Comparison of Gabapentin and Metoclopramide for Treating Hyperemesis Gravidarum
Phase: PHASE2
Conditions: Hyperemesis Gravidarum
Sponsor: State University of New York at Buffalo

 
University at Buffalo Institutional Review Board (UBIRB) 
Office of Research Compliance | Clinical and Translational Research Center Room 5018 
875 Ellicott St. | Buffalo, NY 14203 
UB Federalwide Assurance ID#: FWA00008824 
PROTOCOL TITLE: Comparison of gabapentin and metoclopramide for treating 
hyperemesis gravidarum. 
Page 1 of 42 
 
  
NCT Number: NCT02163434 
 
Document Date: 5/2/2016 
 
PROTOCOL TITLE: 
Include the full protocol title. 
Response: Comparison of gabapentin and metoclopramide for treating 
hyperemesis gravidarum. 
PRINCIPAL INVESTIGATOR: 
Name 
Department 
Telephone Number 
Email Address 
Response: Thomas Guttuso, Jr., MD 
Department of Neurology 
716-829-5454  
tguttuso@buffalo.edu 
VERSION NUMBER: 
Include the version number of this protocol. 
Response: 9 
DATE: 
Include the date of submission or revision. 
Response: 5.2.16 
Grant Applicability: 
Describe whether or not this protocol is funded by a grant or contract and if so, 
what portions of the grant this study covers. 
Response: This study is being supported by the National Institute of 
Health (NIH) 
 

 
 
Page 2 of 42 
Revised: December 7, 2020 
Table of Contents 
1.0 
Objectives ............................................................................................................ 3 
2.0 
Background .......................................................................................................... 3 
3.0 
Inclusion and Exclusion Criteria ......................................................................... 11 
4.0 
Study-Wide Number of Subjects (Multisite/Multicenter Only) ........................... 13 
5.0 
Study-Wide Recruitment Methods (Multisite/Multicenter Only) ......................... 13 
6.0 
Multi-Site Research (Multisite/Multicenter Only) ............................................... 13 
7.0 
Study Timelines.................................................................................................. 14 
8.0 
Study Endpoints ................................................................................................. 15 
9.0 
Procedures Involved ........................................................................................... 16 
10.0 
Data and Specimen Banking ............................................................................... 19 
11.0 
Data Management............................................................................................... 20 
12.0 
Provisions to Monitor the Data and Ensure the Safety of Subjects ...................... 22 
13.0 
Withdrawal of Subjects....................................................................................... 25 
14.0 
Risks to Subjects ................................................................................................ 26 
15.0 
Potential Benefits to Subjects ............................................................................. 30 
16.0 
Vulnerable Populations ....................................................................................... 30 
17.0 
Community-Based Participatory Research .......................................................... 31 
18.0 
Sharing of Results with Subjects ......................................................................... 31 
19.0 
Setting ................................................................................................................ 31 
20.0 
Resources Available ........................................................................................... 32 
21.0 
Prior Approvals .................................................................................................. 34 
22.0 
Recruitment Methods ......................................................................................... 34 
23.0 
Local Number of Subjects .................................................................................. 35 
24.0 
Confidentiality.................................................................................................... 35 
25.0 
Provisions to Protect the Privacy Interests of Subjects ........................................ 35 
26.0 
Compensation for Research-Related Injury ......................................................... 36 
27.0 
Economic Burden to Subjects ............................................................................. 36 
28.0 
Consent Process.................................................................................................. 37 
29.0 
Process to Document Consent in Writing ............................................................ 41 
30.0 
Drugs or Devices ................................................................................................ 41 
 

 
 
Page 3 of 42 
Revised: December 7, 2020 
1.0 
Objectives 
1.1 Describe the purpose, specific aims, or objectives. 
Response:  
Aim 1.  To compare the efficacy and tolerability of gabapentin and 
metoclopramide in the treatment of HG. 
Aim 2. (1)  (Exploratory)  To assess the change from Baseline in efficacy 
measures after 2 weeks of open-label gabapentin; and (2) (Descriptive) to 
assess the mean gabapentin dose, duration of gabapentin treatment and 
frequency of rescue metoclopramide pills required by patients during the 
entire open-label gabapentin phase of the study. 
1.2 State the hypotheses to be tested. 
Response: Is gabapentin more effective than metoclopramide for the 
treatment of nausea and vomiting in women with hyperemesis 
gravidarum?  
2.0 
Background 
2.1 Describe the relevant prior experience and gaps in current 
knowledge. 
See section 2.3. 
2.2 Describe any relevant preliminary data.  
Response: See description above in Section 2.3 
 
2.3 Provide the scientific or scholarly background for, rationale for, and 
significance of the research based on the existing literature and how 
will it add to existing knowledge. 
Response:  
Hyperemesis gravidarum (HG) is a disease of severe nausea, vomiting, and 
anorexia associated with early pregnancy leading to dehydration and weight loss.  HG has 
been coined a “heart-sink problem” for gynecologists because of the frustration of not 
being able to cure such distressed women and because of the prolonged and repeated 
hospital admissions.1  A recent meta-analysis of HG randomized controlled trials 
concluded that there are no effective treatments for this condition.2  As a result, more 
than 50,000 HG patients a year require hospital admission for intravenous (iv) hydration 
or parenteral nutrition.3,4  It is estimated that about 206 hours of paid work are lost for 
each woman with nausea and vomiting of pregnancy.5 
 
HG also inflicts significant psychosocial burden on patients.  In a recent on-line 
survey of 808 women with HG, 15.2% reported electively terminating at least one 
pregnancy due to HG.6  The top 3 reasons for terminating were “No hope for relief” 
(87.0%), “Unable to care for self or family” (66.7%), and “Emotional distress” (60.2%).  
In this same survey, an additional 12.7% of women with HG reported that they “almost” 
terminated a pregnancy due to HG.  Therefore, about 28% of babies whose mothers have 

 
 
Page 4 of 42 
Revised: December 7, 2020 
HG are at high risk for death.  There is a large clinical need for a safe and effective 
treatment for HG that will bring meaningful benefit and, consequently, decrease the high 
rate of associated fetal mortality. 
 
Eight of the 9 published HG randomized controlled trials (RCTs) have 
assessed their primary outcome measures while subjects were inpatients, where 
subjects experience very high placebo effects especially regarding rates of emesis 
(placebo effect mean of 82%).1,7-13  Even though patients’ symptoms improve greatly 
when they are inpatients, about 35% require readmission after discharge.14  It is this 
phenomenon of symptom recurrence in the outpatient setting that is refractory to 
antiemetic treatment that embodies the challenge for patients living with HG and for 
clinicians caring for HG patients.  Future RCTs, therefore, should focus on outcomes 
assessed in the outpatient setting in patients with refractory disease in order to truly 
assess the clinically meaningful benefit of an HG therapy. 
 
Dr. Guttuso was the first to report on open-label gabapentin’s benefit for 
refractory nausea and vomiting15,16 and theorized that gabapentin may be effective 
for HG.  An open-label pilot study was performed examining the tolerability and 
effectiveness of gabapentin in the treatment of HG (see Appendix).17 
 
 
Preliminary studies: 
 
This clinical study protocol was first submitted to the FDA as Investigational 
New Drug (IND) 79,612 and was approved by the University at Buffalo’s 
Institutional Review Board (IRB), and later by the Sisters of Charity Hospital’s IRB, 
before any subjects were enrolled.  All subjects provided written informed consent. 
 
We initially enrolled 7 subjects with HG from March 2008-March 2009.  
Subjects were supplied with gabapentin 300mg capsules and took the first dose at the 
time of enrollment.  They were given instructions on how to slowly increase the dose 
to a minimum of 1,200mg/day and a maximum of 3,600mg/day.  After 14 days of 
therapy, gabapentin was discontinued for 2 days to determine if symptoms recurred.  
If there was a > 50% increase in nausea or vomiting while off gabapentin, gabapentin 
could be resumed on Day 17 and for the remainder of the pregnancy, if necessary.   
 
The primary outcome measures were percent reduction in nausea and 
emesis/retching from Baseline to the mean of Days 12-14 based on subjects’ daily 
recordings on the validated Motherisk-PUQE (pregnancy-unique quantification of 
nausea and emesis) diary.18   
 
Results: 
 
The median gestational age at the time of enrollment was 8 weeks.  All 7 subjects 
had at least 3+ ketonuria and >5% weight loss from their pre-pregnancy weight at 
Baseline.  The mean number of anti-emetics tried before enrolling was 2.4.  The first 3 
subjects were enrolled as inpatients and managed as outpatients while the other 4 subjects 
were enrolled and managed as outpatients. Gabapentin’s onset of action appeared to be 
very rapid with all 7 subjects experiencing a ≥50% decrease in nausea by Day 2 of 
gabapentin therapy and complete resolution of emesis by Day 4.  The 3 subjects enrolled 
as inpatients were discharged 2, 3, and 2 days after starting gabapentin, respectively.  

 
 
Page 5 of 42 
Revised: December 7, 2020 
None of the subjects required admission/readmission for hyperemesis after starting 
gabapentin.  The mean reductions in nausea and emesis from Baseline to Days 12-14 
were 80% and 94%, respectively, and 84% and 98%, respectively, from Baseline to Days 
19-21.19  There was a >3x increase in mean nausea and a >7x increase in mean emesis 
scores associated with discontinuing gabapentin during Days 15-16.  These data and oral 
nutrition scores are summarized in Figure 1.  Subjects gained an average 0.85 pounds 
from Baseline to Day 21.  The mean maximum daily gabapentin dose was 1,843mg. 
 
 
Figure 1: Mean nausea, emesis and nutrition scores (n=7) 
 
 
 
On Day 12, the amount of relief experienced from gabapentin on the 7-point 
Likert scale was reported as “6” by 4 subjects and “7” by 3 subjects.  The degree of 
satisfaction with gabapentin was recorded as “Satisfied” by 4 subjects and “Very 
Satisfied” by 3 subjects. 
 
Subjects 8 & 9 were enrolled as inpatients and had been reporting excellent 
benefit from the gabapentin therapy until Days 15-16 when they discontinued gabapentin 
and subsequently experienced severe recurrence of HG symptoms.  These 2 subjects 
failed to complete any of their Motherisk-PUQE diaries. 
 
Subject 10 was enrolled as an inpatient and experienced a 100% resolution of 
emesis and a near full resolution of nausea and impaired nutritional intake by Days 12-
14.  She discontinued gabapentin after 10 weeks of therapy and did well for 2 weeks but 
then had recurrence of refractory HG and was admitted to the hospital.  After failing to 
respond to intravenous metoclopramide, ondansetron and prochlorperazine, she resumed 
gabapentin and experienced full resolution of symptoms.  
Subject 11 was enrolled as an inpatient at 10 weeks gestation and experienced full 
resolution of nausea, emesis and anorexia after initiating gabapentin.  This subject was 
able to discontinue gabapentin after 4 weeks without recurrence of symptoms. 
Four subjects experienced mild-moderate side effects of sleepiness or dizziness 
when first starting gabapentin.  These side effects did not interfere with any activities of 
daily living and dissipated or resolved by the second week of therapy in all 4 subjects. 
 
