A Phase III Randomized, Double-blind, Placebo-controlled, Cross-over Study to Evaluate Olanzapine Combined With Fosaprepitant, Ondansetron, and Dexamethasone for Preventing Nausea and Vomiting in Patients With Testicular Cancer Receiving 5-day Cisplatin Combination Chemotherapy
Phase: PHASE3
Conditions: Olanzapine, CINV, Testicular Cancer by AJCC V6 and V7 Stage, Cisplatin
Sponsor: Shi Yanxia

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A Phase III Randomized, Double-blind, Placebo-controlled, Cross-over Study to
Evaluate Olanzapine Combined with Fosaprepitant, Ondansetron, and Dexamethasone
for Preventing Nausea and Vomiting in Patients with Testicular Cancer Receiving 5-
day Cisplatin Combination Chemotherapy
Clinical study protocol
Scheme No.:
Solution version: 1.3
Version date: October 21, 2021.
Principal investigator: Yanxia Shi
Group leader: Sun Yat-Sen University Cancer Center

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Principle Investigator
Signature page
I have read this test protocol (Version no. : 1.3, version date: October 21, 2021) and
agree to carry out this test in accordance with the party protocol and relevant attached
documents. I will provide the scheme to my research team and conduct relevant
discussions with them to ensure that they fully understand the experiment. I may request
termination of the study or discontinuation of inclusion at any time for certain pre-
specified reasons. I may also stop the study because I need to protect the rights and
interests of the subjects. I agree to conduct this trial strictly in accordance with all
applicable and current regulations and clinical Trial Quality Management Practices
(GCP).
At the same time, AS the main researcher of this
experiment, I coordinated the overall process of the
experiment.
Name:
Signature:
Date:
Name of test Center:

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Abstract
Title
A Phase III Randomized, Double-blind, Placebo-controlled,
Cross-over Study to Evaluate Olanzapine Combined with
Fosaprepitant, Ondansetron, and Dexamethasone for Preventing
Nausea and Vomiting in Patients with Testicular Cancer
Receiving 5-day Cisplatin Combination Chemotherapy
Version
number/date
Version 1.3/ 21 October 2021
Categories
Investigator-initiated clinical trial (IIT)
IIT initiator
Professor Shi Yanxia, Cancer Center, Sun Yat-Sen
University
Indication
Germ cell tumor
Study
population
Men diagnosed with germ cell tumor and treated with 5-day
cisplatin (20mg/m2, total 100mg) based chemotherapy
Study design
Phase III Randomized, Double-blind, Placebo-
controlled, Self-control, Cross-over Study
Sample size
A total of 75 patients were enrolled in two sequential
treatment groups (olanzapine-placebo group and placebo-
olanzapine group)
Chemotherapy
EP/BEP/VIP/TIP (cisplatin should be administered with the
dose of 20mg/m2 IVD, D1-5, every 3 weeks
Experimental
drug
Ondansetron: 8mg IV D1-5 30 minutes before chemotherapy;
Dexamethasone: 6mg Po d1-7;
Fosappitan: 150mg IVD D1, D4 60 minutes before
chemotherapy;
Olanzapine/Placebo: 5mg Po D1-7

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Inclusion
criteria
Patients must meet the following criteria for inclusion:
1)
Pathology confirmed germ cell tumor (both
spermatogonoma and non-spermatogonoma) and had no
chemotherapy before;
2)
Men;
3)
Age ≥16 years old;
4)
ECOG score of physical status 0-2;
5)
Chemotherapy regimen containing 5-day cisplatin
(20mg/m2, 100mg total;
6)
No other nausea, vomiting, or use of any antiemetics
within 72 hours prior to enrollment;
7)
There are no clear brain metastases or other reasons for
long-term systemic use of hormones;
8)
The general condition is good, and the blood, liver and
kidney functions meet the following standards:
Hemoglobin: 90 g/L and above
White blood cell count: 3.5 * 109 / L - 10.0 *109 / L
Neutrophil count: 1.5* 109/L or above
Platelet count: 90* 109/L or above
Serum total bilirubin: below 1.5 times the upper limit of
normal
Serum AST, ALT and ALP: the upper limit of normal is
below 2.5 times when the patient is present
9)
Ability to read, understand and complete research
questionnaires and journals, including visual analog scale
(VAS);
10) Understand the study procedure and sign the informed
consent in person to participate in the study

