A Phase IV, Real World Observational Study On The Use Of Akynzeo® (Netupitant/Palonosetron) For The Prevention Of Nausea and Vomiting in Oncology Patients Receiving Highly Emetogenic Chemotherapy (HEC) Over Multiple Cycles.
Conditions: Chemotherapy-Induced Nausea and Vomiting
Sponsor: Purdue Pharma, Canada

CONFIDENTIALITY STATEMENT 
This document contains confidential information owned by the study Sponsor and/or its independent associated companies. Any 
viewing or disclosure of such information that is not authorized in writing by the Sponsor and/or its independent associated 
companies is strictly prohibited unless such disclosure is required by applicable law or regulations. Such information may be used 
solely for the purpose of reviewing or performing this study. In any event, persons to whom the information is disclosed must be 
informed that the information is privileged or confidential and may not be further disclosed by them. These restrictions on disclosure 
will apply equally to all future information supplied that is indicated as privileged or confidential. 
 
 
 
 
Protocol No. CAN-PRO-NEPA-001 
 
 
A Phase IV, Real World Observational Study On The Use Of Akynzeo® 
(netupitant/palonosetron) For The Prevention Of Nausea and Vomiting in Oncology 
Patients Receiving Highly Emetogenic Chemotherapy (HEC) Over Multiple Cycles. 
 
 
  
 
 
Dr. Tom Koutsavlis, MD, MSc, FRCPC, MBA 
VP, Research and Development and Medical Affairs 
 
 
 
________________________________________________________ 
Signature of Sponsor Representative 
Date: (DD-MMM-YYYY) 
 
SPONSOR: 
PURDUE PHARMA 
575 Granite Court 
Pickering, ON   
L1W 3W8  
Tel: 
905-420-6400 
 
1-800-387-5349 
Fax: 
905-420-2503 
Study Product: 
Akynzeo® (netupitant/palonosetron) 
Version: 
Version 1: 05 June 2018  
NCT03649230

Akynzeo® 
Protocol Number: CAN-PRO-NEPA-001 
 
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PURDUE PERSONNEL 
 
Study Manager, Medical Affairs: 
 
 
 
 
 
Loretta Belle Blagrove, RN, BScN, CCRP 
Associate Director, Medical Research 
Office: (905) 420-0905 
Mobile: (905) 409-2379 
Email address: Loretta.BelleBlagrove@Purdue.ca 
 
Medical Director, Medical Affairs 
Jodan Ratz 
Director, Medical Affairs-CNS & Specialty 
Office: (905) 420-4965 
Mobile: (647) 882-4073 
Email address: Jodan.Ratz@Purdue.ca 
 

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TABLE OF CONTENTS 
LIST OF ABBREVIATIONS ....................................................................................................... 7 
INVESTIGATOR AGREEMENT ................................................................................................ 9 
STUDY SYNOPSIS ..................................................................................................................10 
1 
INTRODUCTION ...........................................................................................................14 
1.1 
Background Information ..........................................................................................14 
1.2 
Rationale for the Study .............................................................................................14 
1.3 
Study Drug - Combination of Palonosetron and Netupitant ..................................15 
1.4 
Clinical Studies .........................................................................................................16 
1.5 
Study Population ......................................................................................................18 
2 
STUDY OBJECTIVES ...................................................................................................18 
2.1  
Primary Outcome: Functional Living Index - Emesis (FLIE) ..................................19 
2.2 
Secondary Outcomes ...............................................................................................19 
2.3  
Exploratory Outcomes..............................................................................................19 
3 
STUDY DESIGN ...........................................................................................................19 
3.1 
Study Overview .........................................................................................................19 
3.2 
Study Sites ................................................................................................................20 
3.3 
Sample Size ...............................................................................................................20 
3.4 
Primary Endpoint ......................................................................................................20 
3.5 
Secondary Endpoints ...............................................................................................20 
3.6 
Exploratory Endpoints..............................................................................................21 
3.7 
Safety Assessment ...................................................................................................21 
4 
SUBJECT SELECTION AND WITHDRAWAL ..............................................................21 
4.1 
Inclusion Criteria.......................................................................................................21 
4.2 
Exclusion Criteria .....................................................................................................21 
4.3 
Subject Recruitment and Pre-Screening .................................................................22 
4.4 
Subject Withdrawal Criteria .....................................................................................22 
5 
STUDY PRODUCT ........................................................................................................22 
5.1 
Dosage and Administration .....................................................................................22 
5.2 
Concomitant Medication(s) ......................................................................................22 
6 
STUDY PROCEDURES ................................................................................................23 

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6.1 
Visit 1 / Screening (28 to 0 days prior to visit 2) .....................................................23 
6.2 
Visit 2 (1st Day of cycle 1) .........................................................................................23 
6.3 
Visit 3 (1st Day of cycle 2) .........................................................................................24 
6.4 
Visit 4 (1st Day of cycle 3) .........................................................................................24 
6.6 
Visit 6 / Final Visit (should occur prior to start of next chemotherapy cycle) ......24 
6.7 
Effectiveness Assessments .....................................................................................24 
6.8 
Patient Assessments ................................................................................................25 
6.8.1 
Functional Living Index - Emesis (FLIE) .......................................................25 
6.8.2 
Patient Diary ...................................................................................................25 
6.8.3 
WPAI-NV (Work Productivity Activity Impairment – Nausea and Vomiting)
 
………………………………………………………………………………………….25 
6.8.4 
Health Economics Outcome Research (HEOR) Assessments ....................25 
6.9 
Safety Assessments .................................................................................................26 
7 
STATISTICAL CONSIDERATIONS ..............................................................................26 
7.1 
Overview ....................................................................................................................26 
7.2 
Sample Size Determination ......................................................................................26 
7.3 
Efficacy and Safety Analysis....................................................................................26 
8 
SAFETY ASSESSMENTS ............................................................................................27 
8.1 
Adverse Event Definitions ........................................................................................27 
8.2 
Classification of Adverse Events .............................................................................28 
8.2.1 
Intensity ..........................................................................................................28 
8.2.2 
Causal Relationship to Akynzeo® ..................................................................29 
8.3 
Adverse Event Reporting .........................................................................................29 
9 
PREGNANCY REPORTING .........................................................................................30 
10 
LACK OF EFFICACY ....................................................................................................30 
11 
ETHICAL AND REGULATORY CONSIDERATIONS ...................................................30 
11.1 
Research Ethics Board (REB) ..................................................................................31 
11.2 
Informed Consent .....................................................................................................32 
12 
DATA HANDLING AND RECORD KEEPING ...............................................................33 
12.1 
Confidentiality and Privacy ......................................................................................33 
12.2 
Source Documents ...................................................................................................34 
12.2.1 
Direct Access to Source Documents ........................................................35 
12.3 
Subject Screening Form and Subject Identification Form .....................................35 
12.4 
Case Report Forms (CRFs) ......................................................................................35 
12.5 
Record Retention ......................................................................................................36 

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13 
QUALITY ASSURANCE AND QUALITY CONTROL ....................................................36 
13.1 
Monitoring .................................................................................................................36 
13.2 
Auditing .....................................................................................................................36 
13.3 
Inspecting ..................................................................................................................36 
14 
STUDY FINANCES .......................................................................................................37 
14.1 
Funding .....................................................................................................................37 
14.2 
Insurance ...................................................................................................................37 
15 
USE OF INFORMATION AND PUBLICATION .............................................................37 
16 
REFERENCES ..............................................................................................................38 
17 
APPENDICES ...............................................................................................................40 
Appendix 1: Subject Information and Informed Consent Form........................................41 
Appendix 2: Patient Diary ...................................................................................................49 
Appendix 3: FLIE questionnaire .........................................................................................59 
Appendix 4: WPAI-NV questionnaire .................................................................................62 
Appendix 5: HEC and MEC Emetogenicity ........................................................................64 
Appendix 6: Safety Reporting Forms .................................................................................65 
Appendix 7: Pregnancy Forms ...........................................................................................74 
Appendix 8: Study Drug Access Card ...............................................................................79 

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LIST OF TABLES 
Table 1:Time and event schedule ..........................................................................................13 
 
 
 
 
 
 
 

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LIST OF ABBREVIATIONS 
 
 
 
5-HT3 
5-hydroxytryptamine type 3 
AC 
Anthracycline-Cyclophosphamide 
AE 
Adverse Event 
CINV 
Chemotherapy-Induced Nausea and Vomiting 
CNS 
Central Nervous System 
CP 
Complete Protection 
CR 
Complete Response 
CRO 
CRF 
Contract Research Organization 
Case Report Forms 
CTCAE 
Common Terminology Criteria for Adverse Events 
DMP 
Data Management Plan 
EC 
Ethics Committee 
ECOG 
Eastern Cooperative Oncology Group 
eCRF 
Electronic Case Report Form 
ED 
Emergency Department 
EDC 
Electronic Data Capture 
EMA 
European Medicine Agency 
EU 
European Union 
FDA 
Food and Drug Administration 
FDC 
Fixed-Dose Combination 
FLIE 
Functional Living Index-Emesis 
GCP 
Good Clinical Practice 
HEC 
Highly Emetogenic Chemotherapy 
HEOR 
Health Economics Outcomes Research 

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ICH 
ICF 
International Conference on Harmonization 
Informed Consent Form 
MAH 
Marketing Authorization Holder 
MEC 
Moderately Emetogenic Chemotherapy 
NCCN 
National Comprehensive Cancer Network 
N/A 
Not Applicable 
N/D 
Not Done 
NK-1 
Neurokinin-1 
PALO 
RCT 
Palonosetron 
Randomized Controlled Trial 
PIPEDA  
Personal Information Protection and Electronic Documents Act  
SOP 
Standard Operating Procedure 
TEAE 
Treatment-Emergent Adverse Events 
VAS 
RWE 
NEPA 
Visual Analog Scale 
Real World Evidence  
netupitant/palonosetron 
 

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INVESTIGATOR AGREEMENT 
I have read this protocol and agree to conduct the study according to the procedures and terms 
provided herein, including all statements regarding confidentiality, and to complete the study 
within the time designated.  
I assume responsibility for the conduct of this study at my study site. I will ensure that I have 
sufficient resources allocated to this project such that the safety of my patients is protected at all 
times and that I complete my obligations to the sponsor according to the agreed timelines.  I will 
delegate responsibilities only to those who are qualified by training and experience.  I will 
ensure the integrity of the data generated by my team and that all team members are familiar 
with the study protocol and the study medication.  
I agree that I will grant access to the applicable records, my staff allocated to the conduct of this 
protocol, and my facilities for the purposes of monitoring, auditing and any required inspections 
associated with the conduct of this clinical trial. 
I agree to ensure that the confidential information contained in the protocol document will not be 
used for any other purpose other than the evaluation or conduct of the clinical investigation 
without the prior written consent of the Sponsor. 
By my signature below, I acknowledge the foregoing covenants, and confirm my understanding 
of the obligations accorded by the corresponding Clinical Trial Agreement. 
 
