Conditions: Pruritus Nausea/Vomiting
Keywords: intrathecal morphine
Allocation: RANDOMIZED | Intervention model: PARALLEL
Enrollment: 46
Healthy volunteers: no

Brief summary:
This is a prospective randomized, double-blind, placebo-controlled study to compare the incidence and intensity of ITM-induced pruritus and nausea/vomiting using pre-emptive IV ondansetron, followed by scheduled Around The Clock (ATC) ondansetron vs. our control group, where pruritus and PONV are treated with PRN only medications.

Detailed description:
Pruritus is one of the most common and bothersome side effects of intrathecal morphine (ITM) in children, with a reported incidence of 30-60%. Clinicians, who have witnessed unbearable itching and scratching in their young patients after intrathecal morphine, may be reluctant to offer this effective pain control to future patients, for fear of these unpleasant sequelae. A study previously found a 40% incidence of pruritus in young children who received intrathecal morphine for major urologic surgery.

This is a prospective randomized, double-blind, placebo-controlled study to compare the incidence and intensity of ITM-induced pruritus and nausea/vomiting using pre-emptive IV ondansetron, followed by scheduled Around The Clock (ATC) ondansetron vs. control group, where pruritus and PONV are treated with PRN only medications.

Enrollment of 3-17 year olds who are undergoing urologic or orthopedic operative procedures who are scheduled to receive low dose (4-5 mcg/kg) intrathecal morphine for pain management.

Arms:
arm 1: Ondansetron IV X1 intraoperatively (0.1 mg/kg in 5 mLs) Ondansetron IV X 4 (Q 6 hrs for 24 hrs) (0.1 mg/kg in 5 mLs) arm 2: Placebo Comparator: This arm will receive (in a blinded fashion) a volume-matched placebo intraoperatively X1 as well as IV every 6 hrs for 24 hours postoperatively. (X4)

Interventions: intervention 1: Ondansetron intervention 2: Placebo Comparator
Intervention descriptions: intervention 1: This arm will receive (in a blinded fashion) 0.1 mg/kg of Ondansetron IV made up to 5 mLs intra-operatively and Ondansetron IV 0.1 mg/kg made up to 5 mLs every 6 hours for 24 hours postoperatively. intervention 2: This arm will receive (in a blinded fashion) a volume-matched placebo intraoperatively as well as IV every 6 hrs for 24 hours postoperatively.

Protocol document:
Prot_SAP_001.pdf: 
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COVERSHEET 
TITLE: A randomized, double-blinded, placebo-control trial of IV ondansetron to 
prevent pruritus in children who receive intrathecal morphine. 
NCT03262038 
Version Date: 7/3/2018 


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CLINICAL PROTOCOL 
A randomized, double-blinded, placebo-control trial of IV ondansetron to prevent 
pruritus in children who receive intrathecal morphine. 
Study Agents: Ondansetron (Zofran) 
HUM #: 00124202 
Principal Investigator: Liz Putnam MBBS, MD, Assistant Professor, Department of 
Pediatric Anesthesiology 
Co-Investigators: Rebecca Hong MD, Assistant Professor, Department of Pediatric 
Anesthesiology 
Terri Voepel-Lewis PhD, RN, Associate Research Scientist, Department of Pediatric 
Anesthesiology 
John Park MD, Professor, Department of Pediatric Urology 
G Ying Li MD, Assistant Professor, Department of Orthopedic Surgery 
Institution: University of Michigan 
Version and Date: 3.0     3/7/2018 


