height 
2. Medical history: medical disorders, mental health disorders 
3. Obstetrical history, including the outcome of all prior pregnancies 
4. Social history: alcohol, tobacco, and illicit drug use 
5. Depression Screening (Patient Health Questionnaire-2 (PHQ-2) and Patient Health 
Questionnaire-9 (PHQ-9), if necessary) 
6. Intake questionnaire 
7. Concomitant medications – Subjects who use withdrawal mitigating agents such as 
Benadryl or clonidine will not be excluded from the study. Research staff will track 
the use of all concomitant medications. 
8. Project gestational age and estimated date of delivery 
9. Vital signs: blood pressure, heart rate, respiratory rate 
10. Maternal blood work: BUN, creatinine, albumin, total protein, ALT, AST, BUP + M 
concentrations, maternal DNA for drug metabolizing enzymes, and PBMC analysis 
(Pitt site only), (the first sample for PBMC analysis may be drawn at any time during 
pregnancy) 
11. Urine sample will be collected and tested for the presence of drugs of abuse. 
12. Obtain routine medical record release forms and review procedures for the upcoming 
study visit. 
Notes: 
• 
BUN, creatinine, albumin, total protein, ALT, and AST will not be performed if results are 
available in the subject’s medical record as part of the standard of care during this pregnancy 
or if testing was performed during a previous Pre-Study Screening. 

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d) Study Design 
The pharmacologic properties of BUP that inform this specific aim include a long half-life that 
suggests that any dose reduction should not occur more often than every 5 days to allow the 
impact of that dose change to manifest. The long half-life also suggests that a higher reduction 
(i.e. 2 mg) will be well tolerated as the reduction in drug exposure (i.e. the reduction in 
plasma concentrations over time) will be gradual over the ensuing 5 days till a new steady 
state is reached. The third PK and PD characteristic of BUP is that plasma concentrations are 
better sustained above a specified critical value with more frequent dosing.51 Based on 
these pharmacologic characteristics of BUP, we will evaluate three strategies for supervised 
dose reduction. We will recruit 3 groups of pregnant women who are on a stable dose of 
BUP and are committed to supervised dose reduction. Recruitment will occur in our 
Pregnancy Recovery Center (PRC), from offices of other BUP writers, and from the 
Emergency Department (ED) at Magee. We will also enlist Dr. Craig Towers, MD at High 
Risk Obstetrical Consultants, in Knoxville, TN to assist in recruitment of eligible subjects at 
his institution for Specific Aim 4 only, pending IRB approval. Dr. Towers is an expert in dose 
reduction/detoxification during pregnancy and has published extensively on this topic. Dr. 
Towers will adhere to this multicenter protocol and Data Safety Monitoring Plan and report 
periodically to Dr. Caritis. 
At MWH, pregnant women with an opioid use disorder generally come for initiation of 
methadone or BUP as part of a MAT program. They often present to the ED and are told to 
contact the PRC if they wish to start BUP or they are admitted if experiencing withdrawal for 
transition to methadone. Those who prefer to initiate treatment with Suboxone or Subutex 
will be targeted for recruitment. Dr. Towers is a primary provider at High Risk Obstetrical 
Consultants for opioid dependent women and we structured our dose reduction strategy 
based on his experiences. 
Consenting subjects will be assessed for depression at the Pre-Study Screening. The Patient 
Health Questionnaire-2 (PHQ-2) will be administered as a screen for depression. If the PHQ-2 
score is 3 or greater, major depressive disorder is likely and subjects will be further evaluated 
with the Patient Health Questionnaire-9 (PHQ-9). The PHQ-9 is a multipurpose instrument for 
screening, diagnosing, monitoring and measuring the severity of depression. 