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Exclusion
criteria
Patients who meet any of the following criteria will be
excluded:
1)
Digestive tract obstruction, water and electrolyte
disorder;
2)
Have central nervous system diseases (such as primary
brain tumors, uncontrolled seizures, any history of brain
metastases or strokes);
3)
Contraindications to the use of glucocorticoids: ①Viral,
bacterial, fungal and other infections that cannot be
controlled by antibiotics;②Active gastric or duodenal
ulcer;③Severe hypertension, arteriosclerosis, diabetes;
④Osteoporosis;⑤Corneal ulcer;⑥Trauma or
surgical repair period, fracture; ⑦Adeno-cortical
hyperfunction; ⑧Severe mental illness and epilepsy;
⑨patients with cardiac or renal dysfunction;
4)
Patients with mental disabilities or severe emotional or
mental disorders are considered unsuitable for inclusion
in the study;
5)
In addition to malignancy, the patient has an active
infection (e.g. pneumonia, hepatitis) or any uncontrolled
infection diseases (such as diabetic ketoacidosis), and the
researchers believe may contribute to the study's findings
confounding, or exposing patients receiving study drugs
to unnecessary risks;
6)
The patient is currently using any prohibited drugs,
including medicinal marijuana or is currently using
alcohol (Chinese Diagnostic criteria for drug
dependence);
7)
The patient received an unapproved (experimental) drug
treatment within the past 4 weeks;
8)
Taking oral olanzapine or other psychotropic drugs;
9)
A history of hypersensitivity to fosaprepitant, 5-HT3
receptor antagonists or dexamethasone;
10) The patient cannot swallow the drugs;
11) The principal investigator considered the patients
unsuitable for the study;
12) Inability or unwillingness to adhere to research

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protocols
Dose adjustment
See the protocol below for details.
Eliminate drugs
Drugs to be excluded during treatment and observation:
phenytoin or carbamazepine, barbiturates, rifampicin or
rifambutin, hypericum perforatum, terfenadine, cisapride,
amifostine, pimozide, astimidazole, clarithromycin (note:
azithromycin, erythromycin and roxithromycin are
permitted), ketoconazole or itraconazole (fluconazole is
permitted), antiretroviral protease inhibitors; Phenol
thiazine drugs (e.g. prochlorazine), phenylbutanone (e.g.
haloperidol), olanzapine; Psychotropic drugs, benzamide
(e.g. Metoclopramide), domperidone, cannabinol; Herbs
with potential antiemetic effects, scopolamine, etc.
If the
patient develops nausea or vomiting, remedial treatment is
permitted with clinically recommended antiemetics.
Outcome
Measures
Primary Outcome
Complete response (no vomiting and no rescue) rate for the
overall phase (1 to 10 days)
Secondary Outcomes
(1) Minimal nausea, <25 mm on a visual analog scale (VAS)
for acute phase ((1-5 days) and delayed phase (6-10
days), and overall phase (1-10 days);
(2) Complete response rate for acute and delayed phases;
(3) Total control (TC): no vomiting, no rescue antiemetics,

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and no nausea) for acute, delayed, and overall phases;
(4) Incidence and severity of nausea were assessed based on
the Common Terminology Criteria for Adverse Events
(CTCAE);
(5) Number of rescue medications;
(6) Time to Treatment Failure: time to 1st emetic episode or
use of rescue medication;
(7) Hospital Anxiety and Depression Scale (HADS), and The
Functional Living Index-Emesis (FLIE) questionnaire
Adverse events
The primary endpoint events (vomiting, retching, and nausea)
that occurred during the log data collection period (day 1 to
morning 11) were not defined as adverse events unless the
definition of a severe adverse event was met. Adverse events
were graded and recorded according to CTCAE (Version 4.0).
Main Procedure
(1) The screening process begins after the patient signs the
written informed consent;
(2) The study is characterized by randomized, cross-over,
self-control design. For each patient who were randomly
divided into experimental group (olanzapine group) or
control group (placebo) will cross over the other group in
the second cycle of chemotherapy;
(3) Patients filled in self-reported diaries and completed visual
analogue scales for nausea, as well as HADS and FLIE
questionnaires;
(4) During the study period, patients may receive "remedial
treatment" for nausea or vomiting, and patients requiring
remedial treatment are considered to have failed treatment.
Patients receiving remedial treatment must continue to
receive the study drug and complete the log as directed.
Sample size
calculation and
statistical
analysis
Sample size calculation:
The required sample size was calculated to be 75 patients per
arm for the study to have a power of 80%, assuming that the
CR rate will be 75% in the olanzapine group and 50% in the
placebo group, and also assuming a two-sided significance
level of 0.05 and 10% ineligible cases. Due to the cross-over,
self-control design, the final sample size was 75.
Point estimates and confidence intervals for the CR rate will

