Endeavor to Stop Nausea/Vomiting Associated With Pregnancy (E-SNAP)
Phase: PHASE1
Conditions: Pregnancy, Severe Nausea and Vomiting, Hyperemesis Gravidarum
Sponsor: Northwestern University

STU#:  
1 
 
 
Endeavor to Stop Nausea/Vomiting Associated with Pregnancy (E-SNAP) 
NCT05452174 
09/30/2020 
 
 
 
 
 
PROTOCOL TITLE: Endeavor to Stop Nausea/Vomiting Associated with Pregnancy (E-
SNAP)  
 
PRINCIPAL INVESTIGATOR: 
Katherine L. Wisner, M.D., M.S. 
Norman and Helen Asher Professor of Psychiatry and Obstetrics and Gynecology 
Department of Psychiatry and Behavioral Sciences and Obstetrics and Gynecology 
312-695-8441 
katherine.wisner@northwestern.edu 
 
Co-INVESTIGATORS: 
Catherine S. Stika, M.D. 
Clinical Professor, Department of Obstetrics and Gynecology 
847-951-0108 
c-stika@northwestern.edu 
Melissa Goslawski, MD 
Perinatal Mental Health Scholar, Department of Psychiatry 
Physician, Prentice Women’s Hospital Obstetrical Triage  
708-738-4809 
 
Melissa.goslawski@nm.org 
 
 
VERSION DATE:  
04/01/2022 
  
STUDY SUMMARY: 
Investigational Agent(s) 
(Drugs or Devices)
Mirtazapine 
IND / IDE / HDE # N/A
Indicate
Special Population(s)
Children  
 Children who are wards of the state  
 Adults Unable to Consent   
 Cognitively Impaired Adults  
 Neonates of Uncertain Viability  
 Pregnant Women  
 Prisoners (or other detained/paroled individuals)  
 Students/Employees  
Sample Size
25
Funding Source
National Institute of Child Health and Human 
Development (NICHD)

STU#:  
2 
 
Indicate the type of consent 
to be obtained
Written  
Verbal/Waiver of Documentation of Informed Consent 
Waiver of HIPAA Authorization  
Waiver/Alteration of Consent Process   
Site
 Lead Site (Single Site Research Study) 
 Data Coordinating Center (DCC) 
Research Related 
Radiation Exposure
Yes  
 No  
DSMB / DMC / IDMC
Yes  
No 
 
 

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3 
 
OBJECTIVES 
Translational Research in Maternal and Pediatric Pharmacology and Therapeutics (PAR-20-
299) supports research to “enhance the usage of existing drugs or drug repurposing for safer 
and more effective treatment for pregnant women” for “the early and conceptual stages of these 
projects. The primary objective of this proposal is to conduct an early Phase 2 clinical trial to 
determine the acceptability, dosing, tolerability and safety of mirtazapine for severe nausea and 
vomiting of pregnancy (sNVP) that is not adequately responsive to current standard treatments. 
This plan mirrors clinical practice since commonly prescribed antiemetic/ antinauseant drugs will 
be tested for efficacy before treating with mirtazapine.   
Mirtazapine is a promising drug to repurpose for sNVP. It has potent anti-emetic properties and 
is available as an oral disintegrating formulation. It is used off-label to treat NV during cancer 
chemotherapy,1 prevent post-surgical nausea and vomiting 2 and for gastroparesis.3 It is 
marketed as the serotonin-norepinephrine reuptake inhibitor antidepressant Remeron®. 
Mirtazapine has multiple receptor effects beyond those involved in reducing depressive 
symptoms. In cancer and chemotherapy patients, it produces rapid resolution of nausea and 
vomiting by blocking physiologic inputs that coordinate emesis. It is hypothesized that 
repurposing mirtazapine for obstetric use overcomes the challenges of traditional pathways to 
develop new agents because its pharmacokinetics, safety and dosing have been established for 
general populations of patients4 and exposure data are available because it is prescribed to 
pregnant persons with depression.    
Up to 80% of pregnant persons experience NVP that impairs function and reduces quality of 
life.5 Although NVP often resolves by mid-gestation6, symptoms persist into the third trimester in 
15--20% of pregnant persons7. A severe form, hyperemesis gravidarum (HG), affects 0.3-3% of 
pregnant persons6,8 and is the most common reason for hospitalization in the first 20 weeks of 
pregnancy.9  HG is characterized by intractable vomiting, dehydration, electrolyte abnormalities 
and weight loss that may require parenteral nutrition. HG is associated with preterm birth, small-
for–gestational-age newborns,10 and terminations of desired pregnancies in 14.4% of affected 
pregnant persons.11  
Severe NVP (sNVP), defined as 5% weight loss or continuing beyond 20 weeks gestation, is 
associated with neurodevelopmental deficits and altered brain structure in offspring as 
documented by neuroimaging.12 This definition is an entry criterion for the proposed project, 
which includes the most severely affected 15% of pregnant persons with NVP and HG.12  The 
authors of two Cochrane Analyses and a systematic review reported that only low-quality 
evidence is available to direct treatment.13-15 The NICHD report from the Task Force on 
Research Specific to Pregnant Women and Lactating Women16 stated that the drug pipeline for 
conditions specific to pregnancy is “minimal at best” and listed hyperemesis as an area of need 
for treatment research.  
Rapid reduction of sNVP with mirtazapine treatment has been reported in case series of 
pregnant persons17,18 who have not responded to other medications. These cases include 
mothers who requested terminations of desired pregnancies due to inability to tolerate sNVP. 
Reproductive outcomes for mirtazapine do not indicate an elevated risk for birth defects, 
although the number studied is relatively small (≈500). Medications commonly used to treat 
sNVP are first-line drugs; however, a substantial number of pregnant persons do not respond 
adequately and novel therapeutics are urgently needed.  

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Mirtazapine is a compelling candidate to expand therapeutic options for sNVP. This 
exploratory/developmental phase 2 project is designed to determine whether a Phase 3 
randomized controlled trial (RCT) is warranted by establishing the acceptability, tolerability, 
dosing and safety of mirtazapine for sNVP. Mirtazapine is not approved by the FDA for 
treatment of nausea and vomiting of pregnancy (NVP); therefore, in this clinical trial, mirtazapine 
is an investigational product. 
We will conduct a 3-week open trial of 25 pregnant persons who have not responded to at least 
two antiemetic drugs. We hypothesize that mirtazapine will exhibit satisfactory acceptability, 
tolerability and safety in pregnant persons with sNVP. After the initial trial, a continuation period 
or a mirtazapine tapering regimen with monitoring will be offered. The aims of the trial are:  
1. Determine the acceptability of mirtazapine for sNVP that does not respond to two 
standard drugs.      
2. Define the tolerability and safety of an escalating 3-week mirtazapine dose regimen.  
3. Assess the duration of treatment required following the initial 3-week trial and the 
adequacy of a tapering regimen for persons who discontinue mirtazapine.  
4. Determine pregnancy and neonatal outcomes for all enrolled persons. We will collect 
data on delivery outcomes only with the peripartum events scale 
5. Explore the relationship of study drug dose and plasma concentration with side effects 
and pharmacogenetics by obtaining weekly plasma.  
  