Two of these 11 subjects from our pilot study were lost to follow/up despite 
multiple attempts at contact.  Eight of the other 9 subjects delivered at term and one baby 
0
2
4
6
8
10
12
Baseline
Days 12-14 (on
gabapentin)
Days 15-16 (off
gabapentin)
Days 19-21 (on
gabapentin)
Nausea
Emesis & Retching
Nutrition

 
 
Page 6 of 42 
Revised: December 7, 2020 
was found to have hydronephrosis eventually requiring surgical correction.  The other 
subject delivered twins by C-section at 33 weeks gestation.  This pregnancy was 
conceived via in-vitro fertilization (IVF).  One twin had a tethered spinal cord and a 
lumbar skin tag requiring surgical correction while the other twin had no congenital 
defects.  These congenital defects have been reported to the FDA under IND 79,612. 
 
In addition to the 11 subjects enrolled into the pilot study, another HG patient was 
treated with gabapentin by a local nurse practitioner (NP) who was familiar with our 
research.  This patient had a history of HG with 3 previous pregnancies all of which were 
electively terminated due to severe and medically refractory nausea and vomiting.  The 
patient again developed nausea and vomiting with the current pregnancy starting at 6 
weeks gestation.  She was started on metoclopramide 10mg qid x 3 weeks and, 
subsequently, ondansetron 4mg q4 hours was added for persistent nausea and vomiting.  
At 12 weeks gestation the patient had lost 10 pounds over the previous week (=4.3% of 
her pre-pregnancy weight), was found to have 3+ ketonuria, and was no longer able to 
work as a nurse due to persistent nausea and vomiting despite taking both 
metoclopramide and ondansetron, as prescribed.  She told her NP that she was going to 
have to terminate the pregnancy due to the severe and medically refractory symptoms and 
her inability to work. 
After the NP informed the patient on the promising results from the pilot study, 
the patient agreed to first try gabapentin before making a final decision to terminate the 
pregnancy.  After receiving 3 liters of iv hydration, the patient started gabapentin 300mg 
tid on 7/19/11 at 12 weeks gestation.  By the afternoon of 7/20/11, the patient reported 
that her nausea and vomiting had improved by about 90% and she was having no 
difficulty tolerating normal oral nutrition and hydration.  Within a few days, the patient 
returned to her nursing job full-time and continued to work until she delivered.  The 
patient also did not require any more iv hydration throughout the pregnancy.  On 9/9/11, 
gabapentin was increased to 300mg bid and 600mg qhs for some recurrent symptoms 
with good response.  The patient continued to take metoclopramide and ondansteron, as 
needed, which was 1-2x/week.  Metoclopramide and ondansetron were discontinued at 
week 21 and 26 gestation, respectively.  Gabapentin was continued until spontaneous 
labor began at 38 weeks gestation. A healthy baby was delivered by Caesarian section 2 
days later. 
 
Only 1 of the 12 patients treated with gabapentin for HG to date has required 
hospital admission/readmission for HG, which occurred 12 weeks after initiating 
gabapentin.  This markedly contrasts the 20-40% readmission rate within 2 weeks of 
enrollment observed in previous HG trials.1,8,11,14 
 
The promising results from our pilot study and from this additional case using 
gabapentin for HG have been consistent with our previous experiences using gabapentin 
in other patient populations experiencing severe and refractory nausea and/or emesis.15,16  
Subsequent to our initial reports on this novel use of gabapentin, several other groups 
have performed RCTs showing gabapentin to have significant benefit in the prevention or 
treatment of nausea and vomiting.20-22 
 
Gabapentin’s main clinical use is in the treatment of neuropathic pain, which is 
one of its FDA-approved indications.  Gabapentin’s mechanism of action in this 
condition is mediated through its specific neuronal binding site, the alpha-2/delta subunit 
of voltage-gated calcium channels (VGCCs),23,24 most likely by acting as a calcium 

 
 
Page 7 of 42 
Revised: December 7, 2020 
channel antagonist.25,26  In the leading animal model of neuropathic pain, alpha-2/delta 
subunits were shown to upregulate 17x in sensory neuronal cell bodies in response to an 
experimental nerve lesion associated with allodynia and neuropathic pain.27  It has been 
theorized that this dramatic upregulation in alpha-2/delta subunits is not only involved in 
the pathophysiology of neuropathic pain but also is what offers the opportunity for 
gabapentin’s clinical efficacy in this condition.27  It has also been theorized that 
upregulation in this subunit in the nervous system’s temperature regulatory centers in 
response to plummeting estrogen levels at menopause is involved with the 
pathophysiology of hot flashes and accounts for gabapentin’s effectiveness in relieving 
hot flashes and night sweats.28 
In the treatment of HG, we theorize that gabapentin mitigates calcium currents in 
nausea/vomiting centers (such as the area postrema of the medulla) by binding to alpha-
2/delta subunits of that have been upregulated in response to the dramatic increases of 
estrogen and progesterone early in pregnancy.   
 
In terms of gabapentin’s safety during pregnancy, there have been 5 infant major 
congenital malformations (MCMs) reported among 294 first trimester gabapentin 
monotherapy exposures.17,29-32  Two of these 5 MCMs were from our pilot study, as 
described above.  This equals a 1.7% rate (5/294) of infant MCMs.  Comparing this rate 
with that found in the general population, the rate of MCMs detected by the end of the 
first week of life in the Metropolitan Atlanta population between 1968 and 2003 was 
2.1%,33 while the Brigham and Women’s Hospital Surveillance Program reported a 
MCM frequency of 1.6%–2.2% at birth depending on whether chromosomal and genetic 
abnormalities were included in the calculation.34 
 
In conclusion, open-label gabapentin appears to be well tolerated and effective in 
the treatment of HG.  It also does not appear that first trimester use of gabapentin is 
associated with any increased risk of infant MCMs compared to the general population.  
Due to the current lack of any effective HG therapy, a RCT using gabapentin for HG is 
merited.  As noted above, the growing body of literature supporting a significant 
antiemetic effect of gabapentin in other patient populations20-22 further supports the 
merits of continued research on its effects in HG. 
 
We initiated a RCT in 7/2014 comparing the efficacy of gabapentin with 
ondansetron in women with HG and have enrolled 7 subjects as of 6/14/15.  However, 
recently several eligible patients have informed us that they did not want to participate in 
this study due to the publicity stemming from 2 recent studies associating maternal use of 
ondansetron with increased rates of congenital cardiac septal defects.35,36  The Andersen 
et al. study35 has received much media attention, despite the fact that it has not yet been 
published in a peer-reviewed journal, due to the 12/2014 publication of an opinion article 
that highlighted this potential risk of ondansetron and recommended against its use in 
pregnancy.37  Even though a previous report did not associate maternal ondansetron use 
with increased rates of congenital defects,38 I suspect that once the Andersen et al. study 
is formally published, there will be more media attention on this issue, which will serve 
to make it even more difficult for us to enroll into our current clinical trial if we maintain 
the ondansetron treatment arm. 
Due to this new information, that was not anticipated at the time that our study 
protocol was approved, we requested approval from the NIH to change the ondansetron 
treatment arm to a metoclopramide treatment arm.  On 6/5/15, the NIH approved this 

 
 
Page 8 of 42 
Revised: December 7, 2020 
change. 
To date, there have been 3 large studies all demonstrating metoclopramide use to 
be safe during pregnancy without any increased risk for congenital defects.35,39,40  There 
have been no contradictory studies.  Interestingly, the Andersen et al. study was one of 
these studies as this group used first trimester metoclopramide exposures as a control 
group.37  This finding will further strengthen the evidence supporting the safety of 
metoclopramide use in pregnancy once the Andersen et al. study is formally published.  
We anticipate that this safety information will be very reassuring to potential study 
subjects and, as a result, will lead to greatly improved enrollment after changing the 
ondansetron arm to metoclopramide. 
Although ondansetron is considered to be one of the most effective therapies for 
HG in common practice, this has not been confirmed in controlled trials when compared 
to metoclopramide.  A recent randomized controlled trial showed ondansetron to have 
equivalent efficacy to metoclopramide among 160 subjects with HG.41  An earlier 
randomized controlled trial showed ondansetron to only have a significant trend towards 
being more effective than metoclopramide for reducing vomiting but not nausea among 
83 women with HG.42 
We conclude that these safety and efficacy data support the use of 
metoclopramide over ondansetron as the most appropriate treatment arm to compare with 
gabapentin in our current trial. 
Our trial has enrolled 7 subjects, to date.  Most likely only 3 or 4 of these subjects 
have been randomized to ondansetron.  Therefore, changing this treatment arm at this 
early stage should not appreciably affect data evaluation at study completion.  We will 
combine the data from subjects receiving ondansetron, to date, and future subjects 
receiving metoclopramide for analyses of our primary and secondary study endpoints. 
 
2.4 Include complete specific citations/references.  
Response:  
1. 
Nelson-Piercy C, Fayers P, de Swiet M. Randomised, double-blind, placebo-
controlled trial of corticosteroids for the treatment of hyperemesis gravidarum. Bjog 
2001;108:9-15. 
2. 
Jewell D, Young G. Interventions for nausea and vomiting in early pregnancy. 
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3. 
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4. 
Pokras R. Vital and Health Statistics: Detailed Diagnoses and Procedures, 
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Mazzotta P, Maltepe C, Navioz Y, Magee LA, Koren G. Attitudes, management 
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6. 
Poursharif B, Korst LM, Macgibbon KW, Fejzo MS, Romero R, Goodwin TM. 
Elective pregnancy termination in a large cohort of women with hyperemesis gravidarum. 
Contraception 2007;76:451-5. 

 
 
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7. 
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8. 
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9. 
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10. 
Heazell A, Thorneycroft J, Walton V, Etherington I. Acupressure for the in-
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Am J Obstet Gynecol 2006;194:815-20. 
11. 
Safari HR, Fassett MJ, Souter IC, Alsulyman OM, Goodwin TM. The efficacy of 
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12. 
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pilot study of intravenous ondansetron for hyperemesis gravidarum. Am J Obstet 
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Ylikorkala O, Kauppila A, Ollanketo ML. Intramuscular ACTH or placebo in the 
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Yost NP, McIntire DD, Wians FH, Jr., Ramin SM, Balko JA, Leveno KJ. A 
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Guttuso T, Jr., Roscoe J, Griggs J. Effect of gabapentin on nausea induced by 
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17. 
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Koren G, Boskovic R, Hard M, Maltepe C, Navioz Y, Einarson A. Motherisk-
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19. 
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20. 
Ajori L, Nazari L, Mazloomfard MM, Amiri Z. Effects of gabapentin on 
postoperative pain, nausea and vomiting after abdominal hysterectomy: a double blind 
randomized clinical trial. Arch Gynecol Obstet 2012;285:677-82. 
21. 
Cruz FM, de Iracema Gomes Cubero D, Taranto P, et al. Gabapentin for the 
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22. 
Khademi S, Ghaffarpasand F, Heiran HR, Asefi A. Effects of preoperative 
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Taylor CP. The biology and pharmacology of calcium channel (alpha)2(delta) 
proteins. Pfizer Satellite Symposium to the 2003 Society for Neuroscience Meeting. 