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be calculated and will be compared between groups by using
the Mantel-Haenszel test with adjustment for allocation
factors.

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Directory
1.
The background...10
references...13
2. The research purpose...14
2.1 the primary outcome ...14
2.2 the secondary outcome...14
3. The study population...14
3.1 inclusion criteria...14
3.2 exclusion standard...15
4. The study design...16
4.1 sample size calculation...16
4.2 double-blind randomized design...16
5. Research program...16
5.1 Steps and process...16
5.2 The flow chart ...17
5.3 Administration schedule...18
6. Exclude medication...18
7. The effect evaluation...18
7.1 effectiveness evaluation index...18
7.2 safety evaluation index... 19
8. Screening and baseline visit...19
9. Evaluation during the study...20
9.1 Assessment of acute vomiting:...20
9.2 Assessment of delay vomiting...20
10. Termination and exit criteria...21
11. Statistical analysis...21

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11.1 study population...21
11.3 statistical analysis...21
11.3 Processing of exit or missing data...22
11.4 analysis plan...23
12. Adverse event reporting and recording...23
12.1 definition...23
12.2 expected range of adverse events...24
13.3 adverse events associated with drug causality judgement index...24
12.4 Management of adverse events...25
12.4.1 Adverse events recorded...26
12.4.2 Report of serious adverse events...26

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1. Background
Although testicular cancer is rare, accounting for only 1 % of all cancers in males, it is
the most common solid tumor among young men in the 20–39 years old. Since the
introduction of cisplatin-based chemotherapy in the 1970s, the prognosis of patients
with testicular cancer has been dramatically improved, with a 10-year relative survival
approaching 95%. However, treatment-related complications, including acute and long-
term toxicities remain unsolved.
Cisplatin is a chemotherapy agent with the highest emetic. The risk of emetic is more
than 90% when the daily dose of cisplatin is ≥50mg/m2. While the standard dose of
cisplatin is as high as 100mg/m2 in five consecutive days for testicular cancer. Early data
showed that patients with germ cell tumor who received multi-day cisplatin
chemotherapy experienced vomiting for more than 10 times on the first day and lasted for
several days [2]. Severe nausea and vomiting could reduce dietary intake, cause or
aggravate other toxicities, such as fatigue, neutropenia, anemia, and finally might
interfere with implementation of chemotherapy and anti-tumor efficacy. Therefore,
chemotherapy-induced nausea and vomiting (CINV) is one of the most feared side
effects experienced by patients with testicular cancer.
The mechanism of CINV has been elucidated in the past decades. The vomiting center is
pathological located in the side of the medulla oblongata reticular structure, which directly
controls the occurrence of vomiting. Chemotherapeutic drugs can induce the release of a
variety of neurotransmitters which bind of their receptors and play an important role in the
formation of vomiting. The neurotransmitters associated with CINV include 5⁃
hydroxytryptamine (5-HT), substance P/neurokinin -1 (NK-1), cannabinoid, dopamine,
acetylcholine, and histamine. According to the time of vomiting, CINV can be divided
into three categories [2-3]: ①Acute nausea and vomiting: nausea and vomiting occurring
within 24 hours after chemotherapy. This type of nausea and vomiting is often severe and
is mediated by serotonin 3 (5-HT3). In addition, the binding of substance P to its specific
receptor NK-1 also plays an important role in acute vomiting. ②Delayed nausea and
vomiting: nausea and vomiting 24 hours after the administration of chemotherapy drugs,
sometimes lasting for 5-7 days. Delayed CINV may be mediated by various mechanisms,
and the main transmitter is substance P.③Anticipatory nausea and vomiting: caused by
conditioned reflex. It occurs when patients see chemotherapy drugs or other things related