This application was driven by the commitment of our multidisciplinary team to improve 
pharmacotherapy for sNVP as reviewed in our paper on this topic.18 We will obtain critical data 
to determine whether a Phase 3 RCT is warranted and to inform its design. The subsequent 
RCT will have the power to compare mirtazapine to placebo and adjust for the effects of co-
prescribed drugs before and during the trial. This study also will inform the covariate selection 
and sample size estimation for the definitive RCT.     
BACKGROUND 
Although mild nausea and vomiting in pregnancy has not been linked to poor maternal and 
neonatal outcomes, sNVP is associated with preeclampsia, thrombosis, preterm birth, cesarean 
section and small- for-gestational-age neonates. Adding to these established risks are recent 
data from the NIH-funded, 21-site ABCD Study, a long-term study of fetal exposures, brain 
development and child health in the USA. The rate of offspring exposure to severe sNVP 
(defined as maternal weight loss and/or continuation beyond 6 months gestation) was 13.98%, 
which is consistent with the incidence rate of 10–15% in the general population of pregnant 
persons. The ABCD investigators reported that sNVP-exposed offspring had decreased brain 
cortical volume which mediated the relationship between sNVP and developmental deficits in 
language, learning, and motor skills. These structural neurological changes and developmental 
problems persisted through 9–11 years of age. Authors of another recent retrospective cohort 
study (N=469,789 mother-child pairs) reported that offspring exposed to sNVP had a 3-fold 
increase in risk for Autism Spectrum Disorder. These findings highlight the significance and 
potential short- and long-term benefits of treatment for sNVP.    
Despite the frequency and complications of sNVP, only low-quality evidence is available to 
direct treatment. This exploratory/developmental Clinical Trial Planning Grant is a Phase 2 study 
that will provide data on the acceptability, dose regimen, tolerability and safety of mirtazapine 
(Remeron®) for the treatment of sNVP that has not responded to at least two standard 
medications. We will determine whether a larger randomized controlled trial to evaluate 

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mirtazapine’s efficacy for sNVP is warranted. An FDA application for an IND has been submitted 
and a DSMB has been constituted. 
Mirtazapine is prescribed for nausea and vomiting during cancer chemotherapy and pre-
operatively to prevent post-surgical nausea and vomiting. During pregnancy, rapid reduction of 
nausea and vomiting following mirtazapine treatment has been reported in case series of 
persons who have not responded to other medications. Mirtazapine impacts the serotonin 
receptor (similar to the anti-emetic drug ondansetron) as well as three additional receptors 
involved in the physiologic cascade that results in nausea and emesis. Reproductive outcome 
data for mirtazapine do not indicate an increased risk for birth defects, although the number of 
persons studied is relatively small (≈500). Additionally, pharmacogenetic factors that affect 
mirtazapine plasma concentrations and thereby affect its tolerability and safety will be 
considered in the proposed project. 
Mirtazapine is a compelling candidate repurpose to expand therapeutic options for this disabling 
disorder. A total of 26 cases in of mirtazapine for sNVP have been published.17,18 These people 
did not respond to first-line drugs for sNVP (doxylamine/pyridoxine, ondansetron, 
metoclopramide, dimenhydrinate and promethazine). The mirtazapine dose ranged from 15-45 
mg/day, with a modal dose of 30 mg/day. Response was rapid, with reduction of nausea on the 
first day of treatment.28 In a recently published series of seven cases,29 the mean gestational 
age at initiation was 11.6 weeks (range 7–14). The mean treatment duration was 9.1 weeks 
(range 4–24). Mirtazapine’s antiemetic properties derive from multiple effects on the cascade of 
events that culminate in emesis30 31 which do not depend on its antidepressant effects. 
Mirtazapine adds therapeutic value by improving sleep and appetite. These actions of 
mirtazapine do not depend upon the presence of an underlying psychiatric disorder; however, 
people with unremitting sNVP often have depressive and anxiety symptoms secondary to stress 
and functional impairment.   
Mirtazapine provides nausea control with once-daily dosing32 and is available as an orally 
disintegrating tablet. Ondansetron, prochlorperazine and metoclopramide require multiple daily 
doses. In patients with cancer, mirtazapine (15-30 mg) rapidly improved nausea, appetite, 
insomnia and overall function.33 Mirtazapine also is effective in preventing post-anesthesia NV. 
People scheduled for gynecological surgery were randomly assigned to mirtazapine 30 mg plus 
dexamethasone vs. dexamethasone alone. The rate of post-operative NV was 20% vs. 50%, 
respectively (P< 0.01).2 In a meta-analysis, mirtazapine significantly reduced post-operative NV 
vs. placebo (risk ratio=0.44; 95% CI 0.32--0.62).34 For the first time, mirtazapine was identified 
as an option for sNVP by obstetricians in a review published in 2020.35  
Mirtazapine is well-absorbed with or without food and peak plasma concentrations are reached 
in 1 to 2 hours. Hepatic cytochrome P450 (CYP) 2D6 and 1A2 enzymes contribute to the 
formation of the 8-hydroxy metabolite, which has 10% of the parent drug’s activity. CYP3A4 is 
responsible for subsequent metabolism. Mirtazapine is a weak inhibitor of CYP450 enzymes 
and is unlikely to result in significant drug interactions.30  
Variability in pharmacokinetics is associated with variation in genes encoding drug-metabolizing 
enzymes involved in drug elimination or biotransformation. Mirtazapine is primarily metabolized 
by CYP2D6, which has important genetic polymorphisms36,37 that influence drug clearance and 
plasma concentrations. The activity of CYP2D6 varies across pregnancy by genotype. CYP2D6 
substrate drug levels decline in rapid and extensive metabolizers and increase in intermediate 
and poor metabolizers.38 Genotypes that determine the activities of CYP2D6, and minor 
pathways 3A4/5 and 1A2, will be explored for associations with mirtazapine plasma 

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concentrations. Genotypes that increase risk for HG will also be determined. In a genome-wide 
association study for binary (HG) and ordinal (severity of nausea and vomiting) phenotypes of 
pregnancy complications, two loci, chr19p13.11 and chr4q12, were genome-wide significant 
(pௗ<ௗ5ௗ×ௗ10−8) and replicated in an independent cohort.39 The genes implicated at these two loci 
are GDF15 and IGFBP7 respectively, both known to be involved in placentation, appetite, and 
cachexia.  
These analyses will be exploratory due to the limited sample size achievable in an R21 study. 
Physiology of Emesis. Vomiting is a complex neuromuscular 
cascade of events coordinated by the central and autonomic 
nervous systems.40 Neurons that orchestrate emesis are located 
throughout the medulla and organized by a central pattern 
generator (CPG) that coordinates the sequence of events leading 
to emesis. The CPG receives input from the area postrema and 
abdominal vagal afferents. Anti-emetic drugs antagonize 
neurotransmitters (Figure 140) that orchestrate the progression of 
nausea to vomiting. Commonly used anti-emetics antagonize the 
following receptors: muscarinic acetylcholine (mR), dopamine 
(D2), serotonin (5-HT3), histamine (H1) and neurokinin (NK1). Both 
ondansetron and mirtazapine are serotonin (5HT3) receptor 
antagonists40 which prevent vagal afferent signaling to the 
hindbrain; however, mirtazapine offers three additional sites of 
action to impede the emetic process (Figure 140): 1) histamine 
(H1R), which has input directly to the vomiting center; 2) 
muscarinic (mR) which also has input directly into the vomiting 
center; and 3) central presynaptic adrenergic α2 (adrenergic α2R), 
which activates emesis.   
 
STUDY ENDPOINTS: 
The primary outcome is the change in PUQE (Pregnancy Unique Quality of Emesis)43 score. 
Secondary outcomes include: (1) Self-administered Comorbidity Questionnaire, (2) NIH 
PROMIS Global Health scale, (3) Patient Health Questionnaire-9 (depression scale), (4) 
Generalized Anxiety Disorder-7 scale, (5) Asberg Side Effects. Plasma will be obtained for 
quantitation of mirtazapine concentrations at each assessment during mirtazapine treatment. 
DNA will be obtained to explore whether pregnant persons who are most (or least) likely to 
benefit from treatment can be identified through pharmacogenetics.  
STUDY INTERVENTION(S) / INVESTIGATIONAL AGENT(S): 
Mirtazapine has potent anti-emetic properties and is available as an oral disintegrating 
formulation. It is used off-label to treat nausea and vomiting during cancer chemotherapy,1 
prevent post-surgical nausea and vomiting 2 and for gastroparesis.3 It is marketed as the 
serotonin-norepinephrine reuptake inhibitor antidepressant Remeron®. Mirtazapine has multiple 
receptor effects beyond those involved in reducing depressive symptoms. It produces rapid 
resolution of nausea and vomiting by blocking physiologic inputs that coordinate emesis (Figure 
1).  
Figure 1. Neurotransmitters involved in emesis 
and sites of action: α2R=adrenergic α2-receptor; 
CPG=central pattern generator; D2R=dopamine 2-
receptor; Δ9-THC=Δ9-tetra-hydrocannabinol; 
DVC=dorsal vagal complex; 5-HT=serotonin; 
H=histamine; NK=neurokinin; mR=muscarinic; 
mirtazapine’s action indicated by arrows at 
receptor sites that are bolded below and arrows 
are receptor site.            

