Conditions: Postoperative Nausea and Vomiting
Keywords: PONV anesthesia granisetron
Allocation: NA | Intervention model: SINGLE_GROUP
Enrollment: 50
Healthy volunteers: no

Brief summary:
The objective of the study is to evaluate the efficacy and safety of adding transdermal preparation of granisetron (Sancuso ®) to the current postoperative nausea and vomiting (PONV) standard prophylaxis regimen with dexamethasone and ondansetron in patients with the previous history of severe, particularly delayed and/or post-discharge, PONV and undergoing surgical procedure under general anesthesia.

The specific aims of the study include:

1. efficacy of the investigated therapy in prevention of PONV up to 120 hours after surgery
2. incidence and seriousness of the observed side effects
3. ability of patients to self-administer preoperatively and maintain the investigated patch during the perioperative period
4. level of satisfaction with the preoperative PONV prophylaxis.

Detailed description:
Patients will be recruited from the surgical population undergoing preoperative evaluation in Anesthesiology Preoperative Evaluation Clinic at Hershey Med. Ctr. (\~15,000 per year). Selected patients (ASA 1-3, N=60) with history of severe PONV after one or more of previous general anesthesia, and scheduled to undergo surgical procedures with general anesthesia will be enrolled into IRB approved protocol. The patch will be placed by the patient at home 24 - 48 hours before surgery as directed by the doctor. The subsequent standardized general anesthesia protocol for elective surgery will include general endotracheal anesthesia with sevofluran, including standard intraoperative PONV prophylaxis (IV dexamethasone and IV ondansetron, each 4 mg). Postoperative evaluation will include recording of incidence and severity of PONV at the time of discharge from PACU (acute PONV), at 24 hr, 48 hrs, 72 and 120 hrs (delayed or post discharge PONV).

7.2.1 Visit 1 - Anesthesia Preoperative Evaluation Clinic and recruitment and drug dispensation Patient is seen in clinic and identified as having a history of serious PONV, in particular delayed or post discharge PONV. Study will be explained to the patient and consent obtained. The investigational pharmacy will be notified that a study patient has been enrolled and they will prepare the patches for distribution to the patient.

A member of the research team will obtain the assigned patches from the investigational pharmacy and deliver to the anesthesia provider (member of the research team).

The provider will then demonstrate to the patient how to apply the patch and the patient can practice using a placebo patch to show that the correct placement. Patient will then take the actual patch home with them.

7.2.2 Visit 2 - approximately 24-48 hours preoperatively (patient's home) Patient will apply the patch to their upper arm 24-48 hours before scheduled surgical procedure, as instructed during their pre-op anesthesia visit. The patch will then remain in place until 120 hours after surgical procedure. No backup patch will be provided so the patients with the accidently missing patch will need to call their primary surgical service for the standard antiemetic medication.

7.2.3 Visit 3- Day of Surgery Patient will arrive for surgery. A member of the research team will meet them in the SDU and record the time that the patch was applied, and if it has been placed correctly, intact and still in place. Any potential side effects (systemic or local) will be recorded at that time. The subsequent standardized general anesthesia protocol for elective surgery will include general endotracheal anesthesia with sevofluran (no nitrous oxide), muscle relaxants (with reversal), intraoperative IV opioid analgesics, including standard PONV prophylaxis (dexamethasone and ondansetron IV 4 mg).

Early postoperative evaluation will include recording of incidence and severity of PONV at the time of discharge from PACU (acute PONV). The incidence of vomiting or retching will recorded by the nursing staff. Patients with symptoms requiring a rescue antiemetic-nausea score ≥4 on an 11-point Numeric Rating Scale (NRS), retching or vomiting, or patient request-within 6 hours of PACU admission will be given the rescue medication (Benadryl or promethazine). The NRS was an 11-point linear scale on which patients rated their nausea, with 0 meaning no nausea and 10 meaning the worst possible nausea.

The subsequent evaluations will be performed either at the patient's bed (if in the hospital) or by phone call at 24 hr, 48 hrs, 72 and 120 hrs (delayed or post discharge PONV). The patient will be supplied with a diary to record the information that will be requested on the follow-up phone calls.

The primary efficacy endpoint will be complete response (CR), defined as no emetic episode and no rescue medication; the proportions of patients with no emesis and no additional rescue medication in the 120 hours following the completion of surgical procedure and the change from baseline nausea score using the NRS. Treatment-emergent adverse events (TEAEs), regardless of suspected causal relationship to the study medication, will be also recorded throughout and continued until 5 days after surgery.

7.3 Duration of Participation Patient will remain in the study until all time points have been met (maximum 5 days following surgery or 120 hours). At the end of the study the patient will remove and dispose the remaining patch.

Arms:
arm 1: Preoperative administration of granisetron transdemal patch

Interventions: intervention 1: granisetron
Intervention descriptions: intervention 1: Application granisetron transdermal patch preoperatively

Protocol document:
Prot_SAP_000.pdf: 
                                                         