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Table of Contents 
1 
INTRODUCTION ...................................................................................................... 7 
1.1 
INDICATION ........................................................................................................ 7 
1.2 
BACKGROUND AND RATIONALE ................................................................. 7 
1.3 
HYPOTHESIS ....................................................................................................... 7 
1.4 
PREVIOUS HUMAN EXPERIENCE ................................................................. 7 
2 
STUDY OBJECTIVES AND ENDPOINTS ............................................................ 8 
2.1 
OBJECTIVES ........................................................................................................ 8 
2.2 
ENDPOINTS .......................................................................................................... 8 
2.2.1 
PRIMARY ENDPOINT .................................................................................. 8 
2.2.2 
SECONDARY ENDPOINT ............................................................................ 8 
3 
STUDY DESIGN ........................................................................................................ 9 
4 
SUBJECT SELECTION .......................................................................................... 10 
4.1 
SUBJECT RECRUITMENT .............................................................................. 10 
4.1.1 
INCLUSION CRITERIA .............................................................................. 10 
4.1.2 
EXCLUSION CRITERIA............................................................................. 10 
5 
STUDY TREATMENTS.......................................................................................... 12 
5.1 
ALLOCATION TO TREATMENT .................................................................. 12 
5.2 
BREAKING THE BLIND .................................................................................. 12 
5.3 
DRUG SUPPLIES ............................................................................................... 12 
5.3.1 
FORMULATION, PREPARATION AND DISPENSING ........................ 12 
5.3.2 
DRUG STORAGE AND DRUG ACCOUNTABILITY ............................ 12 
6 
STUDY PROCEDURES .......................................................................................... 12 
6.1 
SCREENING........................................................................................................ 12 
6.2 
TREATMENT STUDY PERIOD ...................................................................... 12 
6.2.1 
DAY OF SURGERY THROUGH 24 HOURS POST-OPERATIVE ....... 12 
7 
ASSESSMENTS ....................................................................................................... 15 
7.1 
PRIMARY ENDPOINT ASSESSMENTS ........................................................ 15 
7.2 
SECONDARY ASSESSMENTS ........................................................................ 15 
8 
ADVERSE EVENT REPORTING ......................................................................... 15 
9 
DATA ANALYSIS/STATISTICAL METHODS .................................................. 17 
9.1 
SAMPLE SIZE DETERMINATION ................................................................ 17 
9.2 
DATA ANALYSIS ............................................................................................... 17 
10 MONITORING ......................................................................................................... 17 
10.1 
DATA SAFETY AND MONITORING BOARD (DSMB) .............................. 17 
11 DATA HANDLING AND RECORD KEEPING .................................................. 17 
11.1 
CRFS / ELECTRONIC DATA RECORD ........................................................ 17 
11.2 
RECORD RETENTION ..................................................................................... 17 
12 ETHICS ..................................................................................................................... 18 
12.1 
INSTITUTIONAL REVIEW BOARD (IRB) ................................................... 18 
12.2 
ETHICAL CONDUCT OF THE STUDY ......................................................... 18 
12.3 
STUDY DISCONTINUATION CRITERIA ..................................................... 18 
12.3.1 
STOPPING RULES FOR SAFETY REASONS ........................................ 18 
12.3.2 
RULES FOR DISCONTINUATION OF A SUBJECT ............................. 18 
13 REFERENCES ......................................................................................................... 19 
 


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List of Tables 
Schedule of Activities – Page 13 
 
List of Figures 
Protocol Algorithm:  Appendix A,  Page 20 
 


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PROTOCOL SYNOPSIS  
 
 
Sponsor: Department of Pediatric Anesthesiology 
Name of Investigational Study Agent: Ondanestron (Zofran) 
Study Title: A randomized, double-blinded, placebo-control trial of IV ondansetron to 
prevent pruritus in children who receive intrathecal morphine. 
Study Phase: 4 
Primary Objective: Demonstrate efficacy of Ondansetron (Zofran) to reduce incidence 
and intensity of pruritus as a side effect of IntraThecal Morphine (ITM) 
Study Design: Prospective, randomized, double-blind, placebo controlled 
Study Population: ages 3-17 inclusive 
Diagnosis and Main Criteria for Inclusion  
Each subject must meet the following criteria to be enrolled in this study: 
Scheduled for any procedure necessitating ITM  for pain management. 
Wt </= 100kg 
Ability to use verbal or pictorial scoring scales 
Parental informed consent 
Subject informed assent, as applicable 
 
Subjects who meet any of the following criteria will be excluded from study: 
 
Inability to use verbal or pictorial scoring scales (developmental delay) 
Hypersensitivity to selective 5-HT3 receptor antagonists 
Diagnosed congenital long QT syndrome 
Severe hepatic impairment 
Pregnancy and nursing mothers 
Use of serotonin specific reuptake inhibitors within 14 days 
Use of serotonergic-nonadrenergic reuptake inhibitors within 14 days 
Current use of any medications that prolong QT interval 
Test Product; Dose; and Mode of Administration:  
Intervention group:  
This arm will receive (in a blinded fashion) 0.1 mg/kg of Ondansetron IV diluted in 
normal saline to a volume of 5 mLs intra-operatively and Ondansetron IV  0.1 mg/kg 
diluted in normal saline to a volume of 5 mLs  every 6 hours for 24 hours postoperatively 
(not to exceed 40 mg in 24 hours). 


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Reference or Placebo Therapy; Dose; and Mode of Administration: 
Control group: 
This arm will  receive (in a blinded fashion) a volume-matched placebo (normal saline) 
intraoperatively as well as IV every 6hrs for 24 hours postoperatively. 
Duration of Treatment: Intraoperative time period plus 24 hours from end of surgery.  
Statistical Methods:  
Data will be summarized using descriptive methods. Parametric data will be analyzed 
between groups using unpaired t tests or Mann Whitney U, as appropriate. Rankings of 
pruritus and PONV will be coded as none-mild vs. severe and Chi-squared and Fishers' 
Exact tests will be used to compare these outcomes between groups. Significance will be 
accepted at the 5% level.   
 
