A Phase I, Open Label, Single Dose, Two Parts Study in Male and Female Healthy Subjects to Assess the Safety and Pharmacokinetics of Fosnetupitant 235 mg Administered as IV Bolus and of Derived Netupitant and Netupitant Metabolites
Phase: PHASE1
Conditions: Healthy Volunteers
Sponsor: Helsinn Healthcare SA

 
 
 
 
 
CLINICAL STUDY PROTOCOL 
 
 
Study CRO-PK-22-363 - Sponsor code PNET-22-08 
 
 
A phase I, open label, single dose, two parts study in male and 
female healthy subjects to assess the safety and pharmacokinetics 
of Fosnetupitant 235 mg administered as IV bolus and of derived 
Netupitant and Netupitant metabolites 
 
 
 
 
 Sponsor:  
Helsinn Healthcare SA - Via Pian Scairolo 9,  
CH-6912 Lugano - Switzerland  
Phone: +41 91 985 21 21  
Fax: +41 91 993 21 22  
 
 
NCT number: 
NCT06840769 
 
 
Document date:  
24MAY2023 
 
 

Clinical Study Protocol 
Helsinn Healthcare SA  
CSP CRO-PK-22-363 
Sponsor code PNET-22-08 
Netupitant IV infusion shortening 
CSP final version 3.0, 24MAY23 
 
CROSS Research S.A. 
Page 1 
CONFIDENTIAL 
 
CLINICAL STUDY PROTOCOL 
 
Study CRO-PK-22-363 - Sponsor code PNET-22-08 
 
A phase I, open label, single dose, two parts study in male and 
female healthy subjects to assess the safety and pharmacokinetics 
of Fosnetupitant 235 mg administered as IV bolus and of derived 
Netupitant and Netupitant metabolites 
 
Open label, single dose, two parts (part A and part B), safety and pharmacokinetics phase I 
study. Study Part B will be conducted according to a randomized cross-over design 
 
Investigational product: 
IV fosnetupitant 235 mg free base 20 mL ready to use solution 
for intravenous administration, Patheon Italia S.p.A., Italy 
 
 
Reference product: 
IV Akynzeo (235 mg fosnetupitant/0.25 mg palonosetron) in 20 
mL injectable solution, Baxter Oncology GmbH, Germany 
 
 
Placebo: 
0.9% sodium chloride injection solution ready to use solution 
for intravenous administration (placebo), purchased from the 
market 
 
 
Sponsor: 
Helsinn Healthcare SA - Via Pian Scairolo 9,  
CH-6912 Lugano - Switzerland  
Phone: +41 91 985 21 21 
Fax: 
+41 91 993 21 22 
 
 
Investigator: 
Milko Radicioni, MD - Principal Investigator 
CROSS Research S.A., Phase I Unit, Via F. A. Giorgioli 14 
CH-6864 Arzo, Switzerland 
Phone: +41.91.64.04.450 
Fax: 
+41.91.64.04.451 
Email: clinic@croalliance.com 
 
 
Development phase: 
Phase I 
 
 
Version and date: 
CSP final version 3.0, 24MAY23 
 
This study will be conducted in compliance with the protocol and the principles of Good Clinical Practice (GCP) 
[ICH topic E6 (R2)] and with the local regulatory requirements 
 
Property of the Sponsor 
May not be used, divulged, published or otherwise disclosed without the consent of the Sponsor 
 
This document comprises 99 pages  
 
 

Clinical Study Protocol 
Helsinn Healthcare SA  
CSP CRO-PK-22-363 
Sponsor code PNET-22-08 
Netupitant IV infusion shortening 
CSP final version 3.0, 24MAY23 
 
CROSS Research S.A. 
Page 2 
CONFIDENTIAL 
CLINICAL STUDY PROTOCOL AMENDMENT HISTORY 
 
CSP version 
Reason for change 
Final version 3.0, 
24MAY23 
1) Protocol amendment implemented, as required by the competent Ethics 
Committee, in order to improve the check of safety and tolerability of the 
study treatment in study Part A, with particular attention to the planned 
infusion durations shorter than 30 min, i.e., planned cohorts 2, 3 and 4. 
Therefore, the 10 subjects of cohorts 2, 3 and 4, planned to test decreasing 
infusion durations of 15, 5 and 2 min, respectively, will be sequentially 
treated as subgroups of 3, 3 and 4 subjects.  
  
2) Paragraph 18.3.4 "Reporting Serious Adverse Events" does not clearly 
define the reporting of SUSARs to Swissmedic (Competent Authority). As 
required by the Federal Health Authority, the paragraph is amended in 
accordance with ClinO, Art. 41.  
3) Update of the bioanalytical laboratory denomination. 
 

Clinical Study Protocol 
Helsinn Healthcare SA  
CSP CRO-PK-22-363 
Sponsor code PNET-22-08 
Netupitant IV infusion shortening 
CSP final version 3.0, 24MAY23 
 
CROSS Research S.A. 
Page 3 
CONFIDENTIAL 
2 
PROTOCOL APPROVAL 
 
2.1 
SPONSOR 
 
Helsinn Healthcare SA 
 
Medical Expert: 
 
 
 
 
 
. 
. 
. 
. 
 
Study Coordinator: 
 
 
 
 
 
. 
. 
. 
. 
 
Statistician: 
 
 
 
 
 
. 
. 
. 
. 
 
 
 

Clinical Study Protocol 
Helsinn Healthcare SA  
CSP CRO-PK-22-363 
Sponsor code PNET-22-08 
Netupitant IV infusion shortening 
CSP final version 3.0, 24MAY23 
 
CROSS Research S.A. 
Page 4 
CONFIDENTIAL 
Clinical Pharmacokineticist: 
 
 
 
 
 
. 
.  
. 
. 
 
Drug Safety Specialist: 
 
 
 
 
 
. 
. 
. 
. 
 
 
 

Clinical Study Protocol 
Helsinn Healthcare SA  
CSP CRO-PK-22-363 
Sponsor code PNET-22-08 
Netupitant IV infusion shortening 
CSP final version 3.0, 24MAY23 
 
CROSS Research S.A. 
Page 5 
CONFIDENTIAL 
2.2 
INVESTIGATOR 
Study Title 
A phase I, open label, single dose, two parts study in male and female healthy subjects to
assess the safety and pharmacokinetics of Fosnetupitant 235 mg administered as IV bolus and
of derived Netupitant and Netupitant metabolites 
Study Number 
PNET-22-08 
 
I have read and understood all pages of this clinical trial protocol and I agree that they contain 
all information required to conduct this trial. I agree to conduct the trial as outlined in the 
protocol and to comply with all terms and conditions set out therein. I confirm that I will 
conduct the trial in accordance with local regulations, ICH GCP “ICH Topic E6”, R2, the 
provisions of the Declaration of Helsinki and with the Swiss Ordinance on Clinical Trials with 
the exception of Clinical Trials of Medical Devices 810.305 (ClinO) of 20 September 2013 
(Status as of 26 May 2022) and all applicable regulatory requirements. I will keep strictly 
confidential any information pertaining to the study and/or regarding the Sponsor, using such 
information only to accomplish the present study tasks. I will direct, assist and oversee sub-
Investigator(s) and other relevant staff members under my control and will ensure that all trial 
staff members have access to copies of this protocol and to all information relating to preclinical 
and prior clinical experience (e.g., Investigator’s Brochure), ICH GCP “ICH Topic E6”, R2, 
local regulations and the Declaration of Helsinki to enable them to work in accordance with the 
provisions of these documents.  
I will use only the informed consent form approved by the Institutional Review 
Board/Independent Ethics Committee (IRB/IEC) and will fulfil all responsibilities for 
submitting pertinent information to the IRB/IEC responsible for this trial.  
I agree that Helsinn or its representatives and any local and foreign regulatory authorities shall 
have access to any source documents from which CRF information may have been generated.  
I agree that all documentation supplied to me by Helsinn and CROSS Research SA, Phase I 
Unit, Switzerland concerning this trial will be kept in the strictest confidence. 
 
 
 
 
 
 
________________________________________ __________________ 
(Signature) 
(Date) 
 
Milko Radicioni, MD 
 
CROSS Research SA, Phase I Unit, Switzerland 
 

Clinical Study Protocol 
Helsinn Healthcare SA  
CSP CRO-PK-22-363 
Sponsor code PNET-22-08 
Netupitant IV infusion shortening 
CSP final version 3.0, 24MAY23 
 
CROSS Research S.A. 
Page 6 
CONFIDENTIAL 
2.3 
CRO 
 
CROSS Research S.A., Switzerland 
 
Coordination 
. 
 
 
 
 
 
 
 
 
Date 
 
Signature 
 
 
Clinical Study Protocol Author 
. 
 
 
 
 
 
 
 
 
Date 
 
Signature 
 
 
Biometry Unit Representative 
. 
 
 
 
 
 
 
 
 
Date 
 
Signature 
 
 
Quality Assurance Unit Representative 
. 
 
 
 
 
 
 
 
 
Date 
 
Signature 
 
 
 

Clinical Study Protocol 
Helsinn Healthcare SA  
CSP CRO-PK-22-363 
Sponsor code PNET-22-08 
Netupitant IV infusion shortening 
CSP final version 3.0, 24MAY23 
 
CROSS Research S.A. 
Page 7 
CONFIDENTIAL 
3 
STUDY SYNOPSIS 
 
Title: A phase I, open label, single dose, two parts study in male and female healthy subjects to assess the safety 
and pharmacokinetics of Fosnetupitant 235 mg administered as IV bolus and of derived Netupitant and Netupitant 
metabolites 
 
Protocol number: CRO-PK-22-363 - Sponsor code PNET-22-08 
 
Clinical phase: Phase I 
 
Study design: Open label, single dose, two parts (part A and part B), safety and pharmacokinetics phase I study. 
Study Part B will be conducted according to a randomized cross-over design 
 
Planned nr. of centers / countries: 1 / Switzerland 
 
Investigator and center: Milko Radicioni, MD - CROSS Research Phase I Unit, Via F. A. Giorgioli 14,  
CH-6864 Arzo, Switzerland 
 
Investigational products:  
TEST (T):  
Intravenous (IV) fosnetupitant 235 mg free base 20 mL ready to use solution for 
intravenous administration, Patheon Italia S.p.A., Italy 
 
REFERENCE (R): 
 
IV Akynzeo (235 mg fosnetupitant/0.25 mg palonosetron) in 20 mL injectable solution 
(Baxter Oncology GmbH, Germany) 
 
PLACEBO (P): 
0.9% sodium chloride injection solution ready to use solution for intravenous 
administration (placebo), commercially available product purchased from the market 
 
Dose regimens:  
Part A of the study:  
In cohort 1, 10 healthy volunteers (HV) will receive a dose of T as a one single 30-min IV infusion and additional 
10 subjects will receive a single IV dose of undiluted R (treatment Rα) as a one single 30-min IV infusion of 20 
mL, according to a parallel group design. In each of 3 consecutive cohorts - 2, 3 and 4, - 10 healthy volunteers 
(HV) will receive a single IV dose of T and will be sequentially treated as subgroups of 3, 3, and 4 subjects, 
respectively. 
A staggered approach with decreasing infusion time duration will be applied to the injection of T in cohorts 2, 3 
and 4. Therefore, in each cohort, the T injection duration will vary as follows: 
Cohort 1: 30 min (T or Rα) 
Cohort 2: 15 min (T) 
Cohort 3: 5 min (T) 
Cohort 4: 2 min (T) 
 
At the end of cohort 1 and of each subgroup of cohorts 2, 3 and 4, safety and tolerability results will be evaluated 
by the Investigator and the study Sponsor Medical Expert. Predefined stopping rules will be considered for 
deciding about continuing with the next cohort and a shorter injection duration. If the safety data obtained from a 
treated cohort are considered as not sufficient for taking a decision on the infusion duration de-escalation process 
and if additional safety data are deemed necessary to allow such decision to be taken, the study Investigator and 
the Sponsor Medical Expert may decide to add additional subjects (up to a maximum of 4 subjects per cohort) to 
the 10 subjects of the treated cohort. After cohort 1, if the injection duration of 30 min of T proves to be safe and 
well tolerated, 15 min will be tested in cohort 2. After cohort 2, if the injection duration of 15 min proves to be 
safe and well-tolerated, 5 min will be tested in cohort 3. After cohort 3, if the injection duration of 5 min proves 
to be safe and well-tolerated, 2 min will be tested in cohort 4. 
 
At the end of study Part A, the Sponsor will take a final decision whether to proceed with study Part B with the 
resulting shortest injection duration considered as adequate in terms of safety determined in study Part A. 
 
Part B of the study will follow a 2-way, cross-over randomized design and will include 40 male and female 
subjects. Before entering the crossover phase, each subject will receive P at the shortest infusion duration  
 
 
 

Clinical Study Protocol 
Helsinn Healthcare SA  
CSP CRO-PK-22-363 
Sponsor code PNET-22-08 
Netupitant IV infusion shortening 
CSP final version 3.0, 24MAY23 
 
CROSS Research S.A. 
Page 8 
CONFIDENTIAL 
STUDY SYNOPSIS (cont.) 
 
Dose regimens (continued):  
determined in study Part A. Afterwards, in 2 consecutive crossover periods, each subject will receive T at the 
shortest injection duration considered as safe and well tolerated, determined in study part A, and 20 mL of solution 
of R diluted to 50 mL with 0.9% sodium chloride injection solution and infused in 30 min. 
 
Objectives:  
Primary objective of Part A: 
 To define the shortest safe and tolerable duration of IV injection of T among 4 durations tested in decreasing 
order: 30, 15, 5 and 2 min, respectively. The selected shortest (safe and tolerable) injection duration 
determined in part A will be considered for testing in study Part B.  
Secondary objective of Part A: 
 to characterize the pharmacokinetic profile in plasma of fosnetupitant, netupitant and netupitant metabolites 
M1, M2 and M3 after injection of T administered at the relevant injection duration and after injection of 
undiluted R (defined as Rα). 
 to determine the safety and tolerability of T administered at the relevant injection duration. 
 
Primary objective of Part B: 
 To investigate the exposure equivalence of T, at the shortest injection duration defined as safe in Part A, and 
R, administered as a 30 min diluted infusion. The equivalence in exposure will be estimated in terms of extent 
of exposure to netupitant (AUC0-∞ and AUC0-t).  
Secondary objectives of Part B: 
 To characterize the pharmacokinetic profile in plasma of fosnetupitant, netupitant and netupitant metabolites 
M1, M2 and M3 after administration of T at the shortest injection duration defined as safe in Part A and R 
administered as 30 min diluted infusion. 
 To confirm the safety and tolerability of T administered at the shortest injection duration defined as safe in 
Part A in comparison to R, administered as a 30 min diluted infusion. 
 To assess the effect of T on ECG parameters (HR, QT, QTcF, QTcB, PR and QRS intervals). 
 To assess the effects of the administration of fosnetupitant on the QT interval in the shortest infusion time 
(defined in Part A) compared to placebo, in male and female healthy subjects. 
 
Endpoints 
Primary endpoint of Part A 
 Type, number and frequency of treatment-emergent adverse events collected up to 24 h post-dose.  
Primary endpoint of Part B 
 Area under the plasma concentration-time curve of netupitant from time zero to the time of last measurable 
concentration or to infinity (AUC0-t and AUC0-∞) following administration of T, at the infusion duration 
selected in Part A, and R administered as 30-min diluted infusion. 
Secondary safety endpoints of Part A 
 Vital signs (blood pressure, pulse rate), 12-lead ECG, clinical laboratory tests (blood chemistry, hematology 
and urinalysis), body weight and physical examination 
Secondary safety endpoints of Part B 
 Safety and tolerability parameters of T versus R (treatment-emergent adverse events, vital signs [blood 
pressure, pulse rate], 12-lead ECG, clinical laboratory tests (blood chemistry, hematology and urinalysis), 
body weight and physical examination. 
 Cardiac evaluation: 
• 
Placebo-corrected change from baseline in HR, QT, QTcF, QTcB, PR and QRS intervals. 
• 
Change from baseline in HR, QT, QTcF, QTcB, PR and QRS intervals. 
• 
Categorical outliers for HR, QT, QTcF, QTcB, PR, and QRS intervals. 
• 
Frequency of changes in T-wave morphology and U-wave presence from triplicate 12-lead ECGs 
extracted from continuous recordings. 
 
 
 
 

Clinical Study Protocol 
Helsinn Healthcare SA  
CSP CRO-PK-22-363 
Sponsor code PNET-22-08 
Netupitant IV infusion shortening 
CSP final version 3.0, 24MAY23 
 
CROSS Research S.A. 
Page 9 
CONFIDENTIAL 
STUDY SYNOPSIS (cont.) 
 
Endpoints (continued) 
Secondary PK endpoints of Part A and B 
For plasma fosnetupitant, netupitant and its main metabolites M1, M2 and M3, when applicable: 
 C0, Cmax, tmax, Clast, tlast, AUC0-t (for all analytes with exception of netupitant AUC0-t in Part B, which is the 
primary endpoint), AUC0-24, λz, t½, CL, Vz, MRT 
Secondary PK endpoints of Part B only  
For plasma fosnetupitant, netupitant and its main metabolites M1, M2 and M3, when applicable: 
 AUC0-120, AUC0-∞ (with exception of netupitant AUC0-∞, which is the primary endpoint) 
For plasma fosnetupitant: 
 RAUCfos/netu  
For plasma M1: 
 RAUCM1/netu 
For plasma M2: 
 RAUCM2/netu 
For plasma M3: 
 RAUCM3/netu 
 
Analytics: Fosnetupitant, netupitant and its main metabolites M1, M2 and M3 will be determined in plasma 
samples at a qualified bioanalytical laboratory to Ardena Bioanalysis BV, W. A. Scholtenstraat 7,  
NL-9403 AJ Assen, the Netherlands. Validated liquid chromatography-tandem mass spectrometry methods with 
appropriate lower limits of quantification will be used for the determination of plasma concentrations. 
 
Safety and tolerability assessments: Treatment-emergent adverse events; vital signs (blood pressure, HR), 
physical examinations; laboratory tests; 12-lead ECG and body weight. 
 
Sample size: The planned number of 20 healthy subjects to be included in cohort 1 and 10 healthy subjects to be 
included in each following cohort of Part A of the study was not computed by statistical assumptions.  
The sample size for the netupitant exposure equivalence (netupitant AUC) assessment in Part B of the study will 
be 40 healthy male and female subjects in order to have 34 completed subjects. Drop-outs will not be replaced. 
The sample size was determined by a statistical power calculation to test equivalence based on AUC0-t. The 
assumptions are that the expected ratio of means is 1 (Fosnetupitant 235 mg IV versus Akynzeo IV injection), the 
cross-over ANOVA √MSE (ln scale) is 0.265, and α is 10% (bilateral). A sample size in each sequence group of 
17 (total sample size is 34) is required to have a power of 90%. 
 
Selection criteria: Inclusion criteria: 
1. Informed consent: signed written informed consent before inclusion in the study  
2. Sex and Age: healthy men/women volunteers, 18-55 years old (inclusive) 
3. Body Mass Index (BMI): 18.5-30 kg/m2 inclusive 
4. Vital signs: systolic blood pressure 100-139 mmHg, diastolic blood pressure 50-89 mmHg, pulse rate 50-99 
bpm, measured after 5 min at rest in the sitting position 
5. Full comprehension: ability to comprehend the full nature and purpose of the study, including possible risks 
and side effects; ability to co-operate with the investigator and to comply with the requirements of the entire 
study 
6. Contraception and fertility (women only): women of childbearing potential defined as a non-menopausal 
woman who has not had a bilateral oophorectomy or medically documented ovarian failure and/or at risk for 
pregnancy must agree, signing the informed consent form, to use a highly effective method of contraception 
throughout the study and to continue for 14 days after the last dose of the study treatment.  
Highly effective contraceptive measures include: 
a. 
Hormonal oral, implantable, transdermal, or injectable contraceptives for at least 2 months before the 
screening visit. 
b. A non-hormonal intrauterine device (IUD) for at least 2 months before the screening visit 
c. 
A sterile or vasectomized sexual partner 
d. True (long-term) heterosexual abstinence, defined as refraining from heterosexual intercourse when this 
is in line with the preferred and usual lifestyle of the subject, while periodic abstinence (e.g., calendar, 
ovulation, symptothermal, post-ovulation methods), lactational amenorrhea and withdrawal are not 
acceptable. 
 

Clinical Study Protocol 
Helsinn Healthcare SA  
CSP CRO-PK-22-363 
Sponsor code PNET-22-08 
Netupitant IV infusion shortening 
CSP final version 3.0, 24MAY23 
 
CROSS Research S.A. 
Page 10 
CONFIDENTIAL 
STUDY SYNOPSIS (cont.) 
 
Selection criteria (continued):  
Women of non-child-bearing potential or in post-menopausal status defined as such when there is either: 
a. 
12 months of spontaneous amenorrhea or 
b. 6 months of spontaneous amenorrhea with serum FSH levels > 40 mIU/mL or 
c. 
6 weeks documented postsurgical bilateral oophorectomy with or without hysterectomy 
will be admitted. 
For all women, pregnancy test result must be negative at screening and admission (Day -1). 
7. Contraception (men only): men will either be sterile or agree to use one of the following approved methods 
of contraception from the first study drug administration until at least 14 days after the last administration, 
also in case their partner is currently pregnant: 
a. 
A male condom with spermicide 
b. A sterile sexual partner or a partner in post-menopausal status for at least one year 
c. 
Use by the female sexual partner of an IUD, a female condom with spermicide, a contraceptive sponge 
with spermicide, a diaphragm with spermicide, a cervical cap with spermicide, or hormonal oral, 
implantable, transdermal, or injectable contraceptives for at least 2 months before the screening visit 
Men must accept to inform their partners of the participation in the clinical study. Furthermore, they will not 
donate sperm from the date of the informed consent form’s signature, throughout the study, and for at least 
14 days after the last dose of the study treatment. These requirements are based upon the availability and 
results of reproductive toxicity data. 
Exclusion criteria: 
1. 12-leads Electrocardiogram (ECG) (supine position): clinically significant abnormalities at screening. With 
regards to QTc, the following will be considered as exclusion criterion: mean corrected QT (QTcF) > 450 ms. 
HR < 50 or > 99 bpm. PR < 100 or >220 ms. QRS > 120 ms. Relevantly abnormal T-wave patterns 
2. Physical examination findings: clinically significant abnormal physical findings which could interfere with 
the objectives of the study 
3. Laboratory analyses: clinically significant abnormal laboratory values at screening, indicative of physical 
illness or suggesting the subject’s exclusion, in his/her best interest  
4. Allergy: ascertained or presumptive hypersensitivity to the active principle and/or formulations’ ingredients; 
history of anaphylaxis to drugs or allergic reactions in general, which the investigator considers may affect 
the outcome of the study 
5. Diseases: significant history, in the opinion of the Investigator, of renal, hepatic, gastrointestinal, 
cardiovascular (in particular, heart failure, hypokalemia, family history of Long QT Syndrome, history of 
superficial thrombophlebitis or deep vein thrombosis), respiratory, skin, hematological, endocrine or 
neurological diseases that may interfere with the aim of the study 
6. Medications: medications, including over the counter medications and herbal remedies in the 2 weeks before 
the first visit of the study. Hormonal contraceptives for women are allowed  
7. CYP3A4 inducers and inhibitors: use of any inducer or inhibitor of CYP3A4 enzymes (drugs, food, herbal 
remedies) in the 28 days or in the 7 days, respectively, before the planned first study drug administration and 
during the whole study 
8. Investigative drug studies: participation in the evaluation of any investigational product for 3 months before 
this study. The 3-month interval is calculated as the time between the first calendar day of the month that 
follows the last visit of the previous study and the first day of the present study 
9. Blood donation or significant blood loss: blood donations or significant blood loss in the 3 months before the 
first visit of this study 
10. Drug, alcohol, caffeine, tobacco: history of drug, alcohol [>1 drink/day for women and >2 drinks/day for men, 
defined according to the USDA Dietary Guidelines 2020-2025], caffeine (>5 cups coffee/tea/day) or tobacco 
abuse (≥10 cigarettes/day)  
11. Drug test: positive result at the urine drug screening test at screening or Day -1 
12. Alcohol test: positive salivary alcohol test at Day -1 
13. Diet: abnormal diets (<1600 or >3500 kcal/day) or substantial changes in eating habits in the 4 weeks before 
screening; vegetarians 
14. Pregnancy (women only): positive or missing pregnancy test at screening or Day -1, pregnant or lactating 
women  
15. Netupitant studies: enrolment in a previous study of netupitant or fosnetupitant (alone or in combination with 
palonosetron) 
 
 

Clinical Study Protocol 
Helsinn Healthcare SA  
CSP CRO-PK-22-363 
Sponsor code PNET-22-08 
Netupitant IV infusion shortening 
CSP final version 3.0, 24MAY23 
 
CROSS Research S.A. 
Page 11 
CONFIDENTIAL 
STUDY SYNOPSIS (cont.) 
 