_________________________________________________________ 
Name of Investigator (First Name, Last Name, Title) 
 
_________________________________________________________ 
Institution* 
 
_________________________________________________________ 
Address* 
 
_________________________________________________________ 
 
 
_________________________________________________________ 
Signature of Investigator 
 
        Date: (DD, MMM, YYYY) 
 
 
*   If the address of the investigator changes during the course of the study, written notification will be provided by the investigator to 
the sponsor and the appropriate Ethics Review Board and will not require protocol amendment(s).

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STUDY SYNOPSIS 
TITLE 
A Phase IV, Real World Observational Study On The Use Of 
Akynzeo® (netupitant/palonosetron) For The Prevention Of 
Nausea and Vomiting in Oncology Patients Receiving Highly 
Emetogenic Chemotherapy (HEC) Over Multiple Cycles. 
SHORT TITLE 
Observational study on the use of Akynzeo® in patients 
receiving HEC 
PROTOCOL NUMBER 
CAN-PRO-NEPA-001   
PHASE 
IV 
OBJECTIVES OF THE 
STUDY 
To generate Real World Evidence (RWE) on the quality of life 
by means of the FLIE questionnaire on administration of 
Akynzeo™ in highly emetogenic chemotherapy (HEC), and to 
generate Real World Evidence in support of existing clinical trial 
data.  The study will also assess effectiveness and safety of 
Akynzeo® in the real world setting for the prevention of 
Chemotherapy Induced Nausea and Vomiting (CINV) in 
patients receiving highly emetogenic chemotherapy).  
INDICATION 
Patients with chemotherapy-induced nausea and vomiting who 
are receiving chemotherapy with high emetogenic potential for 
a maximum of 2 days on account of various types of cancer. 
NUMBER OF PATIENTS 
Approximately 200 patients 
STUDY DESIGN 
Real World, Observational study 
STUDY CENTRES 
Multi-centre, up to 20 sites 
PRIMARY OUTCOME: 
• 
Functional Living Index of Emesis (FLIE) – Quality of Life 
SECONDARY OUTCOMES   
• 
Complete Response (CR: no emetic episodes and no use 
of rescue medication) - overall – 0-120 hours (Day 1 to Day 
5) 
• 
Severity of nausea (VAS) - daily 
• 
Time to failure (time to first emetic episode or time to 
rescue) 
• 
Use of rescue medication - daily 
• 
Safety parameters (failure of CR, i.e., nausea and vomiting 
will not be included in the safety records)   
EXPLORATORY 
OUTCOMES  
• 
HEOR (Health Economic and Outcomes research) 
parameters: 
• 
ER visits 
• 
Hospitalizations 
• 
WPAI-NV (Work Productivity Activity Impairment Scale –
Nausea and Vomiting) 

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METHODOLOGY 
• 
FLIE Questionnaire to be completed by the patient at the 
end of the observation period (Day 5/120 hours post each 
cycle) for at least the first 4 consecutive cycles of 
chemotherapy (cycles 1-4) 
• 
Patient Diary to be completed daily starting on the first day 
of chemotherapy treatment (Day 1) until 5 days post 
treatment (Day 5/120 hours post each cycle).   
Diary data for cycles 1 - 4 will be included in the study 
database 
• 
WPAI-NV to be completed by the patient at the end of the 
observation period (Day 5/120 hours post each cycle) for at 
least the first four consecutive cycles of chemotherapy 
(cycles 1-4) 
• 
eCRF will be used for data capture  
TREATMENT  
Akynzeo® (300mg Netupitant/0.5mg palonosetron 
hydrochloride). 
In accordance with the approved Canadian Product 
Monograph; 1 capsule of Akynzeo® administered orally 
approximately 1 hour prior to the start of each chemotherapy 
cycle. 
INCLUSION CRITERIA 
• Patient scheduled to receive a highly emetogenic 
chemotherapy (HEC). 
• Patient scheduled to receive antiemetic prevention with 
Akynzeo® according to the approved Canadian Product 
Monograph as deemed medically necessary by the 
participating physician independently from this study.  
• Age ≥ 18 years. 
• Women of childbearing potential must use effective 
contraception during therapy and up to one month after 
treatment with Akynzeo®. 
• Patient (and/or patient’s authorized legal representative) 
should understand the nature of the study and provide 
written informed consent prior to or at the screening visit.  
• Patient is able and willing to comply with the study protocol 
for the entire length of the study and will follow all study 
requirements, procedures and complete all visits as 
required. 
• Patient is participating in another clinical trial where 
antiemetic treatment is not pre-specified by the study 
protocol. 
EXCLUSION CRITERIA   
(as per Contraindications in the 
approved Canadian Product 
Monograph) 
• Women of child bearing potential who are pregnant, 
planning on becoming pregnant or breast feeding. 
• Hypersensitivity to active substances, excipients or other 
ingredients of Akynzeo®. 
• Concomitant use of pimozide, terfenadine, astemizole, or 
cisapride. 
• Patient is enrolled in another clinical trial where antiemetic 
treatment is pre-specified by the study protocol. 

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STUDY DURATION  
This study will last approximately 20 months from 1st patient 
enrolled until last patient has completed.  The observation 
period for each subject will last 4-6 months.  
RECRUITMENT PERIOD 
Approximately 12 months   
ANALYSIS 
Descriptive statistics will be generated for the primary, 
secondary and exploratory endpoints. 
 
 
 

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Table 1: Time and event schedule  
 
 
*Patient Kit can be distributed at Screening/Visit 1 or Visit 2. All assessments/training should be completed prior to chemotherapy treatment 
1 Patient completes diary on days 1-5 (0-120 hours) post chemotherapy cycle 
2 Patient completes FLIE and WPAI after day 5 of cycle 
Activity 
Screening/ 
Visit 1 
Visit 2 
Cycle 1 
Visit 3 
Cycle 2 
Visit 4 
Cycle 3 
Visit 5 
Cycle 4 
Visit 6/Final visit 
Time period 
 
-28 days to Day 
1, Cycle 1 
Day 1 of 
Cycle 1 
Day 1 of 
Cycle 2 
Day 1 of 
Cycle 3 
Day 1 of 
Cycle 4 
Within 28 days of Cycle 4 
or prior to start of next 
chemotherapy cycle 
Informed consent 
X 
 
 
 
 
 
Inclusion/Exclusion 
X 
 
 
 
 
 
Demographics & Medical History 
X 
 
 
 
 
 
Nausea assessment - physician 
X 
 
 
 
 
 
Current treatments/medications 
X 
 
 
 
 
 
Patient Kit (distribute and provide 
education on use) 
X* 
 
 
 
 
 
Patient Assessments: 
 
 
 
 
 
 
Patient diary, including: 
• Nausea Severity Assessment  
• Rescue medications 
• Adverse Events 
 
X1 
X1 
X1 
X1 
 
• Functional Living Index – Emesis 
(FLIE)  
 
X2 
X2 
X2 
X2 
 
• Work Productivity Activity      
Impairment Scale – Nausea and 
Vomiting (WPAI-NV) 
 
X2 
 
X2 
 
X2 
 
X2 
 
 
Patient Kit - collect and review diary 
and questionnaires 
 
 
X 
X 
X 
X 
Concomitant medication  
 
X 
X 
X 
X 
X  
Adverse event  
 
X 
X 
X 
X 
X  
Study completion assessment/early 
discontinuation 
 
 
 
 
 
X  

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1 INTRODUCTION 
 
This document is a protocol for a human research study. 
This study will be carried out in compliance with the protocol, international standards of Good 
Clinical Practice (GCP) (ICH E6), Tri-council Policy Statement on Ethical Conduct for Research 
Involving Humans (CIHR 2010), applicable regulatory requirements and applicable Institutional 
research policies and procedures.  
 
1.1 Background Information 
Cancer chemotherapy is often associated with nausea and vomiting, which are among the most 
unpleasant and distressing side effects for subjects [1, 2]. Chemotherapy-induced nausea and 
vomiting (CINV) reduces patient’s health-related quality of life (QoL) [3] and may cause 
noncompliance or refusal of potentially life-saving chemotherapeutic regimens [4]. The severity 
and pattern of nausea and vomiting induced by a chemotherapeutic regimen depend on the 
agents used and the doses employed [4]. Accordingly, chemotherapeutic regimens are classified 
as highly or moderately emetogenic [4]. 
CINV is classified as either acute (occurring within the first 24h after chemotherapy) or delayed 
(occurring after the first 24h, extending until 120h). Nausea and vomiting result from stimulation 
of a multi-step reflex pathway controlled by the brain. The vomiting reflex involves both central 
and peripheral components and the emetic response is integrated into the vomiting center [5].  
The standard of care for antiemetic prophylaxis now consists of combinations of agents that 
inhibit several molecular pathways involved in emesis. The concomitant use of these agents is 
currently recommended for patients receiving chemotherapy of high emetic risk [6].  This 
regimen consists of a 5-hydroxytryptamine-3 (5-HT3) receptor antagonist (RA), a neurokinin-1 
(NK1) RA and a corticosteroid, such as dexamethasone. Moreover, the Multinational Association 
of Supportive Care in Cancer and European Society of Medical Oncology MASCC/ESMO 
evidence-based guidelines recommend the triplet antiemetic regimen for carboplatin-based 
regimens [6]. The American Society of Clinical Oncology (ASCO) has also recently 
recommended the addition of olanzapine to this triplet regimen [7] in HEC.   
 
1.2 Rationale for the Study 
Randomized controlled trials (RCTs) are the “gold standard” for generating evidence of the 
efficacy and safety of a drug. However, enrolment criteria, timelines, and atypical comparators 
of RCTs limit relevance to standard clinical practice. Real world data (RWD) provide longitudinal 
information on comparative effectiveness and tolerability of drugs, as well as data on their 
impact on resource use, medical costs, pharmacoeconomic outcomes, and patient-reported 
outcomes. While the randomized nature of the RCT ensures its high internal validity by 
removing bias, their ‘controlled’ nature casts a doubt on their generalizability to the real-world 
population. It is for this reason that trials done in a real-life setting post the marketing 
authorization of a drug are increasingly required [16].  
 