 
 


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1 INTRODUCTION 
1.1 
Indication 
Pruritus is one of the most common and bothersome side effects of intrathecal morphine (ITM) 
in children, with a reported incidence of 30-70% (1, 2, 13, and 15). We previously found a 
40% incidence of pruritus in young children who received intrathecal morphine for major 
urologic surgery (2) (retrospective review, n= 77, anti-pruritic treatment required in 31 cases). 
Clinicians, who have witnessed unbearable itching and scratching in their young patients after 
intrathecal morphine, may be reluctant to offer this effective pain control to future patients, 
for fear of these unpleasant sequelae. 
1.2 
Background and Rationale  
The mechanism of morphine-induced itch is not fully elucidated. (1, 16, 19). However, 
neuraxial opioids induce more frequent and intense itch than peripherally administered doses 
(26). Centrally located Mu-opioid receptors, in the medullary dorsal horn, may play a role, 
and activation of this site with an opioid injection induced a dose related scratch frequency in 
primates (23). The mu opioid receptors, but not other opioid receptor subtypes, appear to 
mediate the neuraxial opioid-induced itch as opposed to intravenously administered opioids 
(21, 22, 25). However, the physiology is more complex, as morphine induced pruritus is not 
always reversed with naloxone (13) and effective treatments for neuraxial induced pruritus 
include partial opioid agonists (1, 13), 5HT3 antagonists (4-7), propofol (13, 24), and 
prostaglandin modulation (19).  
 
1.3 
Hypothesis 
Pre-emptive and continued blocking of 5HT3 receptors with the 5HT3 receptor antagonist 
ondansetron, given intravenously prior to ITM and 6 hourly thereafter, will reduce the 
incidence and intensity of pruritus as a side effect of morphine, in our pediatric patients. 
Secondary outcomes to be studied: Post-operative nausea and vomiting and any adverse 
events.  
 
1.4 
Previous Human Experience 
5HT3 antagonists are considered among the first line of treatments for morphine-induced 
nausea as well as pruritus in adult, particularly obstetric, populations (4, 7, 8, 19). A review 
of placebo RCTs, using prophylactic 5HT3 antagonists for pruritus in neuraxial opioids, 
found NNTT = 7 to reduce pruritus in adults (29). 5HT3 antagonists block the effects of 
morphine in animal studies (3). There is a high density of 5HT3 receptors in the nucleus of 
the facial and trigeminal nerve (20, 25). An “itch center” has been proposed at the spinal 
tract nucleus of the trigeminal nerve (18). More specifically, pre-emptive (27, 28) and 
around-the-clock ondansetron (28) dosing with ondansetron has been shown to reduce itch 
(both incidence and intensity), in adults who received intrathecal opioids.  


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In the pediatric population, case reports (9-11) suggest ondansetron is an effective treatment 
for pruritus, but to date there are no data to support the efficacy of 5HT3 antagonists in 
preventing or treating ITM-related pruritus in children. 
In contrast, antihistamines such as diphenhydramine, while used in many pediatric settings, 
have been shown to be ineffective on opioid-related pruritus, in recent reviews (1, 13). This 
is corroborated by research in primates (23). 
 
 
2 STUDY OBJECTIVES AND ENDPOINTS 
2.1 
Objectives 
 Incidence and severity of pruritus in both study groups 
 Incidence and severity of nausea and vomiting in both study groups 
2.2 
Endpoints 
2.2.1 
Primary Endpoint  
Incidence and severity of pruritus within 24 hours post-operatively 
2.2.2 
Secondary Endpoint 
 Post-operative nausea and vomiting within 24 hours post-operatively 
 Adverse events intra-operatively and within 24 hours post-operatively 
 
 


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3 STUDY DESIGN  
After obtaining IRB approval and informed consent, we will recruit children ages 3-17 years 
(able to use verbal or pictorial scoring scales) who are scheduled to intrathecal morphine for 
a surgical procedure and weigh less than or equal to 100kg.     
We will recruit 130 children, and randomize using a random numbers table, stratifying 
for female gender. The patients who have consented to take part in the study, their families 
and caregivers, their medical team and the trained observers will be blinded to the treatment 
being given.   
Our proposed ondansetron regime comprises an intra-operative bolus dose of 
ondansetron, 0.1mg/kg IV, prior to intrathecal morphine injection, followed by around-the-
clock ondansetron doses, of 0.1mg/kg IV every 6 hours. We will compare this to a 
standardized control regime comprising an intra-operative bolus dose of saline placebo and 
around the clock placebo for 24 hours. 56 patients will comprise each group. All children in 
both groups will be cared for using a standard, current practice, which includes intra-operative 
anti-emetics per our departmental algorithm for PONV (Postoperative nausea and vomiting), 
described below. 
Rescue orders for pruritus and PONV are also summarized below. See the attached 
protocol flowsheet for an overview. Naloxone is routinely ordered, to be given as needed for 
the treatment of respiratory depression or over-sedation only. We will compare our study 
group with the control group over the 24 postoperative hours with blinded observers / 
interviewers. 
 