Study procedures of Part A: 
Day 
Procedures/Assessments 
Notes 
Screening – visit 1 
From Day 
-21 to Day 
-2 
 Explanation to the subject of study aims, procedures and possible risks 
 Informed consent signature 
 Screening number assignment (as S001, S002, etc.) 
 Demographic data and lifestyle recording 
 Medical/surgical history 
 Previous/concomitant medications 
 Full physical examination (body weight, height, body mass index, vital 
signs, physical abnormalities) 
 Triplicate 12-lead ECG recording 
 Laboratory analyses: hematology, blood chemistry, urinalysis and 
virology 
 Serum pregnancy test (women only) 
 Urine multi-drug screening test 
 Adverse events recording  
 Inclusion/exclusion criteria evaluation 
Note: The first two 
letters of the surname 
followed by the first 
two letters of the first 
name will be used in 
the Phase I Unit 
source 
document 
only and will not be 
transferred 
to 
the 
Sponsor 
Visit 2  
Day -1 
 Short physical examination (only if screening physical examination 
performed more than 7 days before Day -1) 
 Recording of concomitant medications  
 Salivary alcohol test 
 Urine pregnancy test (women only) 
 Urine multi-drug screening test 
 Body weight  
 Vital signs measurement 
 Adverse events recording 
 Inclusion/exclusion criteria evaluation 
 Eligibility evaluation 
 Enrolment  
 Subject study number assignment (as 001, 002, etc.) 
Arrival at the Phase 
I Unit in the evening  
Confinement 
until 
the morning of Day 
2 
Standardized 
low-
fat dinner 
Fasting for 10 h 
(overnight) 
Visit 3 
Day 1 
 T or Rα treatment 
 Vital signs measurement: at pre-dose, at the end of injection, then at 
1, 2 and 4 h after end of administration 
 Triplicate 12-lead ECG recording: at pre-dose, at the end of the 
injection and 1, 2 and 4 h after the end of the injection 
 Blood sample collection for pharmacokinetic analysis. See schedule 
in tabular format: Table 4.4 
 Recording of concomitant medications 
 Adverse events recording  
Standardized lunch 
at least 5 h  
post-dose (at 
around 13:00)  
Standardized dinner 
at 
least 
12 
h  
post-dose (at around 
20:00) 
Day 2 
 Vital signs measurement at 24 h after end of administration 
 Triplicate 12-lead ECG recording at 24 h after the end of the injection 
 Blood sample collection for pharmacokinetic analysis. See schedule 
in tabular format: Table 4.4 
 Recording of concomitant medications 
 Short physical examination upon discharge  
 Adverse events recording 
Discharge from the 
Phase I Unit in the 
morning after the 
24-h 
post-dose 
blood 
sample 
collection, 
ECG 
recording and vital 
signs check 
 
 
 

Clinical Study Protocol 
Helsinn Healthcare SA  
CSP CRO-PK-22-363 
Sponsor code PNET-22-08 
Netupitant IV infusion shortening 
CSP final version 3.0, 24MAY23 
 
CROSS Research S.A. 
Page 12 
CONFIDENTIAL 
STUDY SYNOPSIS (cont.) 
 
Study procedures of Part A: 
 
Day 
Procedures/Assessments 
Notes 
Visit 4 - Final Visit/ETV 
Day 7 / 
at ETV in case of 
discontinuation 
 Full physical examination (body weight and physical abnormalities)  
 Recording of concomitant medications 
 Vital signs measurement 
 Triplicate 12-lead ECG recording 
 Urine pregnancy test (women only) 
 Laboratory analyses as at screening, except for virology 
 AE recording 
In case of clinically significant results at the final visit, the subjects will 
be followed-up by the Investigator until the normalization of the 
concerned clinical parameter(s) 
Upon leaving, the 
subjects 
will 
be 
instructed to contact 
immediately 
the 
Investigator in case 
of occurrence of any 
adverse reactions 
In Part A, treatment emergent adverse events collected up to 24 h after the end of the injection (Visit 3, Day 2) 
will be evaluated by the Investigator and the Study Sponsor Medical Expert. At the end of cohort 1 and of each 
subgroup of cohorts 2, 3 and 4, safety and tolerability results will be evaluated by the Investigator and the study 
Sponsor Medical Expert. Predefined stopping rules will be considered for decision about the treatment of the next 
cohort of subjects with a shorter injection duration. If the safety data obtained from a treated cohort are considered 
as not sufficient for taking a decision on the infusion duration de-escalation process, and if additional safety data 
are deemed necessary to allow such decision to be taken, the study Investigator and the Sponsor Medical Expert 
may decide to add additional subjects (up to a maximum of 4 subjects per cohort) to the 10 subjects of the treated 
cohort.  
The shortest injection duration selected on the basis of the safety and tolerability results of Part A will be used in 
Part B. 
Study procedures of Part B: 
 
Day 
Procedures/Assessments 
Notes 
Screening – visit 1 
From Day 
-21 to Day 
-2 
 Explanation to the subject of study aims, procedures and possible risks 
 Informed consent signature 
 Screening number assignment (as S101, S102, etc.) 
 Demographic data and lifestyle recording 
 Medical/surgical history 
 Previous/concomitant medications 
 Full physical examination (body weight, height, body mass index, vital 
signs, physical abnormalities) 
 Triplicate 12-lead ECG recording 
 Laboratory analyses: hematology, blood chemistry, urinalysis and 
virology 
 Serum pregnancy test (women only) 
 Urine multi-drug screening test 
 Adverse events recording 
 Inclusion/exclusion criteria evaluation 
Note: The first two 
letters 
of 
the 
surname followed 
by the first two 
letters of the first 
name will be used 
in the Phase I Unit 
source 
document 
only and will not be 
transferred to the 
Sponsor 
Visit 2 
Day -1 
 Short physical examination (only if screening physical examination 
performed more than 7 days before Day -1) 
 Recording of concomitant medications 
 Salivary alcohol test 
 Urine multi-drug screening test 
 Urine pregnancy test (women only) 
 Body weight 
 Adverse events recording 
 Inclusion/exclusion criteria evaluation 
 Eligibility evaluation 
 Enrolment and randomization  
 Randomization number assignment (as 101, 102, etc.) 
Arrival 
at 
the 
Phase I Unit in the 
evening 
Confinement until 
the morning of 
Day 5 
Standardized low-
fat dinner 
Fasting for 10 h 
(overnight) 

Clinical Study Protocol 
Helsinn Healthcare SA  
CSP CRO-PK-22-363 
Sponsor code PNET-22-08 
Netupitant IV infusion shortening 
CSP final version 3.0, 24MAY23 
 
CROSS Research S.A. 
Page 13 
CONFIDENTIAL 
STUDY SYNOPSIS (cont.) 
 
Study procedures of Part B (continued): 
Day 
Procedures/Assessments 
Notes 
Visit 3 
Day 1 
 P treatment 
 Vital signs measurement: at pre-dose, end of the infusion, 
then at 1, 2 and 4 h after the end of the infusion 
 Continuous 12-lead ECG recording: starting 1 h before 
administration and up to 48 h after the end of the infusion; 
discrete triplicate 12-lead ECGs to be extracted 3 times 
within 1 h before the start of infusion and at the end of the 
infusion and 0.5, 1, 2 and 4 h after the end of the infusion 
 Triplicate 12-lead ECG recording: at pre-dose and at 1 and 
2 h after the end of infusion 
 Recording of concomitant medications 
 Adverse events recording 
Standardized lunch at least 5 
h post-dose (at around 13:00) 
Standardized dinner at least 
12 h post-dose (at around 
20:00) 
 
Day 2 
 Vital signs measurement at 24 h after the end of the infusion 
 Continuous 12-lead ECG recording: continuing up to 48 h 
after the end of the infusion; discrete triplicate 12-lead ECGs 
to be extracted at 24 h after the end of the infusion 
 Triplicate 12-lead ECG recording at 24 h after the end of 
infusion 
 Recording of concomitant medications 
 Adverse events recording 
Standardized 
breakfast, 
lunch and low-fat dinner at 
about 08:00, 13:00 and 20:00 
and then fasting for 10 h 
(overnight) 
Day 3 
 T or R treatment 
 Vital signs measurement: at pre-dose, end of the 
injection/infusion, then at 1, 2 and 4 h after the end of the 
injection/infusion 
 Continuous 12-lead ECG recording: starting shortly before 
T/R administration and up to 48 h after the end of the 
injection/infusion; discrete triplicate 12-lead ECGs to be 
extracted 3 times within 1 h before the start of 
injection/infusion and at the end of the injection/infusion and 
0.5, 1, 2 and 4 h after the end of the injection/infusion 
 Triplicate 12-lead ECG recording: at pre-dose and at 1 and 
2 h after the end of T/R injection/infusion 
 Recording of concomitant medications 
 Blood sample collection for pharmacokinetic analysis. See 
schedule in tabular format: Table 4.4 
 Adverse events recording 
Standardized lunch at least 5 
h post-dose (at around 13:00) 
Standardized dinner at least 
12 h post-dose (at around 
20:00) 
 
Day 4 
 Vital signs measurement at 24 h after the end of T/R 
injection/infusion 
 Continuous 12-lead ECG recording: continuing up to 48 h 
after the end of T/R injection/infusion; discrete triplicate 12-
lead ECG to be extracted at 24 h after the end of T/R 
injection/infusion 
 Triplicate 12-lead ECG recording at 24 h after the end of T/R 
injection/infusion 
 Recording of concomitant medications 
 Blood sample collection for pharmacokinetic analysis. See 
schedule in tabular format: Table 4.4 
 Adverse events recording 
Standardized 
breakfast, 
lunch and dinner at around 
08:00, 13:00 and 20:00 
 
 
 

Clinical Study Protocol 
Helsinn Healthcare SA  
CSP CRO-PK-22-363 
Sponsor code PNET-22-08 
Netupitant IV infusion shortening 
CSP final version 3.0, 24MAY23 
 
CROSS Research S.A. 
Page 14 
CONFIDENTIAL 
STUDY SYNOPSIS (cont.) 
 
Study procedures of Part B (continued): 
Day 
Procedures/Assessments 
Notes 
Visit 3 (continued) 
Day 5 
 Vital signs measurement at 48 h after the end of T/R 
injection/infusion 
 Continuous 12-lead ECG recording: continuing up to 48 h 
after the end of T/R injection/infusion; discrete triplicate 12-
lead ECG to be extracted at 48 h after the end of T/R 
injection/infusion 
 Recording of concomitant medications 
 Blood sample collection for pharmacokinetic analysis. See 
schedule in tabular format: Table 4.4 
 Adverse events recording 
Discharge from the Phase I 
Unit in the morning after the 
48-h post-dose blood sample 
collection, ECG recording 
and vital signs check 
Visit 4 
Day 6 
 Blood sample collection for pharmacokinetic analysis: 72 h 
post-dose 
 Vital signs measurement 
 Recording of concomitant medications 
 Adverse events recording 
Ambulatory visit. Arrival at 
the Phase I Unit in the 
morning. 
Visit 5 
Day 7 
 Blood sample collection for pharmacokinetic analysis: 96 h 
post-dose 
 Vital signs measurement 
 Recording of concomitant medications 
 Adverse events recording 
As visit 4 
Visit 6 
Day 8 
 Blood sample collection for pharmacokinetic analysis: 120 
h post-dose 
 Vital signs measurement 
 Recording of concomitant medications 
 Adverse events recording 
As visit 4 
Visit 7 
Day 9 
 Blood sample collection for pharmacokinetic analysis: 144 
h post-dose 
 Vital signs measurement 
 Recording of concomitant medications 
 Adverse events recording 
As visit 4 
Visit 8 
Day 10 
 Blood sample collection for pharmacokinetic analysis: 168 
h post-dose 
 Vital signs measurement 
 Recording of concomitant medications 
 Adverse events recording 
As visit 4 
Visit 9 
Day 11 
 Blood sample collection for pharmacokinetic analysis: 192 
h post-dose 
 Vital signs measurement 
 Recording of concomitant medications 
 Adverse events recording 
As visit 4 
Visit 10 
Day 12 
 Blood sample collection for pharmacokinetic analysis: 216 
h post-dose 
 Vital signs measurement 
 Recording of concomitant medications 
 Adverse events recording 
As visit 4 
 
 
 

Clinical Study Protocol 
Helsinn Healthcare SA  
CSP CRO-PK-22-363 
Sponsor code PNET-22-08 
Netupitant IV infusion shortening 
CSP final version 3.0, 24MAY23 
 
CROSS Research S.A. 
Page 15 
CONFIDENTIAL 
STUDY SYNOPSIS (cont.) 
 
Study procedures of Part B (continued): 
Day 
Procedures/Assessments 
Notes 
Visit 11 
Day 13 
 Blood sample collection for pharmacokinetic analysis: 240 h post-
dose 
 Recording of concomitant medications 
 Short physical examination 
 Laboratory analyses as at screening, except for virology 
 Vital signs measurement 
 Triplicate 12-lead ECG recording 
 Urine pregnancy test (women only) 
 Adverse events recording 
As visit 4 
Wash-out 
At least 28 days 
A wash-out interval of at least 28 days will elapse between the two 
administrations of active treatment (T and R) of the two study periods 
(Day 3 of period 1 and Day 1 of period 2) 
 
Visit 12 
Day -1 
 Short physical examination 
 Recording of concomitant medications 
 Salivary alcohol test 
 Urine multi-drug screening test 
 Urine pregnancy test (women only) 
 Body weight 
 Laboratory analyses as at screening, except for virology 
 Adverse events recording 
As visit 2 
Visit 13 
Days 1-3 
As Days 3-5 of visit 3. T or R treatment according to the 
randomization list and cross-over design 
As Days 3-5 of visit 
3 
Visit 14 
Day 4 
 Blood sample collection for pharmacokinetic analysis: 72 h post-
dose 
 Vital signs measurement 
 Recording of concomitant medications 
 Adverse events recording 
Ambulatory visit. 
Arrival at the Phase 
I 
Unit 
in 
the 
morning. 
Visit 15 
Day 5 
 Blood sample collection for pharmacokinetic analysis: 96 h post-
dose 
 Vital signs measurement 
 Recording of concomitant medications 
 Adverse events recording 
As visit 14 
Visit 16 
Day 6 
 Blood sample collection for pharmacokinetic analysis: 120 h post-
dose 
 Vital signs measurement 
 Recording of concomitant medications 
 Adverse events recording 
As visit 14 
Visit 17 
Day 7 
 Blood sample collection for pharmacokinetic analysis: 144 h post-
dose 
 Vital signs measurement 
 Recording of concomitant medications 
 Adverse events recording 
As visit 14 
 
 
 

Clinical Study Protocol 
Helsinn Healthcare SA  
CSP CRO-PK-22-363 
Sponsor code PNET-22-08 
Netupitant IV infusion shortening 
CSP final version 3.0, 24MAY23 
 
CROSS Research S.A. 
Page 16 
CONFIDENTIAL 
STUDY SYNOPSIS (cont.) 
 
Study procedures of Part B (continued): 
Day 
Procedures/Assessments 
Notes 
Visit 18 
Day 8 
 Blood sample collection for pharmacokinetic analysis: 168 h post-
dose 
 Vital signs measurement 
 Recording of concomitant medications 
 Adverse events recording 
As visit 14 
Visit 19 
Day 9 
 Blood sample collection for pharmacokinetic analysis: 192 h post-
dose 
 Vital signs measurement 
 Recording of concomitant medications 
 Adverse events recording 
As visit 14 
Visit 20 
Day 10 
 Blood sample collection for pharmacokinetic analysis: 216 h post-
dose 
 Vital signs measurement 
 Recording of concomitant medications 
 Adverse events recording 
As visit 14 
Visit 21 - Final Visit/ETV 
Day 11 of 
period 2 / 
at ETV in case 
of 
discontinuation 
 Blood sample collection for pharmacokinetic analysis: 240 h post-
dose 
 Laboratory analyses as at screening, with the exception of 
virology 
 Vital signs measurement 
 Triplicate 12-lead ECG recording 
 Urine pregnancy test (women only) 
 Full 
physical 
examination 
(body 
weight 
and 
physical 
abnormalities) 
 Recording of concomitant medications 
 Adverse events recording 
In case of clinically significant results at the final visit, the subjects 
will be followed-up by the Investigator until the normalization of the 
concerned clinical parameter(s) 
Upon leaving, the 
subjects will be 
instructed 
to 
contact 
immediately 
the 
Investigator 
in 
case of occurrence 
of 
any 
adverse 
reactions 
Diet and lifestyle:  
In Part A, the subjects will be confined from the evening preceding T or Rα (undiluted R) treatment (study Day -
1) until the morning of Day 2. In Part B, the subjects will be confined from the evening preceding P treatment 
(study Day -1) until the morning of Day 5 in period 1 and from the evening preceding T or R treatment (study Day 
-1) until the morning of Day 3 in period 2. All other study visits will be ambulatory. 
During the subjects’ confinement at the Phase I Unit, they will not take any food or drinks (except water) for about 
10 h (i.e., overnight) before P, T or R. Water will be allowed as desired, except for 1 h before and 1 h after P, T or 
R administration start. In order to maintain adequate hydration, the subjects will be encouraged to drink at least 
180 mL of still mineral water every 2 h for 5 h post-dose, starting at 1 h post-dose. 
On Day 1 (T or Rα administration day) of Part A, on Day 1 in both periods of Part B (P administration day in 
period 1, T or R administration day in period 2) and on Day 3 of period 1 of Part B (T or R administration day), 
the subjects will remain fasted until 5 h post-dose.  
One cup of coffee or tea will be allowed after each meal only; any other coffee, tea or food containing xanthines 
(i.e., coke, energy drinks, chocolate, etc.), alcohol and grapefruit will be forbidden during confinement. In 
particular, grapefruit and any other food or beverage known to interfere with cytochrome P450 will be forbidden 
for 7 days (168 h) before the first study treatment administration until the end of the study. During confinements, 
smoking will be forbidden, and routine ambulant daily activities will be strongly recommended. 
 
 
 
 

Clinical Study Protocol 
Helsinn Healthcare SA  
CSP CRO-PK-22-363 
Sponsor code PNET-22-08 
Netupitant IV infusion shortening 
CSP final version 3.0, 24MAY23 
 
CROSS Research S.A. 
Page 17 
CONFIDENTIAL 
STUDY SYNOPSIS (cont.) 
 
Data analysis:  
The pharmacokinetic analysis and the statistical analysis of pharmacokinetic parameters will be performed at the 
Biometry Unit of the CRO using Phoenix WinNonlin® version 8.3.5 or higher, Certara, Princeton, NJ, USA and 
SAS® version 9.3 (TS1M1) for Windows® or higher. The statistical analysis of safety data will be performed using 
SAS® version 9.3 (TS1M1) for Windows® or higher.  
The pharmacokinetic parameters of fosnetupitant, netupitant and its metabolites will be calculated using a non-
compartmental analysis (NCA) and will be summarized using descriptive statistics. 
At study Part B only, bioequivalence of T selected in Part A and R will be evaluated by analysis of variance 
(ANOVA) of log-transformed netupitant AUC0-t. and AUC0-∞. The statistical analysis will take into account 
treatment, period, sequence and subject within sequence as fixed effects.  
The parametric point estimator, i.e., the T/R netupitant AUC0-t and AUC0-∞ geometric mean ratio, and the 90% 
confidence interval (CI) will be calculated using the adjusted least squares means from the ANOVA. Results for 
the log-transformed exposure measures (AUC0-t and AUC0-∞.) will be back-transformed to obtain point estimators 
(i.e., geometric mean ratio) and two-sided 90% CI as percentages. 
Bioequivalence of the selected T and R will be claimed if the 90% CI for the geometric mean ratio of netupitant 
AUC0-t and AUC0-∞ is entirely contained within the bioequivalence interval of 80.00% - 125.00%. 
The peak time, tmax, of T and R will be analyzed using a non-parametric test applied to untransformed data. 
 
 
 
 

Clinical Study Protocol 
Helsinn Healthcare SA  
CSP CRO-PK-22-363 
Sponsor code PNET-22-08 
Netupitant IV infusion shortening 
CSP final version 3.0, 24MAY23 
 
CROSS Research S.A. 
Page 18 
CONFIDENTIAL 
4 
STUDY SCHEDULE 
 
Table 4.1 
Study procedures of Part A 
ACTIVITIES 
Screening 
Admission 
Active treatment 
administration 
Observation and 
release 
Final visit or ETV8 
Visit 
V1 
V2 
V3 
V4 or ETV8 
Day 
-21 to -2 
-1 
1 
2 
7 
Informed consent 
x 
 
 
 
 
Inclusion/Exclusion 
criteria 
x 
x 
 
 
 
Full physical 
examination  
x 
 
 
 
x 
Short physical 
examination 
 
x1 
 
x 
 
Demographics 
x 
 
 
 
 
Medical and surgical 
history 
x 
 
 
 
 
Previous and 
concomitant treatments 
x 
x 
x 
x 
x 
Height and body mass 
index (BMI) 
x 
 
 
 
 
Body weight 
x 
x 
 
 
x 
Safety laboratory 
(hematology, blood 
chemistry, urinalysis) 
x 
 
 
 
x 
Virology (HBs Ag, HCV 
Ab, HIV) 
x 
 
 
 
 
Pregnancy test  
x2 
x3 
 
 
x3 
Urine drug screen 
x 
x 
 
 
 
Salivary alcohol test 
 
x 
 
 
 
Triplicate 12-lead ECGs  
x 
 
x4 
x6 
x 
Vital signs  
x 
x 
x5 
x6 
x 
Enrolment  
 
x 
 
 
 
Confinement  
 
x 
x 
 
Active Treatment 
administration 
 
 
x 
 
 
PK blood sampling7 
 
 
x ----------------------------- x 
 
Discharge 
 
 
 
x 
 
AE recording9 
x 
x 
x 
x 
x 
1. Only if screening full physical examination performed more than 7 days before Day -1 
2. Women only - serum b-HCG test  
3. Women only - urine test  
4. At pre-dose, at the end of injection, then at 1, 2, 4 and 24 h after end of administration; to be measured after 5 
min at rest in supine position before recording.  
5. At pre-dose, at the end of the injection, then at 1, 2, 4 and 24 h after the end of the injection; to be measured 
after 5 min at rest in sitting position before measurement.  
6. Upon discharge at 24 h after the end of active treatment injection.  
7. See schedule in tabular format (Table 4.4) 
8. Early termination visit (ETV) upon discontinuation in case of premature termination  
9. AEs monitored starting at the screening visit, immediately after informed consent, up to the final visit or ETV 

Clinical Study Protocol 
Helsinn Healthcare SA  
CSP CRO-PK-22-363 
Sponsor code PNET-22-08 
Netupitant IV infusion shortening 
CSP final version 3.0, 24MAY23 
 
CROSS Research S.A. 
Page 19 
CONFIDENTIAL 
Table 4.2 
Study procedures of Part B 
ACTIVITIES 
Screening 
Period 1 
 
Period 2 
Final Visit14 or ETV15 
VISIT 
V1 
V2 
V3 
V4-V11 
V12 
V13 
V14-20 
V21 or ETV 
DAY(s) 
-21 to -2 
-1 
1-2 
3-5 
6 - 13 
-1 
1-3 
4-10 
1114 or ETV15 
Informed consent 
x 
 
 
 
 
28-days wash-out completion 
 
 
 
 
Inclusion/Exclusion criteria 
x 
x 
 
 
 
 
 
 
 
Demographics 
x 
 
 
 
 
 
 
 
 
Medical/Surgical history 
x 
 
 
 
 
 
 
 
 
Full physical examination 
x 
 
 
 
 
 
 
 
x 
Short physical examination 
 
x1  
 
 
x10 
x 
 
 
 
Previous and concomitant treatments 
x 
x 
x 
x 
x 
x 
x 
x 
x 
Height and body mass index (BMI) 
x 
 
 
 
 
 
 
 
 
Body weight 
x 
x 
 
 
 
x 
 
 
x 
Laboratory (hematology, blood chemistry, urinalysis) 
x 
 
 
 
x10 
x 
 
 
x 
Virology (HBs Ag, HCV Ab, HIV) 
x 
 
 
 
 
 
 
 
 
Pregnancy test 
x2 
x3 
 
 
x3, 10 
x3 
 
 
x3 
Urine drug screening 
x 
x 
 
 
 
x 
 
 
 
Salivary alcohol test 
 
x 
 
 
 
x 
 
 
 
Vital signs 
x 
 
x4 
x5 
x 
x 
x5 
x 
x 
Triplicate 12-lead ECGs for immediate safety 
x 
 
x6 
x7 
x10 
 
x7 
 
x 
Continuous ECG monitoring 
 
 
x8 
x9 
 
 
x9 
 
 
Eligibility evaluation 
 
x 
 
 
 
 
 
 
 
Confinement 
 
x 
x 
x 
 
x 
x 
 
 
Randomization 
 
x 
 
 
 
 
 
 
 
Placebo administration 
 
 
x16 
 
 
 
 
 
 
Active treatment administration 
x17
x16
PK blood sampling11 
 
 
 
x 
x 
 
 
x 
x 
x 
Discharge12 
 
 
 
x 
 
 
 
x 
 
x 
AEs monitoring13 
x 
x 
x 
x 
x 
 
x 
x 
x 
x 

Clinical Study Protocol 
Helsinn Healthcare SA  
CSP CRO-PK-22-363 
Sponsor code PNET-22-08 
Netupitant IV infusion shortening 
CSP final version 3.0, 24MAY23 
 
CROSS Research S.A. 
Page 20 
CONFIDENTIAL 
1. At visit 2, only if screening physical examination performed more than 7 days before Day -1 
2. Women only - serum b-HCG test 
3. Women only - urine test 
4. At pre-dose, end of the injection/infusion, then at 1, 2, 4 and 24 h after the end of the injection/infusion; to be measured after 5 min at rest (sitting position). 
5. At pre-dose, end of the injection/infusion, then at 1, 2, 4, 24 and 48 h after the end of the injection/infusion; to be measured after 5 min at rest (sitting position). 
6. At pre-dose and at 1, 2 and 24 h after the end of P injection/infusion; to be measured after subjects remained for 5 min at rest in supine position before recording.  
7. At pre-dose and at 1, 2 and 24 h after the end of T/R injection/infusion; to be measured after subjects remained for 5 min at rest in supine position before recording. 
8. Starting 1 h before P administration and up to 48 h after the end of the injection/infusion; discrete triplicate 12-lead ECGs to be extracted 3 times within 1 h before the start of 
injection/infusion and at the end of the injection/infusion and 0.5, 1, 2, 4 and 24 h after the end of the injection/infusion after 10 min at rest in supine position 
9. Starting shortly before T/R administration and up to 48 h after the end of the injection/infusion; discrete triplicate 12-lead ECGs to be extracted 3 times within 1 h before the start 
of injection/infusion and at the end of the injection/infusion and 0.5, 1, 2, 4, 24 and 48 h after the end of the injection/infusion after 10 min at rest in supine position 
10. On Day 13 only 
11. See schedule in Table 4.4 
12. In the morning after the 48-h post-dose blood sample collection, ECG recording and vital signs check  
13. Starting at the screening visit, immediately after informed consent, up to the final visit/ETV  
14. After the 240-h post-dose blood sampling on Day 11 of Period 2. 
15. Upon discontinuation, in case of early termination 
16. On Day 1 
17. On Day 3 
 