 
 
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Sheraton New Orleans Hotel, New Orleans, LA November 10, 2003. CNS Drug Rev 
2004;10:183-8. 
24. 
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calcium channel. Journal of Biological Chemistry 1996;271:5768-76. 
25. 
Stefani A, Spadoni F, Bernardi G. Gabapentin inhibits calcium currents in isolated 
rat brain neurons. Neuropharmacology 1998;37:83-91. 
26. 
Sutton KG, Martin DJ, Pinnock RD, Lee K, Scott RH. Gabapentin inhibits high-
threshold calcium channel currents in cultured rat dorsal root ganglion neurones. Br J 
Pharmacol 2002;135:257-65. 
27. 
Luo ZD, Chaplan SR, Higuera ES, et al. Upregulation of dorsal root ganglion 
(alpha)2(delta) calcium channel subunit and its correlation with allodynia in spinal nerve-
injured rats. J Neurosci 2001;21:1868-75. 
28. 
Guttuso T, Jr., Kurlan R, McDermott MP, Kieburtz K. Gabapentin's effects on hot 
flashes in postmenopausal women: a randomized controlled trial. Obstet Gynecol 
2003;101:337-45. 
29. 
Hernández-Díaz S, Smith CR, Shen A, et al. Comparative Safety of Antiepileptic 
Drugs during Pregnancy. Neurology 2012;(in press). 
30. 
Molgaard-Nielsen D, Hviid A. Newer-generation antiepileptic drugs and the risk 
of major birth defects. Jama 2011;305:1996-2002. 
31. 
Montouris G. Gabapentin exposure in human pregnancy: results from the 
Gabapentin Pregnancy Registry. Epilepsy Behav 2003;4:310-7. 
32. 
Morrow J, Russell A, Guthrie E, et al. Malformation risks of antiepileptic drugs in 
pregnancy: a prospective study from the UK Epilepsy and Pregnancy Register. J Neurol 
Neurosurg Psychiatry 2006;77:193-8. 
33. 
Correa A, Cragan JD, Kucik JE, et al. Reporting birth defects surveillance data 
1968-2003. Birth Defects Res A Clin Mol Teratol 2007;79:65-186. 
34. 
Nelson K, Holmes LB. Malformations due to presumed spontaneous mutations in 
newborn infants. N Engl J Med 1989;320:19-23. 
35. 
Andersen JT, Jimenez-Solem E, Andersen NL, Poulsen HE. Ondansetron use in 
early pregnancy and the risk of congenital malformations - a registry based nationwide 
cohort study. In: International Society of Pharmaco-Epidemiology; Abstract 25, 
Pregnancy session 1; 2013; Montreal, Canada; 2013. 
36. 
Danielsson B, Wikner BN, Kallen B. Use of ondansetron during pregnancy and 
congenital malformations in the infant. Reproductive toxicology 2014;50:134-7. 
37. 
Koren G. Treating morning sickness in the United States--changes in prescribing 
are needed. Am J Obstet Gynecol 2014;211:602-6. 
38. 
Pasternak B, Svanstrom H, Hviid A. Ondansetron in pregnancy and risk of 
adverse fetal outcomes. N Engl J Med 2013;368:814-23. 
39. 
Matok I, Gorodischer R, Koren G, Sheiner E, Wiznitzer A, Levy A. The safety of 
metoclopramide use in the first trimester of pregnancy. N Engl J Med 2009;360:2528-35. 
40. 
Pasternak B, Svanstrom H, Molgaard-Nielsen D, Melbye M, Hviid A. 
Metoclopramide in pregnancy and risk of major congenital malformations and fetal 
death. JAMA 2013;310:1601-11. 

 
 
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41. 
Abas MN, Tan PC, Azmi N, Omar SZ. Ondansetron compared with 
metoclopramide for hyperemesis gravidarum: a randomized controlled trial. Obstet 
Gynecol 2014;123:1272-9. 
42. 
Kashifard M, Basirat Z, Kashifard M, Golsorkhtabar-Amiri M, Moghaddamnia A. 
Ondansetrone or metoclopromide? Which is more effective in severe nausea and 
vomiting of pregnancy? A randomized trial double-blind study. Clinical and experimental 
obstetrics & gynecology 2013;40:127-30. 
 
3.0 
Inclusion and Exclusion Criteria 
3.1 Describe the criteria that define who will be included or excluded in 
your final study sample.  
Response:  
Eligibility Criteria: 
1) 
Have received at least 2 administrations of intravenous (iv) 
hydration separated by at least 1 week or daily emesis for at least 
the last 7 days and 1 administration of iv hydration. 
2) 
Have at least one of the following: 2-4+ ketonuria, serum potassium 
< 3.4mmol, or >5% weight loss from weight upon entry to prenatal 
care at any time during the current pregnancy. 
3) 
Have failed therapy with at least one antiemetic. 
4) 
Have fetal ultrasound within 6 weeks prior to enrollment confirming 
a normal-appearing, intrauterine, singleton pregnancy of gestational 
age < 16 weeks at time of enrollment. 
5) 
Felt by the patient’s obstetrician or emergency room attending 
physician not to have other medical problems such as bowel 
obstruction, pancreatitis, biliary colic, or peptic ulcer disease that 
could be contributing to the patient’s symptoms. 
6) 
Be >18 years old and not decided to terminate the pregnancy. 
7) 
Have not received or planning to receive a peripherally inserted 
central catheter (PIC line). 
8) 
Have a Motherisk-PUQE score of ≥12 for the 24-hour Baseline 
period. 
9) 
Felt not to have any other significant medical, psychiatric or 
substance abuse problem that would preclude participation in the 
study. 
10) 
Agrees to discontinue any current anti-emetic treatments (including 
antihistamines, ginger, > 10mg/day vitamin B6, serotonin or 
dopamine antagonists, anticholinergics, acupuncture, hypnosis, or 
wrist bands) for the next 3 weeks. 

 
 
Page 12 of 42 
Revised: December 7, 2020 
11) 
Pregnancy not conceived through in-vitro fertilization. 
12) 
Has not previously tried gabapentin for hyperemesis  
13) 
No previous evidence of intolerance to metoclopramide 
14) 
Able to understand and comply with the study procedures and give 
informed consent. 
15) 
Not currently enrolled in another research study. 
3.2 Describe how individuals will be screened for eligibility. 
Response:  
Referred subjects will be interviewed to assess for eligibility.  Eligible 
subjects will be given a verbal overview of the study and then provided 
with a copy of the Consent Form to review.  After the subject has 
reviewed the Consent Form all questions will be answered and subject 
comprehension of study procedures will be confirmed before written 
consent is obtained. 
3.3 Indicate specifically whether you will include or exclude each of the 
following special populations: (You may not include members of 
these populations as subjects in your research unless you indicate 
this in your inclusion criteria.) 
• 
Adults unable to consent 
• 
Individuals who are not yet adults (infants, children, teenagers) 
• 
Pregnant women 
• 
Prisoners 
Response: This study will include pregnant women (at 18 years old) who 
have the capacity to provide consent. Adults who do not have the capacity 
to consent, and prisoners will not be included.  
3.4 Indicate whether you will include non-English speaking individuals.  
Provide justification if you will exclude non-English speaking 
individuals.  
(In order to meet one of the primary ethical principles of equitable 
selection of subjects, non-English speaking individuals may not be 
routinely excluded from research.  In cases where the research is of 
therapeutic intent or is designed to investigate areas that would 
necessarily require certain populations who may not speak English, 
the researcher is required to make efforts to recruit and include non-
English speaking individuals.  However, there are studies in which it 
would be reasonable to limit subjects to those who speak English: 
e.g., pilot studies, small unfunded studies with validated instruments 
not available in other languages, numerous questionnaires, and 
some non-therapeutic studies which offer no direct benefit.)  
 

 
 
Page 13 of 42 
Revised: December 7, 2020 
Response: The validated questionnaires are not available in non-english 
translation.  
 
4.0 
Study-Wide Number of Subjects (Multisite/Multicenter Only) 
4.1 If this is a multicenter study, indicate the total number of subjects to 
be accrued across all sites. 
Response: A total of 60 women with HG will be enrolled into this study. 
5.0 
Study-Wide Recruitment Methods (Multisite/Multicenter Only) 
If this is a multicenter study and subjects will be recruited by methods not under 
the control of the local site (e.g., call centers, national advertisements) describe 
those methods.  Local recruitment methods are described later in the protocol. 
5.1 Describe when, where, and how potential subjects will be recruited. 
Response: Dr. Thornburg and Dr. Guttuso have provided information 
about the study to providers with contact information for the study team 
for the purpose of potential subject referrals.   
5.2 Describe the methods that will be used to identify potential subjects. 
Response: Providers will notify the study team of potential study subjects, 
based on meeting basic inclusion criteria.  In addition, study personnel 
will use the electronic medical record to screen ER patients at the study’s 
enrolling hospitals.  ER patients who may be eligible for this study will 
only be approached or contacted after obtaining approval from their 
Ob/Gyn and ER provider.  A HIPAA waiver for these activities is 
currently approved by the IRB. 
5.3 Describe materials that will be used to recruit subjects. (Attach 
copies of these documents with the application. For advertisements, 
attach the final copy of printed advertisements. When advertisements 
are taped for broadcast, attach the final audio/video tape. You may 
submit the wording of the advertisement prior to taping to preclude 
re-taping because of inappropriate wording, provided the IRB 
reviews the final audio/video tape.) 
Response: Flyers for providers in the ED at WCHOB, Sisters of Charity 
Hospital, and Millard Fillmore Suburban Hospital. Patient flyer for display 
and distribution at private OB/GYN offices and ED waiting rooms.  
6.0 
Multi-Site Research (Multisite/Multicenter Only) 
6.1 If this is a multi-site study where you are the lead investigator, 
describe the processes to ensure communication among sites, such 
as: 
• 
All sites have the most current version of the protocol, consent 
document, and HIPAA authorization. 

 
 
Page 14 of 42 
Revised: December 7, 2020 
• 
All required approvals have been obtained at each site 
(including approval by the site’s IRB of record). 
• 
All modifications have been communicated to sites, and 
approved (including approval by the site’s IRB of record) 
before the modification is implemented. 
• 
All engaged participating sites will safeguard data as required 
by local information security policies. 
• 
All local site investigators conduct the study appropriately. 
• 
All non-compliance with the study protocol or applicable 
requirements will reported in accordance with local policy. 
Response:  
All sites have the most current version of the protocol, consent document, 
and HIPAA authorization. 
All required approvals have been obtained at each site (including approval 
by the site’s IRB of record). 
All modifications have been communicated to sites, and approved 
(including approval by the site’s IRB of record) before the modification is 
implemented. 
All engaged participating sites will safeguard data as required by local 
information security policies. 
All local site investigators conduct the study appropriately. 
All non-compliance with the study protocol or applicable requirements 
will reported in accordance with local policy. 
6.2 Describe the method for communicating to engaged participating 
sites: 
• 
Problems. 
• 
Interim results. 
• 
The closure of a study 
Response:  
Any problems, new information regarding the study medications, changes 
in study status, or reports of AE or SAE’s will be reported to the safety 
monitor, and IRB as per local policy, and also to the other participating 
sites in a timely manner. 
7.0 
Study Timelines 
7.1 Describe the duration of an individual subject’s participation in the 
study. 
About 3-24 weeks depending on the symptomatic need for therapy and the 
subject’s delivery date. 
7.2 Describe the duration anticipated to enroll all study subjects. 

