Clinical trial NCT02755116
Conditions: Postoperative Nausea and Vomiting
Keywords: Nausea Vomiting
Sponsor: Jaime B Hyman
Start date: 2016-04-01; Completion date: 2019-09-05
Enrollment: 180 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
Ambulatory surgery is occurring with rapidly increasing frequency as surgical and anesthetic techniques have improved and pressure to reduce health-care costs has increased. While there are many benefits to recovering from surgery within the home, a significant disadvantage is the lack of rapid access to a healthcare provider when postoperative complications occur. Postoperative nausea and vomiting (PONV) are common after surgery and anesthesia, and recent studies have demonstrated a high incidence of post-discharge nausea and vomiting (PDNV) after ambulatory surgery, particularly in high-risk groups (female gender, age less than 50 years, history of PONV, opioid administration in the post-anesthesia care unit (PACU), and nausea in the PACU). Current practices known to reduce the risk of postoperative nausea and vomiting in the PACU, such as the avoidance of volatile anesthetics and the use of intraoperative ondansetron and steroids, have little effect on the risk of delayed PDNV. Novel strategies to prevent PDNV are needed. Orally administered olanzapine, which has been shown to decrease the incidence of chemotherapy-induced nausea and vomiting, demonstrates promise as a novel strategy for preventing PDNV. It has a long half-life, allowing for a single dose to be administered preoperatively. This study will evaluate whether there is a difference in the incidence and severity of PDNV between patients who receive oral olanzapine versus placebo prior to general anesthesia for ambulatory surgery.

Detailed description:

Arms: arm 1: 10mg pill arm 2: None
Interventions: intervention 1: Olanzapine intervention 2: Placebo
Intervention descriptions: intervention 1: 10mg of olanzapine by mouth prior to anesthetic induction intervention 2: placebo by mouth prior to anesthetic induction

Protocol documents:
Prot_SAP_000.pdf: 


 
Protocol Title: 
Olanzapine for the treatment of Post-Discharge Nausea 
and Vomiting after Ambulatory Surgery 
Principal Investigator 
Name/Contact Info:  
Jaime Hyman, MD 
jaime.hyman@mountsinai.org 
Primary Contact 
Name/Contact Info 
Jaime Hyman, MD 
jaime.hyman@mountsinai.org 
Jacqueline Crittendon 
jacqueline.crittendon@mountsinai.org 
Date Revised: 
1/31/2018 
Study Number: 
GCO#15-1297; HSM# 15-00501 
 
1 
Revised  9/2/14 
MSSM Protocol Template HRP-503a 
Instructions: 
1. Prepare a document with the following sections. Note that, depending on the nature of your research, 
certain sections below may not be applicable. Indicate N/A as appropriate, explaining where possible. 
2. For any items described in the sponsor’s protocol, grant application or other source documents 
submitted with the application, you may reference the title and page numbers of these documents rather 
than cutting and pasting into this document. Do NOT refer to any derived documents, such as the 
Sample Consent document, or other internal documents required with the submission. 
3.  If you reference page numbers, attach those pages to this protocol. 
4. When you write a protocol, keep an electronic copy. You will need to modify this copy when making 
changes. 
 
Brief Summary of Research (250-400 words): 
Ambulatory surgery is occurring with rapidly increasing frequency as surgical and 
anesthetic techniques have improved and pressure to reduce health-care costs has 
increased.  While there are many benefits to recovering from surgery within the home, a 
significant disadvantage is the lack of rapid access to a healthcare provider when 
postoperative complications occur.  Postoperative nausea and vomiting (PONV) are 
common after surgery and anesthesia, and recent studies have demonstrated a high 
incidence of post-discharge nausea and vomiting (PDNV) after ambulatory surgery, 
particularly in high-risk groups (female gender, age less than 50 years, history of PONV, 
opioid administration in the post-anesthesia care unit (PACU), and nausea in the PACU).  
Current practices known to reduce the risk of postoperative nausea and vomiting in the 
PACU, such as the avoidance of volatile anesthetics and the use of intraoperative 
ondansetron and steroids, have little effect on the risk of delayed PDNV.  Novel 
strategies to prevent PDNV are needed.  Orally administered olanzapine, which has been 
shown to decrease the incidence of chemotherapy-induced nausea and vomiting, 
demonstrates promise as a novel strategy for preventing PDNV.  It has a long half-life, 
allowing for a single dose to be administered preoperatively.  This study will evaluate 
whether there is a difference in the incidence and severity of PDNV between patients 
who receive oral olanzapine versus placebo prior to general anesthesia for ambulatory 
surgery. 
1) Objectives: 


 
Protocol Title: 
Olanzapine for the treatment of Post-Discharge Nausea 
and Vomiting after Ambulatory Surgery 
Principal Investigator
Name/Contact Info:  
Jaime Hyman, MD
jaime.hyman@mountsinai.org 
Primary Contact 
Name/Contact Info 
Jaime Hyman, MD 
jaime.hyman@mountsinai.org 
Jacqueline Crittendon 
jacqueline.crittendon@mountsinai.org 
Date Revised: 
1/31/2018 
Study Number: 
GCO#15-1297; HSM# 15-00501 
 
2 
Revised  9/2/14 
Research Question: Does the addition of olanzapine administered prior to anesthetic 
induction reduce the risk of PDNV within the first 24 hours after ambulatory surgery 
relative to placebo? 
 
Primary Objective: Compare the rate of post-discharge nausea or retching/vomiting in 
patients who receive olanzapine versus placebo. 
 
 
Secondary Objectives: 
 
a) Measure the rate of post-discharge retching/vomiting in patients who receive 
olanzapine versus placebo. 
b) Measure the rate of post-discharge nausea in patients who receive olanzapine 
versus placebo. 
c) Measure the severity of post-discharge nausea in patients who receive olanzapine 
versus placebo using an 11-point Likert scale. 
 