STANDARD OF CARE FOR PONV PREVENTION 
As per standard of care, all subjects will receive dexamethasone and diphenhydramine intra-
operatively for PONV prevention. For patients who fall into the “High Risk for PONV” 
category (according to departmental standard of care algorithm), anesthesiologist may, at 
their discretion, consider any of the following:  pre-operatively aprepitant; fluid bolus 
30ml/kg; Total Intravenous Anesthesia (TIVA); Sub-hypnotic dose propofol of 1mg/kg 
infused at 20mcg/kg/min.  
 
STUDY PROCEDURES Pre-Operatively, Intra-Operatively and Post-Operatively:  
 Pre-op: Patients will be consented in clinic whenever possible or on the day of 
surgery and randomized, with gender stratification. Patients, their families and health 
care professionals will be blinded as to whether the patient is in the treatment or 
control group. 
 Intra-op: Induction of general anesthesia per standard of care. Syringe of drug 
labeled “Anti pruritic study drug” to be given IV,  prior to intrathecal morphine 
administration, by anesthesiologist in the OR: 
o Study group: Syringe contains ondansetron 0.1mg/kg, diluted to a volume of 
5 mls (not to exceed 5 mg/dose). 


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o Control group: Syringe contains normal saline, 5 mls. 
 Post-op: Syringe of drug labeled “Anti pruritic study drug” to be given IV, q6h for 
24 hours by RN on the floor: 
o Study group: Syringe contains ondansetron 0.1mg/kg, diluted to a volume of 
5 mls (not to exceed 40 mg in 24 hours or 10 mg/dose). 
o Control group: Syringe contains normal saline, 5 mls. 
STANDARD OF CARE FOR POST-OPERATIVE RESCUE TREATMENT OF 
PRURITUS AND PONV 
Regardless of study group, all subjects will receive standard of care treatment for pruritus 
and or PONV should it be required at any time post-operatively. 
Standard of Care rescue medications for pruritus: 
 
o First line: PRN nalbuphine.  
o Second line PRN diphenhydramine. 
Standard of care rescue medication for PONV: 
 
o First line: PRN prochlorperazine.  
o Second line:. promethazine 
 
 
4 SUBJECT SELECTION 
4.1 
Subject Recruitment 
4.1.1 
Inclusion Criteria 
1. Age: 3-17 years, inclusive and wt </= 100kg 
2. Scheduled for any procedure necessitating ITM 
3. Ability to use verbal or pictorial pain assessment tools and techniques 
4. Informed consent and assent (if applicable) 
4.1.2 
Exclusion Criteria 
 
1. Inability to use verbal or pictorial scoring scales 
2. Hypersensitivity to selective 5-HT3 receptor antagonists 


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3. Diagnosed congenital long QT syndrome 
4. Current use of any medications that prolong QT interval 
5. Severe hepatic impairment  
6. Pregnancy or nursing mothers 
7. Use of serotonin specific reuptake inhibitors within 14 days 
8. Use of serotonergic-noradrenergic reuptake inhibitors within 14 days 
 
 
 


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5 STUDY TREATMENTS 
 
5.1 
Allocation to Treatment 
Subjects will be randomized via previously generated random numbers table and stratifying 
for female gender. 
5.2 
Breaking the Blind 
The randomization can be broken, if necessary per the physicians caring for the subject to 
ensure subject safety.  In the case of such a medical emergency, the blind will be broken by 
the study pharmacist or pharmacy designee. 
5.3 
Drug Supplies 
5.3.1 
Formulation, Preparation and Dispensing 
All study drugs for this study are available on formulary. The study pharmacist will have 
access to the random numbers table denoting group assignment and will prepare the blinded 
study drug for each patient and deliver it the appropriate operating room on the day of 
surgery.  
5.3.2 
Drug Storage and Drug Accountability 
All study medications are stored in accordance with Mott OR Pharmacy standards. Drug 
accountability will be maintained by the study pharmacist and designated and trained Mott 
OR Pharmacy staff.  
6 STUDY PROCEDURES 
6.1 
Screening   
Subjects will be identified 2 ways: 
1. Review of the applicable clinic schedules 
2. Review of the daily Operating Rooms schedule  
6.2 
Treatment Study Period 
6.2.1 
Day of Surgery through 24 hours post-operative 
Preoperatively, the medical history will be reviewed to confirm that no exclusion criteria 
have developed since informed consent.  
In the operating room, the subject will receive an intra-operative bolus dose of study drug 
labeled “antipruritic study drug” (ondansetron, 0.1mg/kg or placebo) IV, prior to intrathecal 