Akynzeo® received authorization from Health Canada in September 2017 for its use in:   

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 the prevention of acute and delayed nausea and vomiting associated with highly 
emetogenic cancer chemotherapy and 
 the prevention of acute nausea and vomiting associated with moderately emetogenic 
cancer chemotherapy that is uncontrolled by a 5-HT3 receptor antagonist alone 
This study is designed to collect clinical data on the real-world use of Akynzeo® in Canada. The 
aim of the study is to support clinical data from the development program by the generation of 
real world evidence on the effectiveness, safety and additional parameters of Akynzeo® in a 
local clinical setting. As a non-interventional study [17], the inclusion of patients will be carried 
out only after the physician has freely decided – on the basis of the patient’s individual situation 
– that the patient will receive Akynzeo® as antiemetic therapy for the prevention of CINV. The 
investigation on the effectiveness and safety profile of Akynzeo® is to take place under everyday 
clinical practice conditions. The parameters of interest for this study will be collected by means 
of a patient diary and then documented in a dedicated electronic case report form by the 
appropriate personnel.  Moreover, patient exclusion criteria will reflect the Product Monograph 
(PM), including “Cautions” and “Warnings” and no additional clinical investigations will be 
performed compared to the routine clinical practice in order to reflect real world use and 
increase study data generalizability.  
This prospective, non-interventional study (NIS) enables the collection of anonymized data 
feeding a larger global registry reflecting patients’ exposure to Akynzeo®. A registry is a 
database of patients exposed to the same specific drug to determine if that drug has a special 
impact [17,18], to determine real life effectiveness and quality of care [19].  
 
1.3 Study Drug - Combination of Palonosetron and Netupitant 
NEPA (Akynzeo®) was developed as an oral fixed combination of the highly selective NK1RA, 
netupitant (300 mg), and the clinically [8] and pharmacologically [9] distinct 5-HT3RA, 
palonosetron (0.5mg).  
Pivotal clinical studies described in section 1.4, which represented the basis for the marketing 
authorization of NEPA, have demonstrated superiority of oral NEPA plus dexamethasone over 
oral palonosetron plus dexamethasone in preventing CINV during the acute (0-24h), delayed 
(25-120h), and overall (0-120h) phases following both cisplatin- [10] and anthracycline-
cyclophosphamide (AC)-based chemotherapy [11,12]. In addition, NEPA was shown to be 
efficacious over multiple cycles in patients receiving either HEC or moderately emetogenic 
chemotherapy (MEC) [13]. 
Akynzeo®, which is the trade name of the medicinal product mentioned above, was approved on 
27 May 2015 by the European Medicines Agency for prevention of acute and delayed nausea 
and vomiting in highly emetogenic cisplatin-based cancer chemotherapy and moderately 
emetogenic cancer chemotherapy in adults [14] and on 27 September 2017 by Health Canada 
in combination with dexamethasone, as once-per-cycle treatment in adult patients for the 
prevention of acute and delayed nausea and vomiting associated with highly emetogenic cancer 
chemotherapy [15]. 
 

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1.4 Clinical Studies  
Three pivotal clinical studies were published simultaneously in the Journal "Annals of Oncology" 
in July 2014. The studies demonstrated that a single oral dose of the combination netupitant 
and palonosetron (NEPA) is efficacious and safe for use in the prevention of CINV. 
 
Study 
Design 
Patient 
population & 
chemotherapy 
Treatment 
arms 
Number of 
CTX 
cycles 
Objective of 
the study 
Study 1: 
Hesketh 
et al. [10] 
Double-blind, 
randomized, 
Phase II dose-
finding study 
N=694; 
chemotherapy-
naive patients; 
cisplatin-based 
HEC 
NEPA100mg + 
Dex 
NEPA200mg + 
Dex 
NEPA300 mg + 
Dex 
PALOoral + Dex 
(APR + ONDiv 
+ Dex; 
explorative) 
One  
cycle 
NEPA dose-
finding;  
efficacy of NEPA 
Study 2: 
Aapro et 
al. [11] 
Double-blind, 
randomized, 
Phase III study 
N=1455; 
chemotherapy-
naive patients; 
AC-based CTX 
NEPA + Dex 
PALOoral + Dex 
Multiple  
cycles 
Superiority of 
NEPA compared 
to PALO 
Study 3: 
Gralla et 
al. [13] 
Double-blind, 
randomized 
Phase III study 
N=413; 
chemotherapy-
naive patients; 
all HEC or MEC 
(except AC) 
NEPA300 mg + 
Dex 
PALOoral + Dex 
APR + 
PALOoral + Dex 
(3:1 
randomization) 
Multiple  
cycles 
Safety of NEPA 
over multiple 
cycles, non-
inferiority 
compared to SoC 
 
Study 1: NEPA – dose-finding Phase II (Hesketh et al. 2014) 
 
The dose of netupitant (300 mg) administered in combination with 0.5 mg palonosetron was 
selected based on the results of a Phase II dose-finding study. This multinational, randomized 
double-blind study assessed three different single oral doses of netupitant (100 mg, 200 mg and 
300 mg) in combination with a fixed oral dose of palonosetron (0.5 mg) and oral dexamethasone 
compared to oral palonosetron (0.5 mg) and oral dexamethasone, prior to a single cycle 
administration of cisplatin-based, highly emetogenic chemotherapy (HEC). Solely for exploratory 
purposes, a treatment arm with the triple combination of aprepitant, ondansetron and 
dexamethasone were included. The study population consisted of 679 adult male or female 
chemotherapy-naive patients with a histologically or cytologically confirmed solid tumour. The 
objective of the study was to determine the optimal dose for netupitant in combination with 0.5 
mg palonosetron for effective and safe prevention of CINV, whereby the complete response 
(CR) rate was measured after 0-120 hours. The highest proportion of patients with CR was in 
the group treated with 300 mg netupitant plus palonosetron (89.6 %), followed by the group with 
200 mg (87.6 %) and the group with 100 mg (87.4 %). The lowest proportion of patients with CR 
was in the group treated with palonosetron alone (76.5 %). All doses of netupitant in 
combination with palonosetron were superior to palonosetron monotherapy. The dose of 300 
mg netupitant showed an advantage over the lower doses. Compared to the regimen with 
aprepitant and ondansetron, there was also a higher proportion of responsive patients in the 
300 mg netupitant group. 
 

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Treatment-related adverse events (AEs) occurred in a total of 333 of the 679 patients (49 %). 
The total proportion of patients with AEs was comparable in the five treatment groups and not 
dependent on the netupitant dose (100 mg: 40.7 %; 200 mg: 51.4 %; 300 mg: 50 %; 
palonosetron monotherapy: 50 %; aprepitant: 53 %). The analysis of AEs, laboratory 
parameters, vital signs and 12-lead ECG showed no safety concerns for the administration of 
palonosetron in combination with netupitant at doses of 100 mg, 200 mg or 300 mg. 
Based on the results obtained for efficacy and safety in this Phase II dose-finding study, 300 mg 
oral netupitant in combination with 0.5 mg of oral palonosetron has been identified as the 
optimum dosage for the combination. [10] 
 
Study 2: Superiority of NEPA in comparison with palonosetron (Aapro et al. 2014) 
 
Based on the results of the dose-finding study by Hesketh et al., the fixed dose combination 
NEPA, consisting of 300 mg netupitant and 0.5 mg palonosetron, was investigated in a 
subsequent double-blind, multicentre, randomized Phase III Study with regard to efficacy in 
comparison with palonosetron. 1455 chemotherapy-naive patients with a median age of 54 
years, who received an anthracycline-cyclophosphamide chemotherapy (AC-based) over 
several cycles, were included. On day 1 of each chemotherapy (CT) cycle, the patients were 
treated either with NEPA (300 mg netupitant / 0.5 mg palonosetron) + 12 mg dexamethasone or 
0.5 mg oral palonosetron + 20 mg dexamethasone. The primary endpoint was complete 
response defined as "no vomiting, no rescue medication" in the delayed phase (> 24 – 120 h 
after CT). Of the 724 evaluable patients in the NEPA-arm, 88.4 % showed a complete response 
in the acute phase and 76.9 % in the delayed phase. In the Palo-arm with 725 evaluable 
patients, the response rates were 85 % for the acute phase and 69.5 % for the delayed phase of 
CINV. NEPA showed a statistically significant higher response rate over the overall period with 
74.3 % compared to 66.6 % for PALO (p = 0.001). 
 
NEPA was also statistically significantly superior to PALO for the secondary endpoints "no 
vomiting" (a), "no severe nausea" (b) and "complete control" (c), both in the delayed phase and 
over the entire period for a): 81.8 % and 79.8 % vs. 75.6 % and 72.1 %, for b): 76.9 % and 74.6 
% vs. 71.3 % and 69.1 % and for c): 67.3 % and 63.8 % vs. 60.3 % and 57.9 %. 
There was no impairment of regular daily activities (based on the Functional Living Index - 
emesis - questionnaire). Overall, the frequency, nature and intensity of the adverse events were 
comparable between the two study arms. In 8.1 % of patients treated with NEPA there were 
treatment-associated side effects (PALO arm: 7.2 %), but there were no serious adverse 
events, no discontinuations of therapy and no deaths. The most common adverse events were 
headache and constipation. 
 
The results of the study showed that in all phases after treatment with moderately emetogenic 
chemotherapy (AC-based considered as MEC at the time of the study), a single oral dose of 
NEPA in combination with a single dose of dexamethasone leads to better complete response 
rates than a single oral dose of palonosetron in combination with a single dose of 
dexamethasone. The authors concluded that future guideline-compliant antiemetic treatment 
could be simplified on the basis of the fixed dose combination. [11] 
 
Study 3: Safety and efficacy of NEPA over repeated cycles (Gralla et al. 2014) 
 
Another pivotal study for clinical use of NEPA was also published by Gralla and colleagues in 
2014. The multicentre, randomized, double-blind phase III study included 413 adult patients with 
solid tumours of different entities, which had not been previously treated with chemotherapy. Of 
these patients, 76 % received a non-AC-based MEC (carboplatin, oxaliplatin, doxorubicin, 

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cyclophosphamide, irinotecan, epirubicin, daunorubicin) and 24 % a HEC (> 90 % cisplatin, the 
rest dacarbazine, carmustine). Of the 412 evaluable patients in a 3:1 randomization, 308 
patients were treated on Day 1 of the CTX with NEPA (300 mg netupitant + 0.5 mg 
palonosetron) + 12 mg dexamethasone. The remaining 104 patients were treated with 125 mg 
aprepitant + 0.5 mg palonosetron + 12 mg dexamethasone on day 1 of the CT followed by 80 
mg aprepitant + 8 mg dexamethasone (only in case of HEC) on days 2 and 3. The primary 
endpoint was defined as the safety profile of NEPA administered over at least 6 CT cycles. The 
efficacy (complete response and prevention of severe nausea) was determined as a secondary 
endpoint. 
 