 
 

Clinical Study Protocol 
Helsinn Healthcare SA  
CSP CRO-PK-22-363 
Sponsor code PNET-22-08 
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Table 4.3 
Tolerance ranges for the vital signs and ECG recording for immediate safety evaluation of Part A 
Scheduled time 
Tolerance range 
Pre-dose (0) of Day 1 
2 h before the start of the injection/infusion 
At the end of injection/infusion 
+10 min 
1, 2 h 
+10 min 
4 h (vital signs) 
±1 h  
4 h (ECG) 
+1 h 
24, 48 h (vital signs) 
±2 h 
24 h (ECG) 
+2 h 
 
 
 
 

Clinical Study Protocol 
Helsinn Healthcare SA  
CSP CRO-PK-22-363 
Sponsor code PNET-22-08 
Netupitant IV infusion shortening 
CSP final version 3.0, 24MAY23 
 
CROSS Research S.A. 
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Table 4.4 
Schedule of PK blood sampling 
 
Blood sampling times after the start of T or R treatment  
 
T injection of 
Reference product 
infusion of 
 
2 min 
5 min 
15 min 
30 min 
30 min 
30 min 
 
Part 
A 
Part 
B 
Part 
A 
Part 
B 
Part 
A 
Part 
B 
Part 
A 
Part 
B 
Part  
A (Rα) 
Part  
 B (R) 
Pre-dose 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
2 min 
X 
X 
 
 
 
 
 
 
 
 
5 min 
X 
X 
X 
X 
 
 
 
 
 
 
10 min 
X 
X 
X 
X 
 
 
 
 
 
 
15 min 
X 
X 
X 
X 
X 
X 
 
 
 
 
20 min 
X 
X 
X 
X 
X 
X 
 
 
 
 
30 min 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
45 min 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
1 h 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
1.5 h 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
2 h 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
3 h 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
4 h 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
8 h 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
12 h 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
24 h 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
48 h 
 
X 
 
X 
 
X 
 
X 
 
X 
72 h 
 
X 
 
X 
 
X 
 
X 
 
X 
96 h 
 
X 
 
X 
 
X 
 
X 
 
X 
120 h 
 
X 
 
X 
 
X 
 
X 
 
X 
144 h 
 
X 
 
X 
 
X 
 
X 
 
X 
168 h 
 
X 
 
X 
 
X 
 
X 
 
X 
192 h 
 
X 
 
X 
 
X 
 
X 
 
X 
216 h 
 
X 
 
X 
 
X 
 
X 
 
X 
240 h 
 
X 
 
X 
 
X 
 
X 
 
X 
T = Fosnetupitant 235 mg in 20 mL IV injectable solution, administered at predefined time durations (30, 15, 5 
and 2 min)  
R = Fosnetupitant/palonosetron 235 mg/0.25 mg (IV Akynzeo FDC) 20 mL liquid formulation diluted to 50 mL, 
and administered in 30 min (Part B)  
Rα = Fosnetupitant/palonosetron 235 mg/0.25 mg (IV Akynzeo FDC) 20 mL liquid formulation, undiluted and 
administered in 30 min (Part A) 
 

Clinical Study Protocol 
Helsinn Healthcare SA  
CSP CRO-PK-22-363 
Sponsor code PNET-22-08 
Netupitant IV infusion shortening 
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CROSS Research S.A. 
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CONFIDENTIAL 
Figure 4.1 
Overall study scheme 
  
Study Part A 
 
 
 
 

Clinical Study Protocol 
Helsinn Healthcare SA  
CSP CRO-PK-22-363 
Sponsor code PNET-22-08 
Netupitant IV infusion shortening 
CSP final version 3.0, 24MAY23 
 
CROSS Research S.A. 
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CONFIDENTIAL 
Study Part B 
 
Safety and PK 
 
 
 
 
 
 
Placebo
(0.9% sodium chloride 
injection solution 
matching IV 
fosnetupitant 20 mL)
40 subjects
Test
(Fosnetupitant IV 235 
mg free base 20 mL) 
20 subjects
Reference
(IV Akynzeo (235 mg 
fosnetupitant/0.25 mg 
palonosetron) 20 mL 
diluted to 50 mL) 
20 subjects
Wash-out
Test
(Fosnetupitant IV 235 
mg free base 20 mL) 
20 subjects
Reference
(IV Akynzeo (235 mg 
fosnetupitant/0.25 mg 
palonosetron) 20 mL 
diluted to 50 mL) 
20 subjects
Period 1
Period 2

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Netupitant IV infusion shortening 
CSP final version 3.0, 24MAY23 
 
CROSS Research S.A. 
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5 
TABLE OF CONTENTS 
Page 
CLINICAL STUDY PROTOCOL 
1 
CLINICAL STUDY PROTOCOL AMENDMENT HISTORY 
2 
2 
PROTOCOL APPROVAL 
3 
2.1 
SPONSOR 
3 
2.2 
INVESTIGATOR 
5 
2.3 
CRO 
6 
3 
STUDY SYNOPSIS 
7 
4 
STUDY SCHEDULE 
18 
5 
TABLE OF CONTENTS 
25 
5.1 
TABLES 
28 
5.2 
FIGURES 
28 
6 
LIST OF ABBREVIATIONS 
29 
7 
STUDY RESPONSIBLE PERSONS 
32 
7.1 
Sponsor 
32 
7.2 
Institutes performing the study 
32 
7.2.1 
Clinical center 
32 
7.3 
Drug assay 
33 
7.4 
Centralized clinical laboratory 
33 
7.5 
Continuous ECG provider 
33 
7.6 
Co-ordination, monitoring, data analysis & reporting 
33 
8 
INTRODUCTION 
34 
8.1 
Background 
34 
8.2 
Netupitant and Fosnetupitant 
35 
8.2.1 
Fosnetupitant pharmacokinetic (PK) profile 
35 
8.2.1.1 
Phase I PK studies of fosnetupitant after 30-min IV infusion to healthy volunteers 
36 
8.2.1.2 
Phase I PK study of fosnetupitant after 30-min IV infusion to cancer patients 
37 
8.3 
Palonosetron 
38 
8.4 
Safety 
38 
8.5 
Study rationale 
39 
8.6 
Risks and benefits 
40 
9 
STUDY OBJECTIVES 
41 
9.1 
Objectives of Part A 
41 
9.1.1 
Primary objective 
41 
9.1.2 
Secondary objective 
41 
9.2 
Objectives of Part B 
41 
9.2.1 
Primary objective 
41 
9.2.2 
Secondary objectives 
41 
10 
CLINICAL SUPPLIES 
42 
10.1 
Treatment 
42 
10.1.1 
Description of products 
42 
10.1.1.1 Test product 
42 
10.1.1.2 Reference product 
42 
10.1.1.3 Test product placebo 
43 
10.1.2 
Dose regimen 
43 
10.1.2.1 Route and method of administration 
44 
10.1.3 
Investigational product distribution 
44 
10.2 
Packaging and labeling 
44 
10.3 
Storage conditions 
45 
10.4 
Drug accountability 
45 

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11 
INVESTIGATIONAL PLAN 
46 
11.1 
Overall study design 
46 
11.2 
Discussion of design 
46 
12 
STUDY POPULATION 
47 
12.1 
Target population 
47 
12.2 
Inclusion criteria 
47 
12.3 
Exclusion criteria 
48 
12.3.1 
Not allowed treatments 
49 
12.4 
Use of contraceptive methods 
49 
13 
STUDY SCHEDULE 
50 
13.1 
Study visits and procedures 
50 
13.2 
Decisional process for escalation to next administration duration 
57 
13.2.1 
Decisional process for treatment of subjects within the cohorts 
57 
13.2.2 
Decisional process for escalation to next administration duration 
57 
13.3 
Diet and lifestyle 
58 
13.3.1 
Restrictions 
59 
14 
DESCRIPTION OF SPECIFIC PROCEDURES 
60 
14.1 
Physical examination 
60 
14.2 
Vital signs 
61 
14.3 
12-lead ECGs 
62 
14.3.1 
12-lead ECGs recorded at the Phase I Unit for immediate safety evaluation 
62 
14.3.2 
Continuous 12-lead ECG 
63 
14.3.3 
Tolerance ranges for ECG recording 
63 
14.4 
Clinical laboratory assays 
64 
14.4.1 
Hematology, blood chemistry, urine analysis 
64 
14.4.2 
Serum virology 
64 
14.4.3 
Urine drug test 
65 
14.4.4 
Pregnancy tests 
65 
14.4.5 
Data management 
65 
14.5 
Sampling for pharmacokinetic analysis 
65 
14.5.1 
Venous blood sampling 
65 
14.5.2 
Analytics 
67 
14.5.3 
Labelling, storage and transport of samples 
67 
14.5.3.1 Samples labelling Please modify as applicable 
67 
14.5.3.2 Samples storage and transport 
67 
14.6 
Total number of samples and blood withdrawn 
68 
15 
ASSIGNMENT OF STUDY TREATMENT 
70 
15.1 
Randomization 
70 
15.2 
Treatment allocation 
70 
15.3 
Blinding 
70 
16 
EVALUATION PARAMETERS 
71 
16.1 
Study endpoints 
71 
16.1.1 
Primary endpoints 
71 
16.1.1.1 Primary endpoint of Part A 
71 
16.1.1.2 Primary endpoint of Part B 
71 
16.1.2 
Secondary endpoints 
71 
16.1.2.1 Secondary safety endpoints of Part A 
71 
16.1.2.2 Secondary safety endpoints of Part B 
71 
16.1.2.3 Secondary PK endpoints of Part A and B 
71 
16.1.2.4 Secondary PK endpoints of Part B only 
72 
16.2 
Pharmacokinetic assessments 
72 
16.2.1 
Pharmacokinetic parameters 
72 
16.3 
Safety assessments 
73 
16.3.1 
Cardiodynamic ECG assessment for Part B 
73 

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17 
STATISTICAL METHODS 
75 
17.1 
Analysis Sets 
75 
17.1.1 
Definitions 
75 
17.1.1.1 Reasons for exclusion from the PK set before bioanalysis 
76 
17.1.1.2 Reasons for exclusion from the PK set B after bioanalysis 
76 
17.2 
Sample size and power considerations 
77 
17.3 
Demographic, baseline and background characteristics 
77 
17.4 
Analysis of pharmacokinetic parameters 
77 
17.4.1 
Descriptive pharmacokinetics 
77 
17.4.2 
Statistical comparison of pharmacokinetic parameters 
77 
17.5 
Safety and tolerability evaluation 
78 
17.5.1 
Adverse events 
78 
17.5.2 
Physical examination 
78 
17.5.3 
Laboratory data 
78 
17.5.4 
Vital signs 
78 
17.5.5 
Body weight 
79 
17.5.6 
ECG for immediate safety 
79 
17.5.7 
Continuous ECG 
79 
18 
DEFINITION AND HANDLING OF AES AND SAES 
80 
18.1 
Applicable SOPs 
80 
18.2 
Definition of Adverse Events 
80 
18.3 
Classification of Adverse Events 
81 
18.3.1 
Severity 
81 
18.3.2 
Relationship to Investigational Medicinal Product 
81 
18.3.3 
Reporting Adverse Events 
82 
18.3.4 
Reporting Serious Adverse Events and Suspected Unexpected Serious Adverse Reactions 
83 
18.3.4.1 Follow-up of SAEs 
83 
18.3.5 
Pregnancy Report 
83 
18.4 
SAEs: contacts 
84 
19 
SUBJECTS’ DISCONTINUATION, STUDY TERMINATION 
85 
19.1 
Withdrawal of subjects 
85 
19.1.1 
Primary reason for discontinuation 
85 
19.1.2 
Discontinuation procedures 
85 
19.2 
Study termination 
86 
20 
DATA MANAGEMENT PROCEDURES 
87 
20.1 
Data collection – CRFs 
87 
20.2 
Unique subject identifier 
87 
20.3 
Database management 
87 
20.3.1 
Coding dictionaries 
88 
21 
STUDY MONITORING, QUALITY CONTROL AND QUALITY ASSURANCE 
89 
21.1 
Monitoring 
89 
21.2 
Quality Control and Quality Assurance 
89 
21.3 
Applicable SOPs 
90 
21.4 
Data access 
90 
21.5 
Audits and inspections 
90 
22 
ETHICAL CONSIDERATIONS 
91 
22.1 
Ethics and Good Clinical Practice (GCP) 
91 
22.2 
Informed consent 
91 
22.3 
Insurance policy 
92 
23 
ADMINISTRATIVE PROCEDURES 
93 
23.1 
Material supplied to the Phase I Unit 
93 
23.2 
Protocol amendments 
93 
23.3 
Study documentation and record keeping 
93 
23.4 
Study subjects’ recruitment 
94 

Clinical Study Protocol 
Helsinn Healthcare SA  
CSP CRO-PK-22-363 
Sponsor code PNET-22-08 
Netupitant IV infusion shortening 
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23.5 
Confidentiality and data protection 
95 
23.5.1 
Subjects Personal Data Processing 
95 
23.5.2 
Investigator Personal Data Processing 
96 
23.6 
Future use of data 
96 
23.7 
Dissemination of Clinical Study Data 
97 
23.8 
Publication policy 
97 
24 
REFERENCES 
99 
 
5.1 
TABLES 
Page 
Table 4.1 
Study procedures of Part A 
18 
Table 4.2 
Study procedures of Part B 
19 
Table 4.3 
Tolerance ranges for the vital signs and ECG recording for immediate safety evaluation 
of Part A 
21 
Table 4.4 
Schedule of PK blood sampling 
22 
Table 13.1.1 
Study procedures of Part A 
52 
Table 13.1.2 
Study procedures of Part B 
53 
Table 14.2.1 
Tolerance ranges for the measurements of vital signs 
62 
Table 14.5.1.1 
Schedule of PK blood sampling 
65 
Table 14.5.1.2 
Tolerance ranges for the scheduled blood sampling times for PK analysis 
66 
 
5.2 
FIGURES 
Page 
Figure 4.1 
Overall study scheme 
23 
Figure 8.2.1 
Structural formula of netupitant (top) and fosnetupitant (bottom) 
35 
Figure 8.3.1 
Structural formula of palonosetron 
38 
 
 
 

Clinical Study Protocol 
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6 
LIST OF ABBREVIATIONS 
 
γ-GT 
g-Glutamyl Transpeptidase 
λz 
Terminal rate constant 
5-HT3 
5-hydroxytryptamine subtype 3 
AE 
Adverse Event 
ALT 
Alanine aminotransferase 
ANOVA 
Analysis of Variance 
AST 
Aspartate aminotransferase 
AUC0-t 
Area Under the concentration-time Curve from time zero to time t of last measurable 
concentration 
AUC0-24 
Area Under the concentration-time Curve from time zero to 24h 
AUC0-120 
Area Under the concentration-time Curve from time zero to 120h 
AUC0-∞ 
Area Under the concentration vs. time Curve up to infinity 
%AUCextra 
Percentage of the residual area (Ct/lz) extrapolated to infinity in relation to the total AUC0-inf 
BQL 
Below Lower Quantification Limit 
BMI 
Body Mass Index 
BP 
Blood Pressure 
BW 
Body Weight 
CDISC 
Clinical Data Interchange Standards Consortium 
CI 
Confidence Interval 
CINV 
Chemotherapy-Induced Nausea and Vomiting 
CL 
Systemic clearance 
Clast 
Last measurable plasma concentration above the lower limit of quantification of the 
bioanalytical method 
C0 
Plasma concentration at the end of the injection or infusion 
Cmax 
Maximum plasma concentration 
CRF 
Case Report Form 
CRO 
Contract Research Organization 
CSP 
Clinical Study Protocol 
CSR 
Clinical Study Report 
CS 
Clinically Significant 
CV 
Coefficient of Variation 
CYP 
Cytochrome 
EC 
Ethics Committee 
ECG 
Electrocardiogram 
ETV 
Early Termination Visit 
FDA 
Food and Drug Administration 
FDC 
Fixed Dose Combination 
FSFV 
First Subject First Visit 
GCP 
Good Clinical Practice 
GDPR 
General Data Protection Regulation 
GLP 
Good Laboratory Practice 
h 
hour 
HBs Ag 
Hepatitis B virus surface antigen 

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HCV Ab 
Hepatitis C virus antibodies 
HEC 
Highly Emetogenic Chemotherapy 
HIV 
Human Immunodeficiency Virus 
HR 
IB 
Heart Rate 
Investigator’s Brochure 
ICH 
International Conference on Harmonization 
IRB/IEC 
Institutional Review Board/Independent Ethics Committee 
IMP 
Investigational Medicinal Product 
IV 
Intravenous 
LC-MS/MS 
Liquid chromatography with tandem mass spectrometry 
liq 
Liquid 
LQL 
Lower Quantification Limit 
LSLV 
Last Subject Last Visit 
MCH 
Mean Cell Hemoglobin 
MCHC 
Mean Cell Hemoglobin Concentration 
MCV 
Mean Cell Volume 
MEC 
Moderately Emetogenic Chemotherapy 
MedDRA 
Medical Dictionary for Regulatory Activities 
MRT 
N 
Mean Residence Time 
Normal 
MSE 
Mean Square Error 
NA 
Not Applicable 
NC 
Not Calculated 
NDA 
New Drug Application 
NK-1 
Neurokinin-1 
OTC 
Over The Counter 
PE 
Point Estimator 
PK 
Pharmacokinetics 
PT 
Preferred Term 
PTAE 
Pre-Treatment Adverse Event 
R 
Reference (treatment) 
Rα 
Reference Alpha (treatment with undiluted R) 
RAs 
Receptor Antagonists 
RAUCM1/netu 
Molecular weight normalized M1 to netupitant AUC0-inf ratio 
RAUCM2/netu 
Molecular weight normalized M2 to netupitant AUC0-inf ratio 
RAUCM/netu 
Molecular weight normalized M3 to netupitant AUC0-inf ratio 
RAUCfos/netu 
Molecular weight normalized fosnetupitant to netupitant AUC0-inf ratio. 
SAE 
Serious Adverse Event 
SBP 
Systolic Blood Pressure 
SD 
Standard Deviation 
SOC 
System Organ Class 
SOP 
Standard Operating Procedure 
SDTM 
Study Data Tabulation Model 
SUSAR 
Suspected Unexpected Serious Adverse Reaction 
T 
Test (treatment) 

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TEAE 
Treatment-Emergent Adverse Event 
t1/2 
Half-life 
tlast 
Time of last measurable plasma concentration above the lower limit of quantification of the 
bioanalytical method 
tmax 
Time to achieve Cmax 
US 
USDA 
United States 
United States Department of Agriculture 
Vz 
Volume of distribution in the post-distribution phase 
WHODDE 
World Health Organization Drug Dictionary Enhanced 
 

Clinical Study Protocol 
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7 
STUDY RESPONSIBLE PERSONS 
 
7.1 
Sponsor 
 
Helsinn Healthcare SA, Via Pian Scairolo 9, CH-6912 Lugano - Switzerland  
Phone: 
+41 91 985 21 21 
Fax: 
+41 91 993 21 22 
Email: 
 
 
Study Coordinator: 
 
 
Medical Expert 
 
 
Responsible Statistician: 
  
 
Clinical Pharmacokineticist: 
  
 
Quality Assurance 
  
 
Drug Safety Physician:  
 
 
7.2 
Institutes performing the study 
 
7.2.1 
Clinical center 
 
CROSS Research SA – Phase I Unit, Via F. A. Giorgioli 14, CH-6864 Arzo, Switzerland 
Phone: 
+41 91 640 44 50 
Fax: 
+41 91 640 44 51 
Email: 
clinic@croalliance.com 
 
Principal Investigator 
Milko Radicioni, MD  
 

Clinical Study Protocol 
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7.3 
Drug assay 
 
Ardena Bioanalysis BV, W. A. Scholtenstraat 7, NL-9403 AJ Assen, the Netherlands 
Phone: 
+31.59.23.44.211 
Fax: 
+31.59.23.44.425  
 
Analytical facilities and procedures are in compliance with GCP and the general principles of 
GLP regulations. 
 
7.4 
Centralized clinical laboratory 
 
Unilabs Ticino, via Rovere 8, CH-6932 Breganzona, Switzerland 
Phone: 
+41.91.960.73.73 
Fax: 
+41.91.960.73.74 
Email: 
 
 
7.5 
Continuous ECG provider 
 
Banook Group, 84 Avenue du 20ème Corps, 5400 Nancy, France 
Phone: 
+33.3.83.39.10.10 
 
Responsible person 
 
 
 
7.6 
Co-ordination, monitoring, data analysis & reporting 
 
CROSS Research S.A. 
Via F. A. Giorgioli 14, CH-6864 Arzo, Switzerland 
 
Coordination 
 
Email: 
 
 
Medical Writing 
 
Email: 
 
 
Biometry Unit Representative 
 
Email: 
statistics@croalliance.com 
 
Quality Assurance Unit Representative 
 
Email: 
qau@croalliance.com 
 
 
 

Clinical Study Protocol 
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8 
INTRODUCTION 
 
8.1 
Background 
 
The negative aspects of nausea and vomiting can influence all facets of a cancer patient's life. 
If nausea and vomiting are not controlled in a cancer patient receiving chemotherapy, they may 
result in serious metabolic problems such as fluids and electrolytes imbalance and nutritional 
status disturbances. In addition, uncontrolled nausea and vomiting may also lead to the decision 
by the patient to stop potentially beneficial cancer therapy.  
There are different pharmaceutical agents used to control chemotherapy-induced nausea and 
vomiting (CINV). However, control of these symptoms is not yet optimal. Thus, the search for 
newer drugs that would improve these symptoms and patients' ability to tolerate the 
chemotherapy is still ongoing (1, 2).  
The development of two classes of antiemetic drugs contributed to some major recent advances 
in controlling CINV. The 5-hydroxytryptamine type 3 (5-HT3) receptor antagonists (RAs) in 
combination with dexamethasone significantly improved the control of acute post 
chemotherapy emesis. However, delayed emesis, which may last for several days, was still a 
challenge with this combination. The control of acute and delayed emesis was improved after 
neurokinin-1 (NK1) RAs had been added to the 5-HT3 RAs and steroids combination. Use of an 
NK1 RAs with a 5-HT3 inhibitor is therefore considered optimal in the prevention of CINV (3). 
 
The oral NEPA fixed-dose combination (FDC) of netupitant and palonosetron is currently 
authorized, under the name Akynzeo® in USA, in EU, in Switzerland and in several other 
countries worldwide. Oral Akynzeo® was approved by the US Food and Drug Administration 
(FDA) in Oct 2014, for the prevention of acute and delayed nausea and vomiting associated 
with initial and repeated courses of chemotherapy, including but not limited to highly 
emetogenic chemotherapy (HEC). In Europe, oral Akynzeo® was approved in May 2015; the 
therapeutic indication is the prevention of acute and delayed nausea and vomiting associated 
with highly emetogenic cisplatin-based cancer chemotherapy and moderately emetogenic 
chemotherapy (MEC). 
In Switzerland, oral Akynzeo® was approved in November 2015, the therapeutic indication is 
the prevention of acute and delayed nausea and vomiting associated with highly and moderately 
emetogenic cancer chemotherapy. Later, the development of an IV FDC of netupitant pro-drug 
(named fosnetupitant) and palonosetron hydrochloride also began. 
Since netupitant is insoluble in water as such, the Sponsor developed fosnetupitant, a water-
soluble phosphorylated pro-drug of netupitant, which is rapidly converted into netupitant in 
vivo following intravenous (IV) administration. Fosnetupitant proved to be safe and well 
tolerated. The pharmacology of fosnetupitant is mainly attributable to netupitant.  
 
IV NEPA FDC was approved in USA in 2018 as Akynzeo® for injection, indicated in 
prevention of acute and delayed nausea and vomiting associated with initial and repeat courses 
of highly emetogenic cancer chemotherapy (NDA 210493). Akynzeo® for injection is a 
lyophilized powder to be reconstituted and further diluted to 50 mL, to be administered as a 30 
min IV infusion, starting 30 min before chemotherapy. The same lyophilized form of IV NEPA 
was approved in EU in March 2020 (EU/1/15/1001/003) for the prevention of acute and delayed 
nausea and vomiting associated with highly emetogenic cisplatin-based cancer chemotherapy 
and moderately emetogenic chemotherapy (MEC) (4). 

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The liquid formulation of IV NEPA was then approved initially in US as a CMC supplement 
of the Akynzeo® for injection NDA (NDA 210493, S-002) with the same indication of the 
lyophilized form. IV NEPA liquid formulation has also been authorized by EMA on 12 Nov 
2021 as Akynzeo® concentrate for solution for infusion, with the same indications of NEPA 
Oral and NEPA lyophilized form. The IV NEPA liquid formulation has also been approved in 
Switzerland on 1 Sep 2022 for the prevention of acute and delayed nausea and vomiting 
associated with highly and moderately emetogenic cancer chemotherapy (4). 
  
With respect to the fosnetupitant pharmacology, details are given in the Investigator’s Brochure 
(5). 
 
8.2 
Netupitant and Fosnetupitant 
 
Fosnetupitant is rapidly converted to netupitant following IV administration; netupitant is a 
potent NK1 RA to be used in combination with other antiemetic drugs against CINV. 
 
Figure 8.2.1 Structural formula of netupitant (top) and fosnetupitant (bottom) 
 
 
 
 
8.2.1 
Fosnetupitant pharmacokinetic (PK) profile 
 
In general, fosnetupitant is rapidly converted into netupitant after IV administration, resulting 
in a limited mean systemic exposure to the pro-drug. The first quantifiable netupitant 
concentrations are promptly observed after the start of the 30 min IV infusion of the pro-drug. 
Fosnetupitant Cmax and AUC increase dose-proportionally with dose increase. Similarly, 
netupitant peak plasma concentrations increase with ascending IV fosnetupitant doses in a dose-
proportional manner, whereas AUC shows a tendency for a higher than dose-proportional 
increase. The elimination of netupitant is slow and is characterized by a long terminal 
elimination half-life. Netupitant metabolites are early detected within 1 h from start of 
fosnetupitant infusion. 