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morphine injection, followed by around-the-clock study drug labeled “antipruritic study 
drug” (ondansetron doses, of 0.1mg/kg or placebo) IV every 6 hours for 24 hours from OR 
end time. 
Subjects in the operating room, recovery room, and PACU will be monitored as per standard 
clinical care.  
Data collection  
For the first 24 hours after surgery, subjects will be visited in the Post Anesthesia Care Unit 
(PACU), the evening of surgery, the next morning and at 24 hours postoperatively (not 
between the hours of 10p-7a) to obtain the presence and degree of adverse effects, our 
primary outcomes. Pruritus will be scored similar to previous pediatric studies, as 0 = none; 
1 = mild/tolerable/not requiring treatment; 2 = severe/intolerable/requiring treatment (12).  
We will use a similar method to quantify the amount of nausea/vomiting each patient 
experiences (0 = no nausea/vomiting; 1 = mild/tolerable nausea/vomiting not requiring 
treatment; 2 = severe/intolerable nausea/vomiting requiring treatment) (14). The following 
data will also be collected: all analgesics, antiemetic, and antipruritic agents used. 
 
 


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SCHEDULE OF ACTIVITIES 
 
Protocol Activity 
Screen 
 
Day of 
surgery 
 
Follow-up: 
 
  
 
 
OR end +24 
hrs  
Informed Consent  
X 
  
  
Review of medical history 
X 
X 
 
Vitals 
X 
X 
 
Randomization 
 
X 
  
Treatment with study 
agent 
 
X 
X 
Pruritus and PONV 
assessment 
 
 
X 
Adverse Event  
Assessment 
 
X 
X 
Concomitant Medication 
X 
X 
X 
 
Note: Pregnancy test is performed as standard of care for all post-menarchal females scheduled for surgery at C. Mott Children’s 
Hospital.  
 


 
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7 ASSESSMENTS  
 
7.1 
Primary Endpoint Assessments 
For the first 24 hours, subjects will be visited in the PACU, the evening of surgery, the next 
morning and at 24+/-3 hours (not between the hours of 10p-7a) to obtain the presence and degree 
of adverse effects, our primary outcomes. Pruritus will be scored similar to previous pediatric 
studies, as 0 = none; 1 = mild/tolerable/not requiring treatment; 2 = severe/intolerable/requiring 
treatment (12). 
7.2 
Secondary Assessments 
 
We will use a similar method to quantify the amount of nausea/vomiting each patient 
experiences (0 = no nausea/vomiting; 1 = mild/tolerable nausea/vomiting not requiring 
treatment; 2 = severe/intolerable nausea/vomiting requiring treatment) (14).  
8 ADVERSE EVENT REPORTING 
 
Adverse Event Definition 
An adverse event (AE) is any untoward medical occurrence in a subject participating in an 
investigational study or protocol regardless of causality assessment.  An adverse event can be an 
unfavorable and unintended sign (including an abnormal laboratory and vital sign findings), 
symptom, syndrome or disease associated with or occurring during the use of an investigational 
product whether or not considered related to the investigational product. 
 
These events may be: 
 
a. Definitely related: clearly associated with study drug/treatment 
b. Probably related:  likely associated with study drug/treatment 
c. Possibly related:  may be associated with study drug or other treatment 
d. Unlikely to be related, or 
e. Definitely not related to the study drug/treatment 
 
For reporting purposes, an AE should be regarded as definitely or probably related to the regimen if 
the investigator believes that at least one of following criteria are met: 
 
a. There is a clinically plausible time sequence between onset of the AE and the administration of 
the study drug or treatment. 
b. There is a biologically plausible mechanism for the study drug or treatment causing or 
contributing to the AE. 
c. The AE cannot be attributed solely to concurrent/underlying illness, other drugs, or procedures.  
d. A potential alternative cause does not exist. 
 
Serious Adverse Events (SAE):  An adverse drug experience occurring at any dose that results in 
any of the following outcomes: 
 


 
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a. 
Death 
b. 
A life-threatening adverse drug experience 
c. 
Inpatient hospitalization or prolongation of existing hospitalization 
d. 
A persistent or significant disability &/or incapacity 
e. 
A congenital anomaly or birth defect 
 
Important medical events that may not result in death, be life-threatening, or require hospitalization 
may be considered a serious adverse drug experience when, based upon appropriate medical 
judgment, they may jeopardize the patient or subject and may require medical or surgical 
intervention to prevent one of the outcomes listed in this definition. A serious adverse experience 
includes any experience that is fatal or immediately life threatening, results in a persistent or 
significant disability/incapacity, requires or prolongs in-patient hospitalization, or is a congenital 
anomaly, cancer, or overdose. 
Other important medical events that may not result in death, not be life-threatening, or not require 
hospitalization may be considered a serious adverse experience when, based upon appropriate 
medical judgment, the event may jeopardize the subject/patient and may require medical or surgical 
intervention to prevent one of the outcomes listed previously. 
 
Expected adverse events are those adverse events that are listed in the protocol, the Investigator’s 
Brochure (current edition) or in the study informed consent document. 
 