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• A PHQ-9 score of ≥ 15 represents moderately severe depression. Subjects with a score 
of ≥ 15 at the Pre-Study Screening will be excluded from participating in the study and 
will be referred to a mental health provider. 
Note: Question 9 on the PHQ-9 is a single screening question on suicide risk. If a subject 
answers yes to question 9, they are ineligible to continue with the study and will be 
immediately referred to a mental health provider for further assessment. 
Once recruited subjects are on a stable dose of Suboxone or Subutex for 2 or more 
weeks, we will initiate one of three dose reduction strategies. We will compare tolerance in 
the same person to an alternating 1 mg vs 2 mg weekly reduction (Magnitude group, n=10). 
In a second group (Frequency group, n=10) we will compare tolerance in the same person 
to an alternating 2 mg reduction occurring weekly vs bi-weekly. All subjects in the 
Magnitude and Frequency groups will be on TID or QID dosing. In a third group (Dosing 
Group, n=10) we will compare tolerance to either the Magnitude or Frequency reduction 
schedule in women who are on a BID dosing regimen. The comparisons in these three 
groups will address those fundamental questions required for development of a 
rational dose reduction strategy. Each of these strategies addresses a specific question 
about maternal accommodation to the specified dose change. The dose reduction 
magnitude of 1 mg vs 2 mg and the frequency of reduction of weekly vs bi-weekly 
selected are based in large part on the work of Sigmon et al.47 but larger and more 
frequent reductions could be considered. We chose this modest reduction strategy as we 
were concerned that more aggressive changes could lead to subject withdrawal and 
dissatisfaction. In the study of Sigmon et al.47, only 50% of participants were opioid 
abstinent with the 4-week taper (i.e.1.75 mg per week). We believe a slower taper 
regimen could improve upon this outcome. Table 1 provides an example of the dose 
reduction strategy assuming, as an example, a starting dose of 16 mg daily. Subjects on 
TID or QID dosing will be assigned to either the Frequency or Magnitude groups based on 
their current dosing. Subjects on BID dosing will be assigned to the Dosing group. 
• Subjects assigned to the Frequency group will have dose reductions of 2 mg on 
alternating intervals of 1 and 2 weeks. 
• Subjects assigned to the Magnitude group will have alternating reductions of 1 
then 2 mg every week. 

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• Subjects in the BID group will be assigned to the Dosing group. The Dosing 
group may follow the Magnitude (alternating 1 mg and 2 mg dose reductions 
weekly) or Frequency (2 mg dose reductions on alternating intervals of 1 and 2 
weeks) dose reduction schedules. 
In all groups, the alternating approach will continue until the subject is Suboxone or 
Subutex free or at the lowest dose tolerable. We appreciate that some subjects may not 
tolerate the recommended dose reduction especially at the lower doses. Subjects that 
experience withdrawal symptoms may be treated with ancillary medications such as 
Benadryl or clonidine. To minimize any risk of relapse, subjects who are intolerant to a 
given reduction will be allowed to go back to the last tolerated dose taken prior to the 
reduction. Visual Analog Scale (VAS) scoring will document their intolerance and this, 
combined with pharmacological data from the subject, will inform our development of an 
optimized pharmacological approach to dose reductions. After the subject has been on 
the higher dose for one week we will re-initiate the dose reduction strategy to which she 
was assigned. We will repeat this process one more time and if she remains intolerant to 
further dose reductions, we will not attempt further reductions but rather will maintain her 
on her current dose. If the subjects desires additional attempts at dose reduction, we will 
accommodate her request. At this time, she may elect to re-initiate the original dose 
reduction strategy or select an alternative reduction strategy. For all subjects, we will 
continue the surveillance approach we have in place throughout the pregnancy, delivery, 
and into the postpartum period. 
In all 3 groups, daily adherence, cravings and sleep measures will be compared 
within and across groups. During the Pre-Study Screening, we will explain the study to the 
subject and ask that she completes an Intake Questionnaire to better understand any 
previous experiences she may have had with opioid treatment or detox programs. We will 
also perform urine and blood testing to assure all entry criteria are fulfilled. 
Once 
consent is obtained, we will initiate a Suboxone or Subutex dose reduction schedule 
similar to the one shown in Table 1. To ascertain the impact of a dose change, all 
subjects will complete 4 daily VAS questionnaires similar to those used by Dunn et al. 46 
to assess withdrawal, cravings, sleep duration and sleep quality. The scales will range 
from a score of 0-10 for each question. Subjects that wish to be contacted via text will be 
sent a daily text with a link to the REDCap website where they can complete the VAS 