2) Background 
Postoperative nausea and vomiting (PONV) are common complications that cause 
significant patient distress and dissatisfaction.  PONV can increase costs, delay  
postanesthesia care unit discharge, and result in unanticipated hospital admission. In rare 
cases, serious medical complications can result, including postoperative bleeding, 
esophageal rupture, and pneumothoraces.1 The incidence of postoperative nausea is 
approximately 50% and the incidence of vomiting is 30%.2 As a result of its frequent 
occurrence and associated complications, PONV is a commonly evaluated quality and 
safety indicator.3 The independent risk factors for PONV include female gender, history 
of PONV, non-smoking status, use of inhalational anesthetics, longer duration of 
anesthetic, use of postoperative opioids, and younger age.4   
 
Ambulatory surgical procedures, which tend to be shorter in duration, are fortunately 
associated with less PONV in the recovery room. Recent studies however, have 
highlighted the magnitude of delayed post-discharge nausea and vomiting (PDNV). A 
large prospective multi-center study found a 37% incidence of PDNV after general 
anesthesia.1 Given the rapidly increasing number of ambulatory surgical procedures 
performed, this amounts to 4.3 million patients with PDNV each year in the United 
States. Interestingly, only 20.7% of these patients suffered from PONV in the PACU 
prior to discharge. Most patients do not alert a healthcare provider when they suffer from 
nausea or vomiting after discharge, causing this frequent complication to remain under-


 
Protocol Title: 
Olanzapine for the treatment of Post-Discharge Nausea 
and Vomiting after Ambulatory Surgery 
Principal Investigator 
Name/Contact Info:  
Jaime Hyman, MD 
jaime.hyman@mountsinai.org 
Primary Contact 
Name/Contact Info 
Jaime Hyman, MD 
jaime.hyman@mountsinai.org 
Jacqueline Crittendon 
jacqueline.crittendon@mountsinai.org 
Date Revised: 
1/31/2018 
Study Number: 
GCO#15-1297; HSM# 15-00501 
 
3 
Revised  9/2/14 
recognized.5 PDNV can be significantly distressing to patients who are at home and no 
longer have access to intravenous antiemetic medication. Furthermore, patients who 
suffer from PDNV do not return to their normal daily activities until the nausea and 
vomiting have resolved.5  
 
Independent predictors of PDNV include female gender, age less than 50 years, history of 
PONV, opioid administration in the PACU, and nausea in the PACU.  A risk score for 
PDNV is based on these five factors.1  Zero, one, two, three, four, and five of these 
factors are associated with a 7%, 20%, 28%, 53%, 60%, and 89% incidence of PDNV. 
Intraoperatively administered ondansetron, which has a half-life of approximately three 
hours, does not reduce the risk of PDNV. There is a trend toward decreased PDNV with 
intraoperative use of glucocorticoids, but the difference does not reach statistical 
significance.  Avoidance of volatile anesthetics in favor of a total intravenous anesthetic 
technique (TIVA), which reduces PONV, does not affect the incidence of PDNV.6  Given 
the high incidence of PDNV and paucity of effective prevention strategies, novel 
approaches for preventing this common complication are needed. 
 
Olanzapine, an atypical antipsychotic medication in the thienobenzodiazepine class, 
antagonizes several receptors implicated in the pathogeneses of nausea and vomiting and 
has promising potential for the prevention of PDNV. Specifically, olanzapine antagonizes 
dopamine (D1, D2, D4), serotonin (5HT2A, 5HT2C, 5HT3), alpha-1 adrenergic, histamine 
(H1), and multiple muscarinic receptors.7 There is strong evidence for the antiemetic 
efficacy of olanzapine for both the prevention and treatment of chemotherapy induced 
nausea and vomiting (CINV).8 A phase I study showed a maximum tolerated dose of 
5mg during the two days prior to chemotherapy and 10mg for the next 7 days.  Two 
phase II studies demonstrated efficacy with a similar protocol.9,10 
 
Three randomized controlled phase III trials including 488 patients in total showed 
significant improvements in CINV prevention with antiemetic regimens that included 
olanzapine 10mg daily during treatment. Additionally, three randomized trials including a 
total of 323 patients showed efficacy for breakthrough CINV treatment with 10mg of 
olanzapine. Importantly, olanzapine was safe and well-tolerated in all trials without 
significant differences in adverse effects (including dizziness, sedation, and 
extrapyramidal symptoms) between treatment and control groups, although the majority 
of the studies were not double-blind. Long-term use of olanzapine is associated with 
weight gain, dyslipidemia, and increased risk of developing diabetes mellitus but these 
complications were not seen with short-term use for CINV prevention or treatment.8  
 
To date, there is one small study examining the efficacy of olanzapine on the prevention 


 
Protocol Title: 
Olanzapine for the treatment of Post-Discharge Nausea 
and Vomiting after Ambulatory Surgery 
Principal Investigator 
Name/Contact Info:  
Jaime Hyman, MD 
jaime.hyman@mountsinai.org 
Primary Contact 
Name/Contact Info 
Jaime Hyman, MD 
jaime.hyman@mountsinai.org 
Jacqueline Crittendon 
jacqueline.crittendon@mountsinai.org 
Date Revised: 
1/31/2018 
Study Number: 
GCO#15-1297; HSM# 15-00501 
 