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IV fosnetupitant chloride hydrochloride dose of 260 mg (corresponding to 235 mg of 
fosnetupitant free base) proved to be equivalent, in terms of exposure to netupitant, to the oral 
300 mg netupitant dose. Indeed, the exposure (AUC0-inf) to netupitant after oral administration 
of the FDC (containing 300 mg netupitant and 0.5 mg palonosetron) is similar to that obtained 
after the IV administration of 260 mg fosnetupitant chloride hydrochloride (corresponding to 
235 mg of fosnetupitant free base).  Netupitant Cmax (840.8 μg/L) following IV fosnetupitant 
administration is higher compared to the netupitant Cmax (477.3 μg/L) achieved after the oral 
administration of the FDC. 
 
8.2.1.1 
Phase I PK studies of fosnetupitant after 30-min IV infusion to healthy volunteers  
 
A Phase I, double-blind, controlled, parallel groups, unbalanced single ascending dose study 
coded PNET-12-23 was performed to assess the safety of IV administered fosnetupitant 
combined with cross-over study extensions to estimate the dose of IV fosnetupitant yielding 
equivalent exposure to netupitant as oral netupitant 300 mg/palonosetron 0.5 mg FDC in healthy 
male and female volunteers (5). The primary objective of this Phase I study was to assess the 
safety of fosnetupitant chloride hydrochloride administered as a single 30-min IV infusion in 
the dose range from 19.5 to 390 mg. 
The secondary objective was to estimate the relative availability factor (Frel IV) for netupitant 
(based on AUC0-inf) when given in form of IV fosnetupitant chloride hydrochloride in 
comparison to the oral netupitant 300 mg/palonosetron 0.5 mg FDC; this allowed to identify 
the IV fosnetupitant chloride hydrochloride dose that yields a netupitant exposure equivalent to 
that provided by a 300 mg dose of oral netupitant. 
 
All study parts were performed under double-blind (within dose cohorts), double dummy 
conditions. 
A total of 160 subjects were randomized in this study. One hundred and fifty-eight (158) 
subjects received at least one dose of fosnetupitant IV or netupitant/palonosetron FDC capsule.  
One hundred fifty-five (155) subjects completed the study. No subject discontinued the study 
due to treatment emergent adverse events (TEAEs). 
 
Plasma concentrations of fosnetupitant at the end of 30-min infusions ranged, on average, from 
553 μg/L, at the lowest dose level (19.5 mg), to 9134 μg/L, at the highest dose level tested (390 
mg). Mean fosnetupitant plasma concentrations declined rapidly within the first 2 h after the 
end of the infusion. 
 
Bi-exponential curves underlie both a rapid fosnetupitant distribution throughout the body and 
an efficient elimination process, this latter being mainly due to a metabolic hydrolysis that gives 
rise to netupitant. A clear-cut mono-exponential terminal phase of fosnetupitant appears to 
emerge from the 2nd hour onwards at the highest doses only, i.e., after administration of the 325 
mg and 390 mg doses, whereas at lower doses mixed distribution/elimination phases can be 
observed from the 1st hour after the end of the infusion up to the time of the last measurable 
concentration of fosnetupitant (2nd hour after the start of the infusion). 
 
Maximum fosnetupitant concentrations were mainly observed at the end of infusion (median 
tmax: 0.25 h to 0.5 h). The mean systemic exposure increased with ascending doses. Mean 
AUC0-t and AUC0-inf ranged respectively from 222 h∙μg/L to 4349 h μg/L and from 416 h∙μg/L 

Clinical Study Protocol 
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to 4353 h∙μg/L for doses in the interval from 19.5 mg to 390 mg. Mean systemic clearance was 
very high and ranged from 78.37 to 96.33 L/h, values close to the human liver blood flow. Mean 
volume of distribution for the pro-drug increased with ascending doses and ranged from 58.3 L 
(at 65 mg) up to 163.1 L (at 390 mg). The apparent terminal elimination half-life of 
fosnetupitant chloride hydrochloride ranged from 0.05 h to 1.24 h in the dosing interval from 
32.5 mg to 390 mg. At 260 mg, the mean half-life was 0.956 h. 
 
After dose escalation from 19.5 mg to 390 mg fosnetupitant chloride hydrochloride, the first 
quantifiable netupitant plasma concentrations were detected at all dose levels at mid infusion 
(15 min). Peak netupitant concentrations were observed at the end of infusion (30 min) at all 
dose levels. Following infusion of fosnetupitant chloride hydrochloride over 30 min, mean 
concentrations of netupitant remained nearly at the same level until 4 h and declined slowly 
afterwards. 
 
Mean Cmax and mean systemic exposure increased with ascending fosnetupitant chloride 
hydrochloride doses (mean Cmax of 66 μg/L and 1310 μg/L, mean AUC0-t of 556 h∙μg/L and 
19647 h∙μg/L, and mean AUC0-inf of 716 h∙μg/L and 23923 h∙μg/L for 19.5 mg and 390 mg 
doses, respectively).  
The elimination of netupitant was slow with a long apparent terminal elimination half-life that 
ranged from 21 h to 182 h. Mean t1/2 ranged from 35 h to 55 h. 
The exposure to netupitant after IV administration of 260 mg fosnetupitant chloride 
hydrochloride (mean AUC0-t of 12014 h∙μg/L and mean AUC0-inf of 13854 h∙μg/L) was 
comparable to the mean systemic exposure to netupitant after oral administration of 300 mg 
netupitant (mean AUC0-t of 11317 h∙μg/L and mean AUC0-inf of 13899 h∙μg/L). 
 
The systemic exposure to the 3 netupitant metabolites M1, M2 and M3 also increases with 
ascending fosnetupitant doses. Cmax of M2 is higher (mean Cmax±SD = 178.74±84.52 ng/mL; 
median tmax = 2 h) and is achieved earlier than M1 (mean Cmax±SD = 23.31±9.26 ng/mL; median 
tmax = 12 h) and M3 (mean Cmax±SD = 46.49±16.86 ng/mL; median tmax = 12 h). All 3 
metabolites are eliminated slowly and M1 (mean t1/2±SD = 159.54±72.62 h) shows a longer 
elimination half-life compared to M2 (mean t1/2±SD = 136.4±107.06 h) and M3 (mean t1/2±SD 
= 111.4±54.13 h) (5). 
 
8.2.1.2 
Phase I PK study of fosnetupitant after 30-min IV infusion to cancer patients 
 
PK of fosnetupitant, netupitant and palonosetron after IV infusion was studied also in 24 adult 
male and female cancer patients after administration of IV NEPA (study NEPA-15-19) (4). 
Fosnetupitant was rapidly converted into netupitant after IV administration, resulting in a 
limited mean systemic exposure to the pro-drug. Exposure to netupitant was similar to that 
reported in healthy volunteers after a single IV infusion of 260 mg of fosnetupitant chloride 
hydrochloride and to that observed in healthy volunteers after oral administration of 300 mg of 
netupitant. This supports the evidence, also in patients, that a 260 mg IV fosnetupitant chloride 
hydrochloride (corresponding to 235 mg of fosnetupitant) dose yields an exposure to netupitant 
equivalent to that which follows a 300 mg netupitant oral dose. 
Palonosetron PK profile was superimposable to that observed in a previous PK study in healthy 
subjects in which a 0.25 mg palonosetron dose was administered as an IV bolus, with the 
obvious exception of Cmax which was lower after 30-min infusion as compared to the IV bolus. 

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There were no apparent gender-based differences in PK parameters of fosnetupitant, netupitant, 
metabolites M1, M2 and M3, and palonosetron. 
 
8.3 
Palonosetron 
 
Palonosetron is a potent and selective 5-HT3 RA with demonstrated efficacy by the IV and oral 
route for the management of nausea and vomiting associated with cancer chemotherapy. Its 
prolonged duration of action offers significant advantages over other 5-HT3 RAs resulting in an 
extended antiemetic protection. In July 2003 the FDA approved palonosetron 0.25 mg IV as a 
30-second bolus for the prevention of acute CINV associated with HEC or MEC, and for 
prevention of delayed CINV associated with MEC (initial and repeat courses). In Europe, IV 
palonosetron was approved via the Centralized Procedure in March 2005.  Palonosetron 0.50 
mg soft gelatine capsules formulation, was approved in the US on August 22, 2008, with the 
indication in the US o of acute nausea and vomiting associated with initial and repeat courses 
of MEC. Marketing authorization was granted in the EEA on May 5, 2010, for the prevention 
of nausea and vomiting associated with MEC in adults. Palonosetron is registered in several 
countries with different trademarks (Aloxi®, Onicit®, Paloxi®). 
 
Figure 8.3.1 Structural formula of palonosetron 
 
 
8.4 
Safety  
 
Overall, palonosetron proved to have a very good safety profile and was well tolerated across 
all adult and pediatric studies, both in the IV and the oral formulations (the latter has been tested 
so far in adults only) and across all geographic regions studied. 
 
In Phase I studies, netupitant administered orally alone or in combination with palonosetron 
(extemporaneous or FDC) as a single dose (up to 600 mg) to 431 subjects and as a daily dose 
for 7 days (up to 450 mg daily for 7 days) to 26 subjects has shown to be generally well 
tolerated. In the Phase II studies, type, frequency, and intensity of adverse events (AEs) were 
comparable across treatment groups receiving oral netupitant at the doses of 100, 200 and 300 
mg in combination with palonosetron. Netupitant daily doses up to 200 mg administered for 8 
consecutive weeks did not raise any safety concern in another Phase II study. 
ECG data and QT intervals collected up to now suggest a low risk for QT prolongation. 
Frequency of AEs, changes in clinical laboratory parameters, vital signs and 12-lead ECGs do 
not suggest any substantial increase in risk when netupitant is combined with palonosetron (4).  
 
Single ascending doses of fosnetupitant chloride hydrochloride ranging from 19.5 mg to 390 
mg were well tolerated after administration of IV infusion solutions at the concentration of 2.6 
mg/mL over 30 min to healthy male and female subjects (5). The safety results were in line 

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with the current knowledge about the safety of netupitant. The most frequently reported TEAEs 
assessed as drug-related were headache, constipation, infusion site thrombosis, abdominal pain, 
fatigue, and dizziness. The proportion of subjects with drug-related TEAEs did not increase 
with ascending fosnetupitant chloride hydrochloride doses. 
The satisfactory local tolerability profile of IV fosnetupitant chloride hydrochloride was 
confirmed by thorough vascular surveillance. 
The good safety and tolerability profile of 30 min IV infusions of fosnetupitant at 130 mg, 195 
mg and 260 mg doses and infusion solution concentrations of 2.6 mg/mL, 3.9 mg/mL and 5.2 
mg/mL was confirmed in a second study in healthy subjects concomitantly administered with 
dexamethasone (5).  
 
Two clinical studies have been completed with the IV fosnetupitant 235mg/palonosetron 0.25 
mg combination. 
Overall, more than 400 male and female cancer patients received the IV NEPA FDC 
combination in more than 1300 chemotherapy cycles from two studies in cancer patients: a 
phase 3 safety study following repeated chemotherapy cycles in cancer patients receiving HEC 
(mainly cisplatin) (4), and a phase 3b safety study in women with breast cancer receiving 
repeated AC-chemotherapy cycles (4).  
Results obtained from these studies confirmed the good local and systemic tolerability profile 
of the IV NEPA FDC, similar to that of the oral Akynzeo® formulation. 
 
8.5 
Study rationale 
 
IV Akynzeo® (fosnetupitant 235 mg/palonosetron 0.25 mg) has been developed and registered 
as lyophilized powder for injection in US in April 2018 and in Europe in March 2020. 
 
Helsinn also developed a liquid pharmaceutical form as a solution for infusion, which has been 
approved by FDA in May 2020, by EMA in November 2021 and by Swissmedic in September 
2022. 
 
The registered Akynzeo® liquid formulation for IV administration is to be diluted with 30 mL 
of either glucose 5% solution for injection, or 0.9% saline solution for injection, up to a final 
volume of 50 mL and administered during 30 min infusion starting approximately 30 min before 
chemotherapy. 
 
With the aim to give the possibility of using IV fosnetupitant with any available 5-HT3 RA, 
resulting therefore in more flexible therapeutic options for prescribers, the Sponsor is 
developing a liquid formulation for infusion, containing exclusively fosnetupitant 235 mg free 
base, the same amount as in the IV fosnetupitant/palonosetron combination product.  
In consideration of possible shortages of dilution solutions for IV administrations, and to 
facilitate and improve the use of the product, the Sponsor focuses on the development of a ready 
to use solution, not requiring additional dilutions, and possibly to be administered as a bolus 
injection instead of a 30 min infusion.  
 
The administration of Akynzeo® liquid formulation without further dilution with 30 mL of 
diluent is not expected to have safety or tolerability issues since the injected quantities of both 
fosnetupitant and palonosetron at the infusion site remain unchanged. Moreover, it should be 
noted that a change in excipients quantity in the formulation at the site of injection is considered 

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to have no impact on tolerability, since local tolerability at the infusion site can be affected by 
excipients only when they are interacting physically and chemically with the active substance 
to keep it in solution or to mask its characteristic (typically when solvents, co-solvent or 
surfactants are present in the formulation) (6). 
 
Therefore, the present study aims at assessing the safety and PK profile of a 235 mg 
fosnetupitant ready to use solution for IV bolus administration. From a clinical point of view, 
the present study will also support fosnetupitant 235 mg IV to be administered as a single agent 
in combination with other antiemetic agents for the proposed indication of prevention of acute 
and delayed nausea and vomiting associated with initial and repeat courses of highly 
emetogenic cancer chemotherapy. 
In addition, the PK profile of fosnetupitant and netupitant with its main metabolites will be 
investigated also after a 30-min infusion of the registered Akynzeo® liquid formulation, 
administered undiluted as a 20-mL volume.  
 
8.6 
Risks and benefits 
 
Healthy male and female subjects will take part in the study. In Part A, each subject will receive 
one single injection of 20 mL of IV fosnetupitant at decreasing infusion durations from 30 min 
to 15, 5 and 2 min in the respective study cohort or a 30-min infusion of the 20 mL (undiluted) 
IV Akynzeo FDC (Rα treatment limited to 10 subjects in cohort 1). Different subjects will be 
treated in each cohort.  In Part B, following a 20-mL saline solution for infusion administered 
as placebo at the infusion duration established in study Part A, new subjects will receive in 2 
study periods a single administration of the 20 mL IV fosnetupitant solution (T, test treatment) 
at the infusion duration established in study Part A and a single 20 mL IV Akynzeo infusion 
diluted to 50 mL and administered in 30 min (R, reference treatment), according to a cross-over 
design.  
 
Blood sampling with cannula insertion and repeated venipuncture may cause minor discomfort. 
The risks associated with blood draws include pain, bleeding and bruising.  
 
No specific benefits for the healthy subjects participating in the current study are foreseen 
except for the medical screening. Subject remuneration will be paid to each participating subject 
after study completion. The remuneration covers loss of time and any inconvenience caused by 
the participation in the study. 
 

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9 
STUDY OBJECTIVES 
 
9.1 
Objectives of Part A 
 
9.1.1 
Primary objective 
 
The primary objective of the study Part A is to define the shortest safe and tolerable duration 
of IV injection of T among 4 durations tested in decreasing order: 30, 15, 5 and 2 min, 
respectively. The selected shortest (safe and tolerable) injection duration determined in Part A 
will be considered for testing in study Part B.  
 
9.1.2 
Secondary objective  
 
The secondary objectives of the study Part A are: 
 
 to characterize the pharmacokinetic (PK) profile in plasma of fosnetupitant, netupitant and 
netupitant metabolites M1, M2 and M3 after injection of T administered at the relevant 
injection duration and after injection of undiluted R (defined as Rα). 
 to determine the safety and tolerability of T administered at the relevant injection duration. 
 
9.2 
Objectives of Part B 
 
9.2.1 
Primary objective 
 
The primary objective of the study Part B is to investigate the exposure equivalence of T, at the 
shortest injection duration defined as safe in Part A, and R, administered as a 30 min diluted 
infusion. The equivalence in exposure will be estimated in terms of extent of exposure to 
netupitant (AUC0-∞ and AUC0-t).  
 
9.2.2 
Secondary objectives 
 
The secondary objectives of the study Part B are: 
 
 To characterize the PK profile in plasma of fosnetupitant, netupitant and netupitant 
metabolites M1, M2 and M3 after administration of T at the shortest injection duration 
defined as safe in Part A and R, administered as 30 min diluted infusion. 
 To confirm the safety and tolerability of T administered at the shortest injection duration 
defined as safe in Part A in comparison to R, administered as a 30 min diluted infusion. 
 To assess the effect of T on ECG parameters (HR, QT, QTcF, QTcB, PR and QRS 
intervals). 
 To assess the effects of the administration of fosnetupitant on the QT interval in the shortest 
infusion time (defined in Part A) compared to placebo, in male and female healthy subjects. 

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10 
CLINICAL SUPPLIES 
 
10.1 
Treatment 
 
The study will be divided into 2 parts. In study Part A, 40 subjects will receive one single IV 
dose of T as a single injection with a varying duration according to the admittance cohort, and 
10 subjects will receive one single IV dose of undiluted R (defined as Rα) as one single 30-min 
IV infusion.  
 
In study Part B, each subject (subjects different from those included in Part A) will undergo a 
2-period, randomized cross-over study, and will receive one single IV dose of T as a single 
injection in one period (at the injection duration selected in Part A) and one single 30-min IV 
infusion of R diluted to 50 mL, in the other period. A wash-out period of at least 28 days will 
elapse between the two consecutive administrations. All the subjects will also receive one single 
IV dose of P (placebo, as 0.9% sodium chloride solution for infusion) in period 1, before 
receiving the first assigned active treatment. 
 
10.1.1 
Description of products 
 
The analytical certificates will be supplied with the investigational medicinal products (IMPs).  
 
10.1.1.1 
Test product 
 
TEST (T) 
 
IMP 
Fosnetupitant free base 235 mg ready to use solution for 
intravenous administration 
Manufacturer of finished 
product  
Patheon Italia S.p.A., Italy 
(GMP compliant)  
Pharmaceutical form 
Injectable solution (20 mL) 
Dose 
Fosnetupitant 235 mg (corresponding to 260 mg of the 
chloride hydrochloride salt) 
Administration route 
IV 
 
10.1.1.2 
Reference product 
 
REFERENCE (R) 
 
IMP 
IV Akynzeo (235 mg fosnetupitant/0.25 mg palonosetron) in 
20 mL injectable solution 
Manufacturer of finished 
product  
Baxter Oncology GmbH, Germany  
(GMP compliant)  
Marketing 
authorization 
holder 
Helsinn Birex Pharmaceuticals Ltd., Ireland 
Pharmaceutical form 
Injectable solution (20 mL) 
Dose 
Fosnetupitant 235 mg (corresponding to 260 mg of the 
chloride hydrochloride salt)/palonosetron 0.25 mg 
Administration route 
IV 
 

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10.1.1.3 
Test product placebo 
 
PLACEBO (P) 
 
IMP 
0.9% sodium chloride injection solution, ready to use solution 
for intravenous administration 
Manufacturer of finished 
product  
Commercially available product purchased from the market  
Pharmaceutical form 
Injectable solution (20 mL) 
Administration route 
IV 
 
10.1.2 
Dose regimen 
 
Part A of the study:  
 
In cohort 1, 10 healthy volunteers (HV) will receive a dose of T as a one single 30-min IV 
infusion and additional 10 subjects will receive a single IV dose of undiluted R (defined as Rα) 
as a one single 30-min IV infusion, according to a parallel group design. In each of 3 
consecutive cohorts (cohorts 2, 3 and 4), 10 healthy volunteers (HV) will receive a single IV 
dose of T at a predefined infusion duration and will be sequentially treated as 3 subgroups of 3, 
3, and 4 subjects, respectively.  
 
A staggered approach with decreasing infusion time duration will be applied, from cohort 1 to 
cohort 4, to the administration of T, as follows: 
 
Cohort 1: 30 min 
Cohort 2: 15 min  
Cohort 3: 5 min  
Cohort 4: 2 min 
At the end of cohort 1 and of each subgroup of cohorts 2, 3 and 4, safety and tolerability results 
will be evaluated by the Investigator and the study Sponsor Medical Expert. Predefined 
stopping rules will be considered for deciding about continuing with the next cohort treatment 
and a shorter injection duration of T (see § 13.2). Predefined stopping rules are applicable for 
subjects treated with T. After cohort 1, if the injection duration of 30 min proves to be safe and 
well tolerated, 15 min injection duration will be tested in cohort 2. If the injection duration of 
15 min proves to be safe and well-tolerated, 5 min injection duration will be tested in cohort 3. 
If the injection duration of 5 min proves to be safe and well tolerated, a 2 min injection will be 
tested in cohort 4. If the safety data obtained from a treated cohort receiving T are considered 
as not sufficient for taking a decision on the infusion duration de-escalation process, and if 
additional safety data are deemed necessary to allow such decision to be taken, the study 
Investigator and the Sponsor Medical Expert may decide to add additional subjects (up to a 
maximum of 4 subjects per cohort) to the 10 subjects of the treated cohort. 
 
Part B of the study will follow a 2-way, cross-over randomized design and will include 40 
subjects.  
 

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All the subjects will receive one single IV dose of P (placebo, as 0.9% NaCl solution for 
infusion) in period 1, at the infusion duration selected in study part A.  
Each subject will then receive T followed by R or R followed by T in period 1 and 2 
respectively, according to the randomization schedule. The duration of T injection will be the 
one selected in study Part A, while R (diluted to 50 mL) will be administered in 30 min. A 
wash-out period of at least 28 days will elapse between the two consecutive administrations of 
T and R (28-day wash-out between Day 3 of period 1 and Day 1 of period 2).  
 
10.1.2.1 
Route and method of administration 
 
T, P, Rα (undiluted R) and R will be administered using a pump at a controlled rate according 
to the scheduled injection/infusion duration.  
 
For the administration of T or P, the whole volume of 20-mL will be injected. 
 
For the administration of Rα, 20 mL of the undiluted injectable solution will be infused in 30 
min (Part A) while for the administration of R, 20 mL of the injectable solution will be first 
diluted with a saline solution (0.9% NaCl) to a volume of 50 mL and then infused in 30 min 
(Part B). 
 
The Investigator will check that all subjects receive T or P or Rα or R appropriately.  
 
10.1.3 
Investigational product distribution 
 
T, P, Rα and R will be only administered to the subjects enrolled in this study by the Investigator 
or by his/her deputy and will be exclusively used for the present clinical study.  
 
10.2 
Packaging and labeling 
 
The primary packaging will be 20R type vials for T, P, Rα and R. 
Identifiable vials of all 3 products will be supplied in excess of the amount necessary for the 
study.  
The vials will be provided secondary packed in sealed racks. It will be the responsibility of the 
Phase I Unit Investigator or deputy to collect the correct number of vials for the specific 
treatment’s preparation.  
Different colors will be used for labeling in order to easily identify T, P and R vials. Moreover, 
each vial will carry a unique identification number used for traceability. A “peel-off” removable 
portion is available on each vial’s label; this will be removed from the site Investigator or deputy 
as soon as the vial is used for treatment preparation and applied on subject’s specific source 
document aimed to track each subject’s treatment.  
The labeling will report all the information requested according to the Annex 13 to the Good 
Manufacturing Practice (published by the Commission in “The rules governing medicinal 
products in the European Community”, Volume 4) (7) as follows: 
a. 
Name, address and telephone number of the Sponsor, contract research organization or 
Investigator (the main contact for information on the product, the clinical study and 
emergency unblinding) 

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b. Pharmaceutical dosage form, route of administration, quantity of dosage units, the name 
and strength 
c. 
The batch and/or code number to identify the contents and packaging operation 
d. A study reference code allowing identification of the study, site, Investigator and Sponsor 
if not given elsewhere 
e. 
The name of the Investigator (if not included in (a) or (d)) 
f. 
Directions for use (reference may be made to a leaflet or other explanatory document 
intended for the study subject or person administering the product) 
g. “For clinical study use only” “Caution New Drug, Limited by Federal (or United States) 
law to investigational use” or similar wording 
h. The storage conditions 
i. 
Period of use (use-by date, expiry date or re-test date as applicable), in month/year format 
and in a manner that avoids any ambiguity 
j. 
“Keep out of reach of children” 
 
Labels will be in English. 
 
10.3 
Storage conditions 
 
The provided IMPs vials for study Parts A and B will be stored at the following conditions: 
room temperature (i.e., 15-25° C) protected from light at the Phase I Unit.  
 
10.4 
Drug accountability 
 
The IMPs will be provided directly to the Investigator by the manufacturer, in excess of the 
amount necessary for the study conduction in order to have an amount of 30 reserve vials 
sufficient to perform all of the release tests required in the application or supplemental 
application. 
 
The diluent and the ancillary material needed for the dilution of R (Part B) will be provided by 
the CRO. 
 
After receipt of the IMP supply, the Investigator will confirm in writing by signing and dating 
standard drug accountability forms. 
 
At the end of the study, adequate accountability of the used, unused and partially used supplies 
of IMPs will be provided to the Sponsor and used and partially used supplies will be destroyed 
on site, following written Sponsor authorization. The relevant certificate of destruction will be 
provided to the study Sponsor. At the end of the study, the reserve samples will be kept at the 
Phase I Unit in compliance with the FDA requirements about retention samples.  
 

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11 
INVESTIGATIONAL PLAN 
 
11.1 
Overall study design 
 
Open label, single dose, two parts (part A and part B), safety and PK phase I study. Study Part 
B will be conducted according to a randomized cross-over design 
 
11.2 
Discussion of design 
 
The study design is based upon that of a previous study of CINVANTI® (aprepitant injectable 
emulsion) published by Ottoboni et al. (8) where it is described that, due to a shortage of small-
volume parental solutions, the American Society of Health-System Pharmacists recommended 
switching the delivery of treatments from infusion to IV push. 
The study design is in compliance with the relevant FDA guidance document for industry on 
bioavailability studies (9).  
 
The selected dose for the fosnetupitant component is 235 mg, corresponding to 260 mg of 
fosnetupitant chloride hydrochloride, previously shown to be equivalent in exposure 
(Netupitant AUC) to the netupitant dose present in the oral NEPA FDC (300 mg of netupitant).  
 