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questionnaire electronically throughout the dose reduction process. Subjects that are 
unable to receive daily text messages will be provided hard copies of the VAS 
questionnaire and instructed to return the completed forms to research staff at their next 
appointment. Clinic visits will occur weekly or biweekly at which time we will monitor 
plasma BUP+M, neurotransmitter and cotinine concentrations and perform a 
comprehensive urinary toxicology test. Additionally, at each clinic visit we will administer 
the Weekly Follow-up and Weekly Smoking and Alcohol Use questionnaires. We will also 
collect any completed VAS forms, if applicable, and perform COWS and Subjective 
Opioid Withdrawal Scale (SOWS) scores to assess current clinical and subjective 
symptoms of withdrawal and satiety. All subjects will receive psychosocial support, as 
needed. The timing of the subject’s scheduled visits will be determined by their healthcare 
provider. 
Since our focus is to assess whether the magnitude of the dose change, frequency of 
dose change and dosing frequency impact adherence during reduction, this 
pharmacodynamic study will be completed when the subjects are off BUP entirely or on 
the lowest tolerable dose. However, we will continue to see the subjects weekly or 
biweekly, monitor their adherence and continue to provide counseling sessions, as 
needed, until the 6-week postpartum visit. We will also evaluate peripheral blood 
mononuclear cells (PBMCs) as a surrogate marker of metabolic enzymes and 
transporters. The expression of drug metabolizing enzymes and transporters in the 
PBMCs will be correlated with the plasma concentrations of BUP and its major 
metabolites. Two maternal blood samples will be drawn for PBMC analysis; one during 
pregnancy and one in postpartum. The first sample will be drawn during the Pre-Study 
Screening; however, if this is not possible, it may be drawn at any time during pregnancy. 
The second sample will be drawn at 4-6 weeks postpartum, but as close as possible to the 
6-week postpartum visit. 
For subjects not enrolled in specific aim 3a or 3b, we will collect a cord blood sample at 
the time of delivery as well as maternal and newborn hair within 3 days of delivery, when 
possible. An additional cord blood sample (10 mL) will be drawn for genetic studies related 
to metabolizing enzymes, if the mother consents. The minimal amount of hair needed is 20 
mg but we will ask for 100 mg which is still a very small amount. Hair will be removed from 
the mothers and baby’s head (if consent is granted). Mother will decide where the hair will 

8 
 
be removed from her and her baby. The collection of these samples will be described in full 
detail during the consent process. 
Note: Subjects that consent to participate in specific aims 3 (Parts 1 or 2) will already have 
the cord blood and hair samples collected as part of that specific aim. The collection of these 
biological samples only applies to those subjects not already enrolled in specific aim 3. 
 
Table 1. 
 
Dose Reduction Schedules if Start Dose is 16 mg Daily 
Group 
Frequency 
Magnitude 
Dosing 
Strategy 
Reduce dose by 2 mg 
weekly then biweekly, 
repeat till dose=0 or at the 
lowest possible dose 
Reduce dose by 1 and 
then 2 mg weekly, repeat 
above till dose=0 or at the 
lowest possible dose 
May elect either the 
Frequency or Magnitude 
dose reduction schedule. 
Dosing 
Frequency 
QID or TID 
QID or TID 
BID 
Dose 
Week 1 
16 
16 
Refer to the appropriate 
dose schedule in the 
Frequency or Magnitude 
columns 
Week 2 
14 
15 
Week 3 
14 
13 
Week 4 
12 
12 
Week 5 
10 
10 
Week 6 
10 
9 
Week 7 
8 
7 
Week 8 
6 
6 
Week 9 
6 
4 
Week 10 
4 
3 
Week 11 
2 
1 
Week 12 
2 
0 
Week 13 
0 
0 
e) Statistics 
The outcome(s) of interest are the pharmacodynamic endpoints that reflect the 
acclimatization of the mu receptors and opioid-affected brain functions. Each subject in a 
group will undergo alternating treatments to minimize any between subject differences that 
would impact the response to the decrease in dose. In this study, we will rely on scores from 
the self-administered VAS questionnaires. We will determine both an average and highest 
value for each of the VAS questionnaires weekly. The average values over the 7 days of 