4 
Revised  9/2/14 
of post-operative nausea and vomiting.  The results are promising in that 57% of patients 
in the placebo group required rescue antiemetic medications in the first 24 hours after 
surgery, whereas 37% of patients who received 10mg of oral olanzapine required 
breakthrough medication. This study included 82 patients undergoing general anesthesia 
for breast surgery who were randomized to receive placebo, olanzapine 5mg, olanzapine 
10mg, or ondansetron 16mg prior to surgery. Outcomes measured were emetic episodes 
and need for rescue medications.  Olanzapine and ondansetron showed similar efficacy in 
reducing nausea and vomiting.  There was a trend toward increased efficacy of 
olanzapine 10mg compared to 5mg, but this did not reach statistical significance. There 
was no difference in frequency of adverse events between groups, including sedation, 
anxiety, restlessness, abnormal muscle movement, and headache.11 
In the case of PDNV, the use of postoperative opioids is likely a significant contributory 
factor, as it occurs hours after the anesthetic agents have been metabolized. This is likely 
why the use of TIVA, which helps prevent PONV, has no effect on the incidence of 
PDNV. One mechanism of opioid-induced nausea and vomiting is mediated through D2 
receptors in the chemoreceptor trigger zone in the medulla oblongata.12 This makes anti-
dopaminergic agents, such as olanzapine, ideal to target opioid induced nausea and 
vomiting.  The half-life elimination of orally administered olanzapine is 21-54 hours.  
The time to peak plasma concentration is approximately 6 hours.  Therefore orally 
administered olanzapine, taken with a small sip of water prior to anesthetic induction, 
demonstrates ideal pharmacokinetics for the prevention of delayed PDNV. Olanzapine’s 
long half-life, low cost, excellent safety profile with short-term use, and targeting of 
multiple receptors implicated in nausea and vomiting (especially D2) make it a hopeful 
prospect for the prevention of PDNV. 
3) Setting of the Human Research 
This study will be conducted at the Icahn School of Medicine at Mount Sinai. 
Consent will be obtained at the Mount Sinai OB/GYN Ambulatory Department at 
1176 5th Avenue Klingenstein Pavilion E level clinic and  OB/Gyn Mount Sinai  
Faculty Practice Associates (FPA) at 5 east 98th st  
Study medications will be administered in the preoperative holding area in the 
sixth floor of the Annenberg Pavilion at 1468 Madison Avenue. The 
intraoperative protocol will take place in the operating room in which the case is 
scheduled. An investigator will evaluate the patient postoperatively in the 
Annenberg sixth floor PACU.  
4) Resources Available to Conduct the Human Research 


 
Protocol Title: 
Olanzapine for the treatment of Post-Discharge Nausea 
and Vomiting after Ambulatory Surgery 
Principal Investigator 
Name/Contact Info:  
Jaime Hyman, MD 
jaime.hyman@mountsinai.org 
Primary Contact 
Name/Contact Info 
Jaime Hyman, MD 
jaime.hyman@mountsinai.org 
Jacqueline Crittendon 
jacqueline.crittendon@mountsinai.org 
Date Revised: 
1/31/2018 
Study Number: 
GCO#15-1297; HSM# 15-00501 
 
5 
Revised  9/2/14 
Prior to initiating this study, all participating investigators and support staff will conduct 
a protocol initiation meeting to ensure adequate knowledge of the study objectives, 
procedures, populations, and human subject protections. A log of meeting attendees will 
be maintained.  The team of investigators includes anesthesiologists with expertise in 
anesthesia for ambulatory procedures, surgeons, and a biostatistician. A study physician 
will be available at all times for subjects to call regarding potential adverse effects related 
to the study drug. 
 
The surgical co-investigators perform approximately 12 ambulatory surgical procedures 
requiring general anesthesia a week, and slightly less than half of those patients are less 
than 50 years old. By this estimation, there should be approximately 6 eligible patient per 
week, or 312 eligible patients in a year.  
  
The Investigational Drug Service within the Mount Sinai Hospital Department of 
Pharmacy will be utilized to randomize consented patients to receive olanzapine versus 
placebo, and to supply the appropriate medication on the day of surgery.  
 
5) Study Design 
a) Recruitment Methods 
Patients who consent to and are scheduled to undergo ambulatory surgery at 
Mount Sinai will be invited by their physician to participate in the study prior to 
the scheduled date of surgery at their routine preoperative visit at their physician’s 
office. Office locations where recruitment will occur include: the Mount Sinai 
OB/GYN Ambulatory Department at 1
 
 
 
, the OB/Gyn Mount Sinai Faculty Practice Associates (FPA) at  
 
Upper East Side Gynecology at 
 
 
, Gramercy Gynecology at 
 
 t, New York Physicians at 
. and the Plastic and 
Reconstructive Surgery Office at 
 
 
. A flyer describing the study 
will be displayed at the first two clinic locations to advertise the study to potential 
participants. The flyer will instruct interested patients to discuss the study with 
their gynecologist, or to contact the principal investigator directly. If a patient tells 
their physician that they are willing to participate, a study investigator will 
describe the study in detail, answer questions, confirm participant understanding, 
and provide the written informed consent form for review. If the patient agrees, 
written informed consent will be obtained at this visit, with opportunity for the 
subject to withdraw at any time prior to the surgical procedure.  


 
Protocol Title: 
Olanzapine for the treatment of Post-Discharge Nausea 
and Vomiting after Ambulatory Surgery 
Principal Investigator 
Name/Contact Info:  
Jaime Hyman, MD 
jaime.hyman@mountsinai.org 
Primary Contact 
Name/Contact Info 
Jaime Hyman, MD 
jaime.hyman@mountsinai.org 
Jacqueline Crittendon 
jacqueline.crittendon@mountsinai.org 
Date Revised: 
1/31/2018 
Study Number: 
GCO#15-1297; HSM# 15-00501 
 
6 
Revised  9/2/14 
 
b) Inclusion and Exclusion Criteria 
Inclusion Criteria: 
1. Adults age ≥ 18 and ≤ 50 years old 
2. Patient scheduled to undergo ambulatory surgery under general 
anesthesia 
3. Willing and able to provide informed consent 
Exclusion Criteria: 
1. Unable to swallow pills 
2. Current use of typical or atypical anti-psychotic medications 
3. History of allergy to olanzapine 
4. Pregnancy/Lactation (subjects of child-bearing potential will have 
a urine pregnancy test performed the day of surgery) 
5. History of QTcF > 450ms or torsades de pointes 
6. Current use of antihypertensive medication 
7. Diabetes Mellitus 
 
8. Clinically significant cardiovascular disease defined as follows: 
a. Myocardial infarction or unstable angina within 6 months 
prior to the day of planned surgery. 
b. History of serious ventricular arrhythmia (i.e.: ventricular 
tachycardia or ventricular fibrillation) or cardiac 
arrhythmias requiring anti-arrhythmic medications, except 
for atrial fibrillation that is well controlled on anti-
arrhythmic medication. 
c. New York Heart Association (NYHA) Class II or higher 
congestive heart failure. 
9. Postural hypotension or vasovagal syncope within 6 months of 
planned surgery. 