The blood sampling times scheduled for the measurement of plasma concentrations of 
fosnetupitant, netupitant and its metabolites are consistent with the known PK profile of the 
analytes.  
 
The evaluation of the bioequivalence between T (administered as per infusion duration selected 
in study Part A) and R will be based on the T/R geometric mean ratio of netupitant AUC0-t and 
AUC0-∞ and their relevant 90% confidence interval (CI). The T/R geometric mean ratio and 
90% CI of AUC0-120 are calculated to compare the exposures after T and R in the time interval 
0-120 h in which acute and delayed chemotherapy induced emesis may occur. The T/R 
geometric mean ratio and 90% CI of netupitant Cmax will also be calculated but not considered 
for the bioequivalence evaluation because Cmax is expected to be higher after IV bolus 
administration (T treatment) as compared to the 30-min IV infusion of diluted R treatment.  
The assessment of T and R bioequivalence will be conducted on netupitant. The prodrug 
fosnetupitant is known to be promptly transformed into netupitant after the administration. 
Netupitant is the active species endowed with antiemetic efficacy in the delayed phase of 
emesis, defined as the period of time from 24 h after start of chemotherapy treatment onwards, 
up to 120 h after start of chemotherapy. Thirty (30) min after the end of the 30-min IV infusion 
in cancer patients, fosnetupitant mean plasma concentration was <1% of Cmax. The prodrug was 
detectable until 2 to 4 h after the start of infusion (mean tlast 3.13 h). Netupitant peak 
concentrations were reached at the end of fosnetupitant infusion and netupitant exposure was 
appreciated for several days after IV administration with MRT and t1/2 values of 162.6 h and 
143.7 h, respectively (10).  
 

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12 
STUDY POPULATION 
 
12.1 
Target population 
 
Male and female adult healthy volunteers aged between 18 and 55 years old.  
 
12.2 
Inclusion criteria 
 
To be enrolled in this study, subjects must fulfil all these criteria: 
1. Informed consent: signed written informed consent before inclusion in the study  
2. Sex and Age: healthy men/women volunteers, 18-55 years old (inclusive) 
3. Body Mass Index (BMI): 18.5-30 kg/m2 inclusive 
4. Vital signs: systolic blood pressure 100-139 mmHg, diastolic blood pressure 50-89 mmHg, 
pulse rate 50-99 bpm, measured after 5 min at rest in the sitting position 
5. Full comprehension: ability to comprehend the full nature and purpose of the study, 
including possible risks and side effects; ability to co-operate with the investigator and to 
comply with the requirements of the entire study 
6. Contraception and fertility (women only): women of childbearing potential defined as a 
non-menopausal woman who has not had a bilateral oophorectomy or medically 
documented ovarian failure and/or at risk for pregnancy must agree, signing the informed 
consent form, to use a highly effective method of contraception throughout the study and to 
continue for 14 days after the last dose of the study treatment. Highly effective contraceptive 
measures include: 
a. Hormonal oral, implantable, transdermal, or injectable contraceptives for at least 2 
months before the screening visit. 
b. A non-hormonal intrauterine device [IUD] for at least 2 months before the screening 
visit 
c. A sterile or vasectomized sexual partner 
d. True (long-term) heterosexual abstinence, defined as refraining from heterosexual 
intercourse when this is in line with the preferred and usual lifestyle of the subject, 
while periodic abstinence (e.g., calendar, ovulation, symptothermal, post-ovulation 
methods), lactational amenorrhea and withdrawal are not acceptable. 
Women of non-child-bearing potential or in post-menopausal status defined as such when 
there is either: 
a. 12 months of spontaneous amenorrhea or 
b. 6 months of spontaneous amenorrhea with serum FSH levels > 40 mIU/mL or 
c. 6 weeks documented postsurgical bilateral oophorectomy with or without 
hysterectomy 
will be admitted. 
For all women, pregnancy test result must be negative at screening and admission (Day -1). 

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7. Contraception (men only): men will either be sterile or agree to use one of the following 
approved methods of contraception from the first study drug administration until at least 14 
days after the last administration, also in case their partner is currently pregnant: 
a. A male condom with spermicide 
b. A sterile sexual partner or a partner in post-menopausal status for at least one year 
c. Use by the female sexual partner of an IUD, a female condom with spermicide, a 
contraceptive sponge with spermicide, a diaphragm with spermicide, a cervical cap 
with spermicide, or hormonal oral, implantable, transdermal, or injectable 
contraceptives for at least 2 months before the screening visit 
Men must accept to inform their partners of the participation in the clinical study. 
Furthermore, they will not donate sperm from the date of the informed consent form’s 
signature, throughout the study, and for at least 14 days after the last dose of the study 
treatment. These requirements are based upon the availability and results of reproductive 
toxicity data. 
 
12.3 
Exclusion criteria 
 
Subjects meeting any of these criteria will not be enrolled in the study: 
1. 12-leads Electrocardiogram (ECG) (supine position): clinically significant abnormalities 
at screening. With regards to QTc, the following will be considered as exclusion criterion: 
mean corrected QT (QTcF) > 450 ms. HR < 50 or > 99 bpm. PR < 100 or >220 ms. QRS > 
120 ms. Relevantly abnormal T-wave patterns 
2. Physical examination findings: clinically significant abnormal physical findings which 
could interfere with the objectives of the study 
3. Laboratory analyses: clinically significant abnormal laboratory values at screening, 
indicative of physical illness or suggesting the subject’s exclusion, in his/her best interest 
4. Allergy: ascertained or presumptive hypersensitivity to the active principle and/or 
formulations' ingredients; history of anaphylaxis to drugs or allergic reactions in general, 
which the investigator considers may affect the outcome of the study 
5. Diseases: significant history, in the opinion of the Investigator, of renal, hepatic, 
gastrointestinal, cardiovascular (in particular, heart failure, hypokalemia, family history of 
Long QT Syndrome, history of superficial thrombophlebitis or deep vein thrombosis), 
respiratory, skin, hematological, endocrine or neurological diseases that may interfere with 
the aim of the study 
6. Medications: medications, including over the counter (OTC) medications and herbal 
remedies in the 2 weeks before the first visit of the study. Hormonal contraceptives for 
women are allowed  
7. CYP3A4 inducers and inhibitors: use of any inducer or inhibitor of CYP3A4 enzymes 
(drugs, food, herbal remedies) in the 28 days or in the 7 days, respectively, before the 
planned first study drug administration and during the whole study 
8. Investigative drug studies: participation in the evaluation of any investigational product for 
3 months before this study. The 3-month interval is calculated as the time between the first 

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calendar day of the month that follows the last visit of the previous study and the first day 
of the present study 
9. Blood donation or significant blood loss: blood donations or significant blood loss in the 3 
months before the first visit of this study 
10. Drug, alcohol, caffeine, tobacco: history of drug, alcohol [>1 drink/day for women and >2 
drinks/day for men, defined according to the USDA Dietary Guidelines 2020-2025 (11)], 
caffeine (>5 cups coffee/tea/day) or tobacco abuse (≥10 cigarettes/day)  
11. Drug test: positive result at the urine drug screening test at screening or Day -1 
12. Alcohol test: positive salivary alcohol test at Day -1 
13. Diet: abnormal diets (<1600 or >3500 kcal/day) or substantial changes in eating habits in 
the 4 weeks before screening; vegetarians 
14. Pregnancy (women only): positive or missing pregnancy test at screening or Day -1, 
pregnant or lactating women  
15. Netupitant studies: enrolment in a previous study of netupitant or fosnetupitant (alone or in 
combination with palonosetron) 
 
12.3.1 
Not allowed treatments 
 
No medication, including OTC and herbal remedies, will be allowed in the 2 weeks before the 
first visit of the study (Screening - Visit 1) and during the whole study duration. In particular, 
the use of CYP3A4 inducers or CYP3A4 inhibitors (drugs, food, herbs) in the 28 days or in the 
7 days, respectively, before the 1st study treatment intake on Day 1 will not be allowed.   
 
Paracetamol will be allowed as therapeutic countermeasure for certain types of AEs according 
to the Investigator’s opinion. Hormonal contraceptives will be allowed.  
 
The intake of any other medication will be reported as a protocol deviation. However, it will 
lead to subject's discontinuation from the study only if the Investigator, together with the 
Sponsor, considers the medication as being able to affect the study assessments or outcome. 
 
12.4 
Use of contraceptive methods 
 
In case of men or women of childbearing potential, the Investigator, in consultation with the 
subject, will select the appropriate method/methods of contraception for the individual 
according to the list of contraception methods of inclusion criteria 6 and 7, and instruct the 
subject or a screened man referring to his partner in their consistent and correct use. Highly 
effective contraceptive measures include those listed in inclusion criteria 6 and 7.  
Moreover, men will not donate sperm from the date of the informed consent form’s signature, 
throughout the study, and for at least 14 days after the last dose of the study treatment. 
At screening and at each study visit, the Investigator will instruct subjects on the need to use 
contraception throughout the study and to continue for 14 days after the last dose of assigned 
treatment. In addition, the Investigator will instruct the subjects to call immediately if a selected 
birth control method is discontinued or if pregnancy is known or suspected. 
 
 

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13 
STUDY SCHEDULE 
 
The schedule of the study is summarized in Table 4.1 for study Part A and in Table 4.2 for study 
Part B. 
 
13.1 
Study visits and procedures 
 
Each subject taking part in study Part A will undergo 4 visits, while each subject participating 
in Part B will undergo 21 visits. 
 
Study Part A foresees, after the screening process, a confinement of approximately one and a 
half days at the Phase I Unit and one ambulatory visit (V4) 7 days post-dose. The maximum 
study duration for study part A will be 28 days, including the screening period. 
Study Part B foresees 2 periods separated by a wash-out interval of at least 28 days between 
the day of T and the day of R treatment administration. After a confinement of approximately 
2 and a half days at the Phase I Unit for the treatment with P, the subjects will remain confined 
for period 1 for approximately 2 further days. Period 2 will consist in a confinement of 
approximately 3 days at the Phase I Unit. In each period, the confinement will be followed by 
8 ambulatory visits, the last of which will be the final visit (Visit 21). The maximum study 
duration for study Part B will be 62 days, including the screening period (Days -21 to -2) and 
assuming a 28-day wash-out period between active treatment (T or R) administration days (Day 
3 of period 1 and Day 1 of period 2).  
 
The first subject first visit (FSFV) is defined as the 1st screening visit performed at the Phase I 
Unit for study part A by the 1st screened subject. The last subject last visit (LSLV) is defined 
as the last visit performed at the Phase I Unit by the last subject in study part B, i.e., the last 
visit foreseen by the study protocol, independently of the fact that the subject is a completer or 
a withdrawn subject. 
 
The following parts, phases, visits and procedures will be performed: 
 
 Part A 
 Screening phase 
 Screening – visit 1: between Day -21 and Day -2 
 Visit 2: Day -1 
 
 Interventional phase 
 Visit 3: Days 1-2 
 
 Final phase 
 Visit 4: Day 7: Final visit or Early termination visit (ETV). In case of early 
discontinuation, discontinued subjects will undergo an ETV. 
 
 Part B 
 Screening phase 

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 Screening – visit 1: between Day -21 and Day -2 
 Period 1 – visit 2: Day -1 
 
 Interventional phase 
 Period 1 – visit 3: Days 1-5 
 Period 1 – visit 4: Day 6 
 Period 1 – visit 5: Day 7 
 Period 1 – visit 6: Day 8 
 Period 1 – visit 7: Day 9 
 Period 1 – visit 8: Day 10 
 Period 1 – visit 9: Day 11 
 Period 1 – visit 10: Day 12 
 Period 1 – visit 11: Day 13 
 Wash-out interval of at least 28 days between the 2 administration days of T and R (Day 
3 of period 1 and Day 1 of period 2) 
 Period 2 – visit 12: Day -1 
 Period 2 – visit 13: Days 1-3 
 Period 2 – visit 14: Day 4 
 Period 2 – visit 15: Day 5 
 Period 2 – visit 16: Day 6 
 Period 2 – visit 17: Day 7 
 Period 2 – visit 18: Day 8 
 Period 2 – visit 19: Day 9 
 Period 2 – visit 20: Day 10 
 
 Final phase 
 Period 2 – visit 21: Day 11: Final visit or Early termination visit (ETV). In case of early 
discontinuation, discontinued subjects will undergo an ETV. 
 

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Table 13.1.1 
Study procedures of Part A 
 
Day 
Procedures/Assessments 
Notes 
Screening – visit 1 
From Day -21 to 
Day -2 
 Explanation to the subject of study aims, procedures 
and possible risks 
 Informed consent signature 
 Screening number assignment (as S001, S002, etc.) 
(§ 20.2) 
 Demographic data and lifestyle recording 
 Medical/surgical history 
 Previous/concomitant medications 
 Full physical examination (body weight, height, body 
mass index, vital signs, physical abnormalities) (§ 
14.1) 
 Triplicate 12-lead ECG recording (§14.3.1) 
 Laboratory analyses: hematology, blood chemistry, 
urinalysis and virology 
 Serum pregnancy test (women only) 
 Urine multi-drug screening test 
 AE recording  
 Inclusion/exclusion criteria evaluation 
Note: The first two 
letters of the surname 
followed by the first 
two letters of the first 
name will be used in 
the Phase I Unit source 
document only and 
will not be transferred 
to the Sponsor 
Visit 2 
Day -1 
 Short physical examination (only if screening 
physical examination performed more than 7 days 
before Day -1) (§ 14.1) 
 Recording of concomitant medications 
 Salivary alcohol test 
 Urine pregnancy test (women only) 
 Urine multi-drug screening test 
 Body weight (§ 14.1) 
 Vital signs measurement (§ 14.2) 
 AE recording 
 Inclusion/exclusion criteria evaluation 
 Eligibility evaluation 
 Enrolment  
 Subject study number assignment (as 001, 002, etc.) 
(§ 20.2) 
Arrival at the Phase I 
Unit in the evening 
Confinement until the 
morning of Day 2 
Standardized 
low-fat 
dinner 
Fasting 
for 
10 
h 
(overnight) 
Visit 3 
Day 1 
 T or Rα treatment 
 Vital signs measurement (§ 14.2) 
 Triplicate 12-lead ECG recording (§14.3.1) 
 Blood sample collection for PK analysis (§ 14.5.1) 
 Recording of concomitant medications 
 AE recording  
Standardized lunch at 
about 13:00 (5 h post-
dose) 
Standardized dinner at 
about 20:00 (12 h post-
dose)  
Day 2 
 Vital signs measurement (§ 14.2) 
 Triplicate 12-lead ECG recording (§14.3.1) 
 Blood sample collection for PK analysis (§ 14.5.1) 
 Recording of concomitant medications 
 Short physical examination upon discharge (§ 14.1) 
 AE recording 
Discharge 
from 
the 
Phase I Unit in the 
morning after the 24-h 
post-dose blood sample 
collection, 
ECG 
recording 
and 
vital 
signs check 

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Day 
Procedures/Assessments 
Notes 
Visit 4 - Final Visit/ETV 
Day 7 / 
at ETV in case 
of 
discontinuation 
 Full physical examination (body weight and physical 
abnormalities) (§ 14.1) 
 Recording of concomitant medications 
 Vital signs measurement (§ 14.2) 
 Triplicate 12-lead ECG recording (§14.3.1) 
 Urine pregnancy test (women only) 
 Laboratory analyses as at screening, except for 
virology 
 AE recording 
In case of clinically significant results at the final visit, 
the subjects will be followed-up by the Investigator 
until the normalization of the concerned clinical 
parameter(s) 
Upon 
leaving, 
the 
subjects 
will 
be 
instructed 
to 
contact 
immediately 
the 
Investigator in case of 
occurrence 
of 
any 
adverse reactions 
 
Table 13.1.2 
Study procedures of Part B 
 
Day 
Procedures/Assessments 
Notes 
Screening – visit 1 
From Day -21 to 
Day -2 
 Explanation to the subject of study aims, procedures 
and possible risks 
 Informed consent signature 
 Screening number assignment (as S101, S102, etc.) 
(§ 20.2) 
 Demographic data and lifestyle recording 
 Medical/surgical history 
 Previous/concomitant medications 
 Full physical examination (body weight, height, body 
mass index, vital signs, physical abnormalities) (§ 
14.1) 
 Triplicate 12-lead ECG recording (§14.3.1) 
 Laboratory analyses: hematology, blood chemistry, 
urinalysis and virology 
 Serum pregnancy test (women only) 
 Urine multi-drug screening test 
 AE recording 
 Inclusion/exclusion criteria evaluation 
Note: The first two 
letters of the surname 
followed by the first 
two letters of the first 
name will be used in 
the Phase I Unit source 
document 
only 
and 
will not be transferred 
to the Sponsor 
Visit 2 
Day -1 
 Short physical examination (only if screening 
physical examination performed more than 7 days 
before Day -1) (§ 14.1) 
 Recording of concomitant medications 
 Salivary alcohol test 
 Urine multi-drug screening test 
 Urine pregnancy test (women only) 
 Body weight (§ 14.1) 
 AE recording 
 Inclusion/exclusion criteria evaluation 
 Eligibility evaluation 
 Enrolment and randomization  
 Subject randomization number assignment (as 101, 
102, etc.) (§ 20.2) 
Arrival at the Phase I 
Unit in the evening 
Confinement until the 
morning of Day 5 
Standardized 
low-fat 
dinner 
Fasting 
for 
10 
h 
(overnight) 

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Day 
Procedures/Assessments 
Notes 
Visit 3 
Day 1 
 P treatment 
 Vital signs measurement (§ 14.2) 
 Continuous 12-lead ECG recording (§ Error! 
Reference source not found.) 
 Triplicate 12-lead ECG recording (§ 14.3.1) 
 Recording of concomitant medications 
 AE recording 
Standardized lunch at 
about 13:00 (5 h post-
dose) 
Standardized dinner at 
about 20:00 (12 h post-
dose)  
Day 2 
 Vital signs measurement (§ 14.2) 
 Continuous 12-lead ECG recording (§ Error! 
Reference source not found.) 
 Triplicate 12-lead ECG recording (§ 14.3.1) 
 Recording of concomitant medications 
 AE recording 
Standardized breakfast, 
lunch 
and 
low-fat 
dinner at about 08:00, 
13:00 and 20:00 and 
then fasting for 10 h 
(overnight) 
Day 3 
 T or R treatment 
 Vital signs measurement (§ 14.2) 
 Continuous 12-lead ECG recording (§ Error! 
Reference source not found.) 
 Triplicate 12-lead ECG recording (§ 14.3.1) 
 Recording of concomitant medications 
 Blood sample collection for PK analysis (§ 14.5.1) 
 AE recording 
Standardized lunch at 
about 13:00 (5 h post-
dose) 
Standardized dinner at 
about 20:00 (12 h post-
dose)  
Day 4 
 Vital signs measurement (§ 14.2) 
 Continuous 12-lead ECG recording (§ Error! 
Reference source not found.) 
 Triplicate 12-lead ECG recording (§ 14.3.1) 
 Recording of concomitant medications 
 Blood sample collection for PK analysis (§ 14.5.1) 
 AE recording 
Standardized breakfast, 
lunch and dinner at 
about 08:00, 13:00 and 
20:00 
Day 5 
 Vital signs measurement (§ 14.2) 
 Continuous 12-lead ECG recording (§ Error! 
Reference source not found.) 
 Triplicate 12-lead ECG recording (§ 14.3.1) 
 Recording of concomitant medications 
 Blood sample collection for PK analysis (§ 14.5.1) 
 AE recording 
Discharge 
from 
the 
Phase I Unit in the 
morning after the 48-h 
post-dose blood sample 
collection, 
ECG 
recording 
and 
vital 
signs check 
Visit 4 
Day 6 
 Blood sample collection for PK analysis: 72 h  
post-dose 
 Vital signs measurement (§ 14.2) 
 Recording of concomitant medications 
 AE recording 
Ambulatory 
visit. 
Arrival at the Phase I 
Unit in the morning. 
Visit 5 
Day 7 
 Blood sample collection for PK analysis: 96 h  
post-dose 
 Vital signs measurement (§ 14.2) 
 Recording of concomitant medications 
 AE recording 
As visit 4 

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Day 
Procedures/Assessments 
Notes 
Visit 6 
Day 8 
 Blood sample collection for PK analysis: 120 h  
post-dose 
 Vital signs measurement (§ 14.2) 
 Recording of concomitant medications 
 AE recording 
As visit 4 
Visit 7 
Day 9 
 Blood sample collection for PK analysis: 144 h  
post-dose 
 Vital signs measurement (§ 14.2) 
 Recording of concomitant medications 
 AE recording 
As visit 4 
Visit 8 
Day 10 
 Blood sample collection for PK analysis: 168 h  
post-dose 
 Vital signs measurement (§ 14.2) 
 Recording of concomitant medications 
 AE recording 
As visit 4 
Visit 9 
Day 11 
 Blood sample collection for PK analysis: 192 h  
post-dose 
 Vital signs measurement (§ 14.2) 
 Recording of concomitant medications 
 AE recording 
As visit 4 
Visit 10 
Day 12 
 Blood sample collection for PK analysis: 216 h  
post-dose 
 Vital signs measurement (§ 14.2) 
 Recording of concomitant medications 
 AE recording 
As visit 4 
Visit 11 
Day 13 
 Blood sample collection for PK analysis: 240 h  
post-dose 
 Recording of concomitant medications 
 Short physical examination (§ 14.1) 
 Laboratory analyses as at screening, with the 
exception of virology 
 Vital signs measurement (§ 14.2) 
 Triplicate 12-lead ECG recording (§ 14.3.1) 
 Urine pregnancy test (women only) 
 AE recording 
As visit 4 
Wash-out 
At least 28 
days 
A wash-out interval of at least 28 days will elapse 
between the two administrations of active treatment (T 
and R) of the two study periods (Day 3 of period 1 and 
Day 1 of period 2) 
 
Visit 12 
Day -1 
 Short physical examination (§ 14.1) 
 Recording of concomitant medications 
 Salivary alcohol test 
 Urine multi-drug screening test 
 Urine pregnancy test (women only) 
 Body weight (§ 14.1) 
 Laboratory analyses as at screening, except for 
virology 
 AE recording 
As visit 2 

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Day 
Procedures/Assessments 
Notes 
Visit 13 
Days 1-3 
As Days 3-5 of visit 3. T or R treatment according to 
the randomization list and cross-over design 
As Days 3-5 of visit 3 
Visit 14 
Day 4 
 Blood sample collection for PK analysis: 72 h  
post-dose 
 Vital signs measurement (§ 14.2) 
 Recording of concomitant medications 
 AE recording 
Ambulatory visit. 
Arrival at the Phase I 
Unit in the morning. 
Visit 15 
Day 5 
 Blood sample collection for PK analysis: 96 h  
post-dose 
 Vital signs measurement (§ 14.2) 
 Recording of concomitant medications 
 AE recording 
As visit 14 
Visit 16 
Day 6 
 Blood sample collection for PK analysis: 120 h  
post-dose 
 Vital signs measurement (§ 14.2) 
 Recording of concomitant medications 
 AE recording 
As visit 14 
Visit 17 
Day 7 
 Blood sample collection for PK analysis: 144 h  
post-dose 
 Vital signs measurement (§ 14.2) 
 Recording of concomitant medications 
 AE recording 
As visit 14 
Visit 18 
Day 8 
 Blood sample collection for PK analysis: 168 h  
post-dose 
 Vital signs measurement (§ 14.2) 
 Recording of concomitant medications 
 AE recording 
As visit 14 
Visit 19 
Day 9 
 Blood sample collection for PK analysis: 192 h  
post-dose 
 Vital signs measurement (§ 14.2) 
 Recording of concomitant medications 
 AE recording 
As visit 14 
Visit 20 
Day 10 
 Blood sample collection for PK analysis: 216 h  
post-dose 
 Vital signs measurement (§ 14.2) 
 Recording of concomitant medications 
 AE recording 
As visit 14 

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Day 
Procedures/Assessments 
Notes 
Visit 21 - Final Visit/ETV 
Day 11 of 
period 2 / 
at ETV in case 
of 
discontinuation 
 Blood sample collection for PK analysis: 240 h  
post-dose 
 Laboratory analyses as at screening, except for 
virology 
 Vital signs measurement (§ 14.2) 
 Triplicate 12-lead ECG recording (§14.3.1) 
 Urine pregnancy test (women only) 
 Full physical examination (body weight and 
physical abnormalities) (§ 14.1) 
 Recording of concomitant medications 
 AE recording 
In case of clinically significant results at the final visit, 
the subjects will be followed-up by the Investigator 
until the normalization of the concerned clinical 
parameter(s) 
 
Upon 
leaving, 
the 
subjects 
will 
be 
instructed to contact 
immediately 
the 
Investigator in case of 
occurrence 
of 
any 
adverse reactions 
 
 
13.2 
Decisional process for escalation to next administration duration  
 
All TEAEs will be recorded in the CRF. TEAEs will be assessed by the Investigator with focus 
on general safety and local tolerability (i.e., any TEAEs appearing after start of injection and 
interesting the injection arm). 
 
Following all planned subject’s safety assessments and before subject’s discharge, the 
Investigator will evaluate the reported TEAEs. 
 
13.2.1 
Decisional process for treatment of subjects within the cohorts 
 
Subjects belonging to cohort 2, 3 and 4 will be sequentially treated as 3 subgroups of 3, 3 and 
4 subjects respectively, in each cohort. 
Following the treatment of the first 3 subjects in the cohort, the collected safety parameters will 
be carefully assessed by the Investigator. In particular, the local tolerability will be evaluated 
in view of confirming the treatment of the next subgroup of 3 subjects in the same cohort. If 
deemed necessary, the study Investigator will contact the Sponsor Medical Expert and seek 
advice. 
The same process will be repeated following the second subgroup of 3 subjects for confirming 
the treatment of the last 4 subjects of the cohort.   
 