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Mirtazapine is available as RemeronSolTab® (oral dissolvable) and tablet forms, which will be 
prescribed for the 3-week trial, and Remeron® tablets will be prescribed for the continuation 
phase. The acquisition and dispensing of the drugs will be under the organizational SOP for the 
Research Pharmacy at Northwestern Medicine.  
An IND will be submitted along with the approved consent form following this review. The IND 
submission is included in the documents section of this application. The sponsor is the PI, Dr. 
Katherine L. Wisner. 
 
PROCEDURES INVOLVED 
Enrollment. The participant will provide demographic data (age, self-identified race and 
ethnicity), height and weight. All prescription, over-the-counter medications, alcohol and other 
drugs taken by the subject in the week prior to study entry and during labor and delivery will be 
recorded.  
Blood pressure, heart rate, fetal heart rate, complete blood count, comprehensive metabolic 
screen (includes electrolytes and liver function studies) and urinalysis will be collected for 
assessment of sNVP. Any electrolyte abnormality will be corrected before the administration of 
mirtazapine. An ECG will be performed in all subjects at baseline, at the end of the initial three 
weeks, and monthly in subjects who continue mirtazapine beyond the three-week study. The 
ECG will be done to evaluate the emergence of QT prolongation, Torsades de Pointes, 
ventricular tachycardia, or other abnormal cardiac findings.  Although maximum QTc interval, 
Tp-e interval and Tp-e/QT ratio are increased in the late pregnancy, they all remain within the 
normal ranges.42  
sNVP Assessment. The Pregnancy 
Unique Quality of Emesis PUQE-
24)(Figure 2)43 was used in studies 
submitted for FDA approval of 
Diclegis® (doxylamine/ 
pyridoxine).44 Subjects will record 
their PUQE score daily (for prior 24 
hours) to track symptom change in a 
secure on-line REDCap system.  
 
Participants. Subjects with clinically 
significant NVP will be recruited. An 
initial score of 10 or more (high moderate/severe NVP) on the PUQE43 scale is required. We 
include the criterion from the study12 that showed the association of sNVP with developmental 
deficits (with weight loss, defined as 5% loss from pre-pregnancy). Pregnant persons will be 
recruited from in- and out-patient practices and the Obstetrical Triage Service, where Co-I’s Drs. 
Catherine Stika and Melissa Goslawski provide care, and from our academic obstetrical 
practices. Upon referral, a research coordinator will contact the participant’s obstetrician, and 
meet with the participant to review eligibility criteria, the study procedures, and obtain written 
consent.  
 
 
Figure 2.  PUQE Scoring System 

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Trial Protocol Overview (Figure 3). 
Acceptability. The participant’s medical status and drug treatment for sNVP will be reviewed by 
the study obstetrician. As in clinical practice, other anti-emetic drugs may be continued if 
desired by the participant and recommended by the obstetrician. The subject’s decision to 
accept or decline will be recorded and she will be asked to provide the reason(s) for her 
decision. Pregnant persons who enroll will be given mirtazapine to begin treatment that evening 
or at a time recommended by the obstetrician. Intervention for pregnant persons who decline to 
participate will be coordinated by their obstetrical care professional. 
Mirtazapine Regimen. The dose of mirtazapine for depression (15-45 mg/day) may not be the 
same as for achieving its antiemetic effect because the targeted receptors differ. We will begin 
with 15 mg, which is the lowest dose of the oral disintegrating tablet available. A telephone or 
telehealth follow-up for side effects will be conducted on day 2. Dose increases will occur 
weekly during the visits as depicted in Figure 3 unless the patient has prohibitive side effects or 
remission of sNVP. Remission is defined as a PUQE score of 3 (no symptoms) or 4 (1 hour or 
less of nausea without retching or vomiting). Side effects assessment will occur the day after 
each dose increase to evaluate tolerability. Reduction to the previous dose will occur if side 
effects are burdensome. Although the modal dose of mirtazapine from case reports is 30 mg, 
tolerability studies in persons with NVP have not been published. Steady-state plasma 
concentrations of mirtazapine occur within 5 days32 and will be achieved across the week prior 
to dose escalations. Weekly plasma concentrations will be obtained to confirm absorption of 
mirtazapine and explore associations with side effects. Sampling will occur at a consistent time 
of day for each woman; ideally, the time will be in the late afternoon during the drug elimination 
phase as close to the trough concentration as feasible. Adverse events will be reviewed by the 
DSMB after every 5 subjects to determine whether a protocol or dosing change is warranted.     
Both compliance with treatment and vomiting within an hour of the dose will be recorded in 
REDCap (along with the daily PUQE score) to evaluate these factors in the interpretation of 
Figure 3:  Data Collection and Measures: Acute Treatment   
Intake 
Week 1, Mirtazapine ODT 
dose =   15 mg 
Week 2, Mirtazapine ODT dose =      
30 mg 
Week 3, Mirtazapine ODT dose =     
45 mg
Days 
1 
 
2 
3 
4 
5 
6 
7 
Visit 
8 
9 
10 
11 
12 
13 
14 
Visit  
15 
16 
17 18 
19 
20 
21 
Visit 
GA, CQ; 
ECG; 
Medical 
Review
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
ECG 
 
 
 
 
 
 
 
DNA, 
Plasma
 
 
 
 
 
 
Plasma 
 
 
 
 
 
 
Plasma 
Wt, Ht, 
BP
 
 
 
 
 
 
Wt; BP 
 
 
 
 
 
 
Wt; BP 
 
 
 
 
 
 
Wt; BP 
PUQE 
GH
→
→ 
→
→
→
→
PUQE 
GH
→
→ 
→ 
→ 
→ 
→ 
PUQE 
GH
→ 
→ 
→
→
→ 
→ 
PUQE 
GH
PHQ-9 
GAD-7 
C-SSRS
 
 
 
 
 
 
PHQ-9 
GAD-7 
C-SSRS
 
 
 
 
 
 
PHQ-9 
GAD-7 
C-SSRS
 
 
 
 
 
 
PHQ-9 
GAD-7 
C-SSRS
ASE 
SS
 
ASE
SS
 
 
 
 
ASE 
SS
 
ASE 
SS
 
 
 
 
ASE 
SS
 
ASE
SS
 
 
 
 
ASE 
SS
Med Log
→
→
→
→
→
→
→
→
→
→
→
→
→
→
→
→
→
→
→
→
→
Arrows in gray areas show daily completion of the PUQE. ODT=orally disintegrating tablet of mirtazapine; GA=Gestational 
age; CQ= Comorbidity Questionnaire; ECG=electrocardiogram; Wt=weight; Ht=height; BP=blood pressure; 
PUQE=Pregnancy Unique Quality of Emesis; GH=PROMIS Global Health; PHQ-9=Patient Health Questionnaire; GAD-
7=Generalized Anxiety Disorder; C-SSRS=Columbia-Suicide Severity Rating Scale; ASE=Asberg Side Effects Rating Scale; 
SS=Serotonin Syndrome Screen; Med Log=Medication Log of prescribed and over the counter medications in the week prior 
to assessment.   