Antiemetic treatment was administered in a total of 1961 CT cycles, including 1446 with NEPA 
and 515 with APR / PALO. 98 % of patients completed cycle 1, 75 % completed 4 cycles and 40 
% of patients completed 6 cycles. 
 
The most common treatment-related adverse events were constipation (3.6 % NEPA vs. 1 % 
AP0R / PALO) and headache (in each case 1 % for NEPA and APR / PALO), whereby the 
frequency did not increase with increasing number of cycles. Overall, the rate of side effects 
during treatment in cycle 1 was 5.2 % (n = 308) for NEPA vs. 2.9 % for APR / PALO (n = 104). 
These rates fell by cycle 6 to 1.6 % for NEPA (n = 124) and 0 % for APR / PALO (n = 43) on 
account of the decreasing number of cases. There were no concerns with regard to the cardiac 
safety of NEPA. 
 
Overall, complete response rates (no vomiting, no rescue medication) were high in both study 
arms over all chemotherapy cycles. NEPA showed a slight, persistent numerical advantage of 
2-7 % compared to APR / PALO.  
 
In this study, Gralla et al. were able to demonstrate consistent efficacy of NEPA associated with 
good tolerability over multiple cycles of highly and moderately emetogenic chemotherapies [13]. 
 
1.5 Study Population 
This study will enroll adult male or female chemotherapy patients of various cancer types who 
are scheduled to receive chemotherapy with high emetogenic potential for a maximum of 2 
days. 
2 STUDY OBJECTIVES 
The primary study objective is to generate Real World Evidence (RWE) on the quality of life by 
means of the FLIE questionnaire on administration of Akynzeo® in highly emetogenic 
chemotherapy (HEC), and to generate Real World Evidence in support of existing clinical trial 
data. 
 
The study will also assess effectiveness and safety of NEPA in the real world setting for the 
prevention of Chemotherapy Induced Nausea and Vomiting (CINV) in patients receiving highly 
emetogenic chemotherapy).  
 

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2.1  Primary Outcome: Functional Living Index - Emesis (FLIE)  
The quality of life of patients can be collected by means of the FLIE questionnaire on 
administration of Akynzeo® during chemotherapy with moderately and highly emetogenic 
agents. 
The Functional Living Index – Emesis questionnaire is a patient reported outcome (PRO) 
validated tool with the objective of assessing the impact of chemotherapy-induced nausea and 
vomiting on patient’s daily function.  
It consists of a nausea domain and a vomiting domain of nine items each where the patient 
should rate how much nausea and vomiting have affected the quality of life. For each question 
the patient will rate how much nausea (or vomiting) has affected an aspect of his quality of life 
during the past five days. Each question uses a visual analogue scale (VAS).   
The investigator shall be responsible for explaining to the patient how the questionnaire should 
be correctly completed.  
2.2 Secondary Outcomes 
The response to Akynzeo® and the necessity for use of a rescue medication will be recorded to 
evaluate effectiveness. The medicinal products used as rescue medication will also be recorded. 
The following parameters will be calculated from information recorded in the patient diary:  
 
• 
Complete Response (CR): no emetic episode and no use of rescue medication in the overall 
period (0-120h/Day 1-5) 
• 
Severity of nausea (daily from Day 1 to Day 5) using a VAS scale (Visual Analogue Scale) 
• 
Time to failure (time to first emetic episode or time to rescue) 
• 
Use of rescue medication (daily from Day 1 to Day 5) 
 
The collection of safety data and adverse events AEs in connection with administration of 
Akynzeo® will be performed.  
2.3  Exploratory Outcomes 
Health economic and outcomes research data will be collected and recoded on the diary card 
specifically emergency department (ED) visits and hospitalizations.   
Work Productivity Activity Impairment scale for Nausea and Vomiting (WPAI-NV) will be 
collected on day 5 of each cycle. 
3 STUDY DESIGN 
3.1 Study Overview 
This two year (approximately), multi-centre, prospective, observational real-world study is 
designed to collect data on the use of Akynzeo® (netupitant/palonosetron) for the prevention of 
nausea and vomiting in oncology patients receiving highly emetogenic chemotherapy (HEC). 
 
The visit schedule is comprised of 6 study visits (Table 1): 
• 
Visit 1/Screening (4 weeks to 0 weeks prior to Visit 2) 
• 
Visit 2: (Day of/but prior to 1st chemotherapy treatment administration) 

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• 
Visit 3: (Day of/but prior to 2nd chemotherapy treatment administration) 
• 
Visit 4: (Day of/but prior to 3rd, chemotherapy treatment administration) 
• 
Visit 5: (Day of/but prior to 4th, chemotherapy treatment administration) 
• 
Visit 6/Final Visit  
 
Visit 1 and 2 can be combined as determined by the investigator.  Patients will report the daily 
occurrence and intensity of nausea and vomiting, rescue medications, adverse events (excluding 
nausea and vomiting) in a diary from Day 1 (chemotherapy treatment day) to Day 5/time point 0-
120 hours post chemotherapy administration of each observation period.  
Safety events occurring between chemotherapy cycles will be reported by the patient. Patient will 
have a follow up period of 28 days post the last-chemotherapy cycle.   
3.2 Study Sites 
The study will enrol up to 20 Canadian sites.  
3.3 Sample Size 
The study will include up to 200 patients.  No formal sample size calculation has been carried 
out. The planned number of patients to be enrolled in the study should be adequate for the 
exploratory purposes and allow a conclusion to be drawn regarding the use of Akynzeo® in the 
Canadian medical environment. 
3.4 Primary Endpoint 
The primary endpoint is the FLIE total score for cycle 1. 
3.5 Secondary Endpoints 
The secondary endpoints are: 
• 
FLIE total score cycles 2-4 
• 
FLIE Nausea domain total score all cycles 
• 
FLIE Vomiting domain total score all cycles 
• 
Complete response-no emesis, no rescue medication during the acute, delayed and 
overall phase all cycles 
• 
No significant nausea during the acute, delayed and overall phase for all cycles 
• 
Time to failure defined as time to first emetic episode or time to rescue medication use 
for all cycles 
• 
Use of rescue medication all cycles 
• 
To descriptively asses the patient diary at screening and over time 
The response to Akynzeo® and the necessity for use of a rescue medication will be recorded to 
evaluate effectiveness. Any medicinal products used as rescue medication will be recorded in 
the patient diary.  
 

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3.6 Exploratory Endpoints 
• 
To descriptively assess HEOR parameters (ER visits, hospitalizations) 
• 
To descriptively assess the WPAI-NV 
 
3.7 Safety Assessment 
Safety will be evaluated by the incidence and type of adverse events (AEs), serious adverse 
events (SAEs) and AEs leading to discontinuation of treatment in all patients. 
4 SUBJECT SELECTION AND WITHDRAWAL 
Protocol waivers will not be provided by the sponsor.  All subjects included in this study must 
meet all of the inclusion criteria and none of the exclusion criteria. Deviations from the protocol 
will be noted as such and will be addressed by the sponsor as appropriate. 
4.1 Inclusion Criteria 
Subjects must satisfy the following criteria to be enrolled in the study: 
1. Patient scheduled to receive a highly emetogenic chemotherapy (HEC). 
2. Patient scheduled to receive antiemetic prevention with Akynzeo® according to the approved 
Canadian Product Monograph as deemed medically necessary by the participating 
physician independently from this study.  
3. Age ≥ 18 years. 
4. Women of childbearing potential must use effective contraception during therapy and up to 
one month after treatment with Akynzeo®. 
5. Patient (and/or patient’s authorized legal representative) should understand the nature of 
the study and provide written informed consent prior to or at the screening visit.  
6. Patient is able and willing to comply with the study protocol for the entire length of the study 
and will follow all study requirements, procedures and complete all visits as required. 
7. Patient is participating in another clinical trial where antiemetic treatment is not pre-specified 
by the study protocol. 
   
4.2 Exclusion Criteria 
Potential subjects who meet any of the following criteria will be excluded from participation in 
the study: 
1. Women of child bearing potential who are pregnant, planning on becoming pregnant or 
breast feeding. 
2. Hypersensitivity to active substances, excipients or other ingredients of Akynzeo®. 
3. Concomitant use of pimozide, terfenadine, astemizole, or cisapride. 
4. Patient currently enrolled in another clinical trial where antiemetic treatment is pre-specified 
by the study protocol. 

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4.3 Subject Recruitment and Pre-Screening 
To recruit subjects for this study, any of the following recruitment methods will be acceptable 
following approval by the Sponsor: review of medical charts from the investigator or sub-
investigator’s clinical practices, referral from other physicians, any type of media advertisement 
and community outreach/engagement. All screened subjects will be recorded on a 
screening/enrolment log. 
Any information to be disseminated to potential subjects (handouts, brochures, subject cards 
etc.) and any advertisements intended to be used for this study (printed ads, posters, flyers, 
spots etc.) must be approved by the site’s REB prior to any use. 
4.4 Subject Withdrawal Criteria 
Subjects may voluntarily withdraw from the study at any time.  If a subject exits the study early 
all final assessments required at the Final visit should be performed and the study 
completion/early termination form outlining the reason for withdrawal should be completed.  No 
data will be collected after the early termination visit date.  Subjects who withdraw from the 
study early will not be replaced.  The investigator should withdraw subjects from the study if 
they feel that it is in the best interest of the subject to be terminated from the study.  Any 
administrative or other reasons for withdrawal must be documented and explained to the 
subject.   
The Sponsor’s access to the relevant subject data will survive the subject’s withdrawal from the 
study. Withdrawal will be documented in the subject’s chart and in the Case Report Form (CRF) 
with a detailed explanation of the reason for the withdrawal and the date of last dose of study 
medication. 
5 STUDY PRODUCT 
Subjects will have access to Akynzeo® as per their usual means for obtaining prescription 
medications utilizing a study drug access card. 
5.1 Dosage and Administration 
Following the screening period patients meeting the inclusion/exclusion criteria will receive their 
dose of Akynzeo® on the day of their chemotherapy administration for each cycle.  Each patient 
will be treated with the recommended dose of Akynzeo® for highly emetogenic chemotherapy, 
including cisplatin based chemotherapy, as per the Canadian Product Monograph. The 
recommended dose of Akynzeo® is 1 capsule of Akynzeo® administered orally approximately 1 
hour prior to the start of each chemotherapy cycle with dexamethasone 12 mg to be 
administered orally 30 minutes prior to chemotherapy. Day 2-4 dexamethasone 8 mg orally 
once daily. 
For anthracycline and cyclophosphamide based chemotherapy the recommended dose of 
Akynzeo is 1 capsule of Akynzeo® administered orally approximately 1 hour prior to the start of 
each chemotherapy cycle with dexamethasone 12 mg to be administered orally 30 minutes prior 
to chemotherapy.  Administration of dexamethasone on days 2-4 is not necessary. 
5.2 Concomitant Medication(s) 
Other treatment considered necessary for the subject’s welfare may be given at the discretion of 
the patients treating physician.  All such therapy must be recorded in the Case Report Form. 
 