13.2.2 
Decisional process for escalation to next administration duration 
 
Following the completion of each cohort, the Sponsor Medical Expert will be provided with a 
summary of the observed tolerability, detailing each TEAE reported up to 60 min after the end 
of infusion of T and up to subject’s discharge on Day 2. The Investigator will provide his 
assessments on severity and relationship to T. The Investigator will also provide a conclusion 
on the systemic and local tolerability related to the administration duration of T tested in the 
cohort, including his suggestion whether to consider safe to proceed with treating the next 
cohort of subjects with the next predefined infusion duration of T. 
 

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If the safety data obtained from a T treated cohort are considered as not sufficient for taking a 
decision on the infusion duration de-escalation process, and if additional safety data are deemed 
necessary to allow such decision to be taken, the study Investigator and the Sponsor Medical 
Expert may decide to add additional subjects (up to a maximum of 4 subjects per cohort) to the 
10 subjects of the treated cohort.  
 
The Sponsor Medical Expert will confirm the Sponsor’s agreement to proceed or not with the 
treatment of the next planned subjects’ cohort / injection duration. 
 
 
Study Part A will be stopped if any of the following criteria is met: 
 
1. Any serious adverse event (SAE) assessed as at least possibly related to T experienced 
within 60 min after the end of T injection by at least one subject in a cohort.  
2. Any AE coded with the same preferred term (PT) occurring to 2 subjects of the same 
cohort with both AEs judged at least as possibly related to T and of severe intensity, 
within 60 min after the end of T injection.   
3. Any AE coded with the same PT occurring to 3 (or more) subjects of the same cohort 
with the AEs judged at least as possibly related to T and of moderate intensity, within 
60 min after the end of T injection.  
At the end of study Part A, the Sponsor will take a final decision whether to proceed with study 
Part B with the resulting shortest injection duration considered as adequate in terms of safety 
determined in study Part A. 
 
The shortest injection duration selected based on the safety and tolerability results of Part A, 
will be applied in Part B. 
 
13.3 
Diet and lifestyle 
 
During the subjects’ confinement at the Phase I Unit, they will not take any food or drinks 
(except water) for about 10 h (i.e., overnight) before P, T or R. Water will be allowed as desired, 
except for 1 h before and 1 h after P, T or R administration start. In order to maintain an adequate 
hydration, the subjects will be encouraged to drink at least 180 mL of still mineral water every 
2 h for 5 h post-dose, starting at 1 h post-dose. 
 
On Day 1 of Part A and B and on Day 3 of period 1 (Part B), the subjects will remain fasted 
until 5 h after the start of injection/infusion. Standardized lunch and dinner will be served at 
approximately 5 h and 12 h after the start of injection/infusion. 
 
On Day -1 of each study part and period, a standardized low-fat dinner will be served.  
 
One cup of coffee or tea will be allowed after each meal only; any other coffee, tea or food 
containing xanthines (i.e., coke, energy drinks, chocolate, etc.), alcohol and grapefruit will be 
forbidden during confinement. In particular, grapefruit and any other food or beverage known 
to interfere with cytochrome P450 will be forbidden for 7 days (168 h) before the first study 
treatment administration until the end of the study. 

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During confinements, smoking will be forbidden.  
During confinement, routine ambulant daily activities will be strongly recommended. 
 
13.3.1 
Restrictions 
 
In Part A, the subjects will be confined from the evening preceding T or Rα (undiluted R) 
treatment (study Day -1) until the morning of Day 2. In Part B, the subjects will be confined 
from the evening preceding P treatment (study Day -1) until the morning of Day 5 in period 1 
and from the evening preceding T or R treatment (study Day -1) until the morning of Day 3 in 
period 2. All other study visits will be ambulatory.  
During confinement, hazardous, strenuous or athletic activities will not be permitted. 

Clinical Study Protocol 
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14 
DESCRIPTION OF SPECIFIC PROCEDURES 
 
NB: the PK sampling times are indicated from the start of infusion, while the timing of safety 
measures is indicated from the end of infusion. 
 
14.1 
Physical examination 
 
Full physical examinations will be performed at the screening and final visit / ETV. Body 
weight (BW) will be also recorded. The following apparatuses/systems will be checked: 
 
 General appearance 
 Chest/respiratory 
 Gastrointestinal 
 Head, eyes, ears, nose and throat 
 Heart/cardiovascular 
 Lymph nodes 
 Metabolic/endocrine 
 Musculoskeletal/extremities 
 Neck (including thyroid) 
 Neurological/psychiatric 
 Skin/dermatologic 
Any abnormalities will be recorded. 
 
Short physical examinations will be performed upon confinements (with measurement of BW), 
discharges and/or end of periods (without measurement of BW) (Table 13.1.2). Information 
about the physical examination will be recorded by the Investigator. The following 
apparatuses/systems will be checked: 
 
 General appearance 
 Chest/respiratory 
 Heart/cardiovascular 
 Lymph nodes 
 Neurologic/psychiatric 
 Skin/dermatologic 
 
Any abnormalities will be recorded. 
 
Significant findings/illnesses, reported after the start of the study and that meet the definition 
of an AE (see § 18), will be recorded in the subject source documents. 

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Date of the physical examination, overall Investigator’s interpretation (as normal or abnormal 
and, if abnormal, clinically significant or not clinically significant) and clinically significant 
abnormalities (if any) will be reported in the individual CRFs. 
 
Subjects will be weighed (kg) lightly clothed without shoes. Height will be measured at 
screening only and BMI will be recorded. BMI will be calculated as weight [kg]/(height [m] x 
height [m]). 
 
Physical examinations will be performed at the following times during the 2 study parts: 
 
Part A 
 
 Screening visit (Full physical examination) 
 Upon confinement on Day -1 only if screening performed more than 7 days before (Short 
physical examination). BW will be measured on both occasions  
 Upon discharge on Day 2 (Short physical examination) 
 Final visit/ETV (Full physical examination) 
 
Part B 
 
 Screening visit (Full Physical Examination) 
 Upon confinement on Day -1 of period 2 (Short physical examination). Also in period 1, 
only if screening performed more than 7 days before (Short physical examination). BW will 
be measured in both periods 
 At the end of period 1 (Day 13) (Short physical examination) 
 Final visit/ETV (Full physical examination) 
 
14.2 
Vital signs 
 
Subjects’ blood pressure (BP) and pulse rate will be measured by the Investigator or his/her 
deputy after 5 min at rest in sitting position.  
 
Measurements will be performed at the following times during the 2 study parts: 
 
Part A 
 
 Screening visit 
 Upon confinement on Day -1  
 On Day 1, at pre-dose, at the end of the injection and 1, 2 and 4 h after the end of the 
injection 
 Upon discharge on Day 2 (24 h after the end of the injection) 
 Final visit/ETV 

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Part B 
 
 Screening visit 
 On Day 1 of each period and on Day 3 of period 1, at pre-dose, at the end of the 
injection/infusion and 1, 2, 4 and 24 h after the end of the injection/infusion 
 Upon discharge on Day 5 of period 1 and on Day 3 of period 2 (48 h after the end of the 
injection/infusion)  
 On Days 6, 7, 8, 9, 10, 11, 12, 13 of period 1 and on Days 6, 7, 8, 9, 10, 11 of period 2 
(Ambulatory visits) (in period 2, coinciding with the final visit measurement) 
 ETV 
 
Actual measurement times for each subject will be recorded in the individual case report forms 
(CRFs). The actual times should not exceed the recommended tolerance ranges presented in the 
following table. Any deviation outside the recommended ranges will be verified through Data 
Clarification Forms and, if confirmed, will be reported as protocol deviation. 
 
Table 14.2.1 
Tolerance ranges for the measurements of vital signs  
Scheduled time 
Tolerance range 
Pre-dose (0) of Day 1 
2 h before the start of the injection/infusion 
At the end of injection/infusion 
+10 min 
1, 2 h 
+10 min 
4 h 
±1 h 
24, 48 h  
± 2 h 
 
14.3 
12-lead ECGs 
 
14.3.1 
12-lead ECGs recorded at the Phase I Unit for immediate safety evaluation 
 
Triplicate 12-lead ECGs will be recorded in supine position after 5 min at rest by the 
Investigator or his/her deputy for immediate safety evaluations.  
 
Triplicate 12-lead ECGs will be recorded at the following times during the 2 study parts: 
 
Part A 
 
 Screening visit 
 On Day 1, at pre-dose, at the end of the injection and 1, 2 and 4 h after the end of the 
injection 
 Upon discharge on Day 2 (24 h after the end of the injection) 
 On Day 7, the final visit 
 ETV 
 
Part B 

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 Screening visit 
 On Day 1 period 1, at pre-dose and 1 and 2 h after the end of the infusion  
 On Day 2 of period 1 (24 h after the end of the infusion) 
 On Day 3 of period 1 and on Day 1 of period 2, at pre-dose and 1 and 2 and 24 h after the 
end of the injection/infusion 
 On Day 13 of period 1 and Day 11 of period 2 (in period 2, coinciding with the final visit 
measurement) 
 ETV 
Triplicate 12-lead ECG parameters and abnormalities will be recorded in the individual CRFs. 
 
14.3.2 
Continuous 12-lead ECG 
 
In Part B, on each dosing day, a continuous 12-lead ECG will be recorded and discrete triplicate 
recordings will be extracted from the continuous Holter ECG monitoring for the data analysis. 
 
Continuous 12-lead ECG will be recorded: 
 On Day 1 period 1, from 1 h before to 48 h after the end of the infusion. In addition, discrete 
triplicate 12-lead ECGs will be extracted 3 times within 1 h before the start of infusion and 
at the end of the infusion and 0.5, 1, 2, 4 and 24 h after the end of the infusion  
 On Day 3 of period 1 and on Day 1 of period 2, from shortly before the injection/infusion 
start to 48 h after the end of the infusion/infusion. In addition, discrete triplicate 12-lead 
ECGs will be extracted at pre-dose 3 times within 1 h before the start of the 
injection/infusion and at the end of the injection/infusion and 0.5, 1, 2, 4, 24 and 48 h after 
the end of the injection/infusion 
 
ECG continuous recording will be performed using appropriate continuous 12-lead recording 
devices with the capacity for digital signal processing, adequately serviced and calibrated. For 
the ECG monitoring, the operator will always apply the same technique for skin preparation, 
lead placement and time of recording. Subjects will rest quietly in a fully supine position for at 
least 10 min before each scheduled timepoint for ECG evaluation. The provider (§ 7.5) will be 
in charge to provide the devices for continuous monitoring, to train the Phase I Unit personnel 
in the use of the device, to extract and to analyze the data. Triplicate 10-sec ECGs will be 
extracted within a time window of 10 min preceding coinciding PK sampling. 
ECG tracings will be electronically stored and sent to the central ECG laboratory for analysis 
at the end of each period. 
 
14.3.3 
Tolerance ranges for ECG recording 
 
Actual ECG recording times will be recorded in the individual CRFs. The actual times of 
recordings should not exceed the recommended tolerance ranges presented in the following 
table. Any deviation outside the recommended ranges, only in study Part A, will be verified 
through Data Clarification Forms and, if confirmed, will be reported as protocol deviation. 

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Actual times of the ECG recordings in Part B will be recorded, but no deviation from the 
scheduled times will be reported. 
 
Table 14.3.1 Tolerance ranges for the discrete ECG recording in Part A  
Scheduled time 
Tolerance range 
Pre-dose (0) of Day 1 
1 h before the start of the injection/infusion 
At the end of injection/infusion 
+10 min 
1, 2 h 
+10 min 
4 h 
+1 h 
24 h 
+2 h 
 
Date/time of the ECG recording, overall Investigator's interpretation (as normal or abnormal 
and, if abnormal, clinically significant or not clinically significant) and clinically significant 
abnormalities (if any) will be reported in the individual CRFs. All clinically significant 
abnormalities after the screening visit will be recorded as AEs. Hard copies of the ECGs will 
be attached to the CRF (See also § 16.3.1). 
 
14.4 
Clinical laboratory assays 
 
14.4.1 
Hematology, blood chemistry, urine analysis 
 
Samples of blood (12 mL) and urine will be collected. The following laboratory analyses will 
be performed at the screening visit: 
 
Hematology 
Leukocytes and leukocyte differential count, erythrocytes, hemoglobin, hematocrit, MCV, 
MCH, MCHC, thrombocytes. 
Blood chemistry 
Electrolytes: sodium, potassium, calcium, chloride, inorganic phosphorus 
Enzymes: alkaline phosphatase, γ-GT, AST, ALT 
Substrates/metabolites: total bilirubin, creatinine, glucose, urea, uric acid, total cholesterol, 
triglycerides 
Proteins: total proteins 
Serum pregnancy test (women): serum b-HCG test. 
Urine analysis 
Urine chemical analysis (stick): pH, specific weight, appearance, color, nitrites, proteins, 
glucose, urobilinogen, bilirubin, ketones, hematic pigments, leukocytes 
Urine sediment (analysis performed only if positive): leukocytes, erythrocytes, flat cells, round 
cells, crystals, cylinders, mucus, bacteria, glomerular erythrocytes 
 
The same analyses, except for the pregnancy test, will be performed at the final visit / ETV of 
Part A and, in Part B, at the end of period 1 (Day 13) and on Days -1 and 11 (corresponding to 
the Final visit/ETV) of period 2. 
 
14.4.2 
Serum virology  
 
Hepatitis B (HBs antigen), Hepatitis C (HCV antibodies), HIV 1/2 (HIV Ag/Ab combo) will 
be assayed at the screening visit in both study Parts.  

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14.4.3 
Urine drug test 
 
A urine drug test will be performed at the Phase I Unit at screening of both study Parts, using a 
urine multi-drug test kit. The test will be repeated upon confinement on Day -1 of Part A and 
in both periods of part B. 
 
14.4.4 
Pregnancy tests 
 
A serum pregnancy test will be performed at the clinical laboratory (7.4) at screening of both 
Parts.  
Urine pregnancy tests will be performed at the Phase I Unit on Day -1 and Final visit / ETV in 
Part A and on Day -1 and 13 of period 1 and Day -1 and 11 of period 2 in Part B (Test on Day 
11 of period 2 corresponding to the Final visit / ETV test).  
 
14.4.5 
Data management  
 
Date/time of samples collections, overall Investigator’s interpretation (as normal or abnormal 
and, if abnormal, clinically significant or not clinically significant) and clinically significant 
findings (if any) will be reported in the individual CRFs. All clinically significant abnormalities 
after the screening visit will be recorded as AEs. Hard copies of the laboratory print-outs will 
be attached to the CRFs. 
 
14.5 
Sampling for pharmacokinetic analysis  
 
14.5.1 
Venous blood sampling  
 
Venous blood samples will be collected from a forearm vein through an indwelling catheter or 
venipuncture at the times summarized in the following table. All blood samples will be 
withdrawn from the contralateral arm with respect to the arm used for the injection/infusion. 
The indwelling catheter will be removed at the end of the confinement or before in case of need.  
 
Table 14.5.1.1 
Schedule of PK blood sampling 
 
 
Blood sampling times after the start of T or R treatment  
 
T injection of 
Reference product 
infusion of 
 
2 min 
5 min 
15 min 
30 min 
30 min 
30 min 
 
Part 
A 
Part B 
Part 
A 
Part 
B 
Part 
A 
Part 
B 
Part 
A 
Part 
B 
Part  
A (Ra) 
Part  
B (R) 
Pre-dose 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
2 min 
X 
X 
 
 
 
 
 
 
 
 
5 min 
X 
X 
X 
X 
 
 
 
 
 
 
10 min 
X 
X 
X 
X 
 
 
 
 
 
 
15 min 
X 
X 
X 
X 
X 
X 
 
 
 
 
20 min 
X 
X 
X 
X 
X 
X 
 
 
 
 
30 min 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
45 min 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
1 h 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
1.5 h 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
2 h 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 

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Blood sampling times after the start of T or R treatment  
 
T injection of 
Reference product 
infusion of 
 
2 min 
5 min 
15 min 
30 min 
30 min 
30 min 
 
Part 
A 
Part B 
Part 
A 
Part 
B 
Part 
A 
Part 
B 
Part 
A 
Part 
B 
Part  
A (Ra) 
Part  
B (R) 
3 h 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
4 h 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
8 h 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
12 h 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
24 h 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
48 h 
 
X 
 
X 
 
X 
 
X 
 
X 
72 h 
 
X 
 
X 
 
X 
 
X 
 
X 
96 h 
 
X 
 
X 
 
X 
 
X 
 
X 
120 h 
 
X 
 
X 
 
X 
 
X 
 
X 
144 h 
 
X 
 
X 
 
X 
 
X 
 
X 
168 h 
 
X 
 
X 
 
X 
 
X 
 
X 
192 h 
 
X 
 
X 
 
X 
 
X 
 
X 
216 h 
 
X 
 
X 
 
X 
 
X 
 
X 
240 h 
 
X 
 
X 
 
X 
 
X 
 
X 
T = Fosnetupitant 235 mg in 20 mL IV injectable solution administered at predefined time durations (30, 15, 5 
and 2 min);  
R = Fosnetupitant/palonosetron 235 mg/0.25 mg (IV Akynzeo FDC) 20 mL liquid formulation diluted to 50 mL 
and administered in 30 min (Part B);  
Rα = Fosnetupitant/palonosetron 235 mg/0.25 mg (IV Akynzeo FDC) 20 mL liquid formulation, undiluted and 
administered in 30 min (Part A). 
 
All the scheduled samples will be collected at the given times counted from the start of the 
injection/infusion. However, if, for whatever reason, a premature interruption of 
injection/infusion is needed or if a duration longer than that initially scheduled is needed, the 
sampling scheduled at the end of injection/infusion is to be moved to the actual end time.  
Actual sampling times for each subject will be recorded in the individual CRFs. The actual 
sampling times should not exceed the recommended tolerance ranges presented in the following 
table. Any deviation outside the recommended ranges will be verified through Data 
Clarification Forms and, if confirmed, will be reported as protocol deviation, although it will 
not automatically lead to the exclusion of the concerned subjects from the PK Sets. 
 
Table 14.5.1.2 
Tolerance ranges for the scheduled blood sampling times for PK analysis 
Sampling time 
Tolerance range 
Pre-dose (0) 
Within 30 min before T or R treatment administration 
2 min, 5 min, 10 min, 15 min, 20 min, 30 min 
0 min 
45 min, 1 h, 1.5 h, 2 h 
± 2 min 
3 h, 4 h, 8 h, 12 h, 24 h 
± 5 min 
48 h, 72 h, 96 h, 120 h, 144 h, 168 h, 192 h, 216 h, 240 h 
± 60 min 
 
Actual sampling times for each volunteer will be recorded in the individual CRFs. 
 
Blood samples (6 mL each) for PK analysis will be collected using an indwelling catheter with 
switch valve during confinement. The indwelling catheter for blood collection will be placed 
on the contralateral arm with respect to the infusion arm. The cannula will be rinsed, after each 
sampling, with about 1 mL of sterile saline solution containing 20 I.U./mL Na-heparin. The 
first 1.5 mL of blood will be discarded at each collection time to wash the cannula out of saline 

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solution and avoid diluting the analyte concentrations. The remaining volume of 4.5 mL of 
blood will then be collected from the catheter and transferred with a syringe into K2EDTA 
tubes. Blood samples will be immediately centrifuged at 1500 g for 15 min at 4° C to obtain 
plasma. If immediate centrifugation is not possible, blood samples will be kept on melting ice 
or in a refrigerator at 4° C for a maximum of 1 h. Each plasma sample will be divided at room 
temperature within a maximum of 4 h from blood centrifugation into 6 pre-labeled tubes: F1 
and F2 (both of at least 200 µL) for the assay of fosnetupitant, N1 and N2 (both of at least 500 
µL) for the assay of netupitant and its metabolites. For the collection of the 3rd aliquots (F3 and 
N3), the remaining plasma will be used. Plasma samples will be stored frozen at ≤-70° C (F and 
N aliquots) until analysis.  
 
If any clinical assessment, such as vital sign measurement or ECG recording, is foreseen at the 
same time-point as blood sampling for PK analysis, blood collection will be performed at the 
scheduled time. Vital signs and ECG recordings for immediate safety evaluation can be 
performed before the pre-dose sampling and after the post-dose samplings, but inside the 
recommended tolerance ranges presented in Table 14.2.1 and Table 14.3.1. Any deviations 
outside the recommended time ranges will be verified through Data Clarification Forms and 
reported as a protocol deviation. Discrete ECGs will be extracted from the continuous 
monitoring by the provider before blood sampling scheduled at the same time point.  
 
14.5.2 
Analytics  
 
The plasma concentrations of fosnetupitant, netupitant and its main metabolites will be 
determined at Ardena Bioanalysis BV, the Netherlands, using validated liquid chromatography-
tandem mass spectrometry (LC-MS/MS) bioanalytical methods with appropriate lower limits 
of quantification (LQL).  
 
Analyses will be performed according to the general Principles of “OECD Good Laboratory 
Practices for testing of chemicals" C(81) 30 (final) and GCP. 
 
The analytical reports will be attached to the final report. 
 
14.5.3 
Labelling, storage and transport of samples  
 
14.5.3.1 
Samples labelling Please modify as applicable 
 
Each sample tube will be clearly and unequivocally identified with a label resistant to the 
storage temperature and reporting: 
Study code 
Study CRO-PK-22-363 - Sponsor code PNET-22-08 
Subject number 
001-066 (for Part A); 101-140 (for Part B) 
Tube identification 
F1, F2, F3, N1, N2, N3,  
Study Part 
Part A/ Part B 
Period  
1 or 2 (Part B only) 
Scheduled sampling time as min or h; see § 14.5.1 
 
14.5.3.2 
Samples storage and transport  
 

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At the Phase I Unit, aliquots N1, N2, N3, F1, F2 and F3 will be stored at ≤-70° C. At the end 
of each collection day, the aliquots will be stored in 2 separate freezers. 
 
All aliquots 1, packed in sufficient solid CO2, will be shipped by an authorized courier from 
CROSS Research S.A. Phase I Unit, Switzerland, to Ardena Bioanalysis BV, the Netherlands. 
Aliquots 1 will remain stored at the laboratory for a maximum time of 3 months after a QA 
audited bioanalytical report is issued. Afterwards, the samples will either be destroyed or 
returned or stored for a longer period in agreement with the Sponsor. In case the sample 
destruction is chosen, a certificate of destruction will be provided to the Sponsor. 
 
The back-up samples (aliquots 2 and 3) will remain stored at CROSS Research S.A., 
Switzerland. These samples could either be: 
 sent to the laboratory for reanalysis, should this become necessary for analytical reasons or 
if any problems occur during the delivery or analysis of aliquots 1, or 
 destroyed at an authorized site, or 
 transferred to the Sponsor upon written request, or 
 stored at CROSS Research S.A., for a maximum time of 5 years 
 
No analyses different from those stated in this protocol and agreed by the subjects when signing 
the informed consent form will be performed unless a new informed consent and a new approval 
from the Ethical Committee is obtained. The subjects may ask to destroy their own samples at 
any time. 
 
14.6 
Total number of samples and blood withdrawn  
 
During the study the following volume of blood will be collected from each subject, in the 
relevant study part:  
 
For routine (safety) laboratories analysis of Part A: 
Screening visit: 
12 mL 
Final visit/ETV: 
12 mL 
 
For routine (safety) laboratories analysis of Part B: 
Screening visit: 
12 mL 
End of period 1: 
12 mL 
Confinement for period 2: 
12 mL 
Final visit/ETV: 
12 mL 
 
For PK analysis: 
Part A:  
from a minimum of 11x6 mL=66 mL to a maximum of 16x6 mL=96 mL, 
depending on durations of injection tested in the cohorts 
Part B: 
from a minimum of 20x2x6 mL=240 mL to a maximum of (20x6 mL) + (25x6 
mL)=270 mL, depending on the injection duration 
 
The maximum total volume of blood which could be withdrawn from each subject in part A 
will be 120 mL (safety + PK analyses), over a maximum study duration of 28 days. 

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The maximum total volume of blood which could be withdrawn from each subject in part B 
will be of 318 mL (safety + PK analyses) over a study duration of 55 days or longer. In either 
case the total volume of blood withdrawn will not exceed a standard blood donation. 

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15 
ASSIGNMENT OF STUDY TREATMENT 
 
15.1 
Randomization  
 
Cohorts of Part A are not randomized. 
  
The randomization lists for Part B will be computer-generated by the Biometry Unit of the 
CRO, using the PLAN procedure of SAS® version 9.3 (TS1M1) (13) or higher (the actual 
version will be stated in the CSR). The randomization list will be attached to the final CSR.  
 
15.2 
Treatment allocation 
 
In cohort 1 of Part A, the subjects will be assigned to one parallel treatment (T or Rα) according 
to their admittance to the Phase I Unit, i.e., the first 10 subjects will receive Rα and the next ten 
T. In study part B, the subjects will be assigned to one of 2 sequences of treatments (e.g., T-R 
or R-T) according to their randomization number that will be given to the subjects on study Day 
-1, period 1.  
 
The treatments will be assigned to the subjects through opaque sealed envelopes. Each envelope 
will report the randomization number on the label and the treatment inside and it will be opened 
at the time of randomization for each patient. The randomization letters will be generated 
through a dedicated SAS program based on the randomization list. The Investigator or his 
deputy in charge of the randomization number assignment will have no access to the complete 
randomization list, thus being unaware of the sequences corresponding to each randomization 
number.  
 
15.3 
Blinding 
 
This is an open-label study. No masking procedure will be applied.  
 

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16 
EVALUATION PARAMETERS 
 
16.1 
Study endpoints 
 
16.1.1 
Primary endpoints 
 
16.1.1.1 
Primary endpoint of Part A 
 
 Type, number and frequency of TEAEs collected up to 24 h post-dose.  
 
16.1.1.2 
Primary endpoint of Part B 
 
 Area under the plasma concentration-time curve of netupitant from time zero to the time of 
last measurable concentration or to infinity (AUC0-t and AUC0-∞) following administration 
of T, at the infusion duration selected in Part A, and R administered as a 30-min diluted 
infusion. 
 