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plasma concentrations. Mirtazapine treatment will continue unless the participant withdraws 
consent, experiences a limiting side effect or an obstetrician decides that the health risk to the 
patient compels discontinuation. At the end of the 3-week trial, subjects will be asked whether 
they prefer to continue mirtazapine, which will also serve as a measure of treatment satisfaction. 
Pregnant persons who choose to stop treatment will be given a taper regimen in reverse order 
of the dose escalation required for the 3-week trial. For example, if a patient is taking 45 mg at 
the end of week 3, she will begin a taper (by week) of 30 to 15 to 7.5  to 0 mg. If she relapses or 
has discontinuation symptoms, the previous effective dose will be given. She may attempt to 
taper again with the same approach. Participants who continue to be treated with mirtazapine in 
the continuation phase will be followed monthly throughout pregnancy unless they withdraw 
consent. 
Maintenance Drug Treatment (Figure 4). For pregnant persons who choose to continue 
treatment, mirtazapine will be prescribed at the dose achieved at the end of the 3-week trial. 
The duration of treatment will be decided by the patient with a study obstetrician based upon her 
response and comfort with drug discontinuation. These data will be novel since no information 
on the duration of treatment with mirtazapine in persons with sNVP is available. For persons 
treated until delivery, maternal and cord blood will be obtained for plasma mirtazapine 
concentration measurement to evaluate placental transfer. If postpartum mirtazapine treatment 
is desired, it will be coordinated with our Collaborative Care Perinatal Services (COMPASS - the 
integrated mental health program in the Obstetrics department), or in the Asher Center in the 
Department of Psychiatry, which Dr. Wisner directs.        
Other Drug Exposure. All prescription and over-the-counter drugs, 
alcohol and substances used by subjects will be recorded at intake 
and weekly visits in the Medication Log. We also will  
record integrative therapies such as ginger and acupuncture. First-
trimester use of cannabis for sNVP is increasing as the number of 
states declaring it legal rises.45 In Illinois, cannabis use became 
legal on January 1, 2020. First-trimester cannabis use in pregnant 
persons with and without sNVP in the Kaiser-Permanente system 
was 11.1% and 5.8%, respectively.45 Cannabinoid agonists such 
as tetrahydro-cannabinol, nabilone, dronabinol and medical 
marijuana have potent anti-nauseant and anti-emetic activity.46 
Cannabinoid hyperemesis syndrome, with cyclic severe nausea 
and vomiting relieved by hot baths, is a rare, paradoxical problem 
in individuals with long-term, high cannabis use.47 However, both 
ACOG48 and FDA49 advise against the use of cannabis in 
pregnancy due to concerns about its impact on fetal 
neurodevelopment. The obstetrical evaluation of inclusion criteria 
will include cannabinoid hyperemesis syndrome in the differential 
diagnosis of HG. 
 
Although we will not have the power to evaluate the effect of 
additional drug exposures in this preparatory R21 grant 
mechanism, we will assess the type and frequency of these 
exposures to inform the approach to statistical adjustment in the 
adequately powered Phase 3 randomized controlled trial.     
 
Figure 4:  Data Collection: 
Continuation Treatment 
Maintenance
(every 4 
weeks) 
Delivery  
Wt, Ht, BP 
PES 
Maternal 
and 
umbilical 
cord blood 
PUQE 
GH 
Plasma  
PHQ-9 
GAD-7 
C-SSRS 
ASE 
SS 
Medication 
Log 
PUQE=Pregnancy Unique 
Quality of Emesis;  
PHQ-9=Patient Health 
Questionnaire;  
GAD-7 =Generalized Anxiety 
Disorder;                              
C-SSRS=Columbia-Suicide 
Severity Rating Scale; 
ASE=Asberg Side Effects; 
SS=Screen for Serotonin 
Syndrome.   
PES, Peripartum Events 
Scale.

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Side Effect Assessment. Before mirtazapine treatment, a comprehensive metabolic profile and 
urinalysis will be obtained as standard of care. An ECG also will be performed. The degree of 
QT prolongation observed with both 45 mg (therapeutic) and 75 mg (supra-therapeutic) doses 
of mirtazapine was not clinically meaningful,47 and QTc ≥500 msec was not observed among 
mirtazapine-treated patients.50 The drug regimen to which mirtazapine may be added will be 
reviewed by Dr. Stika, a fellowship-trained clinical pharmacologist and obstetrician, for QTc 
prolongation risk prior to mirtazapine administration, or Dr. Goslawski, an attending obstetrician-
gynecologist in Obstetrical Triage, or Dr. Wisner, the PI, a perinatal psychopharmacologist. Side 
effects will be assessed with the 14–item Asberg Side Effects (ASE)51 scale, which was adapted 
by our team for SSRI-treated pregnant persons.52,53 The ASE quantifies discomforts from mild to 
severe and a summary of overall distress. Serotonin hyper-stimulation will be reviewed with 
Hunter’s Decision Rules for Diagnosis of Serotonin Toxicity (SS).54 SS is characterized by 
tachycardia, diaphoresis, myoclonus and tremor.55 The incidence of SS is infrequent (9/10,000) 
as shown in a retrospective cohort study56; however, ondansetron, metoclopramide and 
mirtazapine have been associated with SS during monotherapy and with other serotonergic 
drugs57, although rarely in young persons.58 Treatment includes drug discontinuation, 
benzodiazepines and the anti-serotonergic drug cyproheptadine.   
 
Specific Instrument Use 
 
Pregnancy Unique Quality of Emesis (PUQE) 43 scale (Figure 2):  We will utilize the 
PUQE scale to capture the severity of nausea and vomiting in pregnancy based on three 
physical symptoms: nausea, vomiting, and retching over the previous 24 hours. A PUQE score 
of < 6 is considered mild, a score from 7-12 is moderate, and a score of 13+ is considered 
severe. This scale will be entered daily in REDCap directly by the participant. 
 
Self-Administered Comorbidity Questionnaire (SCQ)59: The Comorbidity 
Questionnaire (CQ) assesses comorbid conditions in clinical and health services research. The 
questionnaire is self-administered, short, easily understood, and can be completed by 
individuals without any medical background. It also allows the subject to note the severity of 
each comorbid conditions and their perception of its impact on their function.  
 
9-Item Patient Health Questionnaire (PHQ-9)60: The 9-Item Patient Health 
Questionnaire (PHQ-9) is a self-administered instrument based on the nine DSM-5 criteria listed 
under criterion A for Major Depressive Disorder. The questionnaire includes criteria based 
diagnosis of depressive symptoms, assists in identifying treatment goals, determining severity of 
symptoms, as well as guiding clinical intervention. When considering a diagnosis, the clinician 
will use clinical interviewing skills to determine whether the symptoms are causing clinically 
significant distress or impairment and those symptoms are not better explained or attributed to 
other conditions, such as substance use, medical conditions, or bereavement.  
 
Generalized Anxiety Disorder Scale, 7-item (GAD-7)61: The Generalized Anxiety 
Scale is a 7-item self-report for symptoms consistent with the Diagnostic and Statistical Manual 
of Mental Disorders of generalized anxiety disorder.   
 
Peripartum Events Scale (PES)62: The Peripartum Events Scale (PES) captures data 
from several categories in the birth record. The following categories of events are included: 
medical and obstetric risk factors, time in operating room, fetal monitoring, surgical 
complications, infant anthropometrics and outcome, NICU admission, and postpartum 
complications (such as infection, hemorrhage).  Admission to the special care nursery will also 

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be noted.  We have modified the original measure to align with current obstetrical practices. The 
PES will be completed for all enrolled participants.  
 
PROMIS Global Health63: The PROMIS Global Health item scale assesses overall 
health. The global health items include ratings of the five primary PROMIS domains (physical 
function, fatigue, pain, emotional distress, social health) as well as perceptions of general health 
that cut across domains. Global items allow respondents to weigh together different aspects of 
health to arrive at a “bottom-line” indicator of their health. Similar global health items have been 
found predictive of future health care utilization and mortality. The PROMIS Global Health items 
include the most widely used single self-rated health item (“In general, would you say your 
health is . . .”). Previous research has shown that this item taps physical and mental health 
about equally but reflects physical health more than mental health among respondents at lower 
income levels. PROMIS Global Health items include specific ratings of physical health and 
mental health, as well as a rating of overall quality of life. The remaining items provide global 
ratings of physical function, fatigue, pain, emotional distress, and social health. The PROMIS 
Global Health items can be administered as individual items or combined to produce separate 
physical and mental health summary scores. 
 
Columbia-Suicide Severity Rating Scale (C-SSRS)77: The Columbia-Suicide Severity 
Rating Scale (C-SSRS) is a questionnaire used for suicide assessment that was developed  
with NIMH support. The scale is evidence-supported and is part of a national and international 
public health initiative involving the assessment of suicidality. Suicidal ideation will be assessed 
at baseline, during, and 28 days after treatment cessation if there were any abnormalities during 
the trial.  
 