HRP-592 - Protocol for
Human Subject Research
with Use of Test Article(s)
Protocol Title:
Preoperative use of granisetron transdermal patch for prevention of 
postoperative nausea and vomiting (PONV) in patients with history of severe 
PONV – open label, prospective, pilot study
Principal Investigator:
Name: Piotr K Janicki
Department: Anesthesia
Telephone: 717-531-7988
E-mail Address:pjanicki@hmc.psu.edu
Version Date:
June 14, 2017
Clinicaltrials.gov Registration #:
NCT02457195
Table of Contents
1.0
Objectives
2.0
Background
3.0
Inclusion and Exclusion Criteria
4.0
Recruitment Methods
5.0
Consent Process and Documentation
6.0
HIPAA Research Authorization and/or Waiver or Alteration of Authorization
7.0
Study Design and Procedures
8.0
Data and Specimen Banking For Future Undetermined Research
9.0
Statistical Plan
10.0
Confidentiality, Privacy and Data Management
11.0
Data and Safety Monitoring Plan
12.0
Risks
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13.0
Potential Benefits to Subjects and Others
14.0
Sharing Results with Subjects
15.0
Economic Burden to Subjects
16.0
Number of Subjects
17.0
Resources Available
18.0
Other Approvals
19.0
Subject Stipend (Compensation) and/or Travel Reimbursements
20.0
Multi-Site Research
21.0
Adverse Event Reporting
22.0
Study Monitoring, Auditing and Inspecting
23.0
References
24.0
Appendix
1.0
Objectives
1.1
Study Objectives
The objective of the study is to evaluate the efficacy and safety of adding transdermal preparation of 
granisetron (Sancuso ®) to the current postoperative nausea and vomiting (PONV) standard prophylaxis 
regimen with dexamethasone and diphenydramine  in patients with the previous history of severe, 
particularly delayed and/or post-discharge, PONV and undergoing surgical procedure under general 
anesthesia.
The specific aims of the study include: 
1.
efficacy of the investigated therapy in prevention of PONV up to 120 hours after surgery
2.
incidence and seriousness of the observed side effects
3.
ability of patients to self-administer preoperatively and maintain the investigated patch during 
the perioperative period
4.
level of satisfaction with the preoperative PONV prophylaxis.
1.2
Primary Study Endpoints
Number of complete responders (CR, defined as no nausea or vomiting/retching episodes during 120 
hours postoperatively, no additional antiemetic medication up to 120 hours after surgery)
1.3
Secondary Study Endpoints
Frequency and severity of nausea and vomiting during the observed period, patient satisfaction scores, 
length of stay, frequency of re-admission, frequency and type of side effects
2.0
Background 
2.1
Scientific Background and Gaps
Postoperative nausea and vomiting (PONV) are common and distressing symptoms to patients. 
The general incidence of vomiting is about 30%, the incidence of nausea is about 50%, and in a 
subset of high-risk patients, the PONV rate can be as high as 85%. Unresolved PONV may 
result in prolonged post anesthesia care unit (PACU) stay and unanticipated hospital admission 
that result in a significant increase in overall health care costs. The goal of PONV prophylaxis is 
therefore to decrease the incidence of PONV and thus patient-related distress and reduce health 
care costs. The major shortcoming of currently used antiemetics is their relatively short duration 
of prophylactic activity (e.g., about 4-6 hours for all 5HT3 receptor antagonists- 5HT3RA) 
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requiring its repeated dosing or, for longer acting antiemetics (e.g., scopolamine patch or 
dexamethasone), the presence of significant side effects and limited effectiveness. 
It was reported previously that IV granisetron could be more effective than other 5HT3RA 
antiemetics because of its unique metabolic pathways and stronger 5HT3 receptor affinity. It is 
therefore important to investigate if the administration of granisetron in the prolonged activity 
formulation will provide effective antiemetic prophylaxis beyond 24-48 hours after 
administration.
It is proposed that the non-invasive patch application could extend the available repertoire of the 
current 5HT3RAs oral or IV regimens in PONV.  Sancuso ® was approved by the United States 
(US) Food and Drug Administration (FDA) in September 2008, and is indicated for the 
prevention of nausea and vomiting in patients receiving moderately and/or highly emetogenic 
(HE) chemotherapy regimens of up to 5 consecutive days’ duration. The present study will 
evaluate its effectiveness in the prophylaxis of PONV.
2.2
Previous Data
Granisetron as the hydrochloride (HCl) salt has been approved as an anti-emetic and 
marketed since the early 1990s. Prior to its approval, a comprehensive development program 
was conducted and the data submitted for registration. Currently available granisetron 
formulations (oral and iv) were first marketed in the early 1990s (trade names include 
Kytril ®  and Kevatril ®). Generic oral and iv granisetron formulations are now available. 
In the extensive clinical experience gained since, these formulations have proven highly 
effective in the prevention of CINV, and no post-marketing safety concerns have arisen.
   Clinical Studies of Sancuso ® in CINV (no published work available about its effects in 
PONV)
•
A Phase I PK study (in 6 male and 6 female healthy subjects) demonstrated the 
delivery of granisetron over 5 days from a 15 cm 2 TDS applied to the abdomen. 
Mean maximum observed plasma concentration (C max ) was approximately 1.9 ng/ml 
and the approximate plateau value achieved equated to 1.1 ng/ml (392MD/4/C). 
•
A Phase I relative bioavailability study (in 12 healthy male subjects) of 4-way 
cross-over design, compared 3 dosages of Sancuso ® (15, 33 and 52 cm 2 ) after a 
single 6-day application to the upper arm, to that of a 2 mg once-daily oral dose of 
granisetron for 5 days. Data indicated that average observed plasma concentration 
(C avg ) was reached after 24 hours and maximal concentrations were reached 
48 hours after patch application. Based on C avg, a 52 cm2 TDS applied for 6 days 
resulted in a similar plasma concentration to that obtained with once-daily oral dosing 
of 2 mg granisetron. The pharmacokinetics of granisetron showed dose-proportionality 
(392MD/11/C). 
•
A Phase II study (in 175 patients receiving moderately emetogenic (ME) single-day 
chemotherapy) evaluated efficacy of Sancuso ® for the prevention of acute and 
delayed CINV. Efficacy of Sancuso ® in acute emesis was comparable to the 
reference product, a single oral dose of 2 mg granisetron; in delayed emesis, efficacy 
was no different from placebo TDS. Sancuso ® was well-tolerated (392MD/8/C). 
•
A Phase III multi-national study (in 637 patientsreceiving MEC (moderately emetogenic 
chemotherapy)  and HEC (highly emetogenic chemotherapy) multi-day 
chemotherapy) evaluated the efficacy, tolerability and safety of Sancuso ® in 
prevention of CINV associated with multi-day chemotherapy. The study 
demonstrated non-inferiority of Sancuso ® to oral granisetron in complete control (CC) 
of nausea and vomiting over the course of multi-day ME or HE chemotherapy 
(392MD/15/C and Boccia et al, 2010). 
•
A study to evaluate the skin irritation and sensitization potential of Sancuso ® in 
212 healthy subjects assessed the cumulative skin irritation and sensitization 
potential of Sancuso ® over a 21-day period. The study concluded that Sancuso® and 
its matching placebo are slightly irritant when applied on healthy skin, with a lower 
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number of subjects reporting irritation with the active Sancuso® patch. A low 
sensitization potential was detected for the active Sancuso® patch. Plasma 
concentrations in a subset of 24 subjects were assessed following the first patch 
application, resulting in the apparent dose of the patch of 3.1 mg/24 hours 
(392MD/26/C). 
A Phase I study in 12 healthy subjects investigated the pharmacokinetics, safety and 
tolerability of Sancuso® as add-on therapy to iv granisetron. The results from this 
study indicate that for multiple-day chemotherapy regimens it is possible to 
administer a single iv dose of granisetron on Day 1 (the same day that the patch is 
applied) if the patch is not applied 24-48 hours before the start of chemotherapy, 
allowing granisetron concentrations to achieve target levels immediately on Day 1 
without a subsequent effect on the known PK and safety profile of the Sancuso® 
patch over the following days (392MD/35/C). 
A Phase I study in 12 healthy subjects evaluated the PK and safety profile of the 
co-administration of iv granisetron and the Sancuso® patch, and the PK profile of 
repeat Sancuso® patch application. Following combined iv and transdermal 
administration of granisetron, the plasma concentration vs time profiles exhibited 
three peak concentrations which reflected the iv administration, the concurrent 
transdermal patch application, and the subsequent patch application one week later. 
Sustained mean concentrations of granisetron were observed over the 0 to 24 hours 
period (with a mean increase between 12 and 24 hours). Peak plasma 
concentrations relating to transdermal administration of granisetron were achieved 
approximately 48 hours after each patch application. There was minimal evidence of 
accumulation following the second transdermal administration of granisetron. 
Sancuso® was well tolerated when 2 patches were applied consecutively, each for a 
period of 7 days. Similarly, Sancuso® raised no safety concerns when 
co-administered with an iv dose of granisetron (392MD/41/C). 
A Phase I study (conducted by Solasia Pharma K.K., Japan) investigated the 
pharmacokinetics, safety and tolerability of Sancuso® in 12 healthy male Japanese 
subjects. The PK profile in healthy male Japanese subjects in this study was similar 
to that seen in a previous study in healthy male non-Japanese subjects. Changes in 
the clinical safety assessments were unremarkable and the study drug was 
well-tolerated in healthy Japanese males (SP-0101). 
A Phase I study investigated the effects of Sancuso® on electrocardiogram (ECG) 
parameters, safety and tolerability compared to placebo and moxifloxacin (positive 
control) in 240 healthy adult subjects (120 male and 120 female). No clinically 
significant effect of Sancuso® on ECG parameters was observed (392MD/39/C). 
A Phase I study evaluated the effect of age (Part I) and body mass index (BMI) 
(Part II) on the pharmacokinetics, safety and tolerability of Sancuso® , each in 
30 healthy adult subjects. Quantifiable granisetron concentrations were recorded 
between 24 and 168 hours post application of Sancuso® . Median time of the 
maximum observed plasma concentration (t max ) values ranged between 60.14 and 
72.12 hours across the 5 study groups. No statistically significant differences were 
reported between the age groups or among the BMI groups for the PK parameters of 
C max , area under the plasma concentration-time curve between time 0 and the time 
of last quantifiable sampling point (z) (AUC [0−z] ), area under the plasma 
concentration-time curve between time 0 and infinity (AUC [0−] ) and C avg . It was 
determined that the continuous variables age, BMI and age*BMI (interaction) have 
no predicting properties for these parameters (392MD/40/C). 
A Phase I study evaluated the effect of heat on the pharmacokinetics, safety and 
tolerability of Sancuso ® in 8 healthy male and 8 healthy female subjects. Heat was 
applied using a Cura-Heat ® Back & Shoulder pad with a measured local temperature 
of approximately 42⁰C (107.6⁰
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F). No overall effect of heat on the PK of Sancuso® 