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to chemotherapy. Anticipatory nausea and vomiting is mainly related to spiritual and
psychological factors, and caused by poor control of acute nausea and vomiting.
Prophylactic medication is the key to control CINV. At present, there are three kinds of
drugs widely used in clinical practice: ①5-HT3 receptor antagonists, which specifically
block the binding of 5-HT3 and its receptor, mainly controlling acute nausea and
vomiting.②NK⁃1 receptor antagonist, blocking the binding of substance P to its
receptor, has an inhibitory effect both on acute and delayed nausea and vomiting.③The
antiemetic mechanism of dexamethasone is still unknown, but its efficacy in the
prevention of acute and delayed vomiting has been widely confirmed, and it has been
used as a basic drug for the prevention of CINV. A number of large phase 3 randomized
controlled studies and meta-analyses have confirmed that the combined use of 5-HT3
receptor antagonist, NK⁃1 receptor antagonist and dexamethasone could significantly
reduce the occurrence of CINV induced by highly emetogenic chemotherapeutic drugs
represented by single-day high dose cisplatin, with the control rate of vomiting is
approaching 90%[3, 4].Therefore, this three-drug combination regimen has been
recommended by several international and domestic guidelines such as NCCN/ESMO/
MASCC /CSCO for the prevention of highly emetogenic chemotherapeutic drug-
associated CINV. For patients undergoing multiple days of highly emetogenic
chemotherapy, current guidelines still recommend the use of the triple prophylaxis
regimen based on the results of single-day chemotherapy studies. However, this
recommendation is not supported by sufficient evidence-based medical evidence. A few
small phase II studies have been conducted on CINV associated with multi-day
hyperemetogenic chemotherapy. The only one small sample-sized phase III trial
demonstrated the efficacy of the triplet combination of NK 1 receptor antagonist,5-HT3
antagonists, and dexamethasone in testicular cancer patients who were treated with 5-day
cisplatin combination chemotherapy. Among 71 patients enrolled, 69 could be evaluated.
The complete remission rate of vomiting was 42% for patients treated with the triple
antiemetic regimen, compared with 13% for patients treated with two drugs combination
of 5-HT3 antagonists and dexamethasone [5]. Even if, 42% of overall vomiting control
rate is significantly lower than 90% in patients receiving single-day chemotherapy.
Moreover, prevention of nausea was extremely poor, and the overall control rate in was
only about 25% even for patients treated with the triplet combination [5-7]. Finding a
more effective regimen to prevent or reduce CINV for testicular cancer patients receiving
5-day cisplatin combination chemotherapy is urgently needed.

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At present, several NK-1 receptor antagonists have been successfully developed and
approved for marketing. Aprepitant, the first oral NK1 receptor blocker approved for
clinical use, was launched in the United States in March 2003 and entered the Chinese
market in September 2013.Forsapitan is the prodrug of aprepitan. In humans,
fosaprepitant can be rapidly converted to aprepitan within 30 minutes after the end of
intravenous administration of fosaprepitant, so its clinical efficacy is mainly attributed to
aprepitan. A randomized, parallel, double-blind, positive-controlled trial demonstrated
that fosaprepitant 0.15g intravenously (n=1147) had similar efficacy with aprepitan
capsules 3 days orally (n=1175) in patients receiving cisplatin ≥70mg/m2. Fosaprepitant
was well tolerated [8]. The most commonly reported adverse reactions in clinical
studies included headache and injection site symptoms.
Olanzapine is the second generation of atypical neuroleptics, which is mainly used in
the treatment of schizophrenia. Olanzapine antagonizes various vomit-related
neurotransmitter receptors, such as dopamine receptor, 5-HT2 receptor, and histamine
receptor, and has significant nausea and vomiting prevention effect. Accumulating
evidences support the efficacy of olanzapine for prophylaxis of CINV for highly
emetogenic chemotherapy. However, most studies focus on solid malignancies and
single-day regimens. Moreover, the standard dose of olanzapine (10 mg qd) is
associated with high risk of sedation, drowsiness, and fatigue. Subsequent studies
showed that lowering olanzapine dose to 5mg per day had similar prophylactic effects
on nausea and vomiting compared with 10mg, and significantly reduced the incidence
of excessive sedation and drowsiness [9]. Therefore, many researchers suggest that 5mg
of olanzapine per day may be a more predictive dose for nausea and vomiting. To
improve antiemetic therapies for testicular patients receiving 5-day cisplatin
chemotherapy, the current study aims to explore the efficacy and safety of low-dose
olanzapine combined with nK-1 receptor antagonist (Fosaprepitant), 5-HT3 receptor
antagonist (ondansetron) and dexamethasone quadruplex antiemetics regimen.
reference
1.
Siegel, R.L., K.D. Miller, A. Goding Sauer, S.A. Fedewa, L.F. Butterly, J.C. Anderson,
et al. Colorectal cancer statistics, 2020. CA Cancer J Clin 2020;70 (3) : 145-164.
2.
Herman, T.S., L.H. Einhorn, S.E. Jones, C. Nagy, A.B. Chester, J.C. Dean,et al.
Superiority of nabilone over prochlorperazine as an antiemetic in patients receiving cancer
chemotherapy. N Engl J Med 1979;300 (23) : 1295-7.