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that given dose from the VAS questionnaires will be combined to create a single score for 
each week. A similar approach will be taken for the highest rather than average values. 
Based on the study of Dunn et al 46,47, the mean value for the withdrawal VAS questionnaire 
(scale 1-10) in non-pregnant subjects was 30 with a standard deviation of ~25. These values 
are estimates since graphs were provided but not tabular data. A difference of 25% in the 
VAS combined scores between any of the comparisons would seem clinically meaningful. 
Thus, a sample size of 10 in each group is sufficient to detect a difference in VAS scores 
between any of the comparison groups. The comparisons in the Frequency group will be 
VAS scores between the 1 vs 2 week reductions. The comparisons in the Magnitude group 
would be VAS scores between the 1 and 2 mg reductions. The comparison in the Dose 
group will be a comparison of the VAS scores during the 1 mg and 2 mg reductions. Also, 
VAS scores in the Dose group will be compared to the VAS scores in the Magnitude group 
both at the 1 and 2 mg reductions. The change in mu receptor sensitivity will be 
determined by comparing the BUP+M 
concentration each week to the subjects VAS scores 
on craving and withdrawal symptoms. In women who 
supplement their weekly BUP regimen with other 
opioids detected at the weekly clinic visits 
their VAS questionnaires on withdrawal and craving 
will be scored as 100. Assay Methods: BUP+M will 
be assayed using UPLC-MS-MS. We have developed and validated this assay and with 
the new TQS system the LOQ is 15 ng/ml in plasma. BUP in hair and other tissues will be 
measured by modification of this method and incorporating elements of methods reported 
in the literature 30,31,33. Cotinine will be measured by minor modification of the published 
method 55. 
 
D. Study Procedures 
 
D.1 Screening for Eligibility 
The inclusion/exclusion criteria will be reviewed with the patient’s chart. Any woman who 
appears to be eligible will be informed about the study. If a patient appears to meet the 
criteria for enrollment and expresses interest in the study, she will be told about the study 
and asked to sign the informed consent form. She will be asked to sign a medical records 
Anticipated 
sum of 
mean VAS 
scores 
Percent 
Reduction in 
VAS scores 
Sample 
Size 
120 
0.15 
25 
120 
0.20 
15 
120 
0.25 
10 
120 
0.30 
7 

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release so that the medical records may be obtained. A copy of the signed consent form will 
be provided to the patient. 
D.1.i. Gestational Age Determination 
We will use the criteria recommended by the American Congress of Obstetricians and 
Gynecologists (ACOG). 
D.2 Informed Consent Procedures and Documentation 
 
Written informed consent will be obtained before entry into the trial. Full disclosure of the 
nature and potential risks of participating in the trial will be made. Women who are not 
fluent in English will be enrolled by a person fluent in their language and both verbal 
and written informed consent obtained in that language; if such are not available, they 
will not be included. 
D.3 Specimen Collection 
 
Per standard research procedures for Labor and Delivery samples, Magee Womens Hospital 
employs staff as part of the Obstetric Specimen Procurement Unit (OSPU), which is responsible 
for the collection of research study samples on the Labor and Delivery unit. Labor and Delivery 
samples will only be collected if possible. There is a 3-day window for collection of hair 
samples. Maternal and infant samples will be collected as shown in Table 2. 
D.4 Specimen Analysis and Collection of Negative Control Samples 
 