 
 
Page 15 of 42 
Revised: December 7, 2020 
Response: 12/31/2017 
7.3 Describe the estimated date for the investigators to complete this 
study (complete primary analyses) 
Response: 12/31/2017 
8.0 
Study Endpoints 
8.1 Describe the primary and secondary study endpoints. 
Response:  
Study Endpoint: 
The Study Endpoint will be the mean values from Days 5-7. 
 
Primary Outcome Measure: 
Mean percent change from Baseline to the Study Endpoint in daily 
Motherisk-PUQE scores (pregnancy-unique quantification of emesis and 
nausea scale). 
  
Secondary Outcome Measures: 
i) 
Mean percent change from Baseline to the Study Endpoint in daily 
nausea and emesis/retching scores individually from the Motherisk-
PUQE and from the raw data. 
ii) 
Mean percent change from Baseline to the Study Endpoint in daily 
oral nutrition scores. 
iii) 
For subjects enrolled as inpatients, number of days from enrollment to 
hospital discharge. 
iv) 
Percent of subjects requiring repeat iv hydration or hospital admission 
for HG from the outpatient setting. 
v) 
Mean percent change in NVPQOL39 questionnaire scores from 
Baseline to the Study Endpoint. 
vi) 
Mean satisfaction and mean relief scores at the Study Endpoint as 
determined by the Satisfaction Questionnaire. 
vii) 
Percent of subjects downgrading from an answer of 3-5 at Baseline to 
1-2 at the Study Endpoint on the Hyperemesis Gravidarum Pregnancy 
Termination Consideration (HGPTC) questionnaire. 
viii) 
Percent of subjects choosing to continue their experimental therapy at 
the Study Endpoint as determined by question 3 on the Satisfaction 
Questionnaire. 

 
 
Page 16 of 42 
Revised: December 7, 2020 
ix) 
Maternal side effects and pregnancy outcomes (maternal 
complications, term of delivery, mode of delivery, congenital 
malformations, newborn complications). 
x) 
Mean percent change in laboratory values and weight from Baseline to 
Day 8. 
xi) 
Mean percent change from Baseline to Days 20-22 in daily Motherisk-
PUQE and NVPQOL scores (during open-label gabapentin treatment). 
xii) 
Mean Satisfaction Questionnaire scores at Day 22. 
xiii) 
Percent of subjects downgrading from an answer of 3-5 at Baseline to 
1-2 at Day 22 on the HGPTC questionnaire. 
8.2 Describe any primary or secondary safety endpoints. 
Response: N/A 
 
9.0 
Procedures Involved 
9.1 Describe and explain the study design. 
Response: Randomized, double-blinded, 2-arm, parallel-design 
comparative clinical trial (gabapentin vs. metoclopramide). 
9.2 Provide a description of all research procedures being performed 
and when they are performed, including procedures being performed 
to monitor subjects for safety or minimize risks. 
Response: If eligibility is confirmed, a venous blood draw will be 
performed to be tested for screening blood work consisting of a complete 
blood count with platelets, a chemistry profile including liver function 
tests (AST, ALT, and total bilirubin), and a thyroid stimulating hormone 
(TSH) level.  A fetal ultrasound will only be performed if one hasn’t been 
performed within the previous 6 weeks. 
Subjects will receive instructions (verbal and written) on how to complete 
the Patient Data Form, which they will complete every day for the next 21 
days.  Gabapentin 300mg or metoclopramide 7.5mg will be identically-
appearing and will be initiated as follows: 1 capsule at the time of 
enrollment and 1 capsule at bedtime on Day 1; 1 capsule in the morning, 1 
capsule in the afternoon, and 1 capsule at bedtime on Day 2; 1 capsule in 
the morning, 1 capsule in the afternoon, and 2 capsules at bedtime on Day 
3; 1 capsule in the morning, 2 capsules in the afternoon, and 2 capsules at 
bedtime on Day 4; and then 2 capsules tid on Days 5-7.  For subjects still 
experiencing bothersome nausea or vomiting after Day 5, the dose can be 
increased to 2 capsules qid for Days 6-7.  Gabapentin serum ½ life in 
humans is 5-7 hours, therefore, tid or qid dosing provides adequate full 
day coverage.  A maximum of 8 capsules a day equates to 2,400mg of 
gabapentin or 60mg of metoclopramide a day.  The gabapentin dose 
titration has been chosen based on our experiences with efficacy and 

 
 
Page 17 of 42 
Revised: December 7, 2020 
tolerability of gabapentin over the initial 14 days of treatment in our pilot 
study.  Out of the 12 HG patients receiving gabapentin, 11 experienced 
satisfactory relief at a maximum dose of 2,100mg/day or less, while 1 
subject required 2,700mg/day.  The maximum FDA-approved oral 
metoclopramide dose is 60mg a day for treating nausea and vomiting 
recommended maximum oral metoclopramide dose is 60mg a day for 
treating nausea and vomiting..41   
The titration schedule can be slowed and/or the total daily dose decreased 
if bothersome side effects occur or if the subject requests due to adequate 
symptom control.  Subjects will be contacted by phone at least 4 times a 
week by voice call or text for the first 7 days to monitor subjects’ HG 
symptoms, to monitor for any study drug-related side effects, to confirm 
that subjects are filling out the Patient Data Form every day and to answer 
questions. If a subject cannot be reached at the primary phone number, all 
secondary numbers will be called. If a subject cannot be reached after 3 
days, a letter will be sent to their address instructing them to call the study 
team immediately.   Each subject will be supplied with a bottle of urine 
ketone strips.  More symptomatic subjects with daily vomiting will be 
instructed to check their urine ketones every day and to contact the study 
team for readings of 2-4+ ketones.  More symptomatic subjects will be 
contacted by phone by the study team every day to confirm that urine 
ketones are being checked and to monitor for other symptoms of 
dehydration, such as lightheadedness or dizziness.  Subjects with 2-4+ 
urine ketones who are experiencing frequent vomiting or poor oral 
hydration and subjects otherwise felt to have symptomatic dehydration 
will be told to see their obstetrician or go to the ER that day for further 
evaluation. All subjects’ obstetricians will be notified of their participation 
in this study. 
On about Day 8, subjects will return for a follow-up visit (Visit 2) and 
will bring their completed Data Forms, and all unused study drug with 
them.  If the subject is admitted to the hospital on Day 8, this visit will 
occur at their bedside.  At this visit, the Patient Data Forms will be 
collected and, for subjects who had not received repeat iv hydration during 
the study, the NVPQOL, HGPTC and Satisfaction questionnaires will be 
completed.  A venous blood draw will be performed and tested for the 
screening blood work.  Subjects will be asked about adverse events, 
concomitant medications/treatments, and weight and urine ketone level 
will be recorded. 
 Subjects who have not withdrawn from the study will be offered open-
label gabapentin treatment at Visit 2 that can be continued for the 
remainder of the pregnancy, if necessary.  The open-label gabapentin 
titration will be repeated as described above. Subjects will be informed 
that they may have recurrent symptoms during this titration period. In 
addition, metoclopramide 10mg po qid prn breakthrough vomiting can be 
used during the open-label phase. Subjects will be instructed to limit the 

 
 
Page 18 of 42 
Revised: December 7, 2020 
use of metoclopramide for breakthrough nausea or vomiting to 4 times a 
day, not to exceed 40mg. The Open Label Patient Data Form will be filled 
out daily for an additional 14 days and brought, along with any unused 
study drug to the final follow-up visit (Visit 3) on about Day 22.  If the 
subject is admitted to the hospital on Day 22, this visit will occur at their 
bedside.  At this visit, the Patient Data Forms will be collected and the 
NVPQOL, HGPTC and Satisfaction questionnaires will be completed.  A 
venous blood draw will be performed and tested for the screening blood 
work.  Subjects will be asked about adverse events and concomitant 
medications/treatments, and weight and urine ketone level will be 
recorded. Subjects in the open label phase of the study will be followed up 
with weekly to assess any adverse events or side effects. Subjects will be 
instructed to call the study team sooner if necessary. Subjects will be 
supplied with enough gabapentin and prn metaclopromide to last until 18 
weeks gestation. However, if a subject has been taking metoclopramide 
for 12 weeks, it will be discontinued to minimize the risk of tardive 
dyskinesia (<1%). Subjects needing additional relief from breakthrough 
nausea and vomiting will be instructed to discuss the options with their 
OB/GYN provider.  Only the lowest effective gabapentin dose will be 
used.  Based on the site investigator’s discretion, subjects may be supplied 
with additional gabapentin at 4 weeks intervals after 18 weeks gestation.   
Describe procedures performed to lessen the probability or magnitude of 
risks. 
Response: After enrollment, subjects will be followed up with daily or 
every other day depending on symptom severity, and will be asked about 
side effects, and oral intake status. Subjects will be provided with ketone 
strips and recommendations for IV fluids will be made as necessary.  The 
PI and study coordinator are available for contact at any time, should the 
subject have questions or experience side effects. Titration to the ideal 
dose will occur at the start of the study and appropriate dose adjustments 
can be made at the discretion of the PI if bothersome side effects occur.  
Subjects will be informed, in writing, about the current state of knowledge 
regarding gabapentin’s safety in pregnancy during the informed consent 
process.  Subjects will also be updated with any new safety information 
regarding gabapentin use during pregnancy or distinct from pregnancy that 
comes to light after they are enrolled.  Drs. Guttuso and Thornburg will 
review and sign/date weekly all case report forms, data forms and adverse 
event forms at each respective site. 
9.3 Describe all drugs and devices used in the research and the purpose 
of their use, and their regulatory approval status. 
Response: Gabapentin is currently approved by the Food & Drug 
Administration (FDA) for the treatment of certain types of pain, seizures, 
and restless legs syndrome (the urge to keep moving the legs while laying 
or resting). Gabapentin is being used in this study for the treatment of 

 
 
Page 19 of 42 
Revised: December 7, 2020 
hyperemesis gradivdarum related nausea and vomiting. The Food & Drug 
Administration (FDA) has reviewed all current safety and efficacy data 
regarding the use of gabapentin during pregnancy and for HG and has 
issued the active IND 079,612.   
Maternal use of metoclopramide (Reglan), has not been associated with 
any increased rate of congenital defects in over 30,000 exposures (see 
Background and Significance section).  
9.4 Describe the source records that will be used to collect data about   
subjects. (Attach all surveys, scripts, and data collection forms.) 
Response: data will be collected through the use of:  
Patient Data forms (daily diary) 
Hyperemesis Gravidarum Pregnancy Termination Consideration 
Questionnaire (HGPTC)  
The Nausea and Vomiting of Pregnancy Quality of Life Questionnaire 
(NVPQOL) 
Satisfaction Questionnaire 
(All above documents are currently approved by UBIRB) 
9.5 What data will be collected including long-term follow-up. 
Response: data regarding symptom severity/frequency, oral intake, 
satisfaction of symptom resolution, consideration of pregnancy 
termination and quality of life measures will be collected in the blinded 
and open label phases.   Subjects will be followed until delivery and 
hospital records as well as babies’ pediatrician records will be assessed for 
maternal and fetal outcomes. 
9.6 For HUD uses provide a description of the device, a summary of 
how you propose to use the device, including a description of any 
screening procedures, the HUD procedure, and any patient follow-
up visits, tests or procedures. 
Response: N/A. No HUD’s being utilized in this study.  
10.0 Data and Specimen Banking 
10.1 If data or specimens will be banked for future use, describe where 
the data/specimens will be stored, how long they will be stored, how 
the data/specimens will be accessed, and who will have access to the 
data/specimens. 
Response: N/A. No data or specimen banking will occur 
10.2 List the data to be stored or associated with each specimen. 
Response: N/A. No data or specimen banking will occur 