 
Protocol Title: 
Olanzapine for the treatment of Post-Discharge Nausea 
and Vomiting after Ambulatory Surgery 
Principal Investigator 
Name/Contact Info:  
Jaime Hyman, MD 
jaime.hyman@mountsinai.org 
Primary Contact 
Name/Contact Info 
Jaime Hyman, MD 
jaime.hyman@mountsinai.org 
Jacqueline Crittendon 
jacqueline.crittendon@mountsinai.org 
Date Revised: 
1/31/2018 
Study Number: 
GCO#15-1297; HSM# 15-00501 
 
7 
Revised  9/2/14 
10. Hypotension on day of surgery, defined as a systolic blood 
pressure < 90mm Hg or a diastolic pressure < 60mm Hg.  
11. Seizure disorder 
12. Clinically active prolactinoma 
13. Hepatic disease 
14. Poorly controlled diabetes 
15. Pre-operative blood glucose > 250 mg/dL 
16. Narrow angle glaucoma 
17. Parkinson’s disease 
18. Lewy body dementia 
 
 
c) Number of Subjects 
The majority of PONV interventions in use in current clinical practice 
reduce the risk by approximately 20%. This reduction is additive when 
multiple interventions are used.  Assuming a 37% incidence of PDNV 
based on previous literature, to be powered to find a 20% reduction in risk 
from baseline the study must include 140 patients. 
 
 
d) Study Timelines 
Patients who consent to and are scheduled to undergo ambulatory surgery 
at Mount Sinai will be invited by their physician to participate in the study 
prior to the scheduled date of surgery at their routine preoperative visit. If 
a patient expresses interest in the study after viewing the recruitment flyer, 
arrangement will be made for an investigator to meet with the patient in 
clinic prior to the scheduled surgery to explain the study, screen the 
patient for eligibility, and obtain consent if appropriate. Patients who are 
consented will be randomized prior to their planned surgery. They will be 
followed for postoperative nausea and vomiting for 24 hours after 
discharge by telephone call on post-operative day one.  


 
Protocol Title: 
Olanzapine for the treatment of Post-Discharge Nausea 
and Vomiting after Ambulatory Surgery 
Principal Investigator 
Name/Contact Info:  
Jaime Hyman, MD 
jaime.hyman@mountsinai.org 
Primary Contact 
Name/Contact Info 
Jaime Hyman, MD 
jaime.hyman@mountsinai.org 
Jacqueline Crittendon 
jacqueline.crittendon@mountsinai.org 
Date Revised: 
1/31/2018 
Study Number: 
GCO#15-1297; HSM# 15-00501 
 
8 
Revised  9/2/14 
Based on the enrollment within the first year of the study, we expect to 
have 20-30 patients complete the study per year. Assuming that 
enrollment continues at the current pace, it will take approximately five 
years to enroll the necessary 140 patients. As patients only need to be 
followed for 24 hours after discharge to be assessed for all primary and 
secondary endpoints, we estimate the study will be complete within 2 
weeks of final patient enrollment. 
e) Study Endpoints 
Primary Objective: Compare the rate of post-discharge retching/vomiting or 
nausea in patients who receive olanzapine versus placebo. 
 
Secondary Objectives: 
i) Measure the rate of post-discharge retching/vomiting in patients who receive 
olanzapine versus placebo. 
ii) Measure the rate of post-discharge nausea in patients who receive olanzapine 
versus placebo. 
iii) Measure the severity of post-discharge nausea in patients who receive 
olanzapine versus placebo using an 11-point Likert scale. 
 
f) Procedures Involved in the Human Research 
Subjects who consent to and are scheduled for ambulatory surgery under 
general anesthesia will be invited to participate in the study during a 
routine preoperative visit prior to the day of surgery by a study 
investigator.  The details of the study will be reviewed and written 
informed consent will be obtained. Additionally, a flyer describing the 
study will be displayed at the two participating clinic locations to advertise 
the study to potential participants. The flyer will instruct interested 
patients to discuss the study with their gynecologist, or to contact the 
principal investigator directly. If a patient tells their physician that they are 
willing to participate, a study investigator will describe the study in detail, 
answer questions, confirm participant understanding, and provide the 
written informed consent form for review. Patients who have agreed to 
participate will have a 12-lead electrocardiogram (EKG) obtained in pre-
surgical testing. Alternatively, if an EKG is not obtained prior to the day 
of surgery, it will be performed the same day in the assessment area prior 


 
Protocol Title: 
Olanzapine for the treatment of Post-Discharge Nausea 
and Vomiting after Ambulatory Surgery 
Principal Investigator 
Name/Contact Info:  
Jaime Hyman, MD 
jaime.hyman@mountsinai.org 
Primary Contact 
Name/Contact Info 
Jaime Hyman, MD 
jaime.hyman@mountsinai.org 
Jacqueline Crittendon 
jacqueline.crittendon@mountsinai.org 
Date Revised: 
1/31/2018 
Study Number: 
GCO#15-1297; HSM# 15-00501 
 
9 
Revised  9/2/14 
to surgery. Patient’s with a QTc > 450 ms using the Fridericia formula 
will be excluded.  
Subjects will be counseled verbally to avoid alcohol, benzodiazepines, and 
motor vehicle driving for 24 hours following discharge. 
 