 
DATA AND SPECIMEN BANKING 
 
Subject plasma and blood for DNA extraction will be stored in a -70ºC freezer in the 
Northwestern Core Laboratory. All samples will be de-identified and labeled with the 
Northwestern Medicine clinical research unit ID, the subject ID, the date of collection, the type of 
sample collected (e.g. plasma), and the corresponding timepoint. Samples will not contain 
protected health information or any other type of identifiable information.  
Mirtazapine Assay. Michael Avram, PhD, Scientific Advisor of the Clinical Pharmacology Core, 
will analyze plasma for concentrations of mirtazapine and desmethylmirtazapine by high-
performance liquid chromatography-tandem mass spectrometry after sample preparation by 
solid-phase extraction (see letter of support).64 65 the lower limit of quantitation will be 0.5 ng/mL. 
The linear range of the calibration curve will be 0.5--250 ng/mL. Accuracy will be within ±10% 
and precision 10% or less. Dr. Avram will model the serial concentration data for analyses to 
determine associations with variables (tolerability, side effects, pharmacogenetic data, adverse 
events) and whether remission is associated with mirtazapine concentration, with statistician 
Amy Yang, MS, and our team. 
We will seek consent from our subjects to have their fully de-identified data and biospecimens 
included in the NICHD Data and Specimen Hub (DASH-https://dash.nichd.nih.gov/) for future 
studies.   
SHARING RESULTS WITH PARTICIPANTS 
No research data will be shared with participants. Because this is an open trial of a marketed 
drug, the participants will have direct knowledge of clinical information that may be useful in the 

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future, such as their response to mirtazapine, the efficacious dose, and the duration of treatment 
required.  
STUDY TIMELINES 
It will take approximately 18 months to enroll all study participants (Figure 5). We will evaluate 
subject flow and safety analyses in weekly research meetings, which will be conducted 
throughout the project. 
 
 
 
INCLUSION AND EXCLUSION CRITERIA 
 
 
Figure 5.  Project Time Line
Year 
Study 
Months
Study Tasks 
Cum. 
Enroll
Pre-
Award 
10/21-
02/22 
Submit IRB and IND applications, finalize manual of operations, develop 
recruitment tools, inform obstetrical practices of upcoming E-SNAP study startup 
0 
02/22 
 
01-03 
Finalize and test REDCap database; open recruitment   
0 
04-12 
Enroll 1-2 new subjects/month; DSMB review after every 5 subjects are enrolled 
15 
02/23-
12/23 
13-18 
Enroll 1-2 new subjects/month; DSMB review after every 5 subjects are enrolled 
10 
19-24 
 
Plasma conc and DNA Analyses; Summary Variables and Statistical Analyses; 
Manuscript finalization and submission; Final IRB, DSMB and IRB reviews; Draft 
R01 Phase 3 submission if warranted.   
25= 
target 
  Figure 6:   Inclusion and Exclusion Criteria 
Inclusion Criterion
Rationale
Ages 18-49 years 
Age of adult childbearing persons 
Singleton pregnancy  
Appropriate for initial Phase 2 trial 
Inpatient or outpatient status  
Target is pregnant persons with refractory sNVP 
Care within Prentice Women’s Hospital 
maternity practices  
Retain subjects through pregnancy;  coordinate with 
obstetrical care   
English speaking 
Measures in English, staff are English speaking   
Obstetrician’s evaluation and diagnosis of sNVP 
or HG 
Differentiate from medical disorders  (i.e. pancreatitis, 
appendicitis) 
Tolerance of oral disintegrating tablet at bedtime 
Preparation is appropriate for persons experiencing 
emesis   
PUQE score of 10-15; moderate/high or severe 
Pharmacotherapy is appropriate for this level of 
severity 
Refractory sNVP 
Inadequate response to two commonly used drugs  
Anti-emetics may be continued as in real-world 
practice  
Focus is mirtazapine for sNVP non-responsive to 
other medications  
Exclusion Criterion 
Rationale 
Allergic or adverse reaction to mirtazapine 
Inappropriate treatment  
Patient has bipolar disorder without anti-manic 
drug treatment  
Risk for hypomania/mania induction 
Subjects with active depression, or history of or 
current active suicidal ideation or attempt 
Mitigate risk for suicidality 

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VULNERABLE POPULATIONS 
 
The disease studied, sNVP, is specific to pregnant individuals. Case series studies of pregnant 
persons with sNVP or HG and who were treated with mirtazapine are reviewed in the Research 
Strategy section.  Mirtazapine is FDA-indicated for the treatment of depression, and data on 
reproductive outcomes are available from treatment of this group of people. Additional 
information on pregnancy outcomes and neonates will be collected from the delivery record.     
The potential risk to the fetus is due to the drug intervention, which also holds the prospect of 
direct benefit for the woman through control of her NVP/HG with mirtazapine treatment.  This 
Phase 2 trial is to assess maternal tolerability, dosing, adverse effects and preliminary efficacy.  
No reproductive risks to the fetus have been described but studies are relatively small in terms 
of sample size (about 500 subjects). Outcomes for longer-term reproductive risks are not 
available. However, pregnant persons with NVP/HEG suffer consequences of this disabling 
disorder, and up to 14% of pregnant persons request terminations due to their distress. This 
research will provide important biomedical knowledge which cannot be obtained by any other 
means. The risk is the least possible for achieving the objectives of the research.  Because the 
research holds the prospect of direct benefit to the pregnant woman through disease control, 
the interventions also hold benefit for the fetus who is dependent upon maternal health and 
nutritional sustenance.   
No inducements, monetary or otherwise, will be offered to terminate a pregnancy. Investigators 
and staff engaged in the research will have no part in any decisions as to the timing, method, or 
procedures used to terminate a pregnancy, which will be the responsibility of the patient’s 
obstetrician. Individuals engaged in the study will have no part in determining the viability of a 
fetus or neonate.   
Elucidation of the impact of pharmacogenetics on our capacity to individualize dosing would 
have major impact upon clinical care of pregnant persons who suffer sNVP.  
PARTICIPANT POPULATION(S) 
 
 
Figure 7.  Recruitment Targets   
Accrual 
Number:
Category/Group: 
(Adults/Children 
Special/Vulnerable 
Populations) 
Consented: 
Maximum Number 
to be Consented or 
Reviewed/Collected/
Screened
Enrolled and samples collected: 
Number to Complete the Study or 
Needed to Address the Research 
Question 
Local 
Pregnant persons  
100 
25 
 
RECRUITMENT METHODS 
Authorized research personnel will work with clinicians from the Northwestern Obstetrics and 
Gynecology services and the Obstetrical Triage program to identify potentially eligible 
individuals and approach them about their interest in participating. We have defined several 
eligibility criteria to allow participants to be screened by our study team. Subject burden can be 
reduced and study efficiency improved by asking only those subjects likely to be eligible to 
undergo a full baseline assessment. The screen includes: 1) age 2) gestational age of the fetus, 
3) confirmation of plan to receive care and deliver at Prentice Women’s Hospital (PWH), 4) 

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PUQE score of 10-15, 5) has been treated with at least two anti-emetic/antinauseant drugs with 
inadequate response; and 8) English speaking. 
The inclusion/exclusion criteria will be reviewed in the patient’s chart and documented on the 
screening log. If a patient meets all the inclusion criteria for enrollment, does not have any of the 
exclusion criteria, she will be approached about the study by authorized personnel. Her primary 
obstetrician will be contacted to review the patient’s participation. 
Brochures will be available to provide potential subjects with additional information.  We will also 
post information about this study on our Asher Center and Northwestern Medicine websites, as 
well as post on the NCT site.  
 
 
COMPENSATION FOR PARTICIPATION IN RESEARCH ACTIVITIES 
Participants will be compensated with $35 for each week of the three-week trial. If a participant 
wishes to participate in the continuation period or a mirtazapine tapering regimen, they will 
continue for 5 additional weeks and compensated with $35 each week.  
  