2.3
Study Rationale
Clinical guidelines recommend the use of 5HT3RAs in the prevention of PONV and 
chemotherapy-induced nausea and vomiting (CINV). Granisetron is a potent 5HT3RA, with 
little or no affinity for other serotonin receptors, or for dopamine-D2, histamine-H1, 
benzodiazepine and opioid receptors. 
Oral and intravenous (iv) formulations of granisetron have been marketed for over 
15 years. They are licensed for the prevention of PONV and nausea and vomiting associated 
with initial and repeat courses of emetogenic cancer therapy, including high-dose cisplatin, 
which has a strong emetic effect in more than 90% of patients. 
ProStrakan, Limited has developed a new granisetron formulation, Sancuso® , a transdermal 
delivery system (TDS) (granisetron TDS or patch) for the prevention of CINV.  Sancuso® 
consists of a stable matrix of granisetron base (6% w/w) in a commercially-available adhesive 
(DURO-TAK ® 387-2287), designed to sustain delivery of granisetron over a number of days 
following topical application. Pharmacokinetic evaluation of Sancuso ® has indicated that it 
provides continuous delivery of granisetron over 7 days, providing exposure similar to an oral 
dose of 2 mg per day (Howell et al, 2009). Previous data indicate prolonged activity of this 
preparation in prophylaxis of CINV. There is no data available about the efficacy of this 
formulation in the prophylaxis of PONV.
It should be noted however that there is increasing concern among anesthesiologists and 
surgeons about patients displaying so called post-discharge (or late) form of PONV These 
symptoms occur at least 48-72 hours after the procedure and may last several days (often after 
patient has been already discharged from the medical facility). It is therefore feasible that the 
investigated formulation of granisetron will provide prophylactic antiemetic activity throughout 
the entire period, including acute and delayed phases of PONV.
3.0
Inclusion and Exclusion Criteria
3.1
Inclusion Criteria
o
Patients that are between the ages of 18 and 89
o
Scheduled to undergo surgical procedures with general anesthesia 
o
Seen in the anesthesia clinic at least 24 hours before surgery
o
History of severe PONV after previous general anesthesia
o
Surgical procedures with anticipated duration > 1 hour and no more than 5 hours 
o
American Society of Anesthesiologists (ASA) physical status I to III
3.2
Exclusion Criteria
o
Allergy to granisetron or other 5HT3RA drugs
o
Previous allergic reactions to any drug skin patches
o
Recent (less than 1 month) or current chemo- or radiotherapy
o
Any nausea, vomiting, or retching within 24 hours prior to anesthesia
o
Any type of eye surgeries
o
History or diagnosis of gastrointestinal obstruction or ileus
o
History of serotonin syndrome
o
Unable to sign consent
3.3
Early Withdrawal of Subjects
3.3.1
Criteria for removal from study
•
Serious surgical complications during the patch administration preventing in 
obtaining follow-up results (including re-operation, admission to intensive care unit 
with intubation, death).
•
Inability of patient of keep the transdermal patch for the entire study period (up to 
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120 hours postoperatively)
•
Development of allergic reaction or hypersensitivity
3.3.2
Follow-up for withdrawn subjects
Patients will be routinely followed-up for additional 7 days after the patch removal. 
They will be contacted by phone (if discharged) or visited on the floor (if in the 
hospital). If discharged, they will be provided with the phone number of the PI and 
research staff in case of occurrence of any problems.
4.0
Recruitment Methods
4.1
Identification of subjects
Patients will be identified by the anesthesia providers during their anesthesia pre-op visit in the 
Anesthesia Preoperative Evaluation Clinic (APEC) at Hershey Medical Center (The PI serves as 
current Medical Director of the Clinic).
4.2
Recruitment process
Patient will be asked about the history of previous general anesthesia and, if there is history of 
severe PONV (defined as need to administer additional antiemetic medication postoperatively) 
associated with previous anesthetics, in particular delayed (defined as post-PACU) or post-
discharge, the patient will be offered opportunity to enroll into the study protocol.
4.3
Recruitment materials
None will be used.  The information about previous history of PONV will be obtained during 
routine history and physical evaluation in the Clinic.
4.4
Eligibility/screening of subjects
A detailed PONV history will be used to determine occurrence/severity of previous PONV 
during patient's history and physical evaluation in the Clinic (as it is done anyway for all surgical 
patients seen in APEC). In general the eligible patients experienced 1 or more episode of PONV 
with general anesthesia requiring additional treatment in PACU or had episodes of PONV after 
discharge from PACU or discharge from hospital.
5.0
Consent Process and Documentation 
5.1
Consent Process 
The informed consent for the study will be obtained in APEC 
 