The name and date of surgery of the consenting patient will be given to the 
Investigational Drug Service of the Mount Sinai Pharmacy for 
randomization and preparation of the medication. On the day of surgery, 
an investigator will pick up the medication from the pharmacy for the 
individual subject, and have the subject take the medication with a small 
sip of water in the preoperative holding area within one hour prior to 
entering the operating room. In addition, the patient will be provided with 
a standardized diary to record episodes of vomiting for the first 24 hours 
after discharge and will be provided with verbal and written instructions 
for completing the diary (appendix 1). Subjects will be asked for a 
preferred contact number for the postoperative phone call and permission 
to leave a voicemail will be requested.  
Upon entering the operating room, after application of standard monitors, 
midazolam 2 mg will be administered for anxiolysis. If endotracheal 
intubation is indicated, general anesthesia will be induced using fentanyl 
3-5 mcg/kg and propofol 1.5-2.5 mg/kg and muscle relaxation achieved 
with succinylcholine 1-2 mg/kg or rocuronium 0.6 mg/kg, at the discretion 
of the attending anesthesiologist.  Rocuronium will be administered as 
needed to maintain muscle relaxation during the case. If a laryngeal mask 
airway is to be used rather than an endotracheal tube, anesthesia will be 
induced with propofol 1.5-2.5 mg/kg. Regardless of method of airway 
management, anesthesia will be maintained with sevoflurane at 
concentrations deemed appropriate by the anesthesia provider based on 
intraoperative hemodynamic and respiratory monitoring. Additional doses 
fentanyl will be administered also as deemed appropriate by the anesthesia 
provider based on intraoperative hemodynamic and respiratory 
montitoring. All patients will receive dexamethasone 8 mg immediately 
following induction, and ondansetron 4 mg and ketorolac 30mg 
approximately 30 minutes prior to emergence from anesthesia unless there 
is a specific contraindication.  Intubated patients will receive 
neuromuscular blockade reversal with neostigmine 0.4-0.7 mg/kg prior to 
tracheal extubation. 


 
Protocol Title: 
Olanzapine for the treatment of Post-Discharge Nausea 
and Vomiting after Ambulatory Surgery 
Principal Investigator 
Name/Contact Info:  
Jaime Hyman, MD 
jaime.hyman@mountsinai.org 
Primary Contact 
Name/Contact Info 
Jaime Hyman, MD 
jaime.hyman@mountsinai.org 
Jacqueline Crittendon 
jacqueline.crittendon@mountsinai.org 
Date Revised: 
1/31/2018 
Study Number: 
GCO#15-1297; HSM# 15-00501 
 
10 
Revised  9/2/14 
In the PACU, as needed ondanstron will be ordered as per the department 
standard orderset, (ondansetron 4 mg intravenous every 4 hours). However, the 
standard prochlorperazine 10 mg intravenous once will be removed from the 
orderset to reduce the risk of neuroleptic malignant syndrome or extrapyramidal 
symptoms when administered in combination with olanzapine. The patients’ 
experience of nausea and/or vomiting will be assessed at 30, 60, and 120 minutes 
after surgery by trained study personnel. PACU EPIC records will also be audited 
to record the need for rescue antiemetic medications.  
Prior to discharge from the PACU, subjects will be assessed for signs of 
orthostatic hypotension (a decrease of 20 mmHg in systolic blood pressure or 10 
mmHg in diastolic blood pressure upon standing). Patients who meet the criteria 
for orthostatic hypotension will be evaluated and treated with intravenous fluid 
administration. Upon discharge, patients who had symptoms of orthostatic 
hypotension will be instructed to ambulate with assistance for the first 24 hours 
after discharge. 
 
Information entered into the subjects’ diary will be obtained during a telephone 
interview on the afternoon or evening of the first day following surgery. At this 
time investigators will also screen for adverse events. 
Relevant preoperative, intraoperative, and postoperative data will be obtained 
from the anesthesia record, the EPIC electronic medical record, and the telephone 
interviews and collected on standardized forms by trained study personnel. 
Data to be collected: 
Age 
BMI 
ASA status 
Smoking status 
History of PONV 
History of motion sickness 
Total intraoperative fentanyl (mcg) 
Total intraoperative propofol (mg) 
Total intraoperative rocuronium (mg) 
Total intraoperative neostigmine (mg) 
Total intraoperative Sevoflurane 
Duration of surgery 
Total fentanyl dose in PACU (mcg) 


 
Protocol Title: 
Olanzapine for the treatment of Post-Discharge Nausea 
and Vomiting after Ambulatory Surgery 
Principal Investigator 
Name/Contact Info:  
Jaime Hyman, MD 
jaime.hyman@mountsinai.org 
Primary Contact 
Name/Contact Info 
Jaime Hyman, MD 
jaime.hyman@mountsinai.org 
Jacqueline Crittendon 
jacqueline.crittendon@mountsinai.org 
Date Revised: 
1/31/2018 
Study Number: 
GCO#15-1297; HSM# 15-00501 
 
11 
Revised  9/2/14 
Total oxycodone dose in PACU (mg) 
Rescue antiemetics in PACU (yes/no) 
   Ondansetron total dose (mg) 
Length of PACU stay (minutes) 
Vomiting in PACU (#episodes at least 1 min apart) 
Nausea in PACU (highest number reported on 11 point Likert scale) 
Post-discharge vomiting (#episodes at least 1 minute apart) 
Post-discharge nausea (highest number reported on 11 point Likert scale) 
 
 
g) Specimen Banking 
N/A 
h) Data Management and Confidentiality 
All researchers who will access the data have completed the institutional HIPAA 
certification. Extracted data will be de-identified before being given to the 
statistician for analysis. Any intermediary data files containing extracted PHI will 
be stored on secured hospital servers and destroyed after data analysis is 
complete. All study data at Mount Sinai stored electronically will follow MSMC 
policies. All PHI that is not stored on a limited access Mount Sinai IT maintained 
network drive will be encrypted and password protected. Statistical analysis will 
be carried out by a statistician employed by the Department of Anesthesiology. 
When the de-identified data set are released for analysis, a one-way hash ID will 
be generated for each record.  Only Mount Sinai study investigators with access to 
the full data set will be able to match the hash ID to the original source.  
 