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3.
Hesketh, P.J., S.M. Grunberg, R.J. Gralla, D.G. Warr, F. Roila, R. de Wit, et al. The oral
neurokinin-1 antagonist aprepitant for the prevention of chemotherapy-induced nausea
and vomiting:a multinational, randomized, double-blind, placebo-controlled trial in
patients receiving high-dose cisplatin--the Aprepitant Protocol 052 Study Group. J Clin
Oncol 2003;21 (22) : 4112-9.
4.
Schmoll, H.J., M.S. Aapro, S., Poli-Bigelli, H.K., Kim, K. Park, K., Jordan, et al. Comparison
of an aprepitant regimen with a multiple-day ondansetron regimen, both with
dexamethasone, for antiemetic efficacy in high-dose cisplatin treatment. Ann Oncol
2006;17(6):1000-6.
5.
Albany, C., M.J. Brames, C. Fausel, C.S. Johnson, J. Picus, and L.H. Einhorn. Randomized,
double-blind, placebo-controlled,phase III cross-over study evaluating the oral neurokinin-1
antagonist aprepitant in combination with a 5HT3 receptor antagonist and dexamethasone in
patients with germ cell tumors receiving 5-daycisplatin combination chemotherapy regimens: a
hoosier oncology group study. J Clin Oncol 2012;30 (32) : 3998-4003.
6.
Ioroi, T., J. Furukawa, M. Kume, S. Hirata, Y. Utsubo, N. Mizuta, et al. Phase II study of
palonosetron,aprepitant and dexamethasone to prevent nausea and vomiting induced by
multiple-day emetogenic chemotherapy. Support Care Cancer 2018;26(5):1419-1423.
7.
Olver, I.N., P. Grimison, M. Chatfield, M.R. Stockler, G.C. Toner, V. Gebski,et al. Results of a
7-day aprepitant schedule for the prevention of nausea and vomiting in 5-day cisplatin-based
germ cell tumor chemotherapy. Support Care Cancer 2013;21 (6) : 1561-8.
8.
Grunberg, S., D. Chua, A. Maru, J. Dinis, S. DeVandry, J.A. Boice, et al. Single-dose
fosaprepitant for the prevention of chemotherapy-induced nausea and vomiting
associated with cisplatin therapy:randomized, double-blind study protocol--EASE. J Clin
Oncol 2011;29 (11) : 1495-501.
9.
Hashimoto, H., M. Abe, O. Tokuyama, H. Mizutani, Y. Uchitomi, T. Yamaguchi, et al.
Olanzapine 5 mg plus standard antiemetic therapy for the prevention of chemotherapy-
induced nausea and vomiting (J-FORCE): a multicentre, randomised, double-blind,
placebo-controlled, phase 3 trial. Lancet Oncol 2020;21 (2) : 242-249.