5.1.1 Obtaining Informed Consent
5.1.1.1 Timing and Location of Consent
Consent to participate will be obtained from eligible patients after 
preoperative evaluation in the Anesthesia Preoperative Evaluation Clinic 
(APEC) during the patient’s routine preoperative visit.
5.1.1.2 Coercion or Undue Influence during Consent
The patient will be advised that participation in research studies is voluntary and 
that their decision to participate or not participate will not affect the level of care at 
this institution.
5.1.2 Waiver or alteration of the informed consent requirement
Not applicable
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5.2
Consent Documentation
5.2.1
Written Documentation of Consent
We will obtain a consent form signed by the patient and the person obtaining the 
consent. An original signed copy will be retained by the patient and the research team 
and a copy will be placed in the patient’s medical record. 
5.2.2
Waiver of Documentation of Consent
Not applicable
5.3
Consent – Other Considerations 
Not applicable
6.0
HIPAA Research Authorization and/or Waiver or Alteration 
of Authorization
Authorization will be obtained and documented as part of the consent process.
7.0
Study Design and Procedures
7.1
Study Design 
This will be an open label, prospective pilot study.
7.2
Study Procedures
Patients will be recruited from the surgical population undergoing preoperative evaluation in 
Anesthesiology Preoperative Evaluation Clinic at Hershey Med. Ctr. (~15,000 per year). 
Selected patients (ASA 1-3, N=60) with history of severe PONV after one or more of previous 
general anesthesia, and scheduled to undergo surgical procedures with general anesthesia will be 
enrolled into IRB approved protocol. The patch will be placed by the patient at home 24 – 48 
hours before surgery as directed by the doctor. The subsequent standardized general anesthesia 
protocol for elective surgery will include general endotracheal anesthesia with sevofluran, 
including standard intraoperative PONV prophylaxis (IV dexamethasone and 4 mg and  
diphenydramine  25 mg ). Postoperative evaluation will include recording of incidence and 
severity of PONV at the time of discharge from PACU (acute PONV), and at 120 hrs (delayed 
or post discharge PONV).  The final phone interview will be performed 7 days after patch 
removal in order to capture possible side effects after discontinuation of medication.
7.2.1
Visit 1 - Anesthesia Preoperative Evaluation Clinic and recruitment and 
drug   dispensation
Patient is seen in clinic and identified as having a history of serious PONV, in particular 
delayed or post discharge PONV. Study will be explained to the patient and consent 
obtained.  The investigational pharmacy will be notified that a study patient has been 
enrolled and they will prepare the patches for distribution to the patient. EKG will be 
performed and the results will be recorded preoperatively.
A member of the research team will obtain the assigned patches from the investigational 
pharmacy and deliver to the anesthesia provider (member of the research team). 
The provider will then demonstrate to the patient how to apply the patch and the patient 
can practice using a placebo patch to show that the correct placement. Patient will then 
take the actual patch home with them.  Patient will also be given a PONV diary to take 
home with them.  Upon returning home from surgery, the patient will be asked to record 
their instances of nausea and vomiting on a daily basis for up to five days after surgery.  
At hour 120 post-op, a case manager will telephone the patient and note any recorded 
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instances of nausea and vomiting since the patient has returned home.  The case 
manager will also check the status of the patch and any medications that were taken as a 
result of nausea and vomiting.  One week after removal of patch (120h post-op + 7 
days), a case manager will call the patient a final time to collect adverse events and to 
assess patient satisfaction with the patch.
7.2.2
Visit 2 - approximately 24-48 hours preoperatively (patient’s home)
Patient will apply the patch to their upper arm 24-48 hours before scheduled surgical 
procedure, as instructed during their pre-op anesthesia visit. The patch will then remain 
in place until 120 hours after surgical procedure. No backup patch will be provided so 
the patients with the accidently missing patch will need to call their primary surgical 
service for the standard antiemetic medication.
7.2.3
Visit 3- Day of Surgery
Patient will arrive for surgery.  A member of the research team will meet them in the 
SDU and record the time that the patch was applied, and if it has been placed correctly, 
intact and still in place. Any potential side effects (systemic or local) will be recorded at 
that time. The subsequent standardized general anesthesia protocol for elective surgery 
will include general endotracheal anesthesia with sevofluran (no nitrous oxide), muscle 
relaxants (with reversal), intraoperative IV opioid analgesics, including standard PONV 
prophylaxis (dexamethasone and diphenydramine  25 mg IV ).  
Early postoperative evaluation will include recording of incidence and severity of 
PONV at the time of discharge from PACU (acute PONV). The incidence of vomiting 
or retching will recorded by the nursing staff. Patients with symptoms requiring a rescue 
antiemetic—nausea score ≥4 on an 11-point Numeric Rating Scale (NRS), retching or 
vomiting, or patient request—within 6 hours of PACU admission will be given the first 
line rescue medication promethazine IV 6.25mg as per current standard of care. 
Promethazine will be used as slow infusion bolus (over 5-10 min) in large, good flowing 
peripheral IV. If the first line rescue medication does not work the patient will be given 
ondansetron 4 mg IV). The NRS is an 11-point linear scale on which patients rate their 
nausea, with 0 meaning no nausea and 10 meaning the worst possible nausea. 
The subsequent evaluations will be performed either at the patient's bed (if in the 
hospital) or by phone call at 120 hrs (delayed or post discharge PONV). The patient will 
be supplied with a diary to record the information that will be requested on the follow-
up phone calls.
The primary efficacy endpoint will be complete response (CR), defined as no emetic 
episode and no rescue medication; the proportions of patients with no emesis and no 
additional rescue medication in the 120 hours following the completion of surgical 
procedure and the change from baseline nausea score using the NRS. Treatment-
emergent adverse events (TEAEs), regardless of suspected causal relationship to the 
study medication, will be also recorded throughout and continued until 5 days after 
surgery. 
7.2.4
Visit 3- Follow-up for possible side-effects
The patient will be contacted by phone to record any possible side-effects they may have 
experienced since the removal of the patch.
7.3
Duration of Participation
Patient will remain in the study until the final follow-up phone call has been made (7 days 
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following removal of the patch).
7.4
Test Article(s) (Study Drug(s) and/or Study Device(s))
7.4.1
Description
Granisetron transdermal delivery system - Sancuso® 
7.4.2
Treatment Regimen
Study Subjects will receive one patch and it will be applied to the upper arm. The patch 
will stay in place for 120 hours postoperatively.
7.4.3
Method for Assigning Subject to Treatment Groups
This is an open label study –all study participants will be receiving the patch with the 
actual medication.
7.4.4
Subject Compliance Monitoring
The presence of the undamaged patch will be confirmed the day of surgery and at the 
time of discharge.
 