Unexpected adverse events are those that: 
 
a. are not described in the labeling for Ondansetron 
b. are not anticipated in the study informed consent.  This includes adverse events for which the 
specificity or severity is not consistent with the description in the informed consent. 
 
Unanticipated problem: Per FDA Procedural Guidance for Clinical Investigators, Sponsors, and 
IRBs (January 2009), A serious problem that has implications for the conduct of the study (requiring 
a significant and usually safety-related, change in the protocol such as revising inclusion/exclusion 
criteria or including a new monitoring requirement, informed consent or investigator’s brochure). 
 
Unanticipated problem Reporting: Per 21 CFR 312.66, 312.53 (c)(1)(vii), and 56.108(b)(1), 
should an Unanticipated problem occur during the investigation, the investigator will promptly 
report all unanticipated problems involving risks to human subjects or others to IRBMED.  
 
 
 
The severity or grade of an adverse event may be measured using the following definitions: 
 
Mild:  Noticeable to the subject, but does not interfere with subject’s expected daily activities, 
usually does not require additional therapy or intervention, dose reduction, or discontinuation of the 
study. 
 
Moderate:  Interferes with the subject’s expected daily activities, may require some additional 
therapy or intervention but does not require discontinuation of the study. 
 
Severe: Extremely limits the subject’s daily activities and may require discontinuation of study 
therapy, and/or additional treatment or intervention to resolve. 
 
Event reporting:  The study will comply with the IRB reporting requirements and guidelines. 


 
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All AEs will be recorded by the Investigator from the time the subject signs informed consent until 
hospital discharge.  AEs and serious adverse events (SAEs) will be recorded in the subject’s source 
documents.  All SAEs must be reported to the IRB according to the University of Michigan IRB 
reporting requirements.  
9 DATA ANALYSIS/STATISTICAL METHODS 
9.1 
Sample Size Determination 
Anticipating study drug to result in 50% decrease in pruritus from current rate of pruritus for 
those patients receiving ITM, we need to enroll 56 patients per group to achieve 80% power. 
9.2 
Data Analysis 
Data will be summarized using descriptive methods. Parametric data will be analyzed between 
groups using unpaired t tests or Mann Whitney U, as appropriate. Rankings of pruritus and 
PONV will be coded as none-mild vs. severe and Chi-squared and Fishers' Exact tests will be 
used to compare these outcomes between groups. Significance will be accepted at the 5% level.   
10 MONITORING 
10.1 Data Safety and Monitoring Board (DSMP) 
This study has a DSMP. An interim analysis will be done when we have reached 20 patients per 
group. At this point, the statistician will break the blind, and the PI Dr. Elizabeth Putnam along 
with Co-I Dr. Rebecca Hong will review the incidence of pruritus and nausea and vomiting in 
both groups to examine whether it is higher than expected. 
Events will be reported to the IRB according to the “Standard Adverse Event Reporting 
Guidelines for INTERNAL AEs Occurring at UM”. Accordingly, any non-serious unrelated AE, 
will be reported in aggregate at the IRB continuing review. Serious adverse events (SAEs) will 
be reported within 14 calendar days if related to the study. SAEs that are NOT related to study 
participation will be reported in aggregate at scheduled continuing review. Any study-related 
SAE will be reported within 14 calendar days of becoming aware of the event. Any SAE 
resulting in death or life-threatening outcome will be reported as soon as possible but not later 
than 7 calendar days of becoming aware of the event.  
DATA HANDLING AND RECORD KEEPING 
10.2 CRFs / Electronic Data Record 
We will use paper CRFs and data entry will be performed using StatView in a password 
protected, UM maintained computer. CRFs will be kept in a cabinet in locked research office in 
the department of pediatric anesthesiology. 
10.3 Record Retention 
Records will be retained according to IRBMED Guidelines for record retention. 