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2. Purpose
To investigate the efficacy and safety of low dose of olanzapine in combination with
fosaprepitant, ondansetron, and dexamethasone compared with placebo in combination
with fosaprepitant, ondansetron, and dexamethasone in the prevention of nausea and
vomiting in patients with testicular cancer receiving 5-day cisplatin chemotherapy
2.1 Primary Outcome
Complete response (no vomiting and no rescue) rate for the overall phase (1 to 10
days)
2.2 Secondary Outcomes
(1) Minimal nausea, <25 mm on a visual analog scale (VAS) for acute phase ((1-5
days) and delayed phase (6-10 days), and overall phase (1-10 days);
(2) Complete response rate for acute and delayed phases;
(3) Total control (TC): no vomiting, no rescue antiemetics, and no nausea) for acute,
delayed, and overall phases;
(4) Incidence and severity of nausea were assessed based on the Common
Terminology Criteria for Adverse Events (CTCAE);
(5) Number of rescue medications;
(6) Time to Treatment Failure: time to 1st emetic episode or use of rescue
medication;
(7) Hospital Anxiety and Depression Scale (HADS), and The Functional Living
Index-Emesis (FLIE) questionnaire
3.
Study the population
Men diagnosed with germ cell tumor and treated with 5-day cisplatin (20mg/m2,
total 100mg) based chemotherapy
3.1 Inclusion Criteria
Patients must meet the following criteria for inclusion:
1)
Pathology confirmed germ cell tumor (both spermatogonoma and non-
spermatogonoma) and had no chemotherapy before;
2)
Men;

16
3)
Age ≥16 years old;
4)
ECOG score of physical status 0-2;
5)
Chemotherapy regimen containing 5-day cisplatin (20mg/m2, 100mg total;
6)
No other nausea, vomiting, or use of any antiemetics within 72 hours prior to
enrollment;
7)
There are no clear brain metastases or other reasons for long-term systemic use
of hormones;
8)
The general condition is good, and the blood, liver and kidney functions meet
the following standards:
Hemoglobin: 90 g/L and above
White blood cell count: 3.5 * 109 / L - 10.0 *109 / L
Neutrophil count: 1.5* 109/L or above
Platelet count: 90* 109/L or above
Serum total bilirubin: below 1.5 times the upper limit of normal
Serum AST, ALT and ALP: the upper limit of normal is below 2.5 times when the
patient is present
9)
Ability to read, understand and complete research questionnaires and journals,
including visual analog scale (VAS);
10) Understand the study procedure and sign the informed consent in person to
participate in the study
3.2 Exclusion Criteria
Patients who meet any of the following criteria will be excluded:
1)
Digestive tract obstruction, water and electrolyte disorder;
2)
Have central nervous system diseases (such as primary brain tumors,
uncontrolled seizures, any history of brain metastases or strokes);
3)
Contraindications to the use of glucocorticoids: ①Viral, bacterial, fungal and
other infections that cannot be controlled by antibiotics;②Active gastric or
duodenal ulcer;③Severe hypertension, arteriosclerosis, diabetes; ④
Osteoporosis;⑤Corneal ulcer;⑥Trauma or surgical repair period, fracture;
⑦Adeno-cortical hyperfunction; ⑧Severe mental illness and epilepsy; ⑨
patients with cardiac or renal dysfunction;
4)
Patients with mental disabilities or severe emotional or mental disorders are
considered unsuitable for inclusion in the study;
5)
In addition to malignancy, the patient has an active infection (e.g. pneumonia,
hepatitis) or any uncontrolled infection diseases (such as diabetic ketoacidosis),
and the researchers believe may contribute to the study's findings confounding,
or exposing patients receiving study drugs to unnecessary risks;