7.4.5
Blinding of the Test Article
Not applicable
7.4.6
Receiving, Storage, Dispensing and Return 
7.4.6.1 Receipt of Test Article 
Patches will be obtained from ProStrakan, LTD. and delivered to the 
Investigational Pharmacy at Hershey Medical Center.
7.4.6.2 Storage
Stability studies with 15 cm² Sancuso ® patches made at the development site, 
stored for 6 months at 40°C/75% relative humidity (RH) and for 36 months at 
25°C/60% RH have been completed. Stability studies with 52 cm² Sancuso
 
® 
patches, made at the development site, using the same adhesive matrix 
formulation and stored for 24 months at 25°C/60% RH have been completed.
Stability studies with 52 cm²
 
Sancuso
 
® patches, made at the commercial 
manufacturing site, using the same adhesive matrix formulation and the 
proposed commercial format have been completed,  having  reached 6 months 
storage at 40ºC/75% RH and 36 months storage at 25ºC/60% and 30ºC/65% 
RH.
Taking into account the stability data available, a shelf life of 36 months is 
assigned to the finished product. Each individual Sancuso
 
® patch is supplied in 
a pouch; it is recommended to store pouches at or below 25°C and out of 
direct sunlight, although labels for product supplied in the US will 
currently include the statement “Store at 20 - 25°C (68°-77°F); excursions 
permitted between 15°- 30°C (59°- 86°F). [See United States Pharmacopeia 
(USP) Controlled Room Temperature]”.
7.4.6.3 Preparation and Dispensing
Upon enrollment, the PI will write a prescription for the patch and that will 
be faxed to the pharmacy. The pharmacy will assign a patch to the patient 
and a member of the research team will pick that up from the pharmacy 
and deliver it to the anesthesiologist (research team member). The provider 
will then educate the patient on how to apply the patch to the upper arm 
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area. The patient will have the opportunity to practice applying the patch 
using a placebo patch (supplied by the sponsor). The patient will then take 
the patch home and apply at minimum 24 – 48 hours before surgery as 
hours (no longer than 48 hours) before surgery.
7.4.6.4 Return or Destruction of the Test Article
The test article will be disposed by the patient to regular waste
7.4.6.5  Prior and Concomitant Therapy
Patient will be on no antiemetic medication at the time of enrollment. After 
application of the patch each patient will obtain standard PONV 
prophylaxis in OR consisting of IV dexamethasone 4 mg. and 
diphenydramine 25 mg IV. The first line rescue medication will be 
Promethazine IV 6.25 mg as per current standard of care. Promethazine 
will be used as slow infusion bolus (over 5-10 min) in large, good flowing 
peripheral IV.  If this line of rescue medication does not work the patient 
will receive ondansetron 4 mg IV. 
 
8.0
Data and Specimen Banking For Future Undetermined 
Research
Not applicable
9.0
Statistical Plan
9.1
Sample size determination
We are planning an open label study of cases treated with granisetron patch (no comparison 
group, historical control group). Prior data indicate that the failure rate (at least 1 x PONV 
postoperatively or administration of additional antiemetics) among patients with severe PONV 
is 0.85.  If the true failure rate for experimental subjects is 0.4 (decrease of incidence of PONV 
by half), we will need to study 60 experimental subjects to be able to reject the null hypothesis 
that the failure rates for experimental subjects is equal to historical control with probability 
(power) 0.8.   The Type I error probability associated with this test of this null hypothesis is 
0.05.  We will use an uncorrected chi-squared statistic to evaluate this null hypothesis.
9.2
Statistical methods
The Type I error probability associated with this test of this null hypothesis is 0.05.  We will use 
an uncorrected chi-squared statistic to evaluate this null hypothesis.
10.0
Confidentiality, Privacy and Data Management 
See attached Research Data Plan Review form
 
11.0
Data and Safety Monitoring Plan
This is a low risk therapeutic study with an agent with a known safety profile.
11.1
Periodic evaluation of data
The PI and research coordinator will review cumulative adverse events, early termination of study 
participation, and accrual every six months and report any issues requiring modification of the study or 
alteration of the risk:benefit ratio to the IRB immediately.  A summary of adverse events, study progress 
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and protocol modifications will be included for IRB review in the continuing review.
11.2
Data that are reviewed 
The data to be reviewed will be:
•
Safety data
•
Untoward events
•
Efficacy data
11.3
Method of collection of safety information
Safety information will be collected by the research staff preoperatively and post operatively as 
described in Section 7.2.
11.4
Frequency of data collection
Data and adverse events assessments begin after the patch is placed on the subject.  The research 
staff will evaluate the subject preoperatively on the day of surgery and then follow 
postoperatively with a personal or phone interview 120 hours postoperatively when the patch is 
removed. A second and final phone interview will be performed 7 days after patch removal. 
11.5
Individual’s reviewing the data
Oversight for the conduct of the study will be provided by the PI and the research coordinator will 
monitor the data. They will ensure that all eligible criteria and consent requirements are met prior to a 
subjects’ participation in the study and that the procedures and adverse event reporting occur according 
to the IRB approved protocol.
11.6
Frequency of review of cumulative data
The PI and research coordinator will review cumulative adverse events, early termination of 
study participation, and accrual every six months and report any issues requiring modification of 
the study or alteration of the risk:benefit ratio to the IRB immediately.  A summary of adverse 
events, study progress and protocol modifications will be included for IRB review in the 
continuing review.
11.7
Statistical tests
Not applicable
11.8
Suspension of research
The decision to suspend research will be based on the assessment of all serious adverse events for 
causality and the decision to stop the trial definitively would be based on the related events that are 
unexpected and change in frequency of events.
12.0
Risks
12.1 CONTRAINDICATIONS
Sancuso is contraindicated in patients with known hypersensitivity to granisetron or to any of the 
components of the patch.
12.2 WARNINGS AND PRECAUTIONS
12.2.1 Gastrointestinal
The use of granisetron in patients may mask a progressive ileus and/or gastric distention 
caused by the underlying condition.
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12.2.2 Skin Reactions
In clinical trials with Sancuso, application site reactions were reported that were 
generally mild in intensity and did not lead to discontinuation of use.  The incidence of 
reactions was comparable with placebo.  
If severe reactions, or a generalized skin reaction occur (e.g., allergic rash, including 
erythematous, macular, papular rash or pruritus), the patch must be removed.
12.2.3 Exposure to Sunlight
Granisetron may be affected by direct natural or artificial sunlight. Patients must be 
advised to cover the patch application site, e.g. with clothing, if there is a risk of 
exposure to sunlight throughout the period of wear and for 10 days following its removal 
because of a potential skin reaction [see Nonclinical Toxicology (13.3)].
12.2.4 Serotonin Syndrome
The development of serotonin syndrome has been reported with 5-HT3 receptor 
antagonists.  Most reports have been associated with concomitant use of serotonergic 
drugs (e.g., selective serotonin reuptake inhibitors (SSRIs), serotonin and norepinephrine 
reuptake inhibitors (SNRIs), monoamine oxidase inhibitors, mirtazapine, fentanyl, 
lithium, tramadol, and intravenous methylene blue). Some of the reported cases were 
fatal. Serotonin syndrome occurring with overdose of another 5-HT3 receptor antagonist 
alone has also been reported. The majority of reports of serotonin syndrome related to 5-
HT3 receptor antagonist use occurred in a post-anesthesia care unit or an infusion center.
Symptoms associated with serotonin syndrome may include the following combination 
of signs and symptoms: mental status changes (e.g., agitation, hallucinations, delirium, 
and coma), autonomic instability (e.g., tachycardia, labile blood pressure, dizziness, 
diaphoresis, flushing, hyperthermia), neuromuscular symptoms (e.g., tremor, rigidity, 
myoclonus, hyperreflexia, incoordination), seizures, with or without gastrointestinal 
symptoms (e.g., nausea, vomiting, diarrhea). Patients should be monitored for the 
emergence of serotonin syndrome, especially with concomitant use of Sancuso and other 
serotonergic drugs. If symptoms of serotonin syndrome occur, discontinue Sancuso and 
initiate supportive treatment. Patients should be informed of the increased risk of 
serotonin syndrome, especially if Sancuso is used concomitantly with other serotonergic 
drugs. 
12.2.5 External Heat Sources
A heat pad should not be applied over or in vicinity of Sancuso patch. Patients should 
avoid prolonged exposure to heat as plasma concentration continues increasing during 
the period of heat exposure 
12.3 ADVERSE REACTIONS
12.3.1 Clinical Trials Experience
Because clinical trials are conducted under widely varying conditions, adverse reaction 
rates observed in the clinical trials of a drug cannot be directly compared to rates in the 
clinical trials of another drug and may not reflect the rates observed in clinical practice.
The safety of Sancuso was evaluated in a total of 404 patients undergoing chemotherapy 
who participated in two double-blind, comparator studies with patch treatment durations 
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of up to 7 days.  The control groups included a total of 406 patients who received a daily 
dose of 2 mg oral granisetron, for 1 to 5 days. 
Adverse reactions occurred in 8.7% (35/404) of patients receiving Sancuso and 7.1% 
(29/406) of patients receiving oral granisetron.  The most common adverse reaction was 
constipation that occurred in 5.4% of patients in the Sancuso group and 3.0% of patients 
in the oral granisetron group. 
Table 1 lists the adverse reactions that occurred in at least 3% of patients treated with 
Sancuso or oral granisetron.
Table 1:  Incidence of Adverse Reactions in Double-Blind, Active Comparator 
Controlled Studies in Cancer Patients Receiving Chemotherapy (Events  3% in 
either group)
Body System
Preferred Term
Sancuso TDS
N=404
(%)
Oral granisetron
N=406
(%)
Gastrointestinal disorders
Constipation
5.4
3.0
Nervous system disorders
Headache
0.7
3.0
5-HT3 receptor antagonists, such as granisetron, may be associated with 
arrhythmias or ECG abnormalities. Three ECGs were performed on 588 
patients in a randomized, parallel group, double-blind, double-dummy 
study: at baseline before treatment, the first day of chemotherapy, and 5 to 7 
days after starting chemotherapy.  QTcF prolongation greater than 450 
milliseconds was seen in a total of 11 (1.9%) patients after receiving 
granisetron, 8 (2.7%) on oral granisetron, and 3 (1.1%) on the patch. No 
new QTcF prolongation greater than 480 milliseconds was observed in any 
patient in this study. No arrhythmias were detected in this study.
 Adverse reactions reported in clinical trials with other formulations of 
granisetron include the following:  
Gastrointestinal: abdominal pain, diarrhea, constipation, elevation of ALT 
and AST levels, nausea and vomiting 
Cardiovascular: hypertension, hypotension, angina pectoris, atrial 
fibrillation and syncope have been observed rarely
Central Nervous System: dizziness, insomnia, headache, anxiety, 
somnolence and asthenia
Hypersensitivity: rare cases of hypersensitivity reactions, sometimes severe 
(e.g. anaphylaxis, shortness of breath, hypotension, urticaria) have been 
reported
Other: fever; events often associated with chemotherapy have also been 
reported:  leucopenia, decreased appetite, anemia, alopecia, 
thrombocytopenia.
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12.3.2Postmarketing Experience