 
 
Page 20 of 42 
Revised: December 7, 2020 
10.3 Describe the procedures to release data or specimens, including: the 
process to request a release, approvals required for release, who 
can obtain data or specimens, and the data to be provided with 
specimens. 
Response: N/A. No data or specimen banking will occur 
11.0 Data Management 
11.1 Describe the data analysis plan, including any statistical 
procedures. 
Response:  
The Biostatistics Department at the U of R, under the direction of Xin Tu, 
PhD, will update the data set at least weekly.  Completeness of the data 
will be monitored by each site-PI at each subject visit when data forms 
will be reviewed.  There will not be any interim analyses of the data. 
All statistical tests are two-sided with p<0.05. Descriptive statistics 
(counts and proportions for categorical variables and means and standard 
deviations for continuous outcomes) will be used to depict the 
characteristics of the sample (e.g., age, race, insurance, number of prior 
pregnancy and relevant co-morbid conditions). We will also compare 
baseline characteristics across the two treatment conditions using methods 
appropriate to the data type such as t-tests, chi-square and/or Fisher's exact 
tests. We will also examine associations between the outcome variables 
and patients’ characteristics.  For those significantly associated with 
outcomes, we will treat them as covariates when constructing treatment 
comparisons (see below).   
The primary as well as most of the secondary outcomes are change scores 
of pertinent variables over the two-week treatment period. We will model 
the change of such outcomes using longitudinal data methods based on the 
repeated assessments (e.g., pre-post changes and daily PUQE). For the 
outcomes that are collected once such as Satisfaction Questionnaire scores 
at Day 28, cross-sectional models such as t-test and regression (adjusting 
for the covariates identified) will be used to compare treatment 
differences.   
We will use the two popular approaches, the weighted generalized 
estimating equations (WGEE) and the mixed-effects model (MM)42-44, for 
modeling treatment differences over time. Both approaches will be used 
for assessing treatment differences, which provide valid inference in the 
presence of missing data if the missing value follows the missing at 
random (MAR) assumption, a popular mechanism that applies to most 
studies in practice.43,44 If estimates differ between the two approaches, 
only WGEE results will be reported, as it provides significantly more 
robust inference, especially in the presence of missing data.43-45  Given the 
relatively small sample size in the study, traditional inference based on the 
large sample theory may not provide accurate estimates. We may 

 
 
Page 21 of 42 
Revised: December 7, 2020 
complement the analysis with results based on clustered bootstrap 
methods.46  We will perform intention-to-treat analyses using all subjects 
randomized to the treatment groups who have taken at least one dose of 
study medication and have provided at least 1 day of Patient Diary Data 
over the first week of the study.  All analyses will be conducted using SAS 
9.2 or later.   
11.2 Provide a power analysis. 
Response:  
In our proposed RCT, we anticipate a more conservative treatment effect 
of at least 20% for the Primary Outcome Measure and a mean Baseline 
Motherisk-PUQE score of 22.  Specifically, we anticipate a mean 70% 
decrease in Motherisk-PUQE scores for the gabapentin group (a decrease 
of 15.4 points, from 22 to 6.6) and a 50% decrease in Motherisk-PUQE 
scores for the ondansetron group (a decrease of 11 points, from 22 to 11).  
Therefore, we anticipate a 4.4 point difference (15.4-11) for the Primary 
Outcome Measure and we will assume a conservative SD of 6. 
With these considerations, 30 subjects/group will provide 80% power to 
detect an inter-group difference in the Primary Outcome Measure with a 
two-sided type I error = 0.05. Describe the steps that will be taken secure 
the data (e.g., training, authorization of access, password protection, 
encryption, physical controls, certificates of confidentiality, and 
separation of identifiers and data) during storage, use, and transmission. 
Response: Original subject data forms will be retained in each subject’s 
individual study file and kept secured in a locked cabinet at each 
respective site. Data from the original forms will be entered onto a secure 
electronic database set up through the University of Rochester. Only study 
personnel will have access to entering data on this database.   After study 
completion, Dr. Guttuso will bring the data forms from U of R to his 
locked office at UB.  All data forms will have no subject identifiable 
information on them.  There is no plan to release subject identifiers. 
11.3 Describe any procedures that will be used for quality control of 
collected data. 
Response: Drs. Guttuso and Thornburg will review and sign/date weekly 
all case report forms, data forms and adverse event forms at each 
respective site. 
11.4 Describe how data and specimens will be handled study-wide: 
Response: Data will be entered into a secured study database, by both sites 
study personnel, controlled by the University of Rochester. Only study 
team members have access to this site.  
11.5 What information will be included in that data or associated with the 
specimens? 

 
 
Page 22 of 42 
Revised: December 7, 2020 
Response: questionnaire responses, diary data, adverse event data, IV 
hydration data, and study termination, and pregnancy termination data will 
be stored in the database. All data will be de-identified   
11.6 Where and how data or specimens will be stored? 
Response: original copies of the data will be stored in a study binder 
designated for each subject. Electronic data will be stored on the study 
database. 
11.7 How long the data or specimens will be stored? 
Response: Data will be stored for at least 3 years in accordance with US 
DHHS E6 GCP guidelines 
11.8 Who will have access to the data or specimens? 
Response: only IRB-approved study members will have access to the data. 
Data management personnel will have access to the database for 
maintenance or troubleshooting issues, however all data is de-identified. 
11.9 Who is responsible for receipt or transmission of the data or 
specimens? 
Response: Approved study personnel will transmit de-identified data onto 
the electronic data entry system 
11.10How data and specimens will be transported? 
Response: Data will be kept by the study coordinator from place of 
enrollment to a locked cabinet in the UB OB/GYN offices 
12.0 Provisions to Monitor the Data and Ensure the Safety of Subjects 
12.1 Describe the plan to periodically evaluate the data collected 
regarding both harms and benefits to determine whether subjects 
remain safe.   
Response:  
The Data Monitoring Committee (DMC) will review the study’s progress 
every 6 months and may perform an interim analysis of the data if so 
requested by the NIH.  If there is a significant intergroup difference with a 
p<0.001 or an insignificant intergroup difference with a p>0.70, the DMC 
will be asked to consider terminating the study due to efficacy or futility 
rationale, respectively.  The DMC will consist of: Eva K. Pressman, MD, 
Professor and Chair of Obstetrics & Gynecology, Director of Division of 
Maternal-Fetal Medicine, University of Rochester; J. Christopher Glantz, 
MD, MPH, Professor of Obstetrics and Gynecology, Division of Maternal-
Fetal Medicine, University of Rochester; Changyong Feng, PhD, 
Associate Professor of Biostatistics and Computational Biology, 
University of Rochester; and Sireesha Y. Reddy, MD, Professor and Vice 
Chair of Obstetrics & Gynecology, Texas Tech University Health 
Sciences Center in El Paso.Adverse Events Review:  

 
 
Page 23 of 42 
Revised: December 7, 2020 
For non-serious subject adverse events: 
Subjects will be directly asked by one of the study team members about 
any adverse events during every contact, including the 3 scheduled study 
site visits.  All adverse events (AE’s) will be recorded on the AE report 
form and communicated within 7 business days to our Data Management 
Center at the University of Rochester.  All AE’s will be summarized in an 
Excel file and emailed monthly to the study’s Safety Monitor, Patrick M. 
Mullin, MD, MPH, Assistant Professor of Obstetrics & Gynecology, 
University of Southern California. 
For serious subject adverse events: 
An adverse event will be considered “serious” (SAE) if in the opinion of 
either site Investigator (Drs. Guttuso and Thornburg) the adverse event 
resulted in subject death, a life-threatening adverse event, inpatient 
hospitalization or prolongation of existing hospitalization, a persistent or 
significant incapacity or substantial disruption of the ability to conduct 
normal life functions, or a congenital anomaly/birth defect.  This is the 
definition of SAE according to the FDA’s Guidance for Industry and 
Investigators: Safety Reporting Requirements for INDs and BA/BE 
Studies. 
When a study team member becomes aware of a possible subject SAE, the 
study team member will contact the site PI by phone the same day.  The 
site PI will report the SAE to the study sponsor, Dr. Guttuso, by the 
following day.   
An SAE that is determined by Dr. Guttuso to be a) unexpected, and b) 
reasonably possible to have been caused by either study drug will be 
considered a “Reportable Event”.  Dr. Guttuso will report such events to 
both of the study IRB’s within 5 business days of the study team’s first 
awareness of the event.  Dr. Guttuso will also report the event to the FDA 
as an “IND safety report” within 7 calendar days of the study team’s first 
awareness of the event, per the FDA’s Guidance for Industry and 
Investigators: Safety Reporting Requirements for INDs and BA/BE 
Studies.   All SAE’s will also be communicated to the Data Management 
Center and emailed to the Safety Monitor within 5 business days of the 
study team’s first awareness of the event. 
For example, if a subject was admitted to the hospital for symptoms of 
hyperemesis gravidarum, this would be considered an SAE; however, this 
would not be considered a “Reportable Event” since it was both 
anticipated in this patient population and not considered reasonably 
possible to have been caused by either study drug.  On the other hand, an 
incident of Stevens-Johnson Syndrome or an infant congenital defect 
would be considered “Reportable Events” since they were serious, 
unanticipated and could possibly have been caused by either study drug. 
Flow Chart: 

 
 
Page 24 of 42 
Revised: December 7, 2020 
Day 1: Study team member becomes aware of an SAE and alerts the site-
PI. 
Day 2: Dr. Guttuso is contacted by either the initial study team member 
who became aware of the SAE or by Dr. Thornburg, the study’s other site 
PI. 
Day 3-5: Any SAE determined by Dr. Guttuso to be a Reportable Event 
will be reported to both IRBs, the Safety Monitor and the Data 
Management Center. 
Day 3-15: Dr. Guttuso will report the Reportable Event to the FDA as an 
IND Safety Report. 
Contact Information: 
Dr. Guttuso: 716-361-7957 
Dr. Thornburg: 585-978-1925 
 
12.2 Describe what data are reviewed, including safety data, untoward 
events, and efficacy data. 
Response: See response to 12.1 
12.3 Describe how the safety information will be collected (e.g., with case 
report forms, at study visits, by telephone calls with participants). 
Response: information regarding adverse events will be obtained through 
text or voice calls with subjects, and then entered onto a hard copy form 
kept in the chart as well as in the electronic database.  
12.4 Describe the frequency of data collection, including when safety 
data collection starts. 
Response: data collection and safety data collection occurs upon 
enrollment. 
12.5 Describe who will review the data. 
Response: Maternal and fetal outcomes and adverse events will be 
reviewed monthly by the independent safety monitor, Patrick M. Mullin, 
MD, MPH, Assistant Professor of Obstetrics & Gynecology, University of 
Southern California...  The PI will also review data weekly. 
12.6 Describe the frequency or periodicity of review of cumulative data. 
Response: Completeness of the data will be monitored by each site-PI at 
each subject visit when data forms will be reviewed.   
12.7 Describe the statistical tests for analyzing the safety data to 
determine whether harm is occurring. 
Response: N/A 
12.8 Describe any conditions that trigger an immediate suspension of the 
research. 