17
6)
The patient is currently using any prohibited drugs, including medicinal
marijuana or is currently using alcohol (Chinese Diagnostic criteria for drug
dependence);
7)
The patient received an unapproved (experimental) drug treatment within the
past 4 weeks;
8)
Taking oral olanzapine or other psychotropic drugs;
9)
A history of hypersensitivity to fosaprepitant, 5-HT3 receptor antagonists or
dexamethasone;
10) The patient cannot swallow the drugs;
11) The principal investigator considered the patients unsuitable for the study;
12) Inability or unwillingness to adhere to research protocols
4.
Study design
Phase III Randomized, Double-blind, Placebo-controlled, Self-control, Cross-over
Study
4.1 sample size calculation
The required sample size was calculated to be 75 patients per arm for the study to
have a power of 80%, assuming that the CR rate will be 75% in the olanzapine group
and 50% in the placebo group, and also assuming a two-sided significance level of
0.05 and 10% ineligible cases. Due to the cross-over, self-control design, the final
sample size was 75.
4.2 Double-blind random design
The trial was designed in a double-blind fashion.
that is, at the beginning of randomization, the true status of the treatment will remain
blind to the subjects, the investigator, the data analyst, the sponsor, and all medical
personnel involved in the treatment or clinical evaluation. Olanzapine tablets and
placebo tablet simulators used by patients will use identical packaging, administration
method, label, appearance, taste and smell to hide the true situation of therapeutic drugs.
After unified packaging, drug numbers will be given uniformly. The blind is kept with
the randomizer.
Participants were randomized to treatment order (Olanzapine or placebo first).
Randomization was performed by an independent researcher. For each participant,
treatment conditions were assigned and sealed in opaque envelopes (O for Olanzapine
first and P for placebo first) and provided to the dispensing pharmacist. Participant
codes were allocated sequentially as participants enrolled, and treatments were
prepared and allocated by a pharmacist not affiliated with the study. The pharmacist

18
preparing the treatments did not interact with the researchers or participants, and
treatments were collected by the research assistants. Participants, physicians and study
researchers were blinded to medication allocation. Unblinding of treatment occurred
after the final participant evaluation. Data were coded by one researcher to indicate
which treatment was received first, and those data screened for outliers and missing
data. Data were analyzed by a separate researcher blinded to treatment allocation.
5. Research program
5.1 Steps and process
(1) The screening process begins after the patient signs the written informed consent
(2) Patients were randomly divided into different treatment order groups (Olanzapine
or placebo first)
(3) 2 to 10 days after chemotherapy, log by patients to patients from the beginning
chemotherapy drug infusion 0 hours (1 day) to 10 days (240 hours) to monitor the
effectiveness of, should be in the log report within 24 hours before the onset of
vomiting, use of salvage therapy and a review of daily nausea, should also be
recorded Any vomiting or vomiturition attack, as well as the use of rescue drug time
and date. At days 2 to 6, the visual analog scale (VAS) was used to record the
assessment of nausea in the previous 24 hours.
(4) Patients filled in self-reported diaries and completed visual analogue scales for
nausea 2 to 10 days after chemotherapy, as well as Hospital Anxiety and
Depression Scale (HADS) and Functional Living Index-Emesis (FLIE)
questionnaires of 1 to 10 days on day 11.
(5) Patients may receive "remedial treatment" for nausea or vomiting during the study
period, and those requiring remedial treatment are considered to have failed
because the primary endpoint is complete remission. However, patients receiving
remedial treatment must continue to receive the study drug and complete the log as
directed
5.2 the flow chart
Eligible
patients
Olanzapine
Placebo
Placebo
Olanzapine
1st Cycle
2
nd Cycle
1
：
1
randomization

19
5.3 Administration schedule
Chemotherapy regimens
EP regimen
Cisplatin: 20mg/m 2ivd, D1-5
Etoposide: 100mg/m2 D1-5
BEP regimen
Cisplatin: 20mg/m 2ivd, D1-5
Etoposide: 100mg/m2 D1-5
Bleomycin：30,000 U IV D1,D3,D5
VIP regimen
Cisplatin: 20mg/m 2ivd, D1-5
Etoposide: 75mg/m2 D1-5
Ifosfamide：1.2g/m2 D1-5
Mesna：60% total amount of Ifosfamide, divided into 3 points after 0,3, 6 hours IV
TIP regimen
Cisplatin: 20mg/m 2ivd, D1-5
Etoposide: 75mg/m2 D1-5
Paclitaxel/Nab-paclitaxel：200-250mg/m2 D1
Mesna：60% total amount of Ifosfamide, divided into 3 points after 0,3, 6 hours IV
Preventive antiemetic program
Eligible patients will be randomized to receive prophylactic antiemetic therapy with
olanzapine or placebo combined with a triplet regimen of of NK 1 receptor antagonist,5-
HT3 antagonists, and dexamethasone as follows:
Ondansetron: 8mg IV D1-5 30 minutes before chemotherapy;
Dexamethasone: 6mg Po d1-7;
Fosaprepitant: 150mg IVD D1, D4 60 minutes before chemotherapy;
Olanzapine/Placebo: 5mg Po D1-7
6.
Exclude medication
Drugs eliminated to use during treatment and observation include: phenytoin and
carbamazepine, barbiturate drugs, rifampicin, hypericum perforatum, hypericum
perforatum，fexofenadine，cisapride，amifostine, Pimozide, astemizole,