Biological specimens will be collected and labeled with the study and subject number only 
and stored in locked freezers at MWH or the Magee Women Research Institute or in the 
freezers at participating institutions. Only the study research staff will have access to 
individually identifiable private information. Biological specimens will intermittently be sent to 
Dr. Venkataramanan’s lab at the University of Pittsburgh for analysis. Samples sent for 
analysis will not contain any identifiable information. 
Negative Control Samples: Biological samples from women who are not taking BUP are 
required as negative controls. Subjects potentially eligible as negative controls will be 
identified by reviewing the medical records of patients presenting for prenatal or postpartum 
care at private offices or the MFM offices at MWH. Patients will be approached by their care 
provider or a co-investigator about the study. Healthy volunteers serving as negative controls 
will be recruited prior to delivery or within 6 weeks after delivery. Subjects recruited as 

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negative controls will be asked to sign a separate consent allowing for the collection of 
samples. 
The negative control samples will be collected during pregnancy, delivery or postpartum, as 
requested by Dr. Venkataramanan’s lab, and according to study procedures. The biological 
samples may include any of the following: placenta, umbilical cord blood, umbilical cord 
tissue, maternal hair, infant hair, and meconium. We will enroll up to 5 women for the 
collection of each sample type. 
D.4.i. Eligibility Criteria 
The following criteria apply to healthy volunteers serving as negative controls: 
Inclusion Criteria: 
1. Age between 18 – 45 years 
2. Current pregnancy or delivery within the last 6 weeks 
3. Able to give informed consent and undergo study procedures 
 
Exclusion Criteria: 
1. Currently taking buprenorphine 

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E. Feasibility: 
 
The sample size required in all 4 specific aims is small. Given the large opioid 
population in Pittsburgh (over 700 women with an opioid use disorder delivered at Magee 
between 2013-2015) and that number is increasing making completion of this study very 
feasible. Our MAT clinic sees 150 new patients annually and has received $500,000 from the 
state to increase its outreach efforts. I do not believe sample size will be an issue. 
Recruitment of subjects for specific aim 4, dose reduction may prove challenging since we 
have not offered this option previously at Magee; however, we performed a survey recently of 
potential candidates for dose reduction and detoxification and the response was very 
encouraging. Of 40 women asked if they would consider dose reduction or detoxification, more 
than 50% said they would be interested. Recruitment for specific Aim 1 may be challenging 
because the subject will need to be willing to allow withdrawal to occur in addition to 
spending time in the CRC. Time in the CRC has been an ongoing challenge to recruitment in 
all OPRU studies. Given that all the MAT clinic staff have been involved with our BUP 
research in the past and 2 BUP writers are supported by this grant, I am confident that we 
can recruit sufficient subjects to complete these aims. 
F. Potential Problems & Alternative Strategies 
 
For all specific aims, recruitment must be considered. Although this is unlikely to be 
problematic given our large population, it may be an issue. If recruitment is slower than 
required to achieve our goals, we will approach other research-oriented centers with a large 
opioid using population to assist in recruitment. 
For specific aim 4, possible problems include high drug withdrawal and craving on the 
lowest dose reduction and a high dropout rate. The possibility that even the lowest dose 
reduction will lead to unacceptable rates of dropout and study withdrawal rates is not likely 
given the reasonable dose reduction rates reported by others with dose reductions much 
greater than those proposed. If this does indeed happen then we would target an even 
slower rate of reduction. 
G. Subject Removal Criteria 

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For specific aim 4, if heroin, cocaine, benzodiazepines, barbiturates, phencyclidine 
(PCP), or opioids other than BUP are detected in the urine during the pre-study screening or at 
any time during the study, or if the urine drug screen results from the MAT clinic are positive at any 
time during her dose reduction, she will be dropped from the study and replaced. Subjects who 
do not return their residual drug on more than 3 occasions will be withdrawn from the study. 
H. 
Clinical Data Management 
Data from study participants will be collected on case report forms (CRFs) by research staff. 
These forms and all data relevant to the subjects and their babies will be kept in the subject’s 
research folder which will be kept under lock and key in the office of the study coordinator. All 
data will be entered into a research database which will be on a University of Pittsburgh 
secured and password protected server. 

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