i) Provisions to Monitor the Data to Ensure the Safety of subjects 
MSSM Principal Monitor (PI): 
Last Name: Hyman 
First Name: Jaime 
Academic Title: Assistant Professor 
Department: Anesthesiology 
Mailing Address: One Gustave L. Levy Place, Box 1010, New York, NY 10029 
Phone: 212-241-7473 
E-mail: Jaime.hyman@mountsinai.org  
 


 
Protocol Title: 
Olanzapine for the treatment of Post-Discharge Nausea 
and Vomiting after Ambulatory Surgery 
Principal Investigator 
Name/Contact Info:  
Jaime Hyman, MD 
jaime.hyman@mountsinai.org 
Primary Contact 
Name/Contact Info 
Jaime Hyman, MD 
jaime.hyman@mountsinai.org 
Jacqueline Crittendon 
jacqueline.crittendon@mountsinai.org 
Date Revised: 
1/31/2018 
Study Number: 
GCO#15-1297; HSM# 15-00501 
 
12 
Revised  9/2/14 
MSSM Additional Monitor (Co-investigator): 
Last Name: Demaria 
First Name: Samuel 
Academic Title: Associate Professor 
Department: Anesthesiology 
Mailing Address: One Gustave L. Levy Place, Box 1010, New York, NY 10029 
Phone: 212-241-7473 
E-mail: Samuel.demariajr@mountsinai.org  
 
Dr. Hyman and Dr. Demaria are board certified anesthesiologists with 
expertise in the perioperative management of patients. All subjects will be 
called on post-operative day one by a study investigator. In addition to the 
routine post-operative day one phone call to the patient, all participants 
will receive instructions and a business card in order to have a point of 
contact to report a potential adverse event at any time during or after the 
study period. They will also be specifically informed that they should 
receive emergency department care for any signs and symptoms of 
hypotension.  Patients who will not have anyone present at home after 
discharge will receive a same-day follow-up phone call from the study 
team to screen for adverse events.  
The study remains blinded during the second year of enrollment and no 
interim analysis of efficacy has been performed. No adverse events have 
been reported by any study participants. 
 
All adverse events will be recorded by the research team in a non-
anonymized fashion and reported directly to the Mount Sinai Institutional 
Review Board.   
The study team will report the following to the Institutional Review Board 
and FDA within 5 business days of when they became aware of the event: 
Any event that, in the principal investigator’s opinion, is unexpected and 
at least probably related to the study. 
Any event that is expected but occurring with greater frequency/intensity 
will be reported to the Institutional Review Board and FDA within 5 
business days. 


 
Protocol Title: 
Olanzapine for the treatment of Post-Discharge Nausea 
and Vomiting after Ambulatory Surgery 
Principal Investigator 
Name/Contact Info:  
Jaime Hyman, MD 
jaime.hyman@mountsinai.org 
Primary Contact 
Name/Contact Info 
Jaime Hyman, MD 
jaime.hyman@mountsinai.org 
Jacqueline Crittendon 
jacqueline.crittendon@mountsinai.org 
Date Revised: 
1/31/2018 
Study Number: 
GCO#15-1297; HSM# 15-00501 
 
13 
Revised  9/2/14 
The study team will report the following to the IRB and FDA on an annual 
basis: 
 
All expected adverse events 
The principal investigator will not enroll any new patients until the IRB 
has reviewed and responded to the report. The study team will continue to 
follow patients who are already enrolled.  
 
Enrollment will continue once the IRB approves. 
 
j) Withdrawal of Subjects 
Patients may be withdrawn from the study without their consent if their 
eligibility changes from the time of initial consent to the start of surgery 
or, if in the opinion of the investigator, they are not appropriate for 
olanzapine administration. 
6) Risks to Subjects 
A single dose of 10 mg of olanzapine is expected to be safe with minimal risks to 
subjects based on multiple prior studies of olanzapine in chemotherapy-induced 
nausea and vomiting. The following risks of olanzapine have been described 
based on chronic use: 
 
Likely (>10%) 
Weight gain, dose dependent (5-40%) 
Hypertriglyceridemia (≤39%) 
Hypercholesterolemia (≤39%) 
Somnolence, dose dependent (6-39%) 
Extrapyramidal symptoms (EPS), dose dependent (15-32%) 
Xerostomia (9-22%) 
Weakness (2-20%) 
Dizziness (4-18%) 


 
Protocol Title: 
Olanzapine for the treatment of Post-Discharge Nausea 
and Vomiting after Ambulatory Surgery 
Principal Investigator 
Name/Contact Info:  
Jaime Hyman, MD 
jaime.hyman@mountsinai.org 
Primary Contact 
Name/Contact Info 
Jaime Hyman, MD 
jaime.hyman@mountsinai.org 
Jacqueline Crittendon 
jacqueline.crittendon@mountsinai.org 
Date Revised: 
1/31/2018 
Study Number: 
GCO#15-1297; HSM# 15-00501 
 
14 
Revised  9/2/14 
Accidental injury (12%) 
Insomnia (12%) 
Elevated alanine aminotransferase (ALT) level (5-12%) 
Constipation (9-11%) 
Dyspepsia (7-11%) 
Hyperprolactinemia (30%) 
Hyperglycemia (12.8%) 
 
Less Likely (1-10%) 
Hypotension (2%) 
Postural hypotension (1%) 
Tremor (1%) 
Asthenia (2%) 
Akathisia reactions (2%) 
Parkinsonism reactions (4%) 
 
Rare but Serious (<1%) 
Syncope 
Sudden cardiac death 
Hyperglycemia 
Diabetic coma with ketoacidosis 
Diabetic ketoacidosis 
Acute hemorrhagic pancreatitis 
Venous thromboembolism 
Immune hypersensitivity reaction 
Cerebrovascular disease 
Seizure, status epilepticus 