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6 STUDY PROCEDURES 
The Time and Event Schedule which is found at the end of the protocol synopsis summarizes 
the type (efficacy, safety, etc.) and frequency of each study procedure to be performed in this 
study.  
No study specific procedure will be performed prior to obtaining written consent of the study 
subject. 
6.1 
Visit 1 / Screening (28 to 0 days prior to visit 2) 
The following will be performed at visit 1: 
• 
Signed and dated Informed Consent Form 
• 
Medical history (including oncologic history) 
• 
Demographics 
• 
Eligibility assessment 
• 
Nausea Assessment previous or ongoing 
• 
Pregnancy testing in females of childbearing potential will be performed as per the 
investigators/institutions standard practice for chemotherapy patients 
• 
Assessment of current medications (antiemetic’s, anti-tumor drugs, other concomitant 
medications) 
• 
Patient kit distribution and education on contents (Can also be distributed at Visit 2) 
 
6.2 
Visit 2 (1st Day of cycle 1) 
• 
Akynzeo® taken by patient one hour prior to chemotherapy administration 
• 
Diary completed days 1-5 (0-120 hours post chemotherapy administration) 
• 
Day 1 is defined as a 24-hour period starting at the time chemotherapy is administered 
(0-24 hours) 
• 
Day 2 is defined as 25-48 hours after start of chemotherapy 
• 
Day 3 is defined as 49-72 hours after start of chemotherapy 
• 
Day 4 is defined as 73-96 hours after start of chemotherapy 
• 
Day 5 is defined as 97-120 hours after start of chemotherapy  
• 
FLIE is completed after the end of Day 5/120 hours after start of chemotherapy 
administration  
• 
WPAI-NV completion is completed after the end of Day 5/120 hours after start of 
chemotherapy administration  
• 
Assessment of adverse events 
• 
Assessment of concomitant medications 
 

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6.3 Visit 3 (1st Day of cycle 2) 
• 
Akynzeo® administered, Diary, FLIE and WPAI-NV collection and review  
• 
Distribute diary, FLIE and WPAI-NV for cycle 2 
• 
Assessment of adverse events 
• 
Assessment of concomitant medications 
• 
Note: Patient will complete their daily diary from Day 1 to Day 5 
 
6.4 Visit 4 (1st Day of cycle 3) 
• 
Akynzeo® administered, Diary, FLIE and WPAI-NV collection, review  
• 
Distribute diary, FLIE and WPAI-NV for cycle 3 
• 
Assessment of adverse events 
• 
Assessment of concomitant medications 
• 
Note: Patient will complete their daily diary from Day 1 to Day 5 
 
6.5 Visit 5 (1st Day of cycle 4) 
• 
Akynzeo® administered, Diary, FLIE and WPAI-NV collection and review Distribute diary, 
FLIE and WPAI-NV for cycle 4 
• 
Assessment of adverse events 
• 
Assessment of concomitant medications 
• 
Note: Patient will complete their daily diary from Day 1 to Day 5 
 
6.6 Visit 6 / Final Visit (should occur prior to start of next chemotherapy cycle) 
• 
Collect completed diary cards, FLIE and WPAI-NV 
• 
Assessment of adverse events 
• 
Assessment of concomitant medications 
• 
Complete study completion/early termination form 
 
6.7 Effectiveness Assessments 
The response to Akynzeo® and the necessity for use of a rescue medication will be recorded to 
evaluate effectiveness. Any medicinal products used as rescue medication will also be recorded 
in the patient diary.  
 
The following parameters will be recorded in the patient diary:  
• 
Severity of nausea (daily from Day 1 to Day 5) using a VAS (Visual Analogue Scale) 

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• 
Time to failure (time to first emetic episode or time to rescue) 
• 
Use of rescue medication (daily from Day 1 to Day 5) 
Note: A Complete Response (CR) is defined as no emetic episode and no use of rescue 
medication during the observational period (Day 1 to Day 5). 
6.8 Patient Assessments 
6.8.1 
Functional Living Index - Emesis (FLIE)  
The quality of life of patients will be collected by means of the FLIE questionnaire on 
administration of Akynzeo® during chemotherapy. 
The Functional Living Index – Emesis (FLIE) questionnaire is a patient reported outcome (PRO) 
validated tool with the objective of assessing the impact of chemotherapy-induced nausea and 
vomiting on patient’s daily function.  
It consists of a nausea domain and a vomiting domain of nine items each where the patient 
should rate how much nausea and vomiting have affected the quality of life. For each question 
the patient will rate how much nausea (or vomiting) has affected an aspect of his quality of life 
during the past five days. Each question uses a visual analogue scale (VAS).   
The investigator shall be responsible for explaining to the patient how the questionnaire should 
be correctly completed. 
The FLIE will be completed by the patient on Day 5 of chemotherapy cycles 1, 2, 3 and 4. 
6.8.2 
Patient Diary 
The patient diary will be completed daily for the first five days of each cycle (starting on the day 
chemotherapy is administered). The patient diary will report daily occurrence and intensity of 
nausea (utilizing a VAS) and vomiting, rescue medications, adverse events (excluding nausea 
and vomiting), concomitant medication use for CINV.  
 
The patient diary will be included in the Patient Kit will be distributed at Visit 1 and collected at 
Visits 3 through 6. 
6.8.3 
WPAI-NV (Work Productivity Activity Impairment – Nausea and Vomiting) 
The WPAI-NV is a 7-item questionnaire that assesses the effect of nausea and vomiting on a 
patient’s ability to work and perform regular activities.   
 
The WPAI-NV will be completed by the patient after Day 5 of chemotherapy cycles 1, 2, 3 and 
4. 
6.8.4 
Health Economics Outcome Research (HEOR) Assessments 
The following outcomes of health resource utilisation will be collected: 
 
• 
Hospitalisations  
• 
The number of ER visits 
 
Health resource utilisation will be recorded on the patient diary and collected for all patients 
participating in the study. 

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6.9 Safety Assessments 
Adverse Events 
Adverse events will be reported by the subject (or, when appropriate, by a caregiver, surrogate, 
or the subject’s legally acceptable representative) from the time of giving written informed 
consent through to completion of subject participation, including the follow-up period (28 days 
post Visit 5). Adverse events will be followed by the investigator for a length of time as 
determined by the sponsor. Specific details on adverse event reporting are provided in section 8 
“Safety Assessment”. 
7 STATISTICAL CONSIDERATIONS 
7.1 Overview 
This two year (approximately), multi-centre, prospective, observational study is designed to 
collect clinical data on the real-world use of Akynzeo® in Canada. The aim of the study is to 
support clinical data from the development program by the generation of real world evidence on 
the effectiveness, safety and additional parameters of Akynzeo® in a local clinical setting. 
This study will enroll adult male or female chemotherapy patients of various cancer types who 
are scheduled to receive chemotherapy with high emetogenic potential for a maximum of 2 
days.  Akynzeo® (netupitant/palonosetron) will be used for the prevention of nausea and 
vomiting in oncology patients receiving HEC. 
The primary study objective is to generate RWE on the quality of life by means of the FLIE 
questionnaire. 
 
7.2 Sample Size Determination 
The study is to include up to 200 patients. No formal sample size calculation has been carried 
out. The planned number of patients to be enrolled in the study should be adequate for the 
exploratory purposes and allow a conclusion to be drawn regarding the use of Akynzeo® in real 
life in Canada. 
 
7.3 Efficacy and Safety Analysis 
This is a two year (approximately), multi-centre, prospective, observational study designed to 
collect clinical data on the real-world use of Akynzeo® in Canada.  All analyses will be 
descriptive in nature. 
Before beginning data analysis, plausibility checks will be performed. Implausible or ambiguous 
data will be excluded from analysis.  
Prior to database lock, a statistical analysis plan (SAP) defining all details of analysis will be 
prepared. A table mock-up (TMU) document which will illustrate the details of presentation and 
analysis for data collected in this study will accompany this document.  
The Intent-To-Treat (ITT) population includes all patients who were entered into the study web-
based application and have a date of signed informed consent available. This population will be 
used to provide descriptives for patients enrolled by centre, patient disposition and reasons for 
screen failure. 

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The modified Intent-To-Treat (mITT) population includes all patients who were included in the 
ITT population and fulfilled all entry criteria and received at least one dose of the study 
treatment (Akynzeo®). Missing questionnaires/assessments will not be imputed.  The mITT 
population will be used for the analysis of the primary, secondary and exploratory endpoints not 
including health resource utilisation (ER visits, hospitalizations). This population will also be 
used for demographic, medical history and concomitant medication tables. 
The Safety population includes all patients who received at least one dose of the study 
treatment (Akynzeo®).  This population will be used for all safety analyses and health resource 
utilisation (ER visits, hospitalizations) tables.   
Continuous variables will be summarized descriptively by number of observations, number of 
missing observations, mean, standard deviation, median, 1st quartile, 3rd quartile, minimum and 
maximum.  Categorical variables will be summarized descriptively as frequency counts and 
percentages. 
A number of p-values may be presented in the reported tables for exploratory purposes.  
Statistical testing will be performed at the two-sided 0.05 significance level unless otherwise 
specified.  P-values will not be adjusted for multiple comparisons. 
8 SAFETY ASSESSMENTS 
Timely, accurate, and complete reporting and analysis of safety information from clinical studies 
are crucial for the protection of subjects, investigators, and the sponsor, and are mandated by 
regulatory agencies worldwide. Adverse events will be collected from the time a subject has 
signed an ICF and followed until the end of study-visit 6 (28 days post visit 5/last dose of 
Akynzeo®). 
8.1 Adverse Event Definitions 
According to the currently valid Directive of the European Parliament and of the Council relating 
to the implementation of good clinical practice in the conduct of clinical studies on medicinal 
products for human use (2001/20/EC), an adverse event (AE) is “Any untoward medical 
occurrence in a patient or clinical study subject administered a medicinal product and which 
does not necessarily have a causal relationship with this treatment”. An AE could therefore be 
any unfavourable or unintended sign (for example, an abnormal laboratory finding), symptom or 
any disorder with a temporal relationship to the use of a medicinal product, regardless of 
whether or not it is considered to be related to use of the medicinal product.  
In the context of this study, all adverse events (AEs) from the time of Akynzeo® administration 
over a period of 5 days during the chemotherapy cycles which are part of the observation period 
will be documented on the appropriate pages of the eCRF. 
A serious adverse event (SAE) is defined as an AE that: 
• 
results in death; 
• 
is life-threatening;1 
• 
requires hospitalization or prolongation of existing hospitalization;  
• 
results in persistent or significant disability or incapacity; 
                                               
1 This includes every AE that – in the opinion of the investigator – is life-threatening for the study subject. 
This definition does not include events that may have led to death, if they had occurred in a more severe 
form. 