16.1.2 
Secondary endpoints 
 
16.1.2.1 
Secondary safety endpoints of Part A 
 
 Vital signs (blood pressure, pulse rate), 12-lead ECG, clinical laboratory tests (blood 
chemistry, hematology and urinalysis), body weight and physical examination 
 
16.1.2.2 
Secondary safety endpoints of Part B 
 
 Safety and tolerability parameters of T versus R (TEAEs, vital signs [blood pressure, pulse 
rate], 12-lead ECG, clinical laboratory tests (blood chemistry, hematology and urinalysis), 
body weight and physical examination. 
 Cardiac evaluation: 
• Placebo-corrected change from baseline in HR, QT, QTcF, QTcB, PR and QRS 
intervals. 
• Change from baseline in HR, QT, QTcF, QTcB, PR and QRS intervals. 
• Categorical outliers for HR, QT, QTcF, QTcB, PR, and QRS intervals. 
• Frequency of changes in T-wave morphology and U-wave presence from triplicate 12-
lead ECGs extracted from continuous recordings. 
 
16.1.2.3 
Secondary PK endpoints of Part A and B 
 
For plasma fosnetupitant, netupitant and its main metabolites M1, M2 and M3, when applicable, 
the following parameters will be measured/calculated: 
 C0, Cmax, tmax, Clast, tlast, AUC0-t (for all analytes with exception of netupitant AUC0-t in Part 
B, which is the primary endpoint), AUC0-24, λz, t½, CL, Vz, MRT 
 
 
 

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16.1.2.4 
Secondary PK endpoints of Part B only  
 
For plasma fosnetupitant, netupitant and its main metabolites M1, M2 and M3, when applicable, 
the following parameters will be measured/calculated: 
 AUC0-120, AUC0-∞ (with exception of netupitant AUC0-∞, which is the primary endpoint) 
 
For plasma fosnetupitant, the following parameter will be calculated: 
 RAUCfos/netu 
 
For plasma M1, the following parameter will be calculated: 
 RAUCM1/netu 
 
For plasma M2, the following parameter will be calculated: 
 RAUCM2/netu 
 
For plasma M3, the following parameter will be calculated: 
 RAUCM3/netu 
 
16.2 
Pharmacokinetic assessments 
 
16.2.1 
Pharmacokinetic parameters 
 
The following PK parameters will be measured and/or calculated, when applicable, for plasma 
fosnetupitant, netupitant and its metabolites in both parts, using the validated software Phoenix 
WinNonlin® version 8.3.5 (13) or higher (actual version will be stated in the final report): 
 
C0: 
 
Plasma concentration at the end of the injection or infusion 
 
Cmax: 
Maximum plasma concentration 
 
tmax: 
Time to achieve Cmax 
 
Clast: 
Last measurable plasma concentration above the LQL of the bioanalytical 
method  
 
tlast: 
Time of Clast 
 
AUC0-t: 
Area under the concentration-time curve from time zero to tlast, calculated by 
the linear trapezoidal method 
 
AUC0-24: 
Area under the plasma concentration-time curve from time zero to 24 h 
 
λz: 
Terminal elimination rate constant, calculated, if feasible, by log-linear 
regression using at least 3 points, C0 and Cmax excluded 
 
t1/2: 
Apparent terminal half-life, calculated, if feasible, as ln2/λz 
 
CL: 
Systemic clearance  
 
Vz: 
Apparent volume of distribution in the post-distribution phase 
 

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MRT: 
Mean residence time 
 
The following PK parameters will be calculated for netupitant and its metabolites only in Part 
B: 
 
AUC0-120 
 
Area under the plasma concentration-time curve from time zero to 120 h 
 
AUC0-∞: 
Area under the concentration-time curve from time zero to infinity, calculated, 
if feasible, as AUC0-t + Clast/λz 
 
%AUCextra: 
Percentage 
of 
AUC0-inf 
extrapolated 
from 
tlast 
to 
infinity 
as 
100×[(Clast/lz)/AUC0-inf] 
 
The following PK parameter will be calculated for fosnetupitant only in Part B: 
 
RAUCfos/netu: Molecular weight-normalized fosnetupitant to netupitant AUC0-∞ ratio 
 
The following PK parameter will be calculated for M1 only in Part B: 
 
RAUCM1/netu: Molecular weight-normalized M1 to netupitant AUC0-∞ ratio 
 
The following PK parameter will be calculated for M2 only in Part B: 
 
RAUCM2/netu: Molecular weight-normalized M2 to netupitant AUC0-∞ ratio 
 
The following PK parameter will be calculated for M3 only in Part B: 
 
RAUCM3/netu: Molecular weight-normalized M3 to netupitant AUC0-∞ ratio 
 
The sampling schedule is considered adequate if the ratio AUC0-t/AUC0-∞ equals or exceeds a 
factor of 0.8 (i.e., if %AUCextra is <20%) for more than 80% of the individual PK profiles. This 
assures that the primary variable AUC0-t covers a sufficient percentage of the theoretical total 
extent of exposure. AUC0-∞ values with %AUCextra greater than 20% will be flagged but 
included in the summary statistics. 
 
The quality of log-linear regression (and, consequently, the reliability of the extrapolated PK 
parameters) should be demonstrated by a determination coefficient R2 ≥ 0.8. Individual 
extrapolated parameters, when considered unreliable, will be reported as NC (not calculated).  
 
16.3 
Safety assessments 
 
Safety and general tolerability of T versus R will be based on TEAEs, physical examinations 
including body weight, vital signs, 12-lead ECG and routine hematology, blood chemistry and 
urinalysis laboratory tests. 
 
16.3.1 
Cardiodynamic ECG assessment for Part B 
 
The following ECG parameters will be measured and calculated: HR, PR, QT, Fridericia 
corrected QTc (QTcF), Bazett corrected QTc (QTcB), QRS.  

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T-wave morphology and U-wave presence will be assessed.  
Statistical methodology for the cardiac evaluation endpoints is presented in § 17.5.7. 
 
 

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17 
STATISTICAL METHODS 
 
The data documented in this study and the parameters measured will be evaluated and compared 
using classic descriptive statistics, i.e., geometric mean (PK data only), arithmetic mean, SD, 
CV (%), minimum, median and maximum values for quantitative variables, and frequencies for 
qualitative variables. 
 
Not available data will be evaluated as “missing values”. The statistical analysis of demographic 
and safety data will be performed using SAS® version 9.3 (TS1M1) (13) or higher (the actual 
versions will be stated in the final report). 
The statistical analysis of PK parameters will be performed using Phoenix WinNonlinTM 
version 8.3.5 (14) or higher and SAS® version 9.3 (TS1M1) or higher. 
Further details of the statistical analyses and data presentations to be used in reporting the study 
will be provided in the Statistical Analysis Plan (SAP). 
 
Demographic, safety, and PK analyses will be performed by the Biometry Unit of the CRO (§ 
7.6), while ECG statistical analysis will be performed by the provider of continuous ECG (§ 
7.5).  
 
17.1 
Analysis Sets 
 
17.1.1 
Definitions 
 
A subject will be defined as screened after the signature of the informed consent, regardless of 
the completion of all the screening procedures. 
 
A subject will be defined as eligible if he/she meets all the inclusion/exclusion criteria. 
Otherwise, he/she will be defined as a screen failure.  
 
A subject will be defined as enrolled in the study if he/she is included in the interventional 
phase of the study. The enrolment will be performed through a non-randomized or randomized 
inclusion in the study. 
 
An eligible but not enrolled subject will be defined as a reserve. 
 
 Enrolled set: all enrolled subjects. This analysis set will be used for demographic, baseline 
and background characteristics 
 Safety set: all subjects who receive at least one dose of the IMPs, including partial 
administration. This analysis set will be used for the safety analyses 
 PK set A: all enrolled subjects who fulfill the study protocol requirements in terms of T or 
Rα administration and have evaluable PK data readouts, with no major deviations that may 
affect the PK results. This analysis set will be used for the statistical analysis of the PK 
results of study Part A 
 PK set B: all enrolled subjects who fulfill the study protocol requirements in terms of T 
and R administration and have evaluable PK data readouts for the planned treatment 

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comparisons, with no major deviations that may affect the PK results. This analysis set will 
be used for the statistical analysis of the PK results of study Part B 
 
Each subject will be coded by the CRO Biometry Unit as valid or not valid for the Safety set, 
PK set A and PK set B. Subjects will be evaluated according to the treatment they actually 
receive. 
 
17.1.1.1 
Reasons for exclusion from the PK set before bioanalysis  
 
Reasons for the exclusion of subjects from one period in the PK set are the following: 
 
 intake of concomitant medications or food / beverages which could render the plasma 
concentration-time profile unreliable 
 AEs which could render the plasma concentration-time profile unreliable 
 administration errors which could render the plasma concentration-time profile unreliable 
 other events which could render the plasma concentration-time profile unreliable 
If one of these events occurs, it will be noted in the CRF as the study is being conducted. 
 
17.1.1.2 
Reasons for exclusion from the PK set B after bioanalysis 
 
Exclusion of subjects on the basis of PK reasons is possible only for: 
 subjects with lack of any measurable concentrations or only very low plasma 
concentrations of netupitant. A subject is considered to have very low plasma 
concentrations if his/her AUC is less than 5% of netupitant geometric mean AUC (which 
should be calculated without inclusion of data from the outlying subject) 
 subjects with implausible concentrations (i.e., different from the known, expected 
concentration profiles) of netupitant. The exclusion of these subjects must be justified on 
the basis of sound scientific reasons and mutually agreed between the CRO and the Sponsor 
 subjects with non-zero baseline concentrations > 5% of Cmax 
The samples from the subjects excluded from PK set B after bioanalysis should still be assayed 
and the results listed. Subjects should not be excluded from PK set B if the AUC0-t covers less 
than 80% of the AUC0-∞. 
 
 
 

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17.2 
Sample size and power considerations 
 
The planned number of 20 healthy subjects to be included in cohort 1 and of 10 healthy 
subjects to be included in each following cohort of Part A (cohorts 2, 3 and 4) of the study 
was not computed by statistical assumptions.  
The sample size for the netupitant exposure equivalence (netupitant AUC) assessment in Part 
B of the study, will be 40 healthy male and female subjects in order to have 34 completed 
subjects. Drop-outs will not be replaced. The sample size was determined by a statistical power 
calculation to test equivalence based on AUC0-t. The assumptions are that the expected ratio of 
means is 1 (Fosnetupitant 235 mg IV versus Akynzeo IV injection), the cross-over ANOVA 
√MSE (ln scale) is 0.265, and α is 10% (bilateral). A sample size in each sequence group of 17 
(total sample size is 34) is required to have a power of 90%. 
 
17.3 
Demographic, baseline and background characteristics 
 
Critical demographic characteristics will be examined according to qualitative or quantitative 
data. Qualitative data will be summarized in contingency tables. Quantitative data will be 
summarized using classic descriptive statistics. 
 
17.4 
Analysis of pharmacokinetic parameters 
 
17.4.1 
Descriptive pharmacokinetics 
 
A descriptive PK will be presented. The results will be displayed and summarized in tables and 
figures. Individual curves at actual sampling times and mean curves (+SD) at scheduled 
sampling times will be plotted. Data below the lower quantification limit (BQL) will be 
considered as 0 in the calculations of mean concentrations and “missing data” in individual 
concentration-time plots. For the estimation of PK parameters, BQL concentrations will be 
considered as 0 at early time points (i.e., time points before Cmax) and “missing data” at later 
time points, including the terminal part of the curve. They will be presented as BQL in listings 
and tables. As a consequence of BQL values, calculated geometric means (if requested) could 
be null. For this reason, in the presence of any null value, the geometric mean will be reported 
as not calculated (NC). 
 
17.4.2 
Statistical comparison of pharmacokinetic parameters 
 
According to the current FDA Guideline on the bioavailability and bioequivalence studies (9), 
AUC0-t and AUC0-∞ of plasma netupitant of study Part B will be analyzed using analysis of 
variance (ANOVA). Before analysis, the data will be transformed using a neperian logarithmic 
transformation. The statistical analysis will take into account treatment, period, sequence and 
subject within sequence as fixed effects. The parametric point estimators (PE) for the ratios of 
treatments and 90% CI will be calculated using the adjusted least squares means from the 
ANOVA. Results for the log-transformed exposure measures will be then back-transformed to 
obtain point estimators (i.e., geometric mean ratio) and two-sided 90% CI as percentages. 
 
The statistical method for testing bioequivalence is based upon the 90% CI for the T/R ratio of 
the least square geometric means of the parameters under consideration. Acceptance criterion 

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for bioequivalence will be a 90% CI of the ratio of geometric means (PE) within the 80.00 – 
125.00% range.  
While the equivalence of the selected T and R will be assessed based on the netupitant AUC0-t 
and AUC0-∞ estimates, the T/R geometric mean ratio and the relevant 90% CI will also be 
calculated for other exposure measures, including netupitant AUC0-120 and Cmax. The T/R 
geometric mean ratio and the relevant 90% CI will also be calculated for exposure measures of 
M1, M2 and M3, including AUC0-t, AUC0-∞, AUC0-120 and Cmax. 
The peak time, tmax, of T and R will be analyzed using a non-parametric test applied to 
untransformed data. 
 
17.5 
Safety and tolerability evaluation 
 
17.5.1 
Adverse events 
 
AEs will be coded by System Organ Class (SOC) and PT, using the Medical Dictionary for 
Regulatory Activities (MedDRA). 
AEs will be classified as pre-treatment AEs (PTAEs) and TEAEs, according to the period of 
occurrence, as follows:  
 PTAEs: all AEs occurring from the signature of the informed consent to participate in 
the study up to the first T or R dose, including AEs occurring after P and before T or R 
in Part B  
 TEAEs: all AEs occurring after the first dose of T or R  
Individual PTAEs and TEAEs will be listed in subject data listings. No summary table will be 
provided for PTAEs. TEAEs will be summarized by treatment and overall. The number and 
percentage of subjects with any TEAE and the number of TEAEs will be tabulated by SOC and 
PT, seriousness, relationship to treatment and severity.  
 
17.5.2 
Physical examination 
 
Date of the physical examination, overall investigator’s interpretation (as normal or abnormal 
and, if abnormal, clinically significant or not clinically significant) and clinically significant 
abnormalities (if any) will be listed. 
 
17.5.3 
Laboratory data  
 
Date/time of samples collection, overall investigator’s interpretation (as normal or abnormal 
and, if abnormal, clinically significant or not clinically significant) and clinically significant 
findings (if any) will be listed. All laboratory results will be listed and a table of all the abnormal 
values will be presented. The overall investigator’s interpretation will be summarized using 
tables of frequency.  
 
17.5.4 
Vital signs 
 
Vital signs values will be listed and summarized by descriptive statistics.  
 

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17.5.5 
Body weight  
 
Body weight values at screening and final visit/ETV will be listed and summarized by 
descriptive statistics. 
 
17.5.6 
ECG for immediate safety 
 
Date/time of ECG recordings, overall investigator’s interpretation (as normal or abnormal and, 
if abnormal, clinically significant or not clinically significant) and clinically significant 
abnormalities (if any) will be listed. The overall investigator’s interpretation will be 
summarized using tables of frequency. 
 
17.5.7 
Continuous ECG 
 
For the cardiac safety evaluation and further analyses, 10-sec triplicate ECGs will be extracted 
within a time window of 10 min preceding PK sampling and evaluated (§ 14.3).  
The QT interval will be presented raw and after HR correction using the Fridericia formula as 
primary endpoint. ECG data will be listed and summarized highlighting differences from 
baseline for quantitative variables and frequencies of treatment emergent abnormalities. The 
number of QTc values above 450 ms, 480 ms and 500 ms at each evaluation timepoint will be 
tabulated, jointly with its change from baseline. Likewise, values differing by more than 30 ms 
from the baseline at each time point will be tabulated. 
 
Data from Holter continuous recording will be assessed in blind by the provider (§ 7.5) 
according to a centralized procedure. 
 
The primary analysis will be based on exposure response modeling of the relationship between 
netupitant and its metabolites M1, M2 and M3 and change-from-baseline QTcF (ΔQTcF) with 
the intent to exclude an effect >10 ms at clinically relevant plasma concentrations of netupitant, 
M1, M2 and M3. 
 
In addition, the effect of netupitant on the placebo-corrected ΔQTcF, ΔHR, ΔPR, ΔQRS, ΔQT, 
and ΔQTcB (ΔΔQTcF, ΔΔHR, ΔΔPR, ΔΔQRS, ΔΔQT, and ΔΔQTcB) will be evaluated at each 
post-dose timepoint ('by timepoint' analysis) using the Intersection Union Test. An analysis of 
categorical outliers will be performed for changes in HR, PR, QRS, QT, QTcF, QTcB, T-wave 
morphology and U-wave presence. 
 
See also § 16.3.1. 

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18 
DEFINITION AND HANDLING OF AEs AND SAEs 
 
18.1 
Applicable SOPs 
 
AEs definition, classification and management will follow the Sponsor’s SOPs, based upon 
applicable local and international regulations. The full SOP or an operative summary will be 
made available to the clinical center. 
 
A brief summary of AE definition, classification and management is reported below. 
 
18.2 
Definition of Adverse Events 
 
AE 
As defined by the current ICH Guideline for Good Clinical Practice (15) an AE is: 
Any untoward medical occurrence in a patient or clinical investigation subject administered a 
pharmaceutical product and which does not necessarily have to have a causal relationship with 
this treatment. An AE can therefore be any unfavorable and unintended sign (including an 
abnormal laboratory finding), symptom, or disease temporally associated with the use of a 
medicinal (investigational) product, whether or not considered related to the medicinal 
(investigational) product. 
Within the scope of this study, such untoward medical occurrences would be considered as 
“AEs” even if the subject was not administered the study drugs but had already signed the 
informed consent form. 
AEs include the following types of occurrences: 
 Suspected adverse drug reactions 
 Other medical experiences, regardless of their relationship to the study drugs, such as injury, 
surgery, accidents, increased severity of pre-existing symptoms, apparently unrelated 
illnesses, and significant abnormalities in clinical laboratory values, physiological testing, 
or physical examination findings 
 Reactions from drug overdose, abuse, withdrawal, hypersensitivity, or toxicity. 
 
SAE 
A SAE is any event that suggests a significant hazard, contraindication, side effect, or 
precaution, whether it is considered or not to be associated with the study product. A SAE is an 
AE that meets any of the following criteria: 
 Results in death. This includes any death that occurs during the conduct of a clinical study, 
including deaths that appear to be completely unrelated to the study drugs (e.g., car 
accident). 
 Is life-threatening. This includes any AE during which the subject is, in the view of the 
Investigator, at immediate risk of death from the event as it occurs. This definition does not 
include events that may have caused death if they had occurred in a more severe form. 
 Requires inpatient hospitalization or prolongation of existing hospitalization 
 Results in persistent or significant disability or incapacity 
 Is a congenital anomaly or birth defect 

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 Other medical events that based upon appropriate medical judgment are thought to 
jeopardize the patient and/or require medical or surgical intervention to prevent one of the 
outcomes defining a SAE. 
Unexpected Adverse Event 
An Unexpected Adverse Event is any experience not previously reported (in nature, severity or 
incidence) in the current Investigator’s Brochure for fosnetupitant/netupitant/palonosetron 
(Reference Safety Information) (4). 
Pre-existing Condition 
A pre-existing condition is one that is present at the start of the study. A pre-existing condition 
should be recorded as an AE if the frequency, intensity, or the character of the condition 
worsens during the study period. 
 
18.3 
Classification of Adverse Events 
 
The Investigator will classify AEs based on their severity and relationship to treatment. Every 
effort must be made by the Investigator to categorize each AE according to its severity (see 
below), and its relationship separately either to netupitant, palonosetron or both (see § 18.3.1). 
 
18.3.1 
Severity 
 
For this trial, the intensity of an AE will be rated according to the following definitions: 
 
Mild 
Symptom barely noticeable to subject; does not influence performance or functioning. 
Prescription medication is not ordinarily needed for relief of symptom but may be given because 
of the personality of a subject. 
 
Moderate 
Symptom of a sufficient intensity to make a subject uncomfortable; performance of daily 
activities influenced; subject is able to continue the trial; treatment for symptom may be needed. 
 
Severe 
Symptom causes severe discomfort. May be of such intensity that a subject cannot continue the 
trial. Intensity may cause cessation of treatment; treatment for symptom may be given and/or 
subject hospitalized. 
 
18.3.2 
Relationship to Investigational Medicinal Product 
 
For this trial, an AE cause and effect relationship to the study drug will be classified by the 
Investigator as reported hereafter. 
 
Definitely related 
The event: 
 Follows, in a reasonable temporal sequence, the administration of the drug or the drug level 
that has been established in body fluids or tissues. 
 Follows a known or expected response pattern of the suspected drug. 

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 Is confirmed by improvement after de-challenge or dosage reduction of the drug. 
 Reappears after repeated exposure (re-challenge). 
Probably related 
The event: 
 Follows, in a reasonable temporal sequence, the administration of the drug. 
 Follows a known or expected response pattern of the suspected drug. 
 Is confirmed by improvement after de-challenge or dosage reduction of the drug. 
 Cannot be reasonably explained by the known characteristics of the subject’s clinical state. 
 No re-challenge test or laboratory confirmation is available. 
Possibly related 
The event: 
 Follows, in a reasonable temporal sequence, the administration of the drug. 
 Follows a known or expected response pattern of the suspected drug but could have been 
easily produced by a number of other etiologies. 
Unlikely related 
There is no reasonable temporal association between the drug and the AE or the event could 
have been related to the subject’s clinical state or concomitant treatment(s), or another cause 
adequately explaining the AE is known or is much more probable. 
Not related / None 
Sufficient information exists indicating that etiology is unrelated to the drug. 
Unassessable 
The data are insufficient or contradictory to make a meaningful medical assessment. This 
criterion should be used only in case of insufficient evidence, conflicting data or poor 
documentation. Every effort should be done by the Investigator to make appropriate assessment 
of causal relationship. 
 
18.3.3 
Reporting Adverse Events 
 
AE reporting has to be in accordance with the ICH E6 Guidance on GCP and ICH E2A 
Guidance on Clinical Safety Management (15, 16). 
During the course of the study, all AEs (including SAEs), irrespective of the relatedness to the 
study drugs, must be recorded in detail in the source records and transcribed onto the AEs pages 
of the CRF. During each monitoring visit, the Investigator and the site monitor will review all 
AEs and perform Source Data Verification (SDV). The Investigator will be responsible for 
ensuring that the correct information concerning all AEs is entered on the appropriate CRF 
pages. 
The reporting period for AEs is the period starting from the time of informed consent signature 
and lasting until the Final Visit/ETV. All ongoing serious (SAEs and SADRs) and non-serious 
AEs judged as related to the study treatment will be followed until 14 days after the subject 
completes the study. All unresolved AEs (including SAEs) will be documented on the CRF as 
“ongoing” without further follow-up. 
 

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18.3.4 
Reporting Serious Adverse Events and Suspected Unexpected Serious Adverse 
Reactions 
 
All SAEs occurring from the time of signing of the informed consent until the Final Visit/ETV 
must be reported immediately to the Sponsor.  
Information on the actual fax and phone numbers are provided in the Investigator file as well 
as in § 18.4.  
 
The Investigator or designated study coordinator must complete the Investigational Serious AE 
Form and send it to the Sponsor within 24 h of observation or notification of a SAE. All of 
these events must also be recorded on the appropriate CRF pages. 
It is the responsibility of the Investigator to inform his local EC about SAEs according to the 
local EC requirements. It is the responsibility of the Sponsor to submit applicable SUSAR 
Reports to the Competent Authorities. Reporting of suspected unexpected serious adverse 
reactions (SUSARs) to the relevant EC, in accordance with Swiss Ordinance on Clinical Trials 
with the exception of Clinical Trials of Medical Devices 810.305 (ClinO) of 20 September 2013 
(Status as of 26 May 2022), will also be the responsibility of the CRO (15, 16). 
A safety contact sheet will be provided to the Investigator and will be maintained in the 
Investigator file at the Phase I Unit. Refer to the instructions and definitions for completing the 
Investigational SAE Form for submitting all SAEs to the CRO. 
 
18.3.4.1 
Follow-up of SAEs 
 
For Pharmacovigilance purposes only, when the Phase I Unit receives any information about a 
SAE (related and unrelated) which changes or adds to the information on the initial 
investigational SAE form, the Phase I Unit will fill out a new investigational SAE form and 
tick the “follow-up” box of the SAE form and fax it within 24 h to the Sponsor, especially if 
this new information has an effect on the seriousness, relatedness or expectedness of an AE 
(please refer to § 18.4 for contact details).  
 
18.3.5 
Pregnancy Report 
 
In the unlikely eventuality that a patient becomes pregnant during the trial, the Investigator will 
be requested to complete the Pregnancy Report Form and any relevant document. They must 
be forwarded to the Sponsor e-mail address or sent by fax (see § 18.4). Even though pregnancy 
is not considered as SAE itself, pregnancy has to be reported within the timelines as defined for 
SAE. 
Pregnant subjects will be followed by the Investigator and CRO / Sponsor until the fetus / 
newborn is delivered. At the study end and database closure, reports of Pregnancy Outcome 
will be sent by the sites directly to Helsinn (Drug Safety). The subject’s primary care physician 
(or obstetrician) will be requested by consenting pregnant subjects to provide the Investigator 
with further information on the pregnancy using the Pregnancy Outcome Information Form. If 
pregnancy occurs while the subject is on study treatment or up to 28 days after last study drug 
administration, the subject will be discontinued from the study. 
 
 
 
 

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18.4 
SAEs: contacts 
 
The clinical site can be contacted using the phone and fax numbers stated in this protocol or 
calling the mobile phone number +41 79 822 35 07 (operative 24-h/day, 365 days/year). This 
mobile phone can be called by the study participants to communicate to the clinical staff any 
SAE occurring outside the clinical facility. 
 
Safety contact at CRO: 
Dr. Milko Radicioni 
Phone:  
Fax: 
 
Email:  
 
Sponsor Drug Safety Officer: 
Mario Bertazzoli, MD  
Helsinn Healthcare SA 
Via Pian Scairolo 9 
6912 Lugano, Switzerland 
Phone:   
Fax:  
 
Email:  
(copies to: drug-safety@helsinn.com)  
 
 
 

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Sponsor code PNET-22-08 
Netupitant IV infusion shortening 
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19 
SUBJECTS’ DISCONTINUATION, STUDY 
TERMINATION 
 
19.1 
Withdrawal of subjects 
 
In case of a subject’s premature discontinuation from the study, the primary reason for 
discontinuation will be recorded. 
 