 
Protocol Title: 
Olanzapine for the treatment of Post-Discharge Nausea 
and Vomiting after Ambulatory Surgery 
Principal Investigator 
Name/Contact Info:  
Jaime Hyman, MD 
jaime.hyman@mountsinai.org 
Primary Contact 
Name/Contact Info 
Jaime Hyman, MD 
jaime.hyman@mountsinai.org 
Jacqueline Crittendon 
jacqueline.crittendon@mountsinai.org 
Date Revised: 
1/31/2018 
Study Number: 
GCO#15-1297; HSM# 15-00501 
 
15 
Revised  9/2/14 
Suicidal intent 
Pulmonary embolism 
Death 
Neuroleptic malignant syndrome (NMS) 
Tardive dyskinesia 
Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS) 
 
Specifically, a trial comparing olanzapine versus aprepitant for prevention of CINV 
found no difference in scores between groups in a multi-symptom patient-reported 
outcome measure (MD Anderson Symptom Inventory (MDASI)), including drowsiness 
and fatigue.13 A trial examining the effectiveness of olanzapine for treatment of 
breakthrough CINV similarly found no difference between groups in MDASI scores.14 
Another study comparing olanzapine with 5-hydroxytryptamine 3 (5-HT3) receptor 
antagonists for prevention of CINV found significant improvements in global health 
status, emotional functioning, social functioning, fatigue, nausea and vomiting, insomnia 
and appetite in the olanzapine group. There were no differences in weight, blood lipid or 
blood glucose levels between groups.15 These trials support the safety and tolerability of 
short-term use of olanzapine. 
Unlike the cancer patients receiving olanzapine for the prevention or treatment of CINV, 
patients in this study will be receiving general anesthesia and several other central 
nervous system depressing (CNS) medications, including intraoperative midazolam and 
fentanyl, and postoperative oxycodone. The combination of olanzapine and these 
medications may increase the risk of adverse events not see in the patients studied for 
CINV. These risks include sedation, respiratory depression, extrapyramidal symptoms, 
orthostatic hypotension and cardiac rhythm abnormalities 
 
7) Provisions for Research Related Injury 
Subjects will be monitored during surgery and during recovery from anesthesia. 
Upon discharge, subjects will be provided with a phone number to call should 
they have any concerns related to surgery, anesthesia, or the study.  If necessary, 
subjects will be instructed to return to the hospital should any complication 
requiring medical attention occur. 


 
Protocol Title: 
Olanzapine for the treatment of Post-Discharge Nausea 
and Vomiting after Ambulatory Surgery 
Principal Investigator 
Name/Contact Info:  
Jaime Hyman, MD 
jaime.hyman@mountsinai.org 
Primary Contact 
Name/Contact Info 
Jaime Hyman, MD 
jaime.hyman@mountsinai.org 
Jacqueline Crittendon 
jacqueline.crittendon@mountsinai.org 
Date Revised: 
1/31/2018 
Study Number: 
GCO#15-1297; HSM# 15-00501 
 
16 
Revised  9/2/14 
Subjects who are injured as a result of this study will be treated until the 
resolution of the adverse event and the cost billed to them and/or their insurance 
carrier. Patients will not be compensated for research related injury. 
8) Potential Benefits to Subjects 
It is possible that patients who participate in this study and are randomized to 
receive olanzapine may be less likely to experience post-operative nausea or 
vomiting or that these symptoms may be less severe. 
9) Provisions to Protect the Privacy Interests of Subjects 
The de-identified data will be stored on secure, password-protected servers 
maintained by Mount Sinai Information Technology (IT).  Access to the data will 
only be available to Mount Sinai IT administrators, the primary investigator, and 
co-investigators.  When the de-identified data set are released for analysis, a one-
way hash ID will be generated for each record.  Only study investigators with 
access to the full data set will be able to match the hash ID to the original record.  
All investigators have completed HIPAA training regarding maintaining patient 
PHI confidentiality. 
During preoperative evaluation, subjects will be asked what number they prefer to 
be contacted at after discharge. They will also be asked whether it is ok for an 
investigator to leave a message. All messages will be of a general nature and will 
not contain personal health information. Moreover, post-operative evaluation by 
phone on the day following surgery is routine practice. 
10) 
Economic Impact on Subjects 
There are no costs to subjects for participating in this study. Olanzapine or 
placebo will be provided to the subjects free of charge. There will be no 
additional visits or tests related to study participation. 
11) 
Payment to Subjects 
There is no payment to subjects  
12) 
Consent Process 
Eligible patients will be invited to participate in the study prior to the scheduled 
date of surgery at their preoperative visit. A study investigator will describe the 
study in detail, answer questions, confirm understanding, and provide the consent 
form for review. The voluntary nature of this study will be emphasized, and 
patients who initially agreed to participate may choose to decline participation on 


 
Protocol Title: 
Olanzapine for the treatment of Post-Discharge Nausea 
and Vomiting after Ambulatory Surgery 
Principal Investigator 
Name/Contact Info:  
Jaime Hyman, MD 
jaime.hyman@mountsinai.org 
Primary Contact 
Name/Contact Info 
Jaime Hyman, MD 
jaime.hyman@mountsinai.org 
Jacqueline Crittendon 
jacqueline.crittendon@mountsinai.org 
Date Revised: 
1/31/2018 
Study Number: 
GCO#15-1297; HSM# 15-00501 
 
17 
Revised  9/2/14 
the day of surgery. Participants will be asked about the study to confirm 
understanding prior to providing written informed consent. Only patients who 
speak English or Spanish will be enrolled. Spanish-speaking patients will be 
informed of the details of the study and have all questions answered by a co-
investigator who is fluent in both Spanish and English, and will be provided the 
written consent form in Spanish. SOP HRP-090 will be followed. 
13) 
Process to Document Consent in Writing 
Consent will be documented using the standard PPHS consent template. 
14) 
Vulnerable Populations 
No vulnerable populations will be included in this study. 
15) 
Multi-Site Human Research (Coordinating Center) 
 