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• 
is a congenital anomaly or results in a birth defect or 
• 
significant medical events that may endanger patients or require an intervention to 
prevent the above characteristics or consequences.  
An unexpected adverse event is any event for which, with regard to its nature, severity or 
incidence, no details have been included to date in the current Product Monograph for 
Akynzeo®. The assessment of the "expectedness" of an AE is performed by the sponsor. 
Planned surgical interventions or hospitalizations scheduled before the informed consent form 
was signed but carried out during the study period (study procedures, chemotherapy cycles, 
etc.) are not to be regarded as (serious) AEs. 
The investigator assesses whether or not an event qualifies as a serious adverse event (SAE, 
see criteria above).  
If an adverse event is classified as serious and there is at least reasonable possibility of a 
causal relationship to the administration of Akynzeo®, this represents a serious adverse drug 
reaction (SADR). 
All information on Special Situations from the time of Akynzeo® administration will be 
documented on the appropriate pages of the CRF and transcribed to the AE pages of the eCRF. 
Special situations consist of the following: 
- exposure during pregnancy, embryo/foetal maternal or paternal exposure (even if uneventful), 
- lack of efficacy*,  
- off-label use,  
- overdose,  
- occupational exposure,  
- misuse or abuse (symptomatic or not),  
- medication errors,  
- transmission of infectious agent 
*refer to Section 10 for definition of lack of efficacy  
8.2  Classification of Adverse Events 
The investigator classifies all AEs according to their intensity, seriousness and a potential 
causal relationship to Akynzeo®. 
8.2.1 
Intensity 
In this study the intensity of an AE is evaluated according to the following definitions: 
Mild 
A symptom that is barely perceptible by the study subject; does not affect performance or 
functionality. A prescription medicinal product is usually not required for relief of the symptom, 
but may be administered depending on the personality of the study subject. 
Moderate 

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A symptom that is so strong that the study subject feels uncomfortable, his performance of 
everyday activities is restricted; the study subject may continue to participate in the study; 
treatment of the symptoms may be required. 
Severe 
The symptom causes severe discomfort. The symptom can be so strong that the study subject 
is unable to continue participating in the study. The severity may result in termination of 
treatment with Akynzeo®; the symptom can be treated and/or the study subject may require 
inpatient treatment. 
8.2.2 
Causal Relationship to Akynzeo®  
The investigator classifies all AEs with regard to a possible causal relationship to administration 
of Akynzeo®. In this study the assessment of causality is binary, i.e. the question of a potential 
causal relationship to Akynzeo® is answered by the investigator only with "yes" or "no". 
8.3   Adverse Event Reporting 
Safety Data Collection:  
 
Should the patient experience any AEs or Special Situations and report these to the investigator 
during a visit, the investigator will enter all the information available directly into the EDC system 
within 24 hours. Investigator shall perform a causality assessment (related/not related to CINV 
prophylaxis/treatment) for each AE.  The AE Report Form (Appendix 6a) displays the 
information that the Investigator is initially required to provide. Investigator’s assessment of 
relatedness to medicinal product for which sponsor is MAH or distributor is included in Appendix 
6.  Information on related and non-related Serious AEs, Special Situations and Akynzeo® 
related non-serious AEs will be included on the specified safety report forms (Appendix 6b & 
6c).   
 
The Global Reporting Form for SAEs/AESIs/Special Situations and the Akynzeo®-Related Non-
Serious Adverse Event Forms will be directed to the sponsor‘s pharmacovigilance address 
(ProductInfo@purdue.ca), where the report will be processed by the sponsor‘s 
pharmacovigilance team. An Akynzeo®-related AE that does not meet a seriousness criterion 
shall be sent by the Investigator to the Sponsor email address (ProductInfo@purdue.ca) within 2 
calendar days from Day 0 (investigator adverse event first awareness date). Serious AE, either 
related or non-related and Special Situations, shall be sent within 24 hours of their detection.  
 
Any follow-up information will be directly requested to the investigator by sponsor. Investigator 
will provide the requested follow-up information within 10 calendar days from request for non-
serious AE and 2 business days for serious ones and special situations. Follow up information 
obtained should be forwarded to sponsor within the same timelines as the initial AE information. 
i.e., within 24 hours for Special Situations and Serious AE, whether related or not related, and 2 
calendar days for non-serious Akynzeo® related AEs. In the situation that investigator’s causality 
assessment is either missing or unknown, the Global Reporting Form for SAEs/AESIs/Special 
Situations Report Form will be sent as defined above to the sponsor. Sponsor will perform a 
provisional causality assessment of all AE and do any reasonable effort to obtain a causality 
assessment from investigator for any of the drugs for sponsor is MAH or distributor. The AE 
reports concerning any other drug (sponsor is not MAH or distributor) will be collected in the 
database and may be sent to the sponsor upon request.  For any medicinal products for which 
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responsible to report the correspondent safety information to the MAH or Local Competent 
Authority according to current laws and regulations.  
 
The Global Reporting Form for SAEs/AESIs/Special Situations Report Form included in 
Appendix 6 will be defined on the basis of the agreement with sponsor and in compliance with 
the applicable laws. 
 
An emerging safety issue is an issue that may have a potential major impact on the risk-benefit 
balance of the medicinal product and/or on patients’ or public health and the potential need for 
prompt regulatory action and communication to patients and healthcare professionals. If the 
investigator identifies any issue meeting this definition, it must be reported to the sponsor 
immediately and without delay, together with the rationale for which the data are considered to 
be an emerging safety issue. 
9 PREGNANCY REPORTING 
If a patient becomes pregnant during the study, as soon as information about the pregnancy is 
received, the investigator must inform the sponsor within 24 hours (using the Pregnancy 
Notification Form included in Appendix 7) from the investigational staff becoming aware of it, 
and the subject must be withdrawn from the study without delay. Follow-up information 
regarding the outcome of the pregnancy and any postnatal sequelae in the infant will be 
required. 
10 LACK OF EFFICACY 
 
Lack of efficacy or Unusual Failure in Efficacy is defined as failure of a health product to produce 
the expected/intended effect, which may result in an adverse outcome for the patient, including 
an exacerbation of the condition for which the health product is being used. One example of 
unusual failure in efficacy is a previously well-stabilized condition that deteriorates when the 
patient changes to a different brand or receives a new prescription.  Another example of a case 
that should be reported on an expedited basis is a life-threatening infection where the failure in 
efficacy seems to be due to the development of a newly resistant strain of bacterium previously 
regarded as susceptible.   
 
Lack of efficacy should be reported to the sponsor within 24 hours of the investigational staff 
becoming aware of it using the Global Reporting Form for SAEs/AESIs/Special Situations 
Report Form (Appendix 6). 
 
11 ETHICAL AND REGULATORY CONSIDERATIONS 
The investigator is responsible for ensuring that this study is conducted according to the 
protocol, current International Conference on Harmonization (ICH) guidelines on Good Clinical 
Practice (ICH guidelines), applicable government regulations and Institutional research policies 
and procedures. 
All procedures will conform to the latest revision of the “Declaration of Helsinki”, the guidelines 
for the “Conduct of Clinical Investigations” issued by the Therapeutics Products Directorate 
Canada (1997) and the Tri-Council Policy statement on Ethical Conduct for Research involving 
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11.1 Research Ethics Board (REB) 
The following documents will be submitted to a properly constituted REB for formal approval 
before implementation of the study: 
• 
Final protocol and, if applicable, any amendments 
• 
Sponsor-approved Subject Information Sheet and ICF 
• 
Product Monograph (or equivalent information) and amendments 
• 
Any sponsor-approved written information to be provided to the subjects (e.g. subject 
diaries, subject study participation cards, questionnaires, etc.) 
• 
Sponsor-approved subject recruiting materials (e.g. text for advertisements, flyers, posters, 
etc.) 
• 
Primary Investigator and Co-Investigator(s)’s up-to-date curriculum vitae (and medical 
license if required) 
• 
Information on compensation for study-related injuries or payment to subjects for 
participation in the study, if applicable 
• 
Information on the funding and potential conflicts of interest 
• 
Any other information requested by the REB 
 
Before commencement of the study the investigator must receive from their REB a favorable 
opinion in writing (signed, dated, and referring to the study by its full title and protocol number) 
that states which documents (full name, date and version number) have been reviewed and 
approved.  
In order to comply with internationally accepted guidelines governing good clinical research 
practices, the investigator must also receive a list of the REB’s voting members, their titles or 
occupations, and their institutional affiliations and a statement, that the REB is organized and 
operates according to GCP and the applicable laws and regulations.  
The investigator will provide a copy of this/these document(s) to the sponsor prior to the 
initiation of their site. 
 
Prior to study implementation the REB must provide the sponsor with a signed and dated 
attestation, stating that: 
1. The membership of the REB complies with the requirements defined in Division 5 of the 
Food and Drug Regulations. 
2. The REB carries out its functions in a manner consistent with GCP. 
3. The REB has reviewed and approved the clinical trial protocol and ICF and that the view of 
the REB has been documented in writing. 
 