 
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11 ETHICS 
11.1 Institutional Review Board (IRB) 
Before implementing this study, the protocol, the proposed informed consent form and other 
information to be provided to subjects, must be reviewed by a properly constituted Institutional 
Review Board (IRB). Any amendments to the protocol must be reviewed and approved by 
IRBMED. 
11.2 Ethical Conduct of the Study 
Subject Information and Consent 
The study team member will explain to each subject and parental unit/s (or legally authorized 
representative) the nature of the study, its purpose, the procedures involved, the expected 
duration, the potential risks and benefits involved and any discomfort it may entail.  Each 
subject’s parent will be informed that participation in the study is voluntary and that he/she may 
withdraw from the study at any time and that withdrawal of consent will not affect subsequent 
medical treatment or relationship with the treating physician. 
This parental informed consent will be given by means of a standard written statement, written in 
non-technical language. The subject’s parent should read and consider the statement before 
signing and dating it, and should be given a copy of the signed document. If the subject’s parent 
cannot read or sign the documents, oral presentation may be made or signature given by the 
subject’s legally appointed representative, if witnessed by a person not involved in the study, 
mentioning that the patient’s parent could not read or sign the documents. No patient can enter 
the study before parental informed consent, as well as child assent, if applicable, has been 
obtained. 
Subjects age 10 years and older will be provided an assent document. An age appropriate 
discussion of the study will take place and the child will have opportunity to have all questions 
answered and will sign the document if he/she agrees to participate. A copy will be given to the 
parent. If the child refuses assent, the subject will not be included in the study. 
The informed consent form and pediatric assent forms are considered to be part of the protocol, 
and will be submitted for IRB approval. 
11.3 STUDY DISCONTINUATION CRITERIA 
11.3.1 
Stopping Rules for Safety reasons 
The Study team will review all Serious Adverse Events (SAEs) and make recommendations 
regarding the continuation or discontinuation of the study, as appropriate. 
11.3.2 
Rules for Discontinuation of a Subject 
In the event a patient drops out of the study or is discontinued due to protocol violations, all 
attempts will be made to exit the patient in accordance with the protocol requirements. 
 


 
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12 REFERENCES 
 
References: 
1. Jitpakdee, T. and Mandee, S. 2014. Strategies for preventing side effects of systemic 
opioid in postoperative pediatric patients. Paediatr Anaesth, 24: 561–568.  
2. Putnam EM, Koppera P, Malviya S, Voepel-Lewis T. 2015. Pain outcomes in children 
who received intrathecal vs intravenous opioids for pain control following major urologic 
surgery: a retrospective review. Pediatri Anesth 25: 1280-86. 
3. Carboni, Acquas et al. 1989. 5HT3 receptor antagonists block morphine- and nicotine- but 
not amphetamine- induced reward. Psychopharmacology 97:175-78. 
4. Koju RB, Gurung BS, Dongol Y. 2015 Prophylactic administration of ondansetron in 
prevention of intrathecal morphine-induced pruritus and post-operative nausea and 
vomiting in patients undergoing caesarean section. Anesthesiol Feb 17;15:18 
5. Kronsten, V; Fitzpatrick, E; Baker, A. 2013. Management of Cholestatic Pruritus in 
Paediatric Patients With Alagille Syndrome: The King's College Hospital Experience. 
Journal of Pediatric Gastroenterology & Nutrition. 57 (2):149–154 
6. Pitkanen, Niemi et al. 2003. Effect of tropisetron a 5HT3 receptor antagonist on analgesia 
and nausea after intrathecal morphine. Brit J Anaesth. 71(5) 681-84. 
7. Kung AT, Yang X, et al. 2014. Prevention versus treatment of intrathecal morphine-
induced pruritus with ondansetron. Int J Obstet Anseth 23(3) 222-6. 
8. Szarva, Szilvia et al. A comparison of dexamethasone, ondansetron and dexamethasone as 
prophylactic antiemetic and antipruritic therapy in patients receiving intrathecal morphine 
for major orthopedic surgery. Anesth and Analg. 2003. 97(1): 259-63. 
9. Borgeat A, Stirnemann HR et al. 1999. Ondansetron is effective to treat spinal or epidural 
morphine-induced pruritus. J Ameri Soc Anesthesiol, 90(2): 432-36. 
10. Deshpande PV. 2004. Ondansetron for pediatric uraemic pruitus: a case report. Pediatr 
Nephrol. 19(6) 694-96. 
11. Ameur SB, Chabchoub J et al. 2016. Management of cholestatic pruritus in children with 
Alagille syndrome: Case report and literature review. Achives de Pediatrie 23(12): 1247-
50. 
12. Maxwell, LG; Kaufmann, SC; Bitzer, S; Jackson, E V ; McGready, J; Kost-Byerly, S; 
Kozlowski, L; Rothman, S K; Yaster, M. (2005) The Effects of a Small-Dose Naloxone 
Infusion on Opioid-Induced Side Effects and Analgesia in Children and Adolescents 
Treated with Intravenous Patient-Controlled Analgesia: A Double-Blind, Prospective, 
Randomized, Controlled Study. Anesth & Analg. 2005: 100(4): 953-958 
13. Szarvas S, Harmon D, Murphy D. 2003 Neuraxial Opioid-Induced Pruritus: A Review. J 
of Clin Anesth. 15: 234-49. 
14. Moustafa AAM, Baaror AS and Abdelazim IA. 2016. Comparative study between 
nalbuphine and ondansetron in prevention of intrathecal morphine-induced pruritus in 
women undergoing cesarean section. Anesth Essays Res.10(2): 238–244. 
15. Ganesh, A., Kim, A., Casale, P. and Cucchiaro, G., 2007. Low-dose intrathecal morphine 
for postoperative analgesia in children. Anesthesia & Analgesia, 104(2), pp.271-276. 
16. Kjellberg F, Tramer MR. 2001. Pharmacological control of opioid-induced pruritus: a 
quantative systematic review of randomized trials. European J Anesthesiol 2001, 18: 346-
57. 
17. Scott, P.V. and Fischer, H.B.J. 1982. Spinal opiate analgesia and facial pruritus: a neural 
theory. Postgraduate medical journal, 58(683), pp.531-535. 
18. Hakey CJ. 1999. COX-2 inhibitors. Lancet. 1999: 353: 307-14. 