The following adverse reactions have been identified during post approval 
use of Sancuso. Because these reactions are reported voluntarily from a 
population of uncertain size, it is not always possible to reliably estimate 
their frequency or establish a causal relationship to drug exposure.
General Disorders and Administration Site Conditions: Application site reactions (pain, 
pruritus,  erythema, rash, application site irritation, vesicles.
Cardiac Disorders:  bradycardia, chest pain, palpitations, sick sinus syndrome
12.4 DRUG INTERACTIONS
Granisetron does not induce or inhibit the cytochrome P-450 drug-metabolizing enzyme system 
in vitro.  There have been no definitive drug-drug interaction studies to examine 
pharmacokinetic or pharmacodynamic interaction with other drugs.  However, in humans, 
granisetron hydrochloride injection has been safely administered with drugs representing 
benzodiazepines, neuroleptics and anti-ulcer medications commonly prescribed with antiemetic 
treatments.   Granisetron hydrochloride injection also does not appear to interact with 
emetogenic cancer therapies.  In agreement with these data, no clinically relevant drug 
interactions have been reported in clinical studies with Sancuso.
Because granisetron is metabolized by hepatic cytochrome P-450 drug-metabolizing enzymes 
(CYP1A1 and CYP3A4), inducers or inhibitors of these enzymes may change the clearance and 
hence, the half-life of granisetron.  In addition, the activity of the cytochrome P-450 subfamily 
3A4 (involved in the metabolism of some of the main narcotic analgesic agents) is not modified 
by granisetron hydrochloride in vitro. In in vitro human microsomal studies, ketoconazole 
inhibited ring oxidation of granisetron hydrochloride.  However, the clinical significance of in 
vivo pharmacokinetic interactions with ketoconazole is not known.  In a human pharmacokinetic 
study, hepatic enzyme induction with phenobarbital resulted in a 25% increase in total plasma 
clearance of intravenous granisetron hydrochloride.  The clinical significance of this change is 
not known.
Serotonin syndrome (including altered mental status, autonomic instability, and neuromuscular 
symptoms) has been described following the concomitant use of 5-HT3 receptor antagonists and 
other serotonergic drugs, including selective serotonin reuptake inhibitors (SSRIs) and serotonin 
and noradrenaline reuptake inhibitors (SNRIs).
12.5  Loss of confidentiality 
 There is a possible risk of loss of confidentiality,  however we will take every 
precaution to protect your private health information.
13.0
Potential Benefits to Subjects and Others
13.1
Potential Benefits to Subjects
Patients enrolled into the study might experience less PONV (in particular delayed and post-
discharge) postoperatively
13.2
Potential Benefits to Others
This study may lead to an effective option to PONV therapy in the future.
14.0
Sharing Results with Subjects
Results will not be shared with the study subjects.
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15.0
Economic Burden to Subjects
15.1
Costs 
There are no additional costs to the study subjects to participate in this study.
15.2
Compensation for research-related injury
It is the policy of the institution to provide neither financial compensation nor free medical 
treatment for research-related injury. In the event of injury resulting from this research, medical 
treatment is available but will be provided at the usual charge. Costs for the treatment of 
research-related injuries will be charged to subjects or their insurance carriers. 
16.0
Number of Subjects
We require 60 evaluable patients, with an enrollment of up to 80 patients which would include a 
potential of 20 screen failures. 
17.0
Resources Available
17.1
Facilities and locations
Hershey Medical Center, Hershey, PA
17.2
Feasibility of recruiting the required number of subjects
Patients will be recruited from the surgical population undergoing preoperative evaluation in 
Preoperative Evaluation Clinic at Hershey Med. Ctr. (~15,000 per year)
17.3
PI Time devoted to conducting the research
PI is the Medical Director of APEC
17.4
Availability of medical or psychological resources
Not applicable
17.5 Process for informing Study Team
Meetings will be held periodically as needed to ensure al research team members are informed about the 
protocol and their duties.  Team emails will be used to keep team members up to date on study progress 
and modifications.
18.0
Other Approvals
Approvals will be received from ProStrakan and the FDA (IND)
19.0
Subject Stipend (Compensation) and/or Travel 
Reimbursements
Not applicable
20.0
Multi-Site Research
Not applicable.
21.0
Adverse Event Reporting
21.1
Adverse Event Definitions
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For drug studies, incorporate the following definitions into the below 
responses, as written:
Adverse event
Any untoward medical occurrence associated with the use of the drug in 
humans, whether or not considered drug related
Adverse reaction
Any adverse event caused by a drug
Suspected 
adverse reaction
Any adverse event for which there is a reasonable possibility that the drug 
caused the adverse event.  Suspected adverse reaction implies a lesser 
degree of certainty about causality than “adverse reaction”.
•
Reasonable possibility.  For the purpose of IND safety reporting, 
“reasonable possibility” means there is evidence to suggest a 
causal relationship between the drug and the adverse event.
Serious adverse 
event or Serious 
suspected 
adverse reaction
Serious adverse event or Serious suspected adverse reaction: An 
adverse event or suspected adverse reaction that in the view of either the 
investigator or sponsor, it results in any of the following outcomes: 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. Important medical events that may not 
result in death, be life-threatening, or require hospitalization may be 
considered serious 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. 
Life-threatening 
adverse event or 
life-threatening 
suspected 
adverse reaction
An adverse event or suspected adverse reaction is considered “life-
threatening” if, in the view of either the Investigator (i.e., the study site 
principal investigator) or Sponsor, its occurrence places the patient or 
research subject at immediate risk of death.  It does not include an 
adverse event or suspected adverse reaction that had it occurred in a 
more severe form, might have caused death.
Unexpected 
adverse event or 
Unexpected 
suspected 
adverse reaction.  
An adverse event or suspected adverse reaction is considered 
“unexpected” if it is not listed in the investigator brochure, general 
investigational plan, clinical protocol, or elsewhere in the current IND 
application; or is not listed at the specificity or severity that has been 
previously observed and/or specified.
For device studies, incorporate the following definitions into the below 
responses, as written:
Unanticipated 
adverse device 
effect
Any serious adverse effect on health or safety or any life-threatening 
problem or death caused by, or associated with, a device, if that effect, 
problem, or death was not previously identified in nature, severity, or 
degree of incidence in the investigational plan or IDE application 
(including a supplementary plan or application), or any other 
unanticipated serious problem associated with a device that relates to the 
rights, safety, or welfare of subjects.
21.2
Recording of Adverse Events
All adverse events (serious or non-serious) and abnormal test findings observed or reported to 
study team believed to be associated with the study drug(s) or device(s) will be followed until 
the event (or its sequelae) or the abnormal test finding resolves or stabilizes at a level acceptable 
to the investigator. All adverse events (including those labeled) will be recorded in each patients 
Case Report Form and evaluated for relationship to study drug, severity, date of onset, date of 
resolution and outcome.
An abnormal test finding will be classified as an adverse event if one or more of the following 
criteria are met:
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•
The test finding is accompanied by clinical symptoms
•
The test finding necessitates additional diagnostic evaluation(s) or medical/surgical 
intervention; including significant additional concomitant drug treatment or other 
therapy
Note: Simply repeating a test finding, in the absence of any of the other listed 
criteria, does not constitute an adverse event.  
•
The test finding leads to a change in study drug dosing or discontinuation of subject 
participation in the clinical research study
The test finding is considered an adverse event by the investigator.
21.3
Causality and Severity Assessments
The investigator will promptly review documented adverse events and abnormal test findings to 
determine 1) if the abnormal test finding should be classified as an adverse event; 2) if there is a 