 
 
Page 25 of 42 
Revised: December 7, 2020 
Response:  
Dr. Guttuso will keep a log of Reportable Events.  Subject enrollment will 
be halted and the Safety Monitor notified within 7 business days if any of 
the below thresholds are met: 
Number of Reportable Events     Total Number of Enrolled Subjects 
2                                                    6 
3                                                    12 
4                                                    16 
5                                                    20 
20% 
 
 
 
All enrolled subjects 
The Safety Monitor will be asked to review all AE’s and SAE’s, including 
the reportable events, and make a recommendation on if the study protocol 
should be amended for subject safety or if the study should be terminated. 
If the Safety Monitor recommends a protocol amendment, no further 
subjects will be enrolled until the amendment is approved by both IRB’s 
and the FDA.  Actively enrolled subjects will continue taking their study 
medications.  If the Safety Monitor recommends study termination, all 
enrolled subjects will be contacted within 3 business days and informed 
that they should stop taking all study medications as the risks will then 
outweigh the potential maternal benefit.  The NIH, both IRB’s and the 
FDA will also be notified within 3 business days of the decision to 
terminate the study. 
13.0 Withdrawal of Subjects 
13.1 Describe anticipated circumstances under which subjects will be 
withdrawn from the research without their consent. 
Response: A subject may be removed from the research study by the 
investigator if, it is believed that gabapentin is causing or contributing to 
potentially dangerous side effects. 
13.2 Describe any procedures for orderly termination. 
Response: If a subject is to be removed from the research study, the 
principal investigator will inform the subject of the decision to remove 
them from the research study and recommend appropriate follow up care 
thereafter. 
13.3 Describe procedures that will be followed when subjects withdraw 
from the research, including partial withdrawal from procedures 
with continued data collection. 
Response: Subjects’ data will be collected until the point of study 
withdrawal. Subjects will be assessed for adverse events at the time of 

 
 
Page 26 of 42 
Revised: December 7, 2020 
withdrawal. Maternal and neonatal outcomes will still be collected after 
delivery following withdrawal from the study.  
14.0 Risks to Subjects 
14.1 List the reasonably foreseeable risks, discomforts, hazards, or 
inconveniences to the subjects related the subjects’ participation in 
the research. Include as may be useful for the IRB’s consideration, a 
description of the probability, magnitude, duration, and reversibility 
of the risks. Consider physical, psychological, social, legal, and 
economic risks. 
Response: Gabapentin is currently approved by the Food & Drug 
Administration (FDA) for the treatment of certain types of pain, seizures, 
and Restless Legs Syndrome.  Gabapentin’s most common side effects are 
sleepiness, dizziness, clumsiness, fatigue, and edema.  About 7% of 
patients placed on gabapentin discontinue treatment due to side effects.  
Gabapentin has been in use since 1993 and has no known long-term side 
effects to the patient; i.e., when treatment is discontinued, the patient’s 
side effects all resolve.  In our pilot study using gabapentin for HG in 11 
subjects, 57% of the subjects had mild-moderate sleepiness or dizziness 
that did not interfere with any activities of daily living and resolved or 
improved within a week.  No other adverse events were felt to be related 
to gabapentin therapy. 
The use of anti-seizure medications, in general, has been associated with a 
0.21% increased risk of suicidal thoughts and behaviors (from 0.22% to 
0.43%).  It is not known if this increased risk applies to the use of 
gabapentin, in particular.  Suicidal thoughts or behavior were not 
spontaneously reported by any of the 11 HG subjects receiving open-label 
gabapentin in our pilot study. 
Gabapentin therapy has also been studied in pregnant rats and mice at 
many different doses to determine the risk for birth defects in the rodents’ 
pups (Neurontin Package Insert).  The FDA lists gabapentin as Pregnancy 
Category C.  Two categories of congenital defects were observed in these 
preclinical studies: skeletal and renal.  Delayed ossification of several 
bones were noted in the pups of pregnant mice and rats who received oral 
doses of gabapentin 1/2-4 times the maximum human dose of 
3,600mg/day.  The no effect dose for delayed ossification in mice was 
equivalent to a human dose of 1,800mg/day on a mg/m2 basis.  
Hydronephrosis and hydroureter were observed in the offspring of 
pregnant rats exposed to gabapentin.  The no effect dose for 
hydronephrosis and hydroureter was equivalent to a human dose of 
3,600mg/day.  There were no other congenital malformations observed in 
the offspring of mice, rats, or rabbits given 4-8 times the maximum human 
daily dose on a mg/m2 basis.   
In terms of gabapentin’s safety during pregnancy in humans, there are 4 
antiepileptic pregnancy registries that have reported on rates of infant 

 
 
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Revised: December 7, 2020 
major congenital defects (MCMs) after first trimester gabapentin 
monotherapy exposure.  With updated data now available from 2 
pregnancy registries,30,47 the total number of first trimester gabapentin 
monotherapy exposures with fetal outcome data is 258 (Table 1).  
Gabapentin was likely taken for the duration of most of these pregnancies 
as 75-100% of the mothers in these registries were being treated for 
epilepsy.  The results from these 4 registries, from the gabapentin/HG 
pilot study and from 2 additional pregnancy cases treated with gabapentin 
are summarized in Table 1. 
Table 1: Summary of infant MCMs associated with 1rst trimester maternal 
use of gabapentin monotherapy 
 
Data 
Source 
Total 
Exposures 
MCMs 
Montouris, 
et al.31 
11 
0 
Morrow et 
al.32 
31 
1 
Molgaard-
Nielsen, et 
al.30 
59 
1 
Hernandez-
Diaz, et 
al.47 
145 
1 
Guttuso, 
Jr., et al.17 
10 
2 
Fujii et 
al.48 
36 
0 
Additional 
Cases 
2 
0 
Summary 
294 
5(1.7%) 
Montouris, et al.31: No MCMs in infants of 11 patients on gabapentin 
monotherapy throughout their pregnancies. 
Morrow et al.32: One MCM (ventricular septal defect) among 31 
monotherapy exposures.  All registered women had epilepsy. 
Molgaard-Nielsen, et al.30: One MCM (congenital heart disease) among 59 
monotherapy exposures. 75% of cohort had epilepsy. 
Hernandez-Diaz, et al.47: One MCM (endocardial fibroelastosis with 
extensive hemagiomatosis) among 145 monotherapy exposures.  92% of 
cohort had epilepsy. 

 
 
Page 28 of 42 
Revised: December 7, 2020 
Guttuso, Jr., et al.17: Two MCMs (tethered spinal cord and 
hydronephrosis, both requiring surgical intervention) among 10 infants 
exposed to gabapentin monotherapy for HG.  One MCM was from a twin 
pregnancy conceived through in-vitro fertilization, a technique associated 
with higher rates of infant MCMs.49  These data were submitted to the 
FDA on 12/17/10. 
Fujii et al.48: No MCMs among 36 infants exposed to first trimester 
gabapentin monotherapy.  34% of cohort used gabapentin for epilepsy. 
No MCMs in 2 anecdotal first trimester gabapentin monotherapy 
exposures.  One took gabapentin from preconception to gestation week 34 
for epilepsy and the other from gestation weeks 12-38 for HG. 
Thus, based on these initial 294 exposures, there has been a 1.7% rate of 
infant MCMs associated with maternal first trimester use of gabapentin 
monotherapy.  Comparing this rate with that found in the general 
population, the rate of MCMs detected by the end of the first week of life 
in the Metropolitan Atlanta population between 1968 and 2003 was 
2.1%,33 while the Brigham and Women’s Hospital Surveillance Program 
reported a MCM frequency of 1.6%–2.2% at birth depending on whether 
chromosomal and genetic abnormalities were included in the calculation.34 
Although it has been estimated that about 555 exposures are needed to 
detect a 2-fold increase in MCM rate with 80% power,50 it is reassuring 
that there does not appear to be a trend towards increased risks compared 
to the general population among the initial 258 gabapentin monotherapy 
exposures. 
When considering other newer-generation antiepileptic drugs used during 
the first trimester, the rates of MCMs have remained fairly stable from an 
initial 182 or more exposures to 495 or more exposures.  For example, an 
initial 182, 197 and 197 exposures to oxcarbazepine, levetiracetam and 
topiramate showed MCM rates of 2.2%, 2.0% and 4.1%, respectively.47,50 
After a total of 575, 530 and 495 exposures to oxcarbazepine, 
levetiracetam and topiramate the MCM rates were then 2.6%, 2.1% and 
4.4%, respectively.30,32,47 Thus, there was a 5-18% increase in MCM rates 
observed with additional exposures for these 3 newer-generation 
antiepileptic drugs.  Based on these historical data, one would expect 
similar findings after additional exposures to the newer-generation 
antiepileptic drug gabapentin.  Even if there was a maximum 18% increase 
in the MCM rate after an additional 300 gabapentin exposures, that would 
equate to an MCM rate of about 2.0%, which is still approximately 
equivalent to the MCM rate found in the general population.33 
The FDA cited particular concern regarding the single case of 
hydronephrosis in one of the infants from the gabapentin/HG pilot study 
due to the increased rates of hydronephrosis found in the preclinical 
studies referenced above.  Primarily due to this single case of 
hydronephrosis, the FDA placed a Full Clinical Hold on our 

 
 
Page 29 of 42 
Revised: December 7, 2020 
Investigational New Drug (IND) application #079612 on 4/8/11. The 
above data were submitted to the FDA on 4/23/12 in support of this IND.  
On 5/24/12, Dr. Guttuso received a “Remove Full Clinical Hold” letter 
from the FDA stating, “We have completed the review of your 
submission, and have concluded that the clinical trial can be resumed”.  
The last IND annual report was submitted to the FDA on 8/2/15 and this 
IND remains open and active. 
It is reassuring that there have been no other cases of hydronephrosis 
reported among the other 257 infants exposed to gabapentin in the first 
trimester, which equates to a hydronephrosis rate of 0.4%.  The prevalence 
of hydronephrosis in the general population of newborns has been shown 
to be about 0.5%;51 however, a more recent study showed a 2% rate of 
ultrasound-diagnosed, antenatal urologic findings, such as hydronephrosis, 
among 1000 consecutive births.52  These studies, however, did not report 
on the rates of severe hydronephrosis necessitating surgical intervention, 
such as the case from the gabapentin pilot study.  Nevertheless, it is 
reassuring that first trimester gabapentin exposure currently does not 
appear to be associated with higher rates of infant hydronephrosis in 
humans.  
Alternative treatments for HG, which will be disclosed in the informed 
consent, include ginger, vitamin B6, compazine, metoclopramide, 
methylprednisolone, and ondansetron.  
The use of metoclopramide during the first trimester of pregnancy has not 
been associated with any increased risk for physical birth defects among 
over 30,000 infants.  It is not known if taking gabapentin or 
metoclopramide during pregnancy will affect development after birth but 
no such risks have been identified to date.  
The most common side effects caused by metoclopramide are sleepiness, 
diarrhea and restlessness.  Metoclopramide can rarely (<1%) cause 
movement problems such as hand shaking, slowed walking, muscle 
stiffness or abnormal movements in the face or neck (tardive dyskinesia).  
With prolonged use of metoclopramide (>12 weeks), some of these 
movement problems can be permanent even after stopping 
metoclopramide.  For this reason, if a subject chooses to enroll in this 
study, we will ask them to stop taking metoclopramide if they are still 
taking it 12 weeks after enrolling into this study. 
14.2 If applicable, indicate which procedures may have risks to the 
subjects that are currently unforeseeable. 
Response: there are no procedures associated with this study. 
 