If a participant enters into the study early in pregnancy (gestational age of 5 weeks), they will 
have monthly visits after the 8 weeks is completed, for a maximum total of 10 visits.  
  
Compensation will be provided in a form of a check at the end of each week during their follow-
up visit. 
 
WITHDRAWAL OF PARTICIPANTS 
A participant will be withdrawn from the research without their consent if there is: 1) refusal to 
follow the medication protocol, and/or 2) refusal to answer study questionnaires, 3) the 
participant fails to respond to contact attempts from the study team.  
RISKS TO PARTICIPANTS 
The potential risks of this study include exposure to an additional medication, mirtazapine, 
which has antiemetic/antinauseant properties. People eligible for this study will have already 
accepted two drugs to treat sNVP. This plan mirrors clinical practice since commonly prescribed 
antiemetic/ antinauseant drugs prescribed in standard practice will be given before mirtazapine.   
Reproductive Exposure Data. Djulus et al.66 and Winterfeld et al.67 conducted prospective 
studies of the rate of birth defects in infants exposed to mirtazapine in utero. Djulus et al. 
included three groups (104 women per group) of pregnant women with depression and 
exposure to mirtazapine, other antidepressants or non-teratogenic drugs. The malformation rate 
did not significantly differ by either drug exposure group compared to the non-teratogen group. 
Birth weights were similar across groups. As anticipated, the preterm birth rate was higher in 
both antidepressant-treated groups compared to the non-teratogen exposure group. The 
relationship between antidepressant exposure and preterm birth is attributable to factors 
associated with the underlying depression (confounding by indication) rather than the drug 
exposure.68 In Winterfeld et al.’s study, mirtazapine-exposed women were compared to two 
groups including women exposed to selective serotonin reuptake inhibitors (SSRI) and without 
mental illness (all groups with N=357). No significant differences in rates of birth defects were 
observed across the three groups. Gestational age at birth, birth weight, and miscarriage rates 
were similar across groups. In a case series of 56 women by Smit et al.69, no malformations 

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were observed in the newborns of 26 women exposed to mirtazapine in the first trimester. Of 54 
infants exposed in the third trimester, 14 (26%) had poor neonatal adaptation, similar to the rate 
observed after SSRI exposure. Birth weights were within the normal range. Preterm births 
occurred in 9% of exposed newborns vs. 7.7% of the general population. In summary, although 
the total number of women with first-trimester exposure to mirtazapine is relatively small 
(N=487), the results do not suggest a signal for birth defects. The majority of large-scale studies 
of populations of women who have taken antidepressant medications similar to mirtazapine, 
neither birth defects nor neurodevelopmental problems (including autism70) have been 
associated with the use of these drugs71. Additional data on pregnancy and newborn outcomes 
associated with mirtazapine exposure in the context of sNVP will be obtained in the proposed 
R21 study and included in the later Phase 3 RCT, if such a trial is supported by data from this 
R21 study. 
Pharmacotherapy with any drug for NVP is associated with benefits and harms that must be 
balanced by the physician and patient. Commonly used drugs, such as ondansetron, 
metoclopramide, and prochlorperazine also have treatment benefits and harms that must be 
balanced against the risks associated with sNVP. Ondansetron use increased from less than 
1% prior to 2000 to 13% in 2014.72 Data from the National Birth Defects Prevention and Slone 
Birth Defects Studies showed that ondansetron exposure was not associated with an elevated 
risk for the majority of defects; however, increased risks were observed for cleft palate (adjusted 
OR=1.6, 95% CI 1.1-2.3) and renal agenesis-dysgenesis (OR=1.8, 95% CI 1.1-3.0) in the Birth 
Defects Study.72 Huybrechts et al 73 evaluated 1,816,414 pregnancies with 88,467 (4.9%) and 
reported that first-trimester exposure to ondansetron was not associated with overall congenital 
or cardiac malformations but with a small increased risk of oral clefts (RR=1.24 (95% CI, 1.03-
1.48). 
In a large retrospective cohort study, infants exposed to metoclopramide in the first trimester 
were compared to unexposed infants. No significant differences in congenital malformations, 
birth weight, preterm delivery or perinatal death were observed.74 Although data for 
prochlorperazine are limited14, no consistent evidence of teratogenesis exists for the use of 
phenothiazine drugs in the treatment of NVP. Chronic maternal use of metoclopramide and 
prochlorperazine increase the risk for maternal extrapyramidal movement disorders and 
neonates have experienced agitation, hyper- or hypotonia, tremor, somnolence and respiratory 
distress. 
Blood sampling will be done to allow the plasma assay for mirtazapine concentrations. The 
phlebotomy services will be obtained from the Diagnostic and Treatment Center on the second 
floor of Arkes Pavilion, Prentice Women’s laboratory services, or the Asher Center clinical 
research laboratory. All are accessible through indoor walkways from Prentice Women’s 
Hospital. There are minimal risks to phlebotomy, which are rare and include bruising, pain, 
infection and mild maternal anxiety. The amount of blood that will be drawn at enrollment for 
study purposes is 3 ml (thyroid hormones) and 5 ml (DNA sample), for a total of 8 ml, and 5 ml 
at each follow up assessment for plasma concentrations of mirtazapine.   
POTENTIAL BENEFITS TO PARTICIPANTS 
There is no definitive benefit to participants from whom data will be collected. Pregnant persons 
may benefit from the additional education about the disorder and possibly from treatment with 
the promising drug mirtazapine. The additional monitoring by study staff may be perceived as 
supportive.   

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The dearth of information about the treatment of sNVP has been identified in systematic 
reviews, meta-analyses and the recent NICHD-led Task Force on Research Specific to 
Pregnant Women and Lactating Women (PRGLAC). Data to inform the acceptability, tolerability, 
dosing and design of a subsequent randomized controlled trial to expand pharmacotherapy 
would be a major contribution in the care of pregnant persons. 
According to the Code of Federal Regulations, Title 45 Part 46, Subpart B, research may be 
conducted in people when preclinical studies, including studies on pregnant animals, and 
clinical studies, including studies on non-pregnant persons, have been conducted and provide 
data for assessing potential risks to pregnant persons and fetuses. This is the case for 
mirtazapine, which is FDA-indicated for the treatment of depression. This Phase 2 trial will be 
submitted for review prior to implementation to our IRB and to the FDA for an IND. Additionally, 
research is acceptable when the risk to the fetus is caused solely by interventions or procedures 
that hold out the prospect of direct benefit for the woman or the fetus. The purpose of this Phase 
2 study is the development of important biomedical knowledge which cannot be obtained by any 
other means. 
DATA MANAGEMENT AND CONFIDENTIALITY 
Data will be collected and managed using Research Electronic Data Capture (REDCap) housed 
at Northwestern University’s Clinical and Translational Sciences Institute (CTSA), NUCATS. 
REDCap is a secure, web-based application designed for research studies that provides an 
intuitive interface for validated data entry, audit trails for tracking data manipulation and export 
procedures, and automated export procedures for seamless data downloads to common 
statistical packages, and procedures for importing data from external sources.  
Multiple procedures will be used to protect the confidentiality of the participants in this study. 
Names of participants will not appear on any written records, which include interview forms, self-
report forms, or checklists. Code numbers will be used for all computerized data. Confidentiality 
will be preserved by using numbers (different than medical record numbers) rather than names 
in the computer files. A separate file (stored in a secure file with limited access) will map patient 
names and numbers. Access to files will be restricted to appropriate personnel as designated by 
the PI.  All persons on the study team who have access to any subject-related data are required 
to complete training and testing for research certification. Hard copy files, such as written 
consent forms, are double-locked and separate from research data for the subject. 
Data communication between data entry computers and database servers will be encrypted via 
a VPN client. Access to the VPN connection will require user authentication via username and 
password. Firewall software will restrict communication to traffic to the database server that is 
absolutely critical for conducting research. All unwanted inbound traffic will be blocked at the 
firewall. Anti-virus software will guard against the intrusions that typically attack through 
malicious email and removable media. Privacy protection and malware detection software will 
be active in real-time as additional assurance that unwanted cookies or browser plug-ins are not 
slowing performance of the device. The data management and information technology staff 
(data managers, programmers, statisticians) will have access to the database, but not 
information linking the study ID to the subject’s name.  
Subject plasma will be stored in a -70ºC freezer in the Northwestern Core Laboratory. These 
samples will be labeled with the Northwestern Medicine clinical research unit ID, the subject ID, 
the date of collection, the type of sample collected (e.g. “plasma”), and the corresponding 
timepoint. Only study personnel will have access to data and will be responsible for 