 
Page 20 of 21 
 
19. Ko MC. 2015. Neuraxial Opioid-Induced Itch and Its Pharmacological Antagonism. 
Pharmacology of Itch. DOI 10.1007/978-3-668-44605-8_17. Springer-Verlag Berlin 
Heidelberg 2015.  
20. Tecott LH, Maricq AV, & Julius D. 1993. Nervous system distribution of the serotonin 5-
HT3 receptor mRNA. PNAS 1993 90 (4) 1430-1434. 
21. Ko MC, Song MS, Edwards T, Lee H, Naughton NN. 2004. The role of central mu 
opioids receptors in opioid-induced itch in primates. J Pharmacol Exp Ther. 310: 169-176. 
22. Ko MC, Naughton NN. 2000. An experimental itch model in monkeys: characterization of 
intrathecal morphine-induced scratching and antinociception. Anesthesiology 92:795-805.  
23. Thomas DA, Williams GM, et al. 1993. The medullary dorsal horn. A site of action of 
morphine in producing facial scratching in monkeys. Anesthesiology 79: 548-554. 
24. Torn K, Tuominen M et al. 1994 Effects of subhypnotic doses of propofol on the side 
effects of intrathecal morphine. Br J Anaesth 1994: 73: 411-2. 
25. Armstrong S, Fernando R.  2016 Side effects and efficacy of neuraxial opioids in pregnant 
patients at delivery:  a comprehensive review.  Drug Safety 39(5) 381-399. 
26. Ko JS, Choi SJ, et al. 2009.  Intrathecal morphine combined with intravenous patient-
controlled analgesia is an effective and safe method for immediate postoperative pain 
control in live liver donors.  Liver Transplantation 2009; 15(4): 381-389. 
27. Iatrou CA, Dragoumanis CK et al. 2005. Prophylactic Intravenous Ondansetron and 
Dolasteron in Intrathecal Morphine Induced Pruritus: A randomized double blinded 
placebo control study. Anesth and Analag; 101: 1516-20. 
28. Dimitriou V, Yoyagis GS. Opioid-induced pruritus: repeated versus single dose 
ondansetron administration in preventing pruritus after intrathecal morphine. Brit J 
Anaesth 1999; 83:822-3. 
29. Bonnet M-P, Marret E, et al. Effect of prophylactic 5-HT3 receptor antagonists n pruritus 
induced by neuraxial opioids: a quantitative systematic review. Brit J Anaesth. 2008; 
101(3): 311-19. 
 
 
 


 
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CONTROL GROUP n=56: 
Placebo  drug: 5ml normal saline IV labeled 
“antipruritic study drug”  
STUDY GROUP n=56: 
Ondansetron 0.1mg/kg IV diluted to 5ml 
labeled “antipruritic study drug”  

Intrathecal morphine placed (10 minutes after study drug given) 

Anti-emetics:  Dexamethasone 0.15mg/kg (max 4mg) 
Diphenhydramine 0.3mg/kg (max 12.5mg) 

If patient meets criteria for High Risk of PONV consider: aprepitant; 
TIVA; IV fluid bolus 30ml/kg; subhypnotic propofol infusion. 
ITM side effects? 
Intra-operative plan 
PATIENTS RECRUITED: 

3-17 years and </= 100 kg 

Scheduled to have low dose intrathecal morphine for orthopedic or urology surgery 
Patients randomized to Control or Study group with gender stratification 
CONTROL GROUP: 
Placebo 5ml normal saline labeled “antipruritic study 
drug” to be given IV 6 hourly for 24 hours  
STUDY GROUP: 
Ondansetron 0.1mg/kg diluted to 5ml labeled 
“antipruritic study drug” to be given IV 6 hourly for 
24 hours  
PONV? 
Itch? 
1st Line: Nalbuphine 0.03mg/kg 
 
If pruritus not improved after 30 minutes: 
 
2nd Line: Diphenhydramine 0.3mg/kg (max 12.5mg) 
1st Line:  Prochloperazine 2.5mg <40kg or 5mg >40kg PO or 
0.1mg/kg. 
 
If PONV not improved after 30 minutes:  
 
2nd Line:  Promethazine 3.125mg <40kg or 6.25mg >40kg IV  
If symptoms still inadequately treated, contact MD (APS Fellow). Further orders at provider’s discretion. 
Post-operative 24 hours 
APPENDIX A – Protocol Algorithm