reasonable possibility that the adverse event was caused by the study drug(s) or device(s); and 3) 
if the adverse event meets the criteria for a serious adverse event.
If the investigator’s final determination of causality is “unknown and of questionable 
relationship to the study drug(s) or device(s)”, the adverse event will be classified as associated 
with the use of the study drug(s) or device(s) for reporting purposes.  If the investigator’s final 
determination of causality is “unknown but not related to the study drug(s) or device(s)”, this 
determination and the rationale for the determination will be documented in the respective 
subject’s case history.
21.4
Reporting of Adverse Reactions and Unanticipated Problems to the FDA  
21.4.1 Written IND Safety Reports
The Sponsor-Investigator will submit a written IND Safety Report (i.e., completed FDA 
Form 3500A) to the responsible new drug review division of the FDA for any observed 
or volunteered adverse event that is determined to be a serious and unexpected, 
suspected adverse reaction.  Each IND Safety Report will be prominently labeled, “IND 
Safety Report”, and a copy will be provided to all participating investigators (if 
applicable) and sub-investigators.
Written IND Safety Reports will be submitted to the FDA as soon as possible and, in no 
event, later than 15 calendar days following the Sponsor-Investigator’s receipt of the 
respective adverse event information and determination that it meets the respective 
criteria for reporting.
For each written IND Safety Report, the Sponsor-Investigator will identify all 
previously submitted IND Safety Reports that addressed a similar suspected adverse 
reaction experience and will provide an analysis of the significance of newly reported, 
suspected adverse reaction in light of the previous, similar report(s) or any other 
relevant information.
Relevant follow-up information to an IND Safety Report will be submitted to the 
applicable review division of the FDA as soon as the information is available and will 
be identified as such (i.e., “Follow-up IND Safety Report”).
If the results of the Sponsor-Investigator’s follow-up investigation show that an adverse 
event that was initially determined to not require a written IND Safety Report does, in 
fact, meet the requirements for reporting; the Sponsor-Investigator will submit a written 
IND Safety Report as soon as possible, but in no event later than 15 calendar days, after 
the determination was made.
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21.4.2 Telephoned IND Safety Reports – Fatal or Life-threatening Suspected 
Adverse Reactions
In addition to the subsequent submission of a written IND Safety Report (i.e., completed 
FDA Form 3500A), the Sponsor-Investigator will notify the responsible review division 
of the FDA by telephone or facsimile transmission of any unexpected, fatal or life-
threatening suspected adverse reaction. 
The telephone or facsimile transmission of applicable IND Safety Reports will be made 
as soon as possible but in no event later than 7 calendar days after the Sponsor-
Investigator’s receipt of the respective adverse event information and determination that 
it meets the respective criteria for reporting.
21.5
Reporting Adverse Reactions and Unanticipated Problems to the Responsible 
IRB
In accordance with applicable policies of The Pennsylvania State University Institutional 
Review Board (IRB), the investigator will report, to the IRB, any observed or reported harm 
(adverse event) experienced by a subject or other individual, which in the opinion of the 
investigator is determined to be (1) unexpected; and (2) probably related to the research 
procedures. Harms (adverse events) will be submitted to the IRB in accordance with the IRB 
policies and procedures.
21.6
Reporting Adverse Reactions and Unanticipated Problems to ProStrakan, Ltd.
The investigator will also provide ProStrakan with a copy of the FDA form 3500A completed 
for all serious adverse events.  The information will include the investigator’s assessment of 
causality.  This information will be sent to the Company within 10 days of receipt of the adverse 
event reported by the investigator.  A copy of the completed FDA 3500A form submitted to the 
FDA will be sent to Drugsafety@prostrakan.com.  The company will enter all safety 
information in the Global Safety Database along with the investigator’s assessment of 
relationship of the event to the study medication.  Any follow up information will also be sent to 
the Company within 10 days of receipt of the information by the Investigator on a completed 
FDA 3550A form. The investigator agrees to respond to questions from the Company regarding 
reports of serious adverse events and for clarification of adverse event information submitted.
21.7
Unblinding Procedures
Not applicable
21.8
Stopping Rules
The decision to suspend research will be based on the assessment of all serious adverse events 
for causality and the decision to stop the trial definitively wold be based on the related events that are 
unexpected and change in frequency of events.
22.0
Study Monitoring, Auditing and Inspecting
22.1
Study Monitoring Plan
22.1.1 Quality Assurance and Quality Control
The protocol data will be recorded on data collection forms by trained research staff via 
participant interview, telephone survey, and electronic medical record abstraction. The 
participant will complete a paper daily diary. The data will be double-data entered into 
REDCap (Research Electronic Data Capture application) in a timely fashion.  Data 
validation error checks will be programmed into REDCap to minimize the entry of 
erroneous data. Data entry discrepancies will be reviewed and resolved by a Clinical 
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Research Coordinator. 
Data monitoring will be conducted by Data Management staff in the Department of 
Public Health Sciences. During the monitoring visits the PHS staff will verify the 
presence of all essential and regulatory documents, review the participant informed 
consents, perform source document verification, confirm the eligibility criteria for all 
participants, audit the accuracy of data stored in REDCap against the data collection 
forms, compare adverse events and concomitant medications recorded against the 
electronic medical record, ensure that all protocol deviations/violations are recorded, 
determine the timeliness of data entry, and ensure that all data errors have been resolved. 
The initial data monitoring visit will occur after five participants have completed the 
study. The frequency of monitoring will continue to be evaluated based upon previous 
findings, protocol changes, changes in the research team, or indications of poor data 
quality or participant safety issues.
22.1.2 Safety Monitoring
The Principal Investigator will confirm that all adverse events (AE) are correctly 
recorded on the AE data collection forms by the research coordinators; be available to 
answer any questions that the research coordinators may have concerning the AEs; and 
will notify the IRB, FDA, sponsor, Company and/or DSMB of all applicable AEs as 
appropriate.  All assessments of AEs will be made by a licensed medical professional 
who is an investigator on the study.
The research coordinators will complete the appropriate AE forms and assist the 
Principal Investigator in preparing reports to the IRB, FDA, Company and/or DSMB of 
all Unanticipated Problems/Serious Adverse Events (SAEs).
The Public Health Sciences Data Monitoring staff will confirm that the AEs are 
correctly recorded on the data collection forms and entered into the REDCap database.  
The monitor will confirm that the AEs are consistent with the source documents are 
reported to the appropriate regulatory bodies in the timeframe required.
23.0
References
Bloomer, J.C. et al. Characterisation of the cytochrome P450 enzymes involved in the in
vitro metabolism of granisetron. Br J Clin Pharmacol 1994; 38: 557-66.
Blower, P.R. 5-HT 3 receptor antagonists and the cytochrome P450 system: clinical
implications. Cancer J 2002; 8: 405-14.
Boccia, R.V. et al. Efficacy and tolerability of transdermal granisetron for the control of
chemotherapy-induced nausea and vomiting associated with moderately and highly
Emetogenic multi-day chemotherapy: a randomised, double-blind, phase III study.
Support Care Cancer 2010; Sep 12.
Clark, R.A. and Gralla R.J. Delayed emesis: a dilemma in antiemetic control. Support
Care Cancer 1993; 4: 182-5.
Clarke, S.E. et al. Metabolism and disposition of 14 C-granisetron in rat, dog and man
after intravenous and oral dosing. Xenobiotica 1994; 24: 1119-31.
Cupissol, D. et al. Evaluation of the bioequivalence of tablet and capsule formulations of
granisetron in patients undergoing cytotoxic chemotherapy for malignant disease. J.
Pharm Sci 1993; 82: 1281-14.
Approval: 2/1/2019