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transmission of data. Approved study personnel and Clinical Research Unit Core Lab staff will 
have access to specimens and will be responsible for transmission of specimens. Deidentified 
specimens will be transported to Purdue University using FedEx delivery services for analysis.  
Multiple procedures will be used to protect the confidentiality of the participants in this study. 
Names of participants will not appear on any written records, which include interview forms, self-
report forms, or checklists. Code numbers will be used for all computerized data. Confidentiality 
will be preserved by using numbers (different than medical record numbers) rather than names 
in the computer files. A separate file (stored in a secure file with limited access) will map patient 
names and numbers. Access to files will be restricted to appropriate personnel as designated by 
the PI.  All persons on the study team who have access to any subject-related data are required 
to complete training and testing for research certification. Hard copy files, such as written 
consent forms, are double-locked and separate from research data for the subject. 
Data communication between data entry computers and database servers will be encrypted via 
a VPN client. Access to the VPN connection will require user authentication via username and 
password. Firewall software will restrict communication to traffic to the database server that is 
absolutely critical for conducting research. All unwanted inbound traffic will be blocked at the 
firewall. Anti-virus software will guard against the intrusions that typically attack through 
malicious email and removable media. Privacy protection and malware detection software will 
be active in real-time as additional assurance that unwanted cookies or browser plug-ins are not 
slowing performance of the device. The data management and information technology staff 
(data managers, programmers, statisticians) will have access to the database, but not 
information linking the study ID to the subject’s name.  
We will seek consent from our subjects to have their de-identified data and biospecimens 
included in the NICHD Data and Specimen Hub (DASH-https://dash.nichd.nih.gov/) for future 
studies.  
PROVISIONS TO MONITOR THE DATA TO ENSURE THE SAFETY OF PARTICIPANTS 
The primary patient and safety monitoring function is the responsibility of the PI, Katherine L. 
Wisner, MD, MS. She was a founding member of the NIMH Data Safety and Monitoring Board 
for multi-site clinical trials. Co-Investigators are Catherine S. Stika, MD, and Melissa Goslawski, 
MD. Dr. Stika is a co-PI with Dr. Wisner on the Obstetric-Fetal Pharmacology Center and 
Medical Director of the Obstetrical Triage Service, where pregnant persons seek urgent care for 
sNVP. Dr. Goslawski is an obstetrician who works in the Obstetrical Triage Service. They will 
support recruitment, assessment and monitoring of subjects for the E-SNAP protocol.    
The research team has the responsibility to respond to information that affects the well-being of 
the subject (such as severe dehydration from NVP) consistent with Good Clinical Practice. The 
proposed study does not limit any interventions that would be prescribed for any subject. If a 
subject’s condition worsens during the study and her clinical status dictates removal from the 
study, a study physician will provide the rationale for removal. The study team will confer with 
the patient’s primary obstetrician and to develop a treatment plan for the participant.   
Adverse Events. The adverse event definitions required for an FDA IND will be applied by the 
study team. The occurrence of adverse events will be tracked in the study data base by 

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manager Mr. Erickson and statistician Dr. Kim, who will be responsible for ensuring the 
accurate, timely and secure incorporation of information into the study data base.  
In the Data Safety and Monitoring Plan, Drs. Wisner, Stika and Kim will evaluate safety at 
several levels:  1) the individual subject, 2) the group of subjects as the study data accrue 
through review of all adverse events for patterns, and 3) the integrity of the data and data 
monitoring procedures. The team will evaluate the progress of the study and provide quarterly 
assessments of data quality, timeliness and completion; participant recruitment; accrual and 
retention; participant risk versus benefit; and other factors that affect study outcome. Monitoring 
will include factors external to the study, such as scientific developments that could have an 
impact on the therapeutic options, safety of the participants or the ethics of the study.  All 
adverse events will be reported to the Northwestern IRB, DSMB and FDA as required.  
A Data Safety and Monitoring Board (DSMB) will be constructed for this project. The E-SNAP 
project includes pregnant persons being treated with mirtazapine, which meets the definition of 
a NIH clinical trial. It will also be submitted to the FDA for review for an IND, since the 
investigation involves pregnant persons, “a patient population that significantly increases the 
risk (or decreases the acceptability of the risk) associated with the use of the drug product (21 
CFR 312.2(b)(1)(iii)).”  
The DSMB will include external academic faculty members in the following areas:  one 
maternal-fetal medicine specialist who has expertise in reproductive outcomes associated with 
drug exposure; an obstetrician-gynecologist with an interest in sNVP; and a reproductive 
pharmacoepidemiologist. The board will conduct quarterly phone conferences to review study 
materials relevant to data integrity and safety as defined above. Flow through the study, side 
effects and adverse event frequency, withdrawals and post-enrollment hospitalizations will be 
reviewed. A formal Consort Chart will be generated as the study evolves.75  
The DSMB will review specifically the frequency of adverse study-associated events in all 
subjects as follows:  1) acceptability data; 2) the tolerability of the mirtazapine dosage regimen; 
3) mirtazapine discontinuation and reason(s) for discontinuation; 4) emergency room visits; 5) 
post-enrollment hospitalizations, durations and interventions; 6) additional medication 
exposures during the three week and optional maintenance study periods; 7) the adequacy of 
the tapering regimen to mitigate discontinuation symptoms, the number of pregnant persons 
who experience recurrence of sNVP and the number tapers that are attempted; 8) patient 
complaints to the study team or IRB; and, 9) reproductive outcomes for both the mother and the 
neonate on the Peripartum Events Scale, which will be compared to the outcomes of data from 
in-utero SSRI antidepressants. These findings will be evaluated and summarized by 
neonatology consultant Malika Shah, MD.   
The DSMB meetings will occur by teleconference. The data will be summarized and provided 
prior to the phone consultations to the DSMB members. The tables below summarize the 
activities of the DSMB.  
YEAR 01
YEAR 02
Prior to initial meeting:  discuss and sign 
agreement and expectations for DSMB 
participation; develop format for minutes at all 
meetings.  
Continue quarterly teleconferences; adjust data 
delivery format as appropriate per DSMB input. 
 

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PROVISIONS TO PROTECT THE PRIVACY INTERESTS OF PARTICIPANTS 
Subjects will be informed regarding staff who will have access to their data. Topics covered in 
questionnaires are consistent with standard of care evaluations and are not expected to induce 
any additional discomfort or distress.   
Authorized research personnel may have access to enrolled subjects’ medical records at the 
designation of the Principal Investigator in compliance with EDW policy. 
COMPENSATION FOR RESEARCH-RELATED INJURY 
The university or researchers will not pay for medical care required because of a bad outcome 
resulting from participation in this research study. This does not keep participants from seeking 
to be paid back for care required because of a bad outcome. 
ECONOMIC BURDEN TO PARTICIPANTS 
There is no cost to subjects to participate in this study.   
CONSENT PROCESS 
Written informed consent will be obtained in the place in which the subject was recruited (the 
Obstetrical Triage Unit, Prentice Women’s Hospital or the Asher Center), or with electronic 
consent through REDCap. We have integrated this flexible approach due to the unpredictable 
effects of the pandemic. The time devoted to the consent discussion is estimated to be 30 
minutes, but study personnel will provide as much time as is necessary for the participant to 
review the consent and ask questions.  
When the participant agrees to enroll in this study, her electronic signature with time stamp and 
certification will be collected through REDCap. A digital PDF copy of the signed consent form 
will be offered to the participant after consent is signed. REDCap will serve as the central 
repository of signed consent forms. Only authorized study personnel will have access to 
REDCap via VPN. 
The REDCap electronic consent will use the same language as the IRB stamped consent, will 
have a version stamp in the footer, and will contain the same required signature fields: 
Initial meeting:  Review protocol, establish the 
data to be reviewed by the DSMB; set additional 
quarterly phone conferences with option for as 
needed meetings. A particular focus will be 
assessment of the tolerability of the dosing 
strategy and the potential need for modification. 
 