19.1.1 
Primary reason for discontinuation 
 
Primary reason for discontinuation from the study could be one of the following: 
 
 adverse event: Any (significant) adverse event that in the opinion of the investigator or 
concerned subject is not compatible with study continuation. For the definition of AE, 
please refer to § 18.2. 
 death 
 lost to follow-up: the loss or lack of continuation of a subject to follow-up 
 non-compliance with study drug: an indication that a subject has not agreed with or 
followed the instructions related to the study medication 
 physician decision: a position, opinion or judgment reached after consideration by a 
physician with reference to the subject 
 pregnancy 
 protocol deviation: an event or decision that stands in contrast to the guidelines set out by 
the protocol 
 study terminated by sponsor: an indication that a clinical study was stopped by its sponsor 
 technical problems: a problem with some technical aspect of a clinical study, usually 
related to an instrument 
 withdrawal by subject: study discontinuation requested by a subject for whatever reason 
 other: different than the ones previously specified 
 
19.1.2 
Discontinuation procedures 
 
For any subject discontinuing the study, the investigator will:  
 ask the subject to undergo, as far as possible, a final medical visit (ETV) to examine the 
subject's health conditions and perform the required blood sampling for the laboratory 
assays. This examination will verify that all values tested at screening have remained within 
a clinically acceptable range (i.e., not clinically significant changes compared to screening) 
 arrange for alternative medical care of the withdrawn subject, if necessary 
 record the subject decision about the use of collected biological samples 
 report in the CRF date and time of the last dose administration, and date and primary reason 
of study discontinuation 

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 record in the CRF any follow-up, if the subject is withdrawn for an AE 
In either study part, discontinued subjects will not be replaced after assignment of the study 
number (Part A) or randomization number (part B). 
 
Subjects who will not be assigned a study number (Part A) or randomization number (part B) 
in the evening of Day -1 and discontinuing at that time, will be replaced by reserve subjects.  
 
19.2 
Study termination 
 
The study will be considered terminated at the date of the last visit of the last subject entered in 
study part B or upon completion of any follow-up procedure described in protocol. The 
Investigator and the Sponsor have the right to discontinue the study at any time for reasonable 
medical and/or administrative reasons. As far as possible, this should occur after mutual 
consultation. Reasons for discontinuation must be documented appropriately. 
 
With respect to the stopping rules defined for study Part A only, please refer to § 13.2.  
 
 

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20 
DATA MANAGEMENT PROCEDURES 
 
20.1 
Data collection – CRFs 
 
The investigator must ensure that the clinical data required by the study protocol are carefully 
reported in the CRFs. He must also check that the data reported in the CRFs correspond to those 
in the subject’s source documents for all subjects who have been included in the study.  
To ensure legibility, the CRFs should be filled out in English, in block capitals with a ball-point 
pen (not pencil, felt tip or fountain pen). Any correction to the CRFs' entries must be carried 
out by the investigator or a designated member of staff. Incorrect entries must not be covered 
with correcting fluid, or obliterated, or made illegible in any way. A single stroke must be drawn 
through the original entry. Corrections must be dated and initialed. In the interest of 
completeness of data acquisition, the questions which are repeated in each section of the CRFs 
should be answered in full, even if there are no changes from a previous examination. The 
investigator must provide a reasonable explanation for all missing data. 
The CRFs will be completed, signed by the investigator, sent to the CRO Biometry Unit for 
data management procedures and finally sent to the sponsor.  
Subject’s source documentation (i.e., volunteer’s medical records and study source documents) 
will be maintained at the Phase I Unit. Source data verification will be regularly performed by 
the study monitors (See also § 21.1). The sponsor and the CRO are responsible for the data 
management of this study including quality checking of the data, each one for their respective 
activities. 
 
20.2 
Unique subject identifier 
 
All the subjects who sign the informed consent form for each part of the present study will be 
coded with “unique subject identifiers” when data are extracted from the study database into 
the domains of the CDISC SDTM model. The unique subject identifier consists of the sponsor 
study code (i.e., PNET-22-08), the 3-digit site number (i.e., 001), the 4-digit screening number 
for Part A (e.g., S001, S002, etc.) or the 4-digit screening number for Part B (e.g., S101, S102, 
etc.) and, if applicable, the 3-digit subject study number for Part A (e.g., 001, 002, etc.) or the 
3-digit subject randomization number for Part B (e.g., 101, 102, etc.). Study code, site number, 
screening number and subject study or randomization number are separated by slashes (“/”). 
The last 8 digits of the unique subject identifier (enrolled subjects), corresponding to the subject 
screening and subject study or randomization numbers separated by a slash, or the last 4 digits 
of the unique subject identifier (not enrolled subjects), corresponding to the subject screening 
number, will appear as subject identifier in the individual listings and figures of the clinical 
study report and will be used to identify the subjects in in-text tables or wording (if applicable). 
 
20.3 
Database management 
 
The CRO will provide a double data entry with total re-entry of data by a second data entrist 
and discrepancy resolution by a third individual and will update and verify the database and 
create the final SAS data sets. The final data file will be transferred to the sponsor in the agreed 
format with all the other study documentation. 
 

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Sponsor code PNET-22-08 
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20.3.1 
Coding dictionaries 
 
Medical/surgical history and underlying diseases, clinically significant physical examination 
abnormalities and AEs will be coded using the Medical Dictionary for Regulatory Activities 
(MedDRA™). 
Previous and concomitant medications will be coded using the WHO Drug Dictionary 
Enhanced (WHODDE). The version of the coding dictionaries will be stated in the study report. 

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Sponsor code PNET-22-08 
Netupitant IV infusion shortening 
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21 
STUDY MONITORING, QUALITY CONTROL AND 
QUALITY ASSURANCE 
 
21.1 
Monitoring 
 
The monitoring visits will be conducted by appropriate staff selected by the CRO.  
 
Monitoring activities, including monitoring purpose, selection and qualifications of monitors, 
extent and nature of monitoring, monitoring procedures, monitoring reports will comply with 
ICH-GCP chapter 5.18 requirements. 
 
Adequate time and availability for monitoring activities should be ensured by the investigator 
and key study personnel. 
 
Data verification is required and will be done by direct comparison with source documents, 
always giving due consideration to data protection and medical confidentiality. In this respect 
the investigator will assure support to the monitor at all times. 
 
The Investigator agrees, by written consent to this protocol, to fully co-operate with compliance 
checks by allowing authorized individuals to have access to all the study documentation. In 
addition to the monitoring activities performed by the study monitor, the sponsor and/or 
sponsor’s delegates could perform on-site study audits in order to ensure the study compliance 
with the study procedures, the ICH-GCP guidelines and the applicable regulatory requirements. 
The auditing activities may also be conducted after study completion.  
 
21.2 
Quality Control and Quality Assurance  
 
The CRO has implemented and maintains a Quality System with written SOPs to ensure that 
the study is conducted in compliance with the protocol and all effective amendments, ICH-
GCP, and the applicable regulatory requirement(s) and that data have been reliably and 
correctly generated, recorded, processed and reported, in agreement with the ALCOAC++ 
principles (Attributable-Legible-Contemporaneous-Original-Accurate-Complete-Consistent-
Enduring-Available-Traceable). 
 
The clinical site(s) is responsible for implementing and maintaining quality assurance and a 
quality control system to ensure that the study is conducted and data are generated, documented 
(recorded), and reported in compliance with the protocol, ICH-GCP, and the applicable 
regulatory requirement(s). 
 
The CROs and the sponsor will be responsible for their respective activities. 
 
The sponsor may transfer any or all the sponsor’s trial-related duties and functions to a CRO, 
but the ultimate responsibility for the quality and integrity of the trial data always resides with 
the sponsor. 
 
 
 

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21.3 
Applicable SOPs 
 
The Sponsor, the Phase I Unit and the CRO will follow their respective SOPs in the conduct of 
the respective activities, unless otherwise stated in written agreements. SOPs will be made 
available for review, if required. 
 
21.4 
Data access 
 
The investigator and the CRO will ensure that all raw data records, medical records, CRFs and 
all other documentation that is relevant to this study will be made accessible for monitoring 
activities, audits, IEC review, and regulatory inspections. 
 
21.5 
Audits and inspections 
 
The sponsor, independent bodies acting on behalf of the sponsor and the CRO have the right to 
perform audits according to ICH-GCP responsibilities. 
 
The study may also be inspected by regulatory authorities. If a regulatory authority notifies the 
Investigator of an inspection or visits the site unannounced for purposes of conducting an 
inspection, the investigator must inform the study sponsor and the CRO immediately.  
 
The investigator and the CRO agree, by written consent to this protocol, to fully co-operate and 
support audits and inspections compliance checks by allowing authorized individuals to have 
access to all the study documentation. 
 
 
 

Clinical Study Protocol 
Helsinn Healthcare SA  
CSP CRO-PK-22-363 
Sponsor code PNET-22-08 
Netupitant IV infusion shortening 
CSP final version 3.0, 24MAY23 
 
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22 
ETHICAL CONSIDERATIONS 
 
22.1 
Ethics and Good Clinical Practice (GCP) 
 
The study will be performed in accordance with the relevant guidelines of the Declaration of 
Helsinki. 
The approval of the study protocol by the local (Canton Ticino) IEC and by the Federal Health 
Authorities (Swissmedic) will be obtained before the start of the study.  
 
The present clinical study will be carried out according to the current revision of Good Clinical 
Practice (GCP), ICH topic E6 (R2), and the applicable local law requirements. 
 
22.2 
Informed consent 
 
Before being enrolled into the clinical study, the subjects must have provided their written 
consent to participate, after the Investigator has explained to them, clearly and in details, the 
scope, the procedures and the possible consequences of the clinical study or relevant study Part. 
Information will be given in both oral and written form. The information sheet and informed 
consent form will be prepared in the local language by the CRO and must be approved by the 
EC and may further be updated as new important information becomes available that may affect 
subject’s willingness to participate or continue in the trial.   
It will include all the elements required by law according to the ICH-GCP recommendations 
and regulatory requirements.  
 
The informed consent form will inform potentially eligible subjects about the nature of the 
study drugs, their efficacy and safety profile, the route of administration, and the human 
experience available. It will also outline the steps of the protocol, as they will apply to the 
individual, including the number of visits and types of procedures/assessments/measurements 
to be performed so that the individual has a clear picture of the risks, inconveniences and 
benefits that may accrue from the trial. The subject must be made aware that he/she may refuse 
to join the trial or may withdraw his/her consent at any time without prejudicing further medical 
care and that he/she is covered by the sponsor indemnity insurance in the event of a trial related 
injury. Contact details to report and discuss suspected trial-related injuries will be provided. 
The subjects must also know that their personal medical records may be reviewed in confidence 
by the staff of sponsor or representatives to the extent permitted by the Data Protection Laws 
or other applicable regulations and by regulatory authorities and IRB/EC and that personal 
information will be collected and retained in a confidential database under the control of the 
Investigator/study site. Conditions for ensuring the codification/de-identification of data and 
the methods used to ensure the security and confidentiality of the database should be explained. 
Consent will always be expressed in writing after the subject has had adequate time to review 
the information and to ask questions, if need be.  
Adequate time and opportunity to satisfy questions will be given to the subjects and the time 
will be recorded. The signed information sheet and informed consent form must be obtained 
before conducting any study-specific procedures (i.e., all of the procedures described in the 
protocol). 
 

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Subjects will be provided with information prepared in the local language, the processing of 
personal data will be in strict compliance with the “Data Protection Laws", as defined below 
(see § 23.5). 
 
The Investigator will be supplied with an adequate number of blank informed consent forms to 
be used. The forms will be signed and dated by both the Investigator and the subject.  
A copy of the signed form will be given to the subject. 
 
To ensure medical confidentiality and data protection, the signed informed consent forms will 
be stored in the Investigator's study file according to the regulatory requirements (see § 23.3). 
The Investigator will allow inspection of the forms by authorized representatives of the sponsor, 
EC members and regulatory authorities. He will confirm, by signing and dating the forms, that 
informed consent has been obtained. 
 
22.3 
Insurance policy 
 
An insurance cover has been issued in favor of the subjects participating in this clinical study. 
The insurance is in compliance with the local regulation and with the requirements of the Health 
Authorities. 
 
 

Clinical Study Protocol 
Helsinn Healthcare SA  
CSP CRO-PK-22-363 
Sponsor code PNET-22-08 
Netupitant IV infusion shortening 
CSP final version 3.0, 24MAY23 
 
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23 
ADMINISTRATIVE PROCEDURES 
 
23.1 
Material supplied to the Phase I Unit 
 
Beside the investigational product(s), the following study material will be supplied to the Phase 
I Unit: 
 final version of the study protocol 
 CRF for each subject plus some spare copies  
 copy of the investigator’s brochure (IB) relative to the IMPs  
 informed consent forms 
Moreover, before the start of the study, the investigator(s) will be provided with the following 
documents: ICH guidelines, confidentiality agreement (if applicable), protocol amendments (if 
any), declaration of Helsinki, insurance statement, SAE forms, financial agreement (if 
applicable), confidential subject identification code list form, drug accountability forms, 
investigator and study staff list form.  
 
23.2 
Protocol amendments 
 
In order to obtain interpretable results, neither the Investigator nor the sponsor will alter the 
study conditions agreed upon and set out in this protocol with the only exception when 
immediate changes are necessary to protect the safety, rights, and welfare of the subjects. 
Amendments should be made by mutual agreement between the Investigator and the sponsor. 
Any amendment must be set out in writing, giving the reasons, and being signed by all 
concerned parties. The amendment becomes then part of the protocol. The study code, the title 
of the study, the progressive number and the date of the amendment must be recorded on the 
first page of the document. Exhaustive justifications that motivate the amendment to the 
protocol should clearly be addressed in the document. 
 
All substantial amendments will be submitted to the concerned Regulatory Authorities, as 
applicable. The amendment(s)/modification(s) will be applicable only after approval, unless the 
changes consist of urgent safety measures to protect study subjects. 
 
Non substantial amendments will be notified according to the current regulations. 
 
In the event of an isolated, unforeseen instance resulting in a protocol deviation, the Investigator 
is to document this deviation and notify it to the CRO study project leader as soon as possible, 
in writing. In no instance should this increase the subject’s risk or affect the validity of the study 
data. 
 
23.3 
Study documentation and record keeping 
 
The Investigator should ensure the accuracy, completeness, legibility, and timeliness of the data 
reported to the sponsor in the CRFs and in all required reports. 
 

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The Investigator must keep source documents for each subject in the study. All information on 
the CRFs must be traceable to these source documents, which are generally stored in the 
subject's medical file. The source documents should contain all demographic and medical 
information, including laboratory data, ECGs, etc., and the original signed informed consent 
forms. 
 
Data reported on the CRF that are derived from source documents should be consistent with the 
source documents or the discrepancies should be explained. 
 
The Investigator and the sponsor should maintain the study documents as specified in the 
“Essential Documents for the Conduct of a Clinical Trial” chapter 8 of ICH-GCP and as 
required by the applicable regulatory requirement(s).  
 
These are documents which individually and collectively permit evaluation of a study and the 
quality of the data produced and include groups of documents, generated before the study 
commences, during the clinical study, and after termination of the study and include but are not 
limited to, study protocol, amendments, submission and approval of EC, raw data of subjects 
including lab tests and ECG tracing, insurance contracts, certificate of analysis of the IMP(s), 
drug accountability records, signed informed consent forms, confidential subjects identification 
code, CRFs, curricula vitae of the Investigator and other participants in the study, study staff 
lists and responsibilities, monitoring reports and final study report. 
 
The Investigator and the sponsor should take measures to prevent accidental or premature 
destruction of these documents. Should the Investigator or the CRO wish to assign the study 
documentation to another party or move to another location, the sponsor should promptly be 
notified. 
 
All the essential study documents should be retained at the study site(s) in accordance to the 
applicable statutory terms and/or until the sponsor inform the Investigator/study site(s) in 
writing when the trial related records are no longer needed and in any case in accordance with 
FDA regulation 21 CFR 312.62(b) and (c) and ICH-GCP, national and international regulations. 
By signing the protocol, the investigator and the sponsor agree to adhere to these requirements. 
 
23.4 
Study subjects’ recruitment 
 
Study participants will be recruited from the volunteers’ database maintained by the CRO. This 
database contains a pool of volunteers that are contacted whenever necessary to enrol subjects 
in a new study. Before the start of the new study, the principal investigator and other relevant 
staff discuss with the volunteers’ recruiter the study recruitment needs and specific 
requirements. On the basis of this information, the volunteers’ recruiter queries the database, 
contacts potential participants to propose the study and evaluate their interest and availability. 
In addition to the volunteers’ database, new subjects often call or email the CRO asking to 
become a research volunteer, after hearing of the clinical site activities from other volunteers 
or friends or after checking the company web site. 
 
The CRO and its clinical site have detailed SOPs on the recruitment process. 
 

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23.5 
Confidentiality and data protection 
 
The Investigator shall keep secret from third parties any confidential information disclosed or 
provided by the sponsor, including but not limited to this protocol, CRF, and any other study 
information. Furthermore, prior to the study start-up, the CRO shall sign a confidentiality 
agreement with the Sponsor. 
The processing of personal data of natural persons involved in the study is carried out in 
accordance with any applicable “Data Protection Laws", including without limitation the Swiss 
Federal Law on Data Protection (Law 235.1 of 19 June 1992 and subsequent updates), the 
Regulation (EU) 2016/679 of the European Parliament and of the Council on the protection of 
nature persons with regard to the processing of personal data and on the free movement of such 
data (hereinafter, GDPR”), as well as any other country regulations in that are similar, 
equivalent to or that are intended to or implement and/or modify the laws that are identified in 
above in relation to the protection of personal data. Both the controller and the processor are 
obliged to observe the rules and obligations coming from the applicable Data Protection Laws, 
as well as to set up the relevant processes for data subjects’ rights fulfilment. Each subject 
entering the study will be assigned a unique subject number (subject ID code) (see § 20.2). Any 
subject records or datasets that are transferred from the study site to the sponsor or to authorized 
vendors will be coded and will contain the subject ID code; subject names or any information 
which would make the subject identifiable will not be transferred. The Investigator must ensure 
that the subject’s confidentiality will be strictly maintained and that their identities are protected 
from unauthorized access. In order to respect the subject’s privacy, all the subject’s records, 
study reports, and communications, will identify the subject by the assigned unique subject ID 
code.  The first two letters of the surname followed by the first two letters of the first name of 
the study subjects will be used in the Phase I Unit source document only and will not be 
transferred to the Sponsor. Laboratory specimens must be labelled in such a way as to protect 
subject identity while allowing the results to be recorded to the proper subject. The Investigator 
must keep a screening log showing the unique subjects’ numbers and associated names, for 
subjects screened and for all subjects enrolled in the trial. This log must be kept strictly 
confidential. The subject’s confidentiality will be maintained and will not be made publicly 
available, to the extent permitted by the applicable laws and regulations. The Sponsor of this 
study is the owner of all the data, information or material collected during the study according 
to the approved study protocol. Whether personal/coded or anonymous data are processed 
within the study, it will always be a protected information processing. Therefore, the CRO shall 
accept and implement appropriate technical and organizational security measures required by 
standard and regulations. The sponsor may transmit the personal data to recipients, such as 
sponsor, service providers and advisors and/or health authorities, located in third countries 
whose data protection laws may not offer equivalent protection only by taking all necessary 
steps to ensure the confidentiality, integrity and availability of personal data in accordance with 
applicable Data Protection Laws. 
 
23.5.1 
Subjects Personal Data Processing  
 
Under the applicable Data Protection Laws, the sponsor, as well as the CRO and the Investigator 
are responsible for this study and will act as data controllers. Specifically, the Phase I Unit/CRO 
remains responsible when the Investigator uses uncoded subject data (or not coded) for medical 
or non-medical purposes. The controller of personal data, who determines the purposes and 

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means of processing within the overall study is the sponsor. The subject cannot be included in 
the study without a signed explicit informed consent form. The responsible for acquiring and 
storing of subject informed consent form is the Investigator/designee and/or the study site. The 
specific purposes of the study and of the data collection are described in the informed consent 
form, and information that the subject has been adequately notified about the processing of 
his/her data should be reported in the CRF. Medical records may be examined by the Quality 
Assurance Unit of the CRO in accordance with internal CRO procedures as well as by Clinical 
Quality Assurance auditors or other authorized personnel appointed by the sponsor, by 
appropriate IRB/IEC members, and by inspectors from regulatory authorities. Further data 
processing in the study is in the coded regime, where the persons accessing any databases or 
registries based on their access rights are unable to identify the subject (directly or indirectly) 
without the use of additional information, as long as such additional information is kept 
separately and subject to technical and organizational measures to ensure non-attribution to an 
identified or identifiable individual. The Investigator is the contact person for the subject’s 
rights fulfilment. The Investigator shall be familiarized with rules for personal data processing. 
 
23.5.2 
Investigator Personal Data Processing  
 
The sponsor who receives information on Investigators, including sub-investigator(s) and study 
staff (directly or indirectly, through the CRO) is the Controller of the Investigators’ personal 
data and the CRO is a Joint-Controller of the Investigators’ personal data. The processors are 
other vendors (permitted sub-processors) managing the study. Within the study, the personal 
data of the Investigators are processed by the CRO and other authorized vendors on the basis 
of the creation of access accounts and communication during the study course. On the basis of 
a legitimate purpose, the Investigators data might be communicated to, and processed by the 
controllers or the processors (or permitted sub-processors) to ensure the smooth running of the 
study and high quality of collected data. In such a case, the investigators are properly informed 
about their data processing. Permitted sub-processors undertake to provide adequate notices to 
the Investigators (in a form provided by and on behalf of the sponsor/CRO) and undertake to 
ensure that all Investigators have acknowledged to the processing of their personal data as 
required for the following purposes: (a) the conduct of the study; (b) review by governmental 
or regulatory agencies, public authorities or pharmaceutical industries associations, CRO, the 
sponsor and its agents and affiliates; and (c) compliance with legal or regulatory requirements 
including those on disclosure of transfers of values from pharmaceutical companies to 
healthcare professionals and healthcare organizations; and (d) storage in databases for use in 
selecting study staff, and institutions for future clinical trials. 
23.6 
Future use of data 
The personal information collected during this study (including any biological samples 
remaining at the end of 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 medicinal products; (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. Personal information collected during this study may be stored and used for future 
research. The sponsor may agree on sharing upon request from qualified scientific and medical 
researchers anonymized individual subject-level data, study-level clinical trial data, and 

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Sponsor code PNET-22-08 
Netupitant IV infusion shortening 
CSP final version 3.0, 24MAY23 
 
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protocols from clinical trials in patients for medicines and indications approved in the US and 
the EU, as necessary for conducting legitimate research. Medical researchers can request said 
data for new research. 
 
23.7 
Dissemination of Clinical Study Data 
 
The sponsor is committed to following high ethical standards for reporting study results for its 
innovative medicine, including the timely communication and publication of clinical trial 
results, whatever their outcome. The sponsor assures that the key design elements of this 
protocol will be posted on a publicly accessible database, e.g., www.clinicaltrials.gov. In 
addition, results of this trial will be posted publicly according to local regulations. These posts 
(whether or not on the websites) will not include any information that allow identification of 
individual subjects.  
 A clinical study report will be prepared and provided to the regulatory agency(ies), as 
appropriate. The sponsor will ensure that the report meets the standards set out in the ICH 
Guideline for Structure and Content of Clinical Study Reports (ICH E3 Guidance on CSR). 
Note that an abbreviated report may be prepared in certain cases.  
 All data generated in this study required to be publicly available will follow all local and 
global regulations. Requests to delay submission of study results will follow the appropriate 
regulatory procedures, if warranted. 
 Peer reviewed publication(s) of the study results will follow the publication policy detailed 
in section 23.8. 
 
23.8 
Publication policy 
 
The sponsor agrees that the study results (including negative and inconclusive as well as 
positive results) can be made publicly available by the investigator publishing in peer reviewed 
journals, presenting results at scientific congresses and posting information and results on 
internet-based public registers and databases. 
Study results will be communicated in full to the competent Health Authorities by the 
submission of a complete clinical study report. 
 
As the sponsor agrees that the study results can be published by the investigator(s), the 
investigator agrees to submit any manuscript (abstract, publication, paper, etc.) to the sponsor 
before any public disclosure. 
This will be done in order to ensure that clinical study results are reported in an objective, 
accurate and balanced manner. The sponsor reviews the proposed manuscripts, before 
submission, within a reasonable period of time (30-90 days in relation with the complexity of 
the work). 
 
The investigator will also be provided by the sponsor with the clinical study report and the 
results of any additional analysis, tables, figures, etc. undertaken for the purposes of the article, 
in order to take responsibility for the content of the publication(s). 
On an exceptional basis, the sponsor may temporarily delay registration of certain data elements 
(e.g., compound, name, outcome, measures, etc.) to seek necessary intellectual property 

Clinical Study Protocol 
Helsinn Healthcare SA  
CSP CRO-PK-22-363 
Sponsor code PNET-22-08 
Netupitant IV infusion shortening 
CSP final version 3.0, 24MAY23 
 
CROSS Research S.A. 
Page 98 
CONFIDENTIAL 
protection. This is because early disclosure of such data could, in some circumstances, prevent 
or negatively impact patentability. 
 
According to The Federal Act on Research involving Human Beings and the Ordinance on 
Clinical Trials in Human Research, the study will be registered and published in a WHO 
primary register or clinicaltrials.gov as well as in the supplementary federal database.  
 

Clinical Study Protocol 
Helsinn Healthcare SA  
CSP CRO-PK-22-363 
Sponsor code PNET-22-08 
Netupitant IV infusion shortening 
CSP final version 3.0, 24MAY23 
 
CROSS Research S.A. 
Page 99 
CONFIDENTIAL 
24 
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1This document is based on CRO template frm-0284, v. 2.0