14.3 If applicable, indicate which procedures may have risks to an 
embryo or fetus should the subject be or become pregnant. 
Response: See response to 14.1 

 
 
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Revised: December 7, 2020 
 
14.4 If applicable, describe risks to others who are not subjects. 
Response: N/A 
 
15.0 Potential Benefits to Subjects 
15.1 Describe the potential benefits that individual subjects may 
experience from taking part in the research. Include as may be 
useful for the IRB’s consideration, the probability, magnitude, and 
duration of the potential benefits. 
Response: Subjects may experience a reduction in their HG symptoms.  If 
gabapentin is found to be an effective treatment for HG in this RCT, it 
could markedly improve the quality of life for patients with HG, decrease 
the over 50,000 hospital admissions in the US every year for HG, increase 
work hours for women with HG, and potentially decrease the approximate 
9,000 pregnancies terminated each year in the US due to HG (15% of 
60,000 annual HG patients).  
15.2 Indicate if there is no direct benefit. Do not include benefits to 
society or others. 
Response: N/A 
 
16.0 Vulnerable Populations 
16.1 If the research involves individuals who are vulnerable to coercion 
or undue influence, describe additional safeguards included to 
protect their rights and welfare. 
• 
If the research involves pregnant women, review 
“CHECKLIST: Pregnant Women (HRP-412)” to ensure that 
you have provided sufficient information. 
• 
If the research involves neonates of uncertain viability or non-
viable neonates, review “CHECKLIST: Neonates (HRP-413)” 
or “HRP-414 – CHECKLIST: Neonates of Uncertain Viability 
(HRP-414)” to ensure that you have provided sufficient 
information. 
• 
If the research involves prisoners, review “CHECKLIST: 
Prisoners (HRP-415)” to ensure that you have provided 
sufficient information. 
• 
If the research involves persons who have not attained the 
legal age for consent to treatments or procedures involved in 
the research (“children”), review the “CHECKLIST: Children 
(HRP-416)” to ensure that you have provided sufficient 
information. 

 
 
Page 31 of 42 
Revised: December 7, 2020 
• 
If the research involves cognitively impaired adults, review 
“CHECKLIST: Cognitively Impaired Adults (HRP-417)” to 
ensure that you have provided sufficient information. 
• 
Consider if other specifically targeted populations such as 
students, employees of a specific firm or 
educationally/economically disadvantaged persons are 
vulnerable to coercion or undue influence.  The checklists 
listed above for other populations should be used as a guide to 
ensure that you have provided sufficient information.  
Response: The consent document will be reviewed in full detail with 
potential subjects. Details regarding the currently available information on 
gabapentin exposure in pregnant women and its potential effects to the 
fetus will be explained in-depth and comprehension by the enrollee will be 
confirmed. 
17.0 Community-Based Participatory Research 
17.1 Describe involvement of the community in the design and conduct of 
the research. 
Response: N/A 
Note: “Community-based Participatory Research” is a collaborative 
approach to research that equitably involves all partners in the 
research process and recognizes the unique strengths that each 
brings. Community-based Participatory Research begins with a 
research topic of importance to the community, has the aim of 
combining knowledge with action and achieving social change to 
improve health outcomes and eliminate health disparities. 
18.0 Sharing of Results with Subjects 
18.1 Describe whether or not results (study results or individual subject 
results, such as results of investigational diagnostic tests, genetic 
tests, or incidental findings) will be shared with subjects or others 
(e.g., the subject’s primary care physicians) and if so, describe how 
it will be shared. 
Response: study results will be shared with subjects after the completion 
of the data analysis for the study. Any new findings related to a subject’s 
condition or care throughout the duration of the study will be 
communicated to the subject and if applicable, their primary care provider 
or OBGYN. Any new information about the investigational medication 
during the study will be communicated to subjects promptly.  
19.0 Setting 
19.1 Describe the sites or locations where your research team will 
conduct the research.  

 
 
Page 32 of 42 
Revised: December 7, 2020 
Response: Subjects are being enrolled from Women & Children’s Hospital 
of Buffalo, Sisters of Charity Hospital, Millard Fillmore Suburban 
Hospital, and Dent Neurological Infusion Center. Referrals to this study 
can be made from VNA of WNY and MacAuley-Seton. 
19.2 Identify where your research team will identify and recruit potential 
subjects. 
Response: Subjects are being enrolled from the emergency departments or 
inpatient units at Women & Children’s Hospital of Buffalo, Sisters of 
Charity Hospital, Millard Fillmore Suburban Hospital, or as outpatients by 
referrals from VNA of WNY and MacAuley-Seton home infusion 
services, and the Dent Neurologic Infusion Center. 
19.3 Identify where research procedures will be performed. 
Response: Initial procedures (consenting and baseline questionnaires) will 
be performed either in the ED, inpatient setting, or the womens health 
clinic at WCHOB.  Follow-up visits will occur at WCHOB’s Women’s 
Health Clinic 
19.4 Describe the composition and involvement of any community 
advisory board. 
Response: N/A 
19.5 For research conducted outside of the organization and its affiliates 
describe: 
• Site-specific regulations or customs affecting the research for 
research outside the organization. 
• Local scientific and ethical review structure outside the 
organization. 
Response: The IRB for the Catholic Health system, as well as the IRB for 
the University of Rochester also review this study as needed. 
20.0 Resources Available 
20.1 Describe the qualifications (e.g., training, experience, oversight) of 
you and your staff as required to perform their role. When 
applicable describe their knowledge of the local study sites, culture, 
and society. Provide enough information to convince the IRB that 
you have qualified staff for the proposed research. Note- If you 
specify a person by name, a change to that person will require prior 
approval by the IRB. If you specify people by role (e.g., coordinator, 
research assistant, co-investigator, or pharmacist), a change to that 
person will not usually require prior approval by the IRB, provided 
that person meets the qualifications described to fulfill their roles. 
Response:  

 
 
Page 33 of 42 
Revised: December 7, 2020 
Thomas Guttuso, Jr., MD- Principal Investigator; Associate Professor 
of Neurology, Obstetrics & Gynecology; extensive prior experience 
conducting clinical trials.  
Rachel LaPorta, MA, BSN, RN – Primary Study coordinator; Previous 
experience working as an IRB administrator and as a clinical research 
coordinator for various industry sponsored and investigator initiated 
clinical trials. Currently working on various projects as a clinical research 
coordinator for the UB OB/GYN department.  
Describe other resources available to conduct the research: For example, 
as appropriate: 
20.2 Justify the feasibility of recruiting the required number of suitable 
subjects within the agreed recruitment period. For example, how 
many potential subjects do you have access to? What percentage of 
those potential subjects do you need to recruit? 
Response: There will be 2 enrolling sites: University at Buffalo, Buffalo, 
NY (UB) and University of Rochester, Rochester, NY (U of R).  The PI, 
Dr. Guttuso at UB, and the Co-investigator, Dr. Thornburg at U of R, will 
perform or direct all of the study activities.  We anticipate enrolling about 
24-30 subjects/year, in total, based on recent HG presentation rates. 
20.3 Describe the time that you will devote to conducting and completing 
the research. 
Response: PI: 33% ; Study Coordinator 33% 
20.4 Describe your facilities. 
Response: All study visits will occur in a hospital or clinic setting 
depending on patient status (ED, inpatient or outpatient). All settings have 
private areas where study visits can be conducted in confidence.  
20.5 Describe the availability of medical or psychological resources that 
subjects might need as a result of an anticipated consequences of the 
human research. 
Response: The principal investigator and co-investigator are both 
medically trained physicians to provide medical care or referral to the 
appropriate provider in the event of consequences requiring 
reporting/follow-up associated with this research. Any adverse events will 
be documented and communicated to other providers involved in the 
subject’s care.  
20.6 Describe your process to ensure that all persons assisting with the 
research are adequately informed about the protocol, the research 
procedures, and their duties and functions. 
Response: All study personnel duties are outlined on the core data form.  
Prior to addition of study staff and approval by the IRB, roles are reviewed 
and agreed upon based on clinical skill. All required protocol training and 

 
 
Page 34 of 42 
Revised: December 7, 2020 
GCP training is documented. Experience and expertise of study staff is 
taken into consideration and study staff roles are in compliance with the 
protocol. 
21.0 Prior Approvals 
21.1 Describe any approvals that will be obtained prior to commencing 
the research. (E.g., school, external site. funding agency, laboratory, 
radiation safety, or biosafety approval.) 
Response: IRB Approval obtained.  
 
22.0 Recruitment Methods 
22.1 Describe when, where, and how potential subjects will be recruited. 
Response: After notification by a provider to a study team member, 
subjects will be recruited upon presentation to the ED or inpatient unit and 
will be consented there.  
22.2 Describe the source of subjects. 
Response: Subjects will be referred by providers in the inpatient setting, 
ED or outpatient clinic setting from WCHOB, MFS or SOCH. WNY 
VNA and McAuley-Seton Home Care, and Dent Neurologic Infusion 
Center, will also refer interested home-infusion patients diagnosed with 
hyperemesis gravidarum.  
22.3 Describe the methods that will be used to identify potential subjects. 
Response: Providers are given a basic list of criteria that could qualify a 
subject for the study. If a subject qualifies based on the basic criteria, a 
member of the study team is contacted to interview the patient further and 
obtain consent.  
22.4 Describe materials that will be used to recruit subjects. (Attach 
copies of these documents with the application. For advertisements, 
attach the final copy of printed advertisements. When advertisements 
are taped for broadcast, attach the final audio/video tape. You may 
submit the wording of the advertisement prior to taping to preclude 
re-taping because of inappropriate wording, provided the IRB 
reviews the final audio/video tape.) 
Response: recruitment methods include verbal description of the study 
(prior to presenting consent form); post cards mailed to private practices 
(for providers); patient flyers to be posted in private practice offices  
22.5 Describe the amount and timing of any payments to subjects. 
Response: Subjects will be reimbursed for parking for follow-up visits at 
the Women’s Health Clinic.  At the completion of day 22, subjects will be 
reimbursed $20 for time and travel.  