Duggan S.T. and Curran M.P. Transdermal granisetron. Drugs 2009; 69(18): 2597-605.
EMA 2007 Guideline on non-clinical and clinical development of medicinal products for
the treatment of nausea and vomiting associated with cancer chemotherapy.
GPMP/EWP/4937/03.
Gan TJ, Diemunsch P, Habib AS, Kovac A, Kranke P, Meyer TA, Watcha M, Chung F,
Angus S, Apfel CC, Bergese SD, Candiotti KA, Chan MT, Davis PJ, Hooper VD,
Lagoo-Deenadayalan S, Myles P, Nezat G, Philip BK, Tramèr MR; Society for
Ambulatory Anesthesia. Consensus guidelines for the management of postoperative
nausea and vomiting. Anesth Analg. 2014 Jan;118(1):85-113.
Gregory, R.E. et al. 5-HT 3 receptor antagonists for the prevention of CINV; a comparison
of their pharmacology and clinical efficacy. Drugs 1998; 55: 173-89.
Howell J. et al. Pharmacokinetics of a granisetron transdermal system for the treatment
of chemotherapy-induced nausea and vomiting. J Oncol Pharm Pract 2009; 5: 223–31.
Janicki PK, Sugino S. Genetic factors associated with pharmacotherapy and
background sensitivity to postoperative and chemotherapy-induced nausea and
vomiting. Exp Brain Res. 2014 Aug;232(8):2613-25. doi: 10.1007/s00221-014-3968-z.
Epub 2014 May 4. PubMed PMID: 24792505.
Janicki PK, Schuler HG, Jarzembowski TM, Rossi M 2nd. Prevention of
postoperative nausea and vomiting with granisetron and dolasetron in relation to 
CYP2D6 genotype. Anesth Analg. 2006 Apr;102(4):1127-33. PubMed PMID: 16551910.
Janicki PK. Cytochrome P450 2D6 metabolism and 5-hydroxytryptamine type 3
receptor antagonists for postoperative nausea and vomiting. Med Sci Monit. 2005
Oct;11(10):RA322-8. Epub 2005 Sep 26. Review. PubMed PMID: 16192915.
PHARMO Institute for Drug Outcomes Research, 2012. Retrospective Observational
Study Evaluating SANCUSO® (granisetron transdermal patch) Use using Medical
Records Data in the Netherlands. [Protocol].
Nakamura, H. et al. CYP1A1 is a major enzyme responsible for the metabolism of
granisetron in human liver microsomes. Curr Drug Metabol 2005; 6: 469-80.
Tuca A. Use of granisetron transdermal system in the prevention of chemotherapy-
induced nausea and vomiting: a review. Cancer Manag Res 2009; 2: 1-12.
24.0
Appendix
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