 
N/A 
16) 
Community-Based Participatory Research 
N/A 
17) 
Sharing of Results with Subjects 
Results will not be shared with individual subjects. Overall study findings 
describing the outcome of the study will be published in a peer-reviewed journal. 
18) 
IRB Review History 
This is a new IRB application 
 
19) 
Control of Drugs, Biologics, or Devices 
Note: The IDS has its own forms that must be completed and a review process 
that must be followed before the IDS representative will sign off on Appendix B 
for submission to the PPHS. 
The Investigational Drug Service of the Mount Sinai Pharmacy will handle storage of the 
study medications. After consent is obtained, the subjects name, medical record, and date 
of surgery will be given to the research pharmacist for randomization. On the day of 
surgery, an investigator will obtain the medication from the pharmacy and bring it 
directly to the subject who will take it immediately under direct supervision of the 
investigator. 
 


 
Protocol Title: 
Olanzapine for the treatment of Post-Discharge Nausea 
and Vomiting after Ambulatory Surgery 
Principal Investigator 
Name/Contact Info:  
Jaime Hyman, MD 
jaime.hyman@mountsinai.org 
Primary Contact 
Name/Contact Info 
Jaime Hyman, MD 
jaime.hyman@mountsinai.org 
Jacqueline Crittendon 
jacqueline.crittendon@mountsinai.org 
Date Revised: 
1/31/2018 
Study Number: 
GCO#15-1297; HSM# 15-00501 
 
18 
Revised  9/2/14 
References: 
1. 
Apfel CC, Philip BK, Cakmakkaya OS, et al. Who is at risk for postdischarge 
nausea and vomiting after ambulatory surgery? Anesthesiology 2012;117:475-86. 
2. 
Gan TJ, Diemunsch P, Habib AS, et al. Consensus guidelines for the 
management of postoperative nausea and vomiting. Anesthesia and analgesia 
2014;118:85-113. 
3. 
Haller G, Stoelwinder J, Myles PS, McNeil J. Quality and safety indicators in 
anesthesia: a systematic review. Anesthesiology 2009;110:1158-75. 
4. 
Apfel CC, Heidrich FM, Jukar-Rao S, et al. Evidence-based analysis of risk 
factors for postoperative nausea and vomiting. British journal of anaesthesia 
2012;109:742-53. 
5. 
Carroll NV, Miederhoff P, Cox FM, Hirsch JD. Postoperative nausea and 
vomiting after discharge from outpatient surgery centers. Anesthesia and analgesia 
1995;80:903-9. 
6. 
Apfel CC, Kranke P, Katz MH, et al. Volatile anaesthetics may be the main 
cause of early but not delayed postoperative vomiting: a randomized controlled trial 
of factorial design. British journal of anaesthesia 2002;88:659-68. 
7. 
Bymaster FP, Calligaro DO, Falcone JF, et al. Radioreceptor binding profile of 
the atypical antipsychotic olanzapine. Neuropsychopharmacology : official 
publication of the American College of Neuropsychopharmacology 1996;14:87-96. 
8. 
Hocking CM, Kichenadasse G. Olanzapine for chemotherapy-induced nausea 
and vomiting: a systematic review. Supportive care in cancer : official journal of the 
Multinational Association of Supportive Care in Cancer 2014;22:1143-51. 
9. 
Passik SD, Navari RM, Jung SH, et al. A phase I trial of olanzapine (Zyprexa) 
for the prevention of delayed emesis in cancer patients: a Hoosier Oncology Group 
study. Cancer investigation 2004;22:383-8. 
10. 
Navari RM, Einhorn LH, Passik SD, et al. A phase II trial of olanzapine for the 
prevention of chemotherapy-induced nausea and vomiting: a Hoosier Oncology 
Group study. Supportive care in cancer : official journal of the Multinational 
Association of Supportive Care in Cancer 2005;13:529-34. 
11. 
Ibrahim M, Eldesuky HI, Ibrahim TH. Oral olanzapine versus oral 
ondansetron for prevention of post-operative nausea and vomiting. A randomized, 
controlled study. Egyptian Journal of Anaesthesia 2013;29:89-95. 
12. 
Wood GJ, Shega JW, Lynch B, Von Roenn JH. Management of intractable 
nausea and vomiting in patients at the end of life: "I was feeling nauseous all of the 
time . . . nothing was working". Jama 2007;298:1196-207. 


 
Protocol Title: 
Olanzapine for the treatment of Post-Discharge Nausea 
and Vomiting after Ambulatory Surgery 
Principal Investigator 
Name/Contact Info:  
Jaime Hyman, MD 
jaime.hyman@mountsinai.org 
Primary Contact 
Name/Contact Info 
Jaime Hyman, MD 
jaime.hyman@mountsinai.org 
Jacqueline Crittendon 
jacqueline.crittendon@mountsinai.org 
Date Revised: 
1/31/2018 
Study Number: 
GCO#15-1297; HSM# 15-00501 
 
19 
Revised  9/2/14 
13. 
Navari RM, Gray SE, Kerr AC. Olanzapine versus aprepitant for the prevention 
of chemotherapy-induced nausea and vomiting: a randomized phase III trial. The 
journal of supportive oncology 2011;9:188-95. 
14. 
Navari RM, Nagy CK, Gray SE. The use of olanzapine versus metoclopramide 
for the treatment of breakthrough chemotherapy-induced nausea and vomiting in 
patients receiving highly emetogenic chemotherapy. Supportive care in cancer : 
official journal of the Multinational Association of Supportive Care in Cancer 
2013;21:1655-63. 
15. 
Tan L, Liu J, Liu X, et al. Clinical research of Olanzapine for prevention of 
chemotherapy-induced nausea and vomiting. Journal of experimental & clinical 
cancer research : CR 2009;28:131.