 
 
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Revised: December 7, 2020 
23.0 Local Number of Subjects 
23.1 Indicate the total number of subjects to be accrued locally. 
Response: 40 
 
23.2 If applicable, distinguish between the number of subjects who are 
expected to be enrolled and screened, and the number of subjects 
needed to complete the research procedures (i.e., numbers of 
subjects excluding screen failures.) 
Response: N/A 
 
24.0 Confidentiality 
Describe the local procedures for maintenance of confidentiality. 
24.1 Where and how data or specimens will be stored locally? 
Response: All PHI collected and associated with this study will be kept in 
a binder designated to each subject and stored in a locked cabinet (in a 
room that can be locked as well) at the UB OBGYN offices at 219 Bryant 
St. (Women and Children’s Hospital of Buffalo) 
24.2 How long the data or specimens will be stored locally? 
Response: Data will be stored for at least 3 years in accordance with US 
DHHS E6 GCP guidelines 
24.3 Who will have access to the data or specimens locally? 
Response: Members of the study team approved by the IRB will have 
access to the data.  
24.4 Who is responsible for receipt or transmission of the data or 
specimens locally? 
Response: The primary study coordinator will obtain and transmit de-
identified data onto the designated electronic database. 
24.5 How data and specimens will be transported locally? 
Response: The study coordinator or PI will have possession of all study 
materials upon patient visits. This includes transporting data sheets and 
subject binders. Subject binders will be kept with the research coordinator 
(or whomever is completing the study visit, as approved study staff) at all 
times.  
25.0 Provisions to Protect the Privacy Interests of Subjects 
25.1 Describe the steps that will be taken to protect subjects’ privacy 
interests. “Privacy interest” refers to a person’s desire to place 

 
 
Page 36 of 42 
Revised: December 7, 2020 
limits on whom they interact or whom they provide personal 
information. 
Response: full disclosure of who may have access to a subject’s 
information is disclosed in the informed consent document and HIPAA 
Authorization 
25.2 Describe what steps you will take to make the subjects feel at ease 
with the research situation in terms of the questions being asked and 
the procedures being performed. “At ease” does not refer to 
physical discomfort, but the sense of intrusiveness a subject might 
experience in response to questions, examinations, and procedures. 
Response: A full description of types of information being collected 
during the study will be disclosed to the subject as outlined in the consent 
document and during the informed consent process. Subjects will be 
reminded that their participation is voluntary and that they do not need to 
provide information/complete questionnaires or procedures that they are 
not comfortable with and that this will not affect their medical care or 
relationship with their provider.  
25.3 Indicate how the research team is permitted to access any sources of 
information about the subjects. 
Response: Subjects will read, understand, and sign a HIPAA 
Authorization at the time of consent. 
26.0 Compensation for Research-Related Injury 
26.1 If the research involves more than Minimal Risk to subjects, describe 
the available compensation in the event of research related injury. 
Response: Routinely, the Buffalo General Hospital, Erie County Medical 
Center, Women’s & Children’s Hospital of Buffalo, Millard Fillmore 
Hospital, Sisters of Charity Hospital, Strong Memorial Hospital, Highland 
Hospital and/or the University at Buffalo, State University of New York, 
or University of Rochester its agents, or its employees do not compensate 
for or provide free medical care for human subjects in the event that any 
injury results from participation in a human research project. In the 
unlikely event that a subject becomes ill or injured as a direct result of 
participating in this study, they may receive medical care, but it will not be 
free of charge even if the injury is a direct result of study participation.  
26.2 Provide a copy of contract language, if any, relevant to 
compensation for research-related injury. 
Response: N/A 
27.0 Economic Burden to Subjects 
27.1 Describe any costs that subjects may be responsible for because of 
participation in the research. 

 
 
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Revised: December 7, 2020 
Response: There are no costs to subjects for taking part in this study, 
outside of the cost of routine care. 
28.0 Consent Process 
28.1 Indicate whether you will be obtaining consent 
Response: Consent will be obtained from all subjects with the capacity to 
give consent. 
28.2 Describe where  the consent process take place 
Response: Consenting will occur in the ED, inpatient unit, or outpatient 
clinic (Women’s Health Clinic at WCHOB). All consenting procedures 
will occur in a private area.  
28.3 Describe any waiting period available between informing the 
prospective subject and obtaining the consent. 
Response: Subjects will be able to take reasonable amount of time to 
consider participation in the study. Subjects may take the consent 
document home for discussion with family members. 
28.4 Describe any process to ensure ongoing consent. 
Response: Any new information regarding this study that may impact the 
subject’s decision to continue participation in the trial will be 
communicated to the subject as soon as possible. 
28.5 Describe whether you will be following “SOP: Informed Consent 
Process for Research (HRP-090).” If not, describe: 
• 
The role of the individuals listed in the application as being 
involved in the consent process. 
• 
The time that will be devoted to the consent discussion. 
• 
Steps that will be taken to minimize the possibility of coercion 
or undue influence. 
• 
Steps that will be taken to ensure the subjects’ understanding. 
Response: Consent will be obtained according to SOP: Informed Consent 
Process for Research (HRP-090). The PI will confirm the subject’s 
signature, provide a copy of the consent to the subject and store the 
original in their locked office.  
Non-English Speaking Subjects  
28.6 Indicate what language(s) other than English are likely to be 
spoken/understood by your prospective study population or their 
legally authorized representatives. 
Response: N/A. Only English speaking subjects will be enrolled. 
 

 
 
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Revised: December 7, 2020 
28.7 If subjects who do not speak English will be enrolled, describe the 
process to ensure that the oral and written information provided to 
those subjects will be in that language. Indicate the language that 
will be used by those obtaining consent. 
Response: N/A 
 
Waiver or Alteration of Consent Process (consent will not be obtained, 
required information will not be disclosed, or the research involves 
deception) 
28.8 Review the “CHECKLIST: Waiver or Alteration of Consent Process 
(HRP-410)” to ensure you have provided sufficient information for 
the IRB to make these determinations. Provide any additional 
information necessary here: 
Response: N/A 
 
28.9 If the research involves a waiver the consent process for planned 
emergency research, please review the “CHECKLIST: Waiver of 
Consent for Emergency Research (HRP-419)” to ensure you have 
provided sufficient information for the IRB to make these 
determinations. Provide any additional information necessary here: 
Response: N/A 
 
Subjects who are not yet adults (infants, children, teenagers) 
28.10Describe the criteria that will be used to determine whether a 
prospective subject has not attained the legal age for consent to 
treatments or procedures involved in the research under the 
applicable law of the jurisdiction in which the research will be 
conducted. (E.g., individuals under the age of 18 years.) For 
research conducted in NY state, review “SOP: Legally Authorized 
Representatives, Children, and Guardians (HRP-013)” to be aware 
of which individuals in the state meet the definition of “children.” 
Response: N/A 
 
28.11For research conducted outside of NY state, provide information that 
describes which persons have not attained the legal age for consent 
to treatments or procedures involved the research, under the 
applicable law of the jurisdiction in which research will be 
conducted. One method of obtaining this information is to have a 
legal counsel or authority review your protocol along the definition 

 
 
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Revised: December 7, 2020 
of “children” in “SOP: Legally Authorized Representatives, 
Children, and Guardians (HRP-013).” 
Response: N/A 
 
28.12Describe whether parental permission will be obtained from: 
• 
Both parents unless one parent is deceased, unknown, 
incompetent, or not reasonably available, or when only one 
parent has legal responsibility for the care and custody of the 
child. 
• 
One parent even if the other parent is alive, known, competent, 
reasonably available, and shares legal responsibility for the 
care and custody of the child. 
Response: N/A 
 
28.13Describe whether permission will be obtained from individuals other 
than parents, and if so, who will be allowed to provide permission. 
Describe the process used to determine these individuals’ authority 
to consent to each child’s general medical care. 
Response: N/A 
 
28.14Indicate whether assent will be obtained from all, some, or none of 
the children. If assent will be obtained from some children, indicate 
which children will be required to assent. 
Response: N/A 
 
28.15When assent of children is obtained describe whether and how it will 
be documented. 
Response: N/A 
 
Cognitively Impaired Adults 
28.16Describe the process to determine whether an individual is capable 
of consent. The IRB sometimes allows the person obtaining assent to 
document assent on the consent document and does not 
automatically require assent documents to be used. 
Response: N/A. Only adults with the capacity to provide consent will be 
consented. 
Adults Unable to Consent 

 
 
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When a person is not capable of consent due to cognitive impairment, a 
legally authorized representative should be used to provide consent and, 
where possible, assent of the individual should also be solicited. 
28.17List the individuals from whom permission will be obtained in order 
of priority. (e.g., durable power of attorney for health care, court 
appointed guardian for health care decisions, spouse, and adult 
child.)  For research conducted in NY state, review “SOP: Legally 
Authorized Representatives, Children, and Guardians (HRP-013)” 
to be aware of which individuals in the state meet the definition of 
“legally authorized representative.”  The list in the consent template 
signature section corresponds to the priority list for NYS.   
Response: N/A. Only adults with the capacity to provide consent will be 
consented. 
28.18For research conducted outside of NY state, provide information that 
describes which individuals are authorized under applicable law to 
consent on behalf of a prospective subject to their participation in 
the procedure(s) involved in this research. One method of obtaining 
this information is to have a legal counsel or authority review your 
protocol along the definition of “legally authorized representative” 
in “SOP: Legally Authorized Representatives, Children, and 
Guardians (HRP-013).” 
Response: N/A. 
 
28.19Describe the process for assent of the subjects. Indicate whether: 
• 
Assent will be required of all, some, or none of the subjects. If 
some, indicated, which subjects will be required to assent and 
which will not. 
• 
If assent will not be obtained from some or all subjects, an 
explanation of why not. 
• 
Describe whether assent of the subjects will be documented 
and the process to document assent. The IRB allows the person 
obtaining assent to document assent on the consent document 
and does not routinely require assent documents and does not 
routinely require subjects to sign assent documents. 
Response: N/A. only adult subjects (18+ years) will be consented. 
 
28.20For HUD uses provide a description of how the patient will be 
informed of the potential risks and benefits of the HUD and any 
procedures associated with its use. 
Response: N/A 

 
 
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29.0 Process to Document Consent in Writing 
 
If your research presents no more than minimal risk of harm to subjects and 
involves no procedures for which written documentation of consent is normally 
required outside of the research context, the IRB will generally waive the 
requirement to obtain written documentation of consent. 
(If you will document consent in writing, attach a consent document. If you will 
obtain consent, but not document consent in writing, attach a consent script. 
Review “CHECKLIST: Waiver of Written Documentation of Consent (HRP-411)” 
to ensure that you have provided sufficient information. You may use 
“TEMPLATE CONSENT DOCUMENT (HRP-502)”to create the consent 
document or script.) 
29.1 Describe whether you will be following “SOP: Written 
Documentation of Consent (HRP-091).” If not, describe whether and 
how consent of the subject will be obtained including whether or not 
it will be documented in writing. 
Response: Consent will be documented according to the SOP Written 
Documentation of Consent (HRP-091).  
30.0 Drugs or Devices 
30.1 If the research involves drugs or device, describe your plans to store, 
handle, and administer those drugs or devices so that they will be 
used only on subjects and be used only by authorized investigators. 
Response: For the blinded phase of the study, study medications are 
housed in the inpatient pharmacy at each respective enrolling institution. 
Study medication (gabapentin and ondansetron) for the open label phase 
are stored securely in the UB OB/GYN offices. 
If the drug is investigational (has an IND) or the device has an IDE or a 
claim of abbreviated IDE (non-significant risk device), include the 
following information: 
30.2 Identify the holder of the IND/IDE/Abbreviated IDE. 
Response: Thomas Guttuso, Jr., MD 
 
30.3 Explain procedures followed to comply with FDA sponsor 
requirements for the following: 

 
 
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Applicable to: 
FDA Regulation 
IND Studies 
IDE studies 
Abbreviated 
IDE studies 
21 CFR 11 
X 
X 
 
21 CFR 54 
X 
X 
 
21 CFR 210 
X 
 
 
21 CFR 211 
X 
 
 
21 CFR 312 
X 
 
 
21 CFR 812 
 
X 
X 
21 CFR 820 
 
X 
 
Response: All above applicable FDA requirements have been met for this 
IND study.