During the study the investigator (or sponsor where required) will submit the following 
documents to the REB for review and approval, if applicable:  
• 
Protocol amendments 

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• 
Updates to the ICF 
• 
Updates to any written material that is provided to the subjects during the study 
• 
New or revised sponsor-approved recruiting materials 
• 
Revisions to compensation for study-related injuries or payment to subjects for participation 
in the study, if applicable 
• 
Reports of any SAEs or of adverse events which are unexpected, and associated with the 
study drug 
• 
Any new findings on the study drug that could impact subject safety or the conduct of the 
study and/or increase the risk to the subjects 
• 
Deviations from or changes to the protocol to eliminate immediate hazards to the subjects 
• 
Death of a study subject 
• 
Information about any new investigator(s) at the study site 
 
The investigator agrees to send written summaries of the trial status to the REB annually, or 
more frequently, if requested by the REB.  
At least once a year, or as outlined by the site’s REB, the investigator will also seek to obtain 
written approval from the REB to continue the study. A copy of this written approval, (referring to 
the study by protocol title, number and date, including the date of any amendment) will be 
provided to the sponsor. 
The investigator will notify the REB of completion of the study not later than one month following 
study completion or termination.  
A copy of all communication between the investigator and the REB regarding this study will be 
provided to the sponsor’s study monitor. The investigator will maintain an accurate and 
complete record of all submissions made to the REB, including a list of all reports and 
documents submitted. 
11.2 Informed Consent 
Before enrolling a subject into the study, and prior to performing any study related procedures, 
the investigator or an authorized member of the investigational staff must obtain written 
informed consent from the subject or the subject’s legal representative. This consent must be 
obtained by providing the subject or the subject’s legal representative with the current REB-
approved subject information sheet and consent form that is written in a language the subject or 
the subject’s legal representative fluently understands. All subjects or their legal representative 
must have the opportunity to discuss the information provided to them with the investigator / co-
investigator / sub-investigator. 
During the informed consent process the following will be discussed with the subject or the 
subject’s legal representative and be documented: 
• 
Overall study structure and objectives 
• 
All study visits and procedures (e.g. medication dosing, physical exam, blood taking, subject 
questionnaires, diaries, etc.) 
• 
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• 
Subject participation is voluntary and the consent to participate may be withdrawn at any 
time 
• 
Choosing not to participate or withdrawing consent to participate will not affect the subject’s 
future care 
• 
Collection and processing of personal data (i.e. why the sponsor collects, uses and 
discloses personal data and who is responsible for protecting their personal information) 
• 
Direct access of authorized health authorities and sponsor staff to confidential subject 
records 
• 
Any study related questions the subject may have 
 
The subject or the subject’s legal representative will then be given the sponsor and REB-
approved ICF (printed on the investigator’s or institution’s letterhead) and sufficient time to read 
it and discuss the provided information to make an informed decision about their study 
participation. After all questions have been answered to the subject’s or the subject’s legal 
representative’s satisfaction the subject or the subject’s legal representative will sign and date 
the ICF. The form will also be signed and dated by the investigator (or investigator-designated 
research professional obtaining the consent) and a copy of it will be provided to the subject or 
the subject’s legal representative. 
The subject or the subject’s legal representative will be informed that during the course of the 
trial they will be provided with any new information or findings that may affect their willingness to 
participate. 
12 DATA HANDLING AND RECORD KEEPING 
12.1 Confidentiality and Privacy 
Information about study subjects will be kept confidential and managed according to the 
requirements of the Canadian Personal Information Protection and Electronic Documents Act 
(PIPEDA) (2000).  
Only those personal data will be collected and processed that are necessary to investigate the 
efficacy, safety, quality, and utility of the investigational product(s) used in this study. These 
data must be collected in an anonymized manner. 
As part of the informed consent procedure, explicit consent for the collecting and processing of 
personal data will be obtained from the study subject prior to any data collection. Sponsor 
personnel whose responsibilities require access to personal data agree to keep the identity of 
the study subject confidential. 
De-identified personal information collected during the study may also be added to research 
databases and used in the future by the sponsor and other companies and people working for 
or with the sponsor for scientific research purposes to: (i) develop a better understanding of the 
safety and effectiveness of Akynzeo®; (ii) study other therapies for patients; (iii) develop a better 
understanding of diseases included in the study; and (iv) improve the efficacy, design and 
methods of future studies. 
The results of the study may be published in scientific journals and/or presented at scientific 
meetings. In this case, the personal information will be anonymized. 

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De-identified personal information may also be disclosed to the following recipients for the 
purposes identified above: (i) the sponsor and its affiliates; (ii) third service providers engaged to 
assist the sponsor and the Clinical Trial Site including contract research organizations; (iii) the 
Institutional Review Board / Ethics Committee which approved the study; (iv) academic research 
organizations; (v) governmental regulatory agencies and other health authorities; and (vi) the 
sponsor's business partners and licensing partners. As may be required for the above purposes, 
Sponsor may disclose certain personal data to third parties recipients also located in countries, 
which may not have data privacy laws equivalent to those in Canada. In such a case, sponsor 
will take all necessary steps to ensure the safety of data subjects’ personal data in accordance 
with the requirements of the applicable data protection laws. 
 
The sponsor will ensure that the subject’s personal data will be: 
• 
Collected by fair and lawful means 
• 
Collected, used or disclosed reasonably and appropriately, and not used for any purpose 
other than that to which the subject has consented 
• 
Protected by appropriate security measures  
• 
Handled according to the sponsor’s personal information policies. These policies must be 
clear, understandable and readily available. 
 
The subject has the right to: 
• 
Expect the personal information the sponsor holds about them to be accurate, complete and 
up-to-date 
• 
Obtain access to their personal information and ask for corrections if necessary 
• 
Complain about how their personal information are handled if they feel their privacy rights 
have not been respected 
• 
Revoke their authorization for use of their personal data but only under exceptional 
circumstances which can be shown to cause unwarranted and substantial damage or 
distress to the subject and only when the data to be removed can be traced back to the 
subject 
In the event that a subject revokes authorization to collect or use personal data, the investigator 
retains the right to use all information collected prior to the revocation of subject authorization. 
For subjects that have revoked authorization to collect or use personal information, attempts 
should be made to obtain permission to collect at least vital status (i.e. that the subject is alive) 
at the end of their scheduled study period. 
12.2 Source Documents 
Source data is all information in original records (and certified copies of original records) of 
clinical findings, observations, or other activities in a clinical trial necessary for the 
reconstruction and evaluation of the trial. Source data are contained in source documents. 
Examples of these original documents, data and records include: hospital records, clinical and 
office charts, laboratory notes, memoranda, subjects’ diaries or evaluation checklists, pharmacy 
dispensing records, recorded data from automated instruments, copies or transcriptions certified 
after verification as being accurate and complete, microfiches, photographic negatives, 

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microfilm or magnetic media, x-rays, subject files, and records kept at the pharmacy, at the 
laboratories, and at medico-technical departments involved in the clinical trial. 
Source data may be collected by the sponsor, e.g., subject’s diaries. In such cases, a copy of 
the source data will remain at the site. Any source data collected by the sponsor will only 
contain the subjects’ initials and subject number as identifiers. 
Any data that are directly recorded in the CRFs will be considered as source data (e.g. subject 
questionnaires, visual analog scales, etc.). If data are recorded directly in the CRF, then it 
should be noted in the medical records that the assessment was done and by whom and the 
date it was done. 
12.2.1 Direct Access to Source Documents 
By signing the ICF, the subject provides permission that their original medical records can be 
directly accessed for trial-related monitoring, auditing, REB review and regulatory inspection. 
The investigator(s) will provide direct access to all source data/documents for study related 
activities of authorized sponsor personnel, auditors, REB, and regulatory inspectors. 
12.3 Subject Screening Form and Subject Identification Form 
The investigator will complete a subject screening form which lists all subjects who were 
evaluated to determine eligibility for study participation. The screening form will list the date of 
screening, name of the screened subject and their suitability for study inclusion or reason for 
study exclusion. 
The investigator also agrees to complete a subject identification form which allows easy 
identification of each subject during and after the study. The subject identification form will list 
the subject’s name, initials, contact information, baseline number (if applicable), randomization 
number, date randomized and date of study completion or withdrawal. 
This information should enable the study site to contact the study subjects in the event that the 
study drug is later found to endanger the health of the subjects or other persons. 
To maintain subject confidentiality, the subject screening form and subject identification form are 
only filed in the site’s study file and no copies will be retained in the sponsor’s files. Pre-
screening logs may be collected by the sponsor from the sites. These logs may only contain 
subjects’ initials but will not contain subjects’ names.  
12.4 Case Report Forms (CRFs) 
 A CRF is a printed, optical, or electronic document, designed to record all of the protocol-
required information to be reported to the sponsor on each study subject. Case report forms 
(CRFs) will be supplied by the sponsor. For this study Electronic Data Capture will be used. 
All data requested on the CRF must be recorded. Data must be entered into CRFs in English. 
The data obtained are entered by the staff at the study site in the data capture screen of the 
web-based documentation system. According to the data validation plan customized for this 
study the system validates the data entered online.  
The participating physician undertakes to provide all necessary background information to his 
records upon request. This is particularly important if errors in data entry or data transmission 
are suspected. 
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12.5 Record Retention 
The investigator shall retain all essential documents (including the subject identification form) for 
a period of 25 years or for at least 2 years after the last approval of a marketing application in 
Canada or until at least 2 years have elapsed since the formal discontinuation of clinical 
development of the investigational product, whatever occurs later. 
It is the responsibility of the sponsor to inform the investigator/institution as to when these 
documents no longer need to be retained.  
13 QUALITY ASSURANCE AND QUALITY CONTROL 
13.1 Monitoring 
Clinical research personnel from the sponsor or their legally appointed agent will make regular 
visits to the study site to oversee the progress of the study, and to ensure that it is conducted, 
recorded, and reported in accordance with the protocol, standard operating procedures (SOPs), 
GCP, and the applicable regulatory requirements. 
The purposes of monitoring are to verify that the rights and well-being of the subjects are 
protected, the reported trial data are accurate, complete, and verifiable from source documents 
and the conduct of the study is in compliance with the currently approved 
protocol/amendment(s), with GCP, and with the applicable regulatory requirements.  
The first monitoring visit after study initiation should usually be done as soon as possible after 
subject recruitment has started. 
The investigator will ensure that the monitor or other compliance or quality assurance reviewer 
is given access to all study-related documents (e.g. source documents, medical records, CRFs, 
drug accountability records, etc.) and study related facilities (e.g. pharmacy, diagnostic 
laboratory, etc.), and has adequate space to conduct the monitoring visit. 
The sponsor expects that, during monitoring visits, the relevant investigational staff will be 
available and allocate adequate time with the monitor for discussion of any issues or questions 
resulting from the monitoring activities.  
13.2 Auditing 
The investigator will permit study-related audits by the sponsor’s clinical quality assurance 
department, an independent sponsor selected auditor [e.g. Contract Research Organization 
(CRO)], or the site’s REB of all study related activities, documents (e.g., source documents, 
regulatory documents, data collection instruments, study data etc.), and applicable study-related 
facilities (e.g., pharmacy, diagnostic laboratory, etc.). The purpose of an audit is to 
systematically and independently examine trial-related activities and documents to determine 
whether the activities were conducted, and the data were recorded, analyzed, and accurately 
reported according to the protocol, applicable SOPs, GCP and all applicable regulatory 
requirements. 
13.3 Inspecting 
The investigator must be aware that a regulatory authority(ies) may be conducting an official 
review of documents, facilities, records, and other resources that are deemed by the 
authority(ies) to be related to the clinical study. Participation as an investigator in this study 
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quality assurance offices. The Principle Investigator is responsible for informing the sponsor of 
an inspection as soon as he/she becomes aware of it. 
14 STUDY FINANCES 
14.1 Funding 
The sponsor will provide a research grant for the study. A budget will be developed with the 
investigator and all financial aspects of the study will be documented in a separate agreement 
between the sponsor and the investigator/institution.  
14.2 Insurance 
The sponsor maintains a program of comprehensive general liability insurance and product 
liability insurance for the duration of the study at levels sufficient to support the indemnification 
obligations assumed under the separate agreement “Investigator Agreement – Study No. CAN-
PRO-NEPA-001 Responsibilities and Procedures”.  
The investigator also maintains a program of comprehensive general liability insurance for the 
duration of the study at levels sufficient to support the indemnification obligations assumed 
under the separate agreement “Investigator Agreement – Study No.CAN-PRO-NEPA-001 
Responsibilities and Procedures”.  
15 USE OF INFORMATION AND PUBLICATION 
Details concerning the procedures to be followed prior to publication are outlined in a separate 
agreement “Investigator Agreement – Study No. CAN-PRO-NEPA-001 Responsibilities and 
Procedures”. 
Prior to study start, the study will be published in a public study register. The summary of the 
results and/or the final medical report will be published in a publicly-accessible database no later 
than one year after study completion (LPO) and may be presented at a scientific congress. 
 