Quarterly:  Review course of study to date, 
summarize any untoward events, problem solve.  
Data summaries provided to DSMB members at 
least 10 days prior to quarterly conference 
reviews.
Final meeting:  review course of study; 
summarize untoward events, quarterly phone; 
review and generate final report.  

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participant’s initials on pertinent fields; participant’s full name, signature and signature date; and 
person obtaining consent’s full name, signature and signature date.    
NON-ENGLISH SPEAKING PARTICIPANTS 
Participants must speak English, as the clinicians conducting this study are English-speaking 
and measures and assessments are in English. 
WAIVER OR ALTERATION OF CONSENT PROCESS 
Participants must be able to provide written consent. Required information will be disclosed, and 
the research does not involve deception.  
TRIAL STOPPING CRITERIA 
This clinical trial will stop in the instance of any of the following: 
 
Death of a subject during the trial 
 
Grade 3 or higher toxicity in any organ system per the Common Terminology Criteria for 
Adverse Events (CTCAE), version 5.0 developed by the National Cancer Institute 
 
Grade 2 or higher allergic/hypersensitivity reaction 
 
If there are two identical unexpected treatment-related toxicities that are Grade 3 or 
higher, we will suspend accrual pending further review by the Institutional Review Board 
An individual subject will stop participating in the clinical trial in the instance of any of the 
following: 
 
New onset suicidal thoughts or behaviors 
 
Grade 3 or higher drug-related serious adverse event (SAE) based on the CTCAE, 
version 5.0  
 
Acute livery injury [alanine transaminase (ALT) or aspartate transaminase (AST) > 3-fold 
upper limit of normal (ULN), alkaline phosphatase (ALP) or total bilirubin (TBL) > 2 fold 
ULN] 
 
Subjects with serum sodium < 125 mmol/L 
 
PROTECTED HEALTH INFORMATION (PHI AND HIPAA) 
This study involves the creation, use or disclosure of Protected Personal Health 
Information. Protected Personal Health Information includes names, address, dates of 
birth and ages, telephone numbers, email addresses, social security numbers (see 
Compensation section), and medical record numbers.  HIPAA requirements and 
measures to protect PHI will be implemented as described in the Data Management and 
Confidentiality section. 

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QUALIFICATIONS TO CONDUCT RESEARCH AND RESOURCES AVAILABLE 
An interdisciplinary team with a strong commitment to improving care for pregnant persons 
collaborated in the development of this protocol. Northwestern is the sole clinical site for this 
study. The PI is Katherine L. Wisner, MD, MS, is the Norman and Helen Asher Professor of 
Psychiatry and Obstetrics and Gynecology. She has conducted nine NIMH-funded R01 
observational (during pregnancy) and randomized clinical trial (postpartum) studies of mood 
disorders. Dr. Wisner was an author in the joint ACOG-APA Committee’s consensus report for 
managing depression during pregnancy 76 and is the first author of Mental Health and 
Behavioral Disorders, in Obstetrics: Normal and Problem Pregnancies, edited by Gabbe S et al 
(2007, 2012) and Psychotropic Drugs (in Schaefer C et al, Drugs during Pregnancy and 
Lactation: Treatment Options and Risk Assessment, 2014). She is a fellow of the American 
College of Neuropsychopharmacology. Dr. Wisner participated in the FDA Advisory Committee 
to Revise Drug Labeling for Pregnancy and Lactation; FDA Pediatrics Subcommittee, Neonatal 
Effects of SSRI Use; Research Committee, Organization of Teratology Information Services; 
FDA Advisory: Perinatal Depression-Examining the Risks and Benefits of Treatment; CDC 
TRxeating for Two: Safe Medication Use in Pregnancy Expert Meeting.   Drs. Wisner and Stika 
(see below) are Co-PIs on the Northwestern Obstetric-Fetal Pharmacology Research Center 
funded by NICHD.  
The co-I is Catherine S. Stika, MD, Professor of Obstetrics and Gynecology. Dr. Stika 
completed a fellowship in clinical pharmacology and was a consultant for the FDA Guidance for 
Pharmacokinetic studies in pregnancy.  She is the primary author of Drug Therapy in Pregnant 
and Nursing Women, in Principles of Clinical Pharmacology, edited by AJ Atkinson, Jr., in 2001, 
2006 and 2012.  This book serves as the core text for the NIH annual clinical pharmacology 
course.  NIH is developing an on-line video program of lectures and cases, and Dr. Stika will 
prepare the obstetrical section. She has served on the DSMB for the OPRU network from 2005 
– 2014 and was the obstetrical co-PI on the Northwestern Obstetric-Fetal Pharmacology 
Research Center funded by NICHD (2015-2021).  
 
Dr. Goslawski is an obstetrician-gynecologist employed by Northwestern Medicine to work in the 
Obstetrical Triage Unit at Prentice Women’s Hospital. She is also a perinatal psychiatry scholar 
in the Asher Center for the Study and Treatment of Depressive Disorders with Dr. Wisner.  
Achievement of the scientific goals depends upon efficient administrative operations. The 
structure will support efficient communication, study processes and personnel management. 
Katherine L. Wisner, MD, MS, is the principal investigator and administrative leader. Dr. Wisner 
will supervise Ms. Berman and Ms. Habelhah, experienced research coordinators, in the overall 
conduct of research activities. The entire study team will meet weekly for one hour. All meetings 
will be documented by minutes containing a summary and task assignment list with personnel 
responsible for completing the task. These minutes will be available on the internal website. 
Administrative Goals: 
1. Manage resources equitably and efficiently, including budget, resource management and 
liaison to the Northwestern University Office of Sponsored Research. 
2. Support clear, equitable and transparent study-wide procedures, including monitoring 
progress on objectives, distribution of resources, achieving milestones and providing 
constructive feedback. 

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3. Facilitate information flow across partners such as the Northwestern Office of Sponsored 
Research, IRB, DSMB, FDA, research pharmacy, regulatory monitors and clinical research 
unit staff. 
4. Establish a manual of operating procedures (MOP) to ensure regulatory compliance, policy 
development, record-keeping practices, coordinated oversight of recruitment, management 
of subject data and human subject issues. The MOP will include information on all aspects 
of the study, such as organizational structure, screening, inclusion/exclusion criteria; 
treatments, collection, shipping and location of specimens, adverse events, data entry and 
management, statistical analysis and publications. Protocol updates and clarifications from 
study meetings will be included in the dynamic MOP, which will be updated weekly during 
the investigation. The final version of the MOP will contain all information need to construct 
the later definitive clinical trial to be submitted as an R01 if the data from this study are 
supportive. 
5. A decision-making algorithm for data reporting procedures will be developed and placed in 
the MOP. Quality assurance procedures, such as frequent data quality reviews and direct 
observation of research staff conducting procedures, will be devised. Training and ongoing 
supervision of research staff are essential to promoting intervention fidelity. We will develop 
(and modify iteratively) training procedures and scripts for interacting with participants at 
each visit. Training will include review of the MOP, data collection and management 
systems, and quality control procedures. Staff will have hands-on experience with the data 
system by entering mock data and reviewing reporting procedures. 
6. The data team will generate reports for the review of the study team (with attention to 
sections that must be kept blind by the clinical team), as well as for DSMB and FDA review. 
Criteria will include enrollment of participants, frequency of attrition, unanticipated events, 
and protocol violations. We will use quantitative measures compiled from screening, 
enrollment and study visit data entry logs. At regular study team meeting, comprehensive 
reports will include recruitment, retention and other performance parameters; quality control 
for data received; data that include missed visits and protocol violations, and participant 
characteristics. The organizational structure for the E-SNAP project is shown below: 
 
 

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MULTI-SITE RESEARCH  
This is a single-site investigation at Northwestern University Institutional Review Board is the 
IRB of record for this study.  
 
 

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