 

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16 REFERENCES 
 
1. Griffin AM, Butow PN, Coates AE, et al. On the receiving end. V. Patient perceptions 
12. of the side effects of cancer chemotherapy in 1993. Ann Oncol 1996;7:189-95. 
2. Laszlo J, Lucas VS Jr. Emesis as a critical problem in chemotherapy. N Engl J Med 
13. 1981;305:9448-9449. 
3. Onsoba D, Zee B, Warr D, Kaiser L, Latreille J, Peter J. Quality of Life Studies in 
14. Chemotherapy-Induced Emesis. Oncology 1996;53:Suppl 1:92-95. 
4. Gralla RJ. Controlling emesis in patients receiving cancer chemotherapy. Recent 
15. Results Cancer Res 1991;121:68-85. 
5. Borison HL, McCarthy LE. Neuropharmacology of chemotherapy-induced emesis. 
16. Drugs 1983;25:Suppl 1:8-17. 
6. Roila F, Molassiotis A, Herrstadt J, et al. 2016 MASCC and ESMO guideline update for 
the prevention of chemotherapy- and ratiotherapy-induced nausea and vomiting in 
advanced cancer patients. Ann Oncol 2016;27(5):v119-v133. 
7. Hesketh PJ, Kris MG, Basch E, et al. Antiemetics: American Society of Clinical Oncology 
Clinical Practice Guideline Update. J Clin Oncol 2017;JCO2017744789. doi: 
10.1200/JCO.2017.74.4789 [Epub ahead of print]. 
8. Saito M, Aogi K, Sekine I, et al. Palonostron plus dexamethasone for prevention of CINV 
during chemotherapy: double-blind, double-dummy, randomised comparative phase III 
trial.  Lancet Oncol 2009;10(2):115-24. 
9. Rojas C, Raje M, Tsukamoto T, Slusher BS. Molecular mechanisms of 5-HT(3) and NK(1) 
receptor antagonists in prevention of emesis. Eur J Pharmacol 2014;722:26-37. 
10. Hesketh PJ, Rossi G, Rizzi G et al. Efficacy and safety of NEPA, an oral combination of 
netupitant and palonosetron, for prevention of chemotherapy-induced nausea and 
vomiting following highly emetogenic chemotherapy: a randomized dose-ranging pivotal 
study. Ann Oncol 2014;25:1340-6. 
11. Aapro M, Rugo H, Rossi G et al. A randomized phase III study evaluating the efficacy 
and safety of NEPA, a fixed-dose combination of netupitant and palonosetron, for 
prevention of chemotherapy-induced nausea and vomiting following moderately 
emetogenic chemotherapy. Ann Oncol 2014;25:1328-33. 
12. Aapro M, Karthaus M, Schwartzberg L, et al.  NEPA, a fixed oral combination of 
netupitant and palonosetron, improves control of chemotherapy-induced nausea and 
vomiting (CINV) over multiple cycles of chemotherapy: results of a randomized, double-
blind, phase 3 trial versus oral palonosetron. Support Care Cancer 2017;25(4):1127-
1135. 
13. Gralla RJ, Bosnjak SM, Hontsa A, et al. A phase III study evaluating the safety and 
efficacy of NEPA, a fixed-dose combination of netupitant and palonosetron, for 
prevention of chemotherapy-induced nausea and vomiting over repeated cycles of 
chemotherapy. Ann Oncol 2014;25:1333-9. 
14. Akynzeo®) (netupitant/palonosetron) capsules: EU prescribing information. Helsinn 
Healthcare.  
15. Akynzeo® (netupitant/palonosetron) capsules. Canadian Product Monograph. Date of 
Revision: September 27, 2017  
16. Canadian Institutes of Health Research, Natural Sciences and Engineering Research 
Council of Canada, and Social Sciences and Humanities Research Council of Canada, 
Tri-Council Policy Statement: Ethical Conduct for Research Involving Humans, 
December 2010. 

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17. European Parliament and Council. DIRECTIVE 2001/20/EC (EU Clinical Trials 
Directive). 
http://www.ema.europa.eu/docs/en_GB/document_library/Scientific_guideline/2012/06/
WC500129137.pdf 
18. ICH Guideline. E2E: Pharmacovigilance Planning. Step 4 version; 18 November 2004. 
19. Frieden T.R. Evidence for Health Decision Making – Beyond Randomized, Controlled 
Trials. N Engl J Med 2017;377:465-75.DOI: 10.1056/NEJMra1614394 
20. Health Canada. Directive on physical requirements for controlled substances. Office of 
Controlled Substances Therapeutic Products Programme, amended December 1999. 
21. International Conference on Harmonization. E6: Good Clinical Practice: Consolidated 
Guideline (ICH E6). 
22. Personal Information Protection and Electronic Documents Act (PIPEDA). Minister of 
Justice. 2000. 
 

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17 APPENDICES 
 
Appendix 1: Subject Information and Informed Consent Form 
Appendix 2: Patient Diary 
Appendix 3: FLIE questionnaire  
Appendix 4: WPAI-NV questionnaire 
Appendix 5: HEC and MEC Emetogenicity 
Appendix 6: Safety Reporting Forms 
Appendix 7: Pregnancy Notification Form 
Appendix 8: Study Drug Access Card 
 
 
 

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Appendix 1: Subject Information and Informed Consent Form 
 
 

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Version 1.0: 05 June 2018  
 
 
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Appendix 2: Patient Diary 
 
 
 
 

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Protocol Number: CAN-PRO-NEPA-001 
 
Version 1.0: 05 June 2018  
 
 
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Protocol Number: CAN-PRO-NEPA-001 
 
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Protocol Number: CAN-PRO-NEPA-001 
 
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Protocol Number: CAN-PRO-NEPA-001 
 
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Protocol Number: CAN-PRO-NEPA-001 
 
Version 1.0: 05 June 2018  
 
 
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Protocol Number: CAN-PRO-NEPA-001 
 
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Protocol Number: CAN-PRO-NEPA-001 
 
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Protocol Number: CAN-PRO-NEPA-001 
 
Version 1.0: 05 June 2018  
 
 
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Protocol Number: CAN-PRO-NEPA-001 
 
Version 1.0: 05 June 2018  
 
 
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Protocol Number: CAN-PRO-NEPA-001 
 
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Appendix 3: FLIE questionnaire  
 
 
 

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Protocol Number: CAN-PRO-NEPA-001 
 
Version 1.0: 05 June 2018  
 
 
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Protocol Number: CAN-PRO-NEPA-001 
 
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Protocol Number: CAN-PRO-NEPA-001 
 
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Appendix 4: WPAI-NV questionnaire 
 
 
 

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Protocol Number: CAN-PRO-NEPA-001 
 
Version 1.0: 05 June 2018  
 
 
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Protocol Number: CAN-PRO-NEPA-001 
 
Version 1.0: 05 June 2018  
 
 
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Appendix 5: HEC and MEC Emetogenicity 
 
 
 
 
 
 
 

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Protocol Number: CAN-PRO-NEPA-001 
 
Version 1.0: 05 June 2018  
 
 
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Page 65 of 80 
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Appendix 6: Safety Reporting Forms  
 
6a. Adverse Event Reporting Form 
 
 
 
 
 
 
 
 
 

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Protocol Number: CAN-PRO-NEPA-001 
 
Version 1.0: 05 June 2018  
 
 
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Page 66 of 80 
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6b. Global Reporting Form for SAEs/AESIs/Special Situations 
 
 
 
 

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Protocol Number: CAN-PRO-NEPA-001 
 
Version 1.0: 05 June 2018  
 
 
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Protocol Number: CAN-PRO-NEPA-001 
 
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Protocol Number: CAN-PRO-NEPA-001 
 
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Protocol Number: CAN-PRO-NEPA-001 
 
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Protocol Number: CAN-PRO-NEPA-001 
 
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6c. Akynzeo®-Related Non-Serious Adverse Event Form 
 
 
 
 

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Protocol Number: CAN-PRO-NEPA-001 
 
Version 1.0: 05 June 2018  
 
 
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Protocol Number: CAN-PRO-NEPA-001 
 
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Protocol Number: CAN-PRO-NEPA-001 
 
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Appendix 7: Pregnancy Forms 
Pregnancy Notification Form 
 
 
 

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Protocol Number: CAN-PRO-NEPA-001 
 
Version 1.0: 05 June 2018  
 
 
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Protocol Number: CAN-PRO-NEPA-001 
 
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Protocol Number: CAN-PRO-NEPA-001 
 
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Pregnancy Outcome Questionnaire 
 

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Protocol Number: CAN-PRO-NEPA-001 
 
Version 1.0: 05 June 2018  
 
 
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Protocol Number: CAN-PRO-NEPA-001 
 
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Appendix 8: Study Drug Access Card 
 
 
 

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Protocol Number: CAN-PRO-NEPA-001 
 
Version 1.0: 05 June 2018  
 
 
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