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clarithromycin (note: allows the use of azithromycin and erythromycin and
Roxithromycin), Ketoconazoleor itraconazole (allows the use of fluconazole),
Nucleoside Reverse Transcriptase Inhibitors，Phenolthiazide (e.g. prochlorazine),
phenylbutanone (e.g. haloperidol), olanzapine psychotropic drugs, benzamide (e.g.
metoclopramide), domperidone, cannabinol, herbs with potential antiemetic effects,
scopolamine, etc. However, if the patient develops nausea or vomiting and requires
"remedial treatment, clinically recommended antiemetics may be used.
7. Efficacy evaluation
7.1 Effectiveness evaluation indicators
Efficacy parameters included the number of vomiting episodes, daily assessment of
nausea symptoms, and use of remedial therapy recorded in patients’ diary from the
beginning of chemotherapy (0 h on day 1) to day 10 (approximately 240 h) after
chemotherapy.
FLIE questionnaires were recorded on day 11.
The primary time frame was 10 days after initiation of chemotherapy infusion, include:
overall CINV (day1-10), acute CINV (day 1 to 5), and delayed CINV(day 6 to 10).
7.2 Safety evaluation indicators
Adverse events: Events associated with the primary end point (vomiting, retching, and
nausea) during the data collection period from day 1 to the morning of day 11 were not
defined as adverse events unless the definition of a severe adverse event was met.
Adverse events were graded and recorded according to CTCAE (Version 4.0).
8.
Screening and baseline visits
Patients signed written informed consent before screening. Any procedure such as tumor
assessment out of screening window, if researchers believe is reasonable and acceptable,
this procedure may not be repeated. The data of qualified patients can only be filled in
the CRF table according to the inclusion criteria. All patients who have signed written
informed consent will be screened from 28 days to 24 hours prior to the start of study
treatment. Including the following:
- 28 ~ 1 days
Signed written informed consent: Date
Demographic characteristics: age, sex
History: including gastrointestinal disease, hypertension, thromboembolic disease,
cardiovascular disease, kidney disease, other major diseases, alcohol intake;

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Cancer and treatment history: time of first visit; Primary diagnosis of germ cell tumor
(date, pathological subtype, TNM stage); Previous treatment (surgical excision of the
primary tumor); Previous chemotherapy (regimen, type [adjuvant, neoadjuvant], time,
course of treatment, dose).
Drug combination: medications that may be related to the occurrence of an adverse
event or related to the management of an adverse event need to be recorded.
Physical examination: A complete physical examination should include head, eyes,
ears, nose, throat, cardiovascular, skin, musculoskeletal, respiratory, digestive,
genitourine-urinary and nervous systems; Abnormalities observed at baseline should be
recorded in the CRF table in the corresponding section of the general history and
baseline conditions; A local, symptom-oriented physical examination should be
performed during subsequent visits; Abnormal signs that change from baseline should
be recorded in the patient notes; New or malignant abnormalities should be recorded as
adverse events in the adverse event related section of the CRF table
Height and weight
ECOG score
Whole-body imaging (when clinically indicated )
ECG
-7 ~ 1 day
Laboratory tests (date, value): blood routine, biochemical, tumor markers.
Patients with fertility requirements should have sperm cryopreservation before
chemotherapy.
9.
Evaluation during the study
9.1 Assessment of acute vomiting:
The time and date of any episodes of vomiting or retching or use of rescue drugs in the
previous 24 hours were recorded in the patient's diary on day 2 from the beginning of
chemotherapy at 0h on day 1 to 120h after chemotherapy (day 5).
The visual analog scale (VAS) was used to record the nausea assessment in the previous
24 hours.

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Adverse events were graded and recorded according to CTCAE (Version 4.0), and
patients experience serious nausea or vomiting can receive remedial treatment. Patients
requiring remedial therapy were considered to have failed treatment. However, patients
receiving remedial treatment must continue to receive the study drug and complete the
log as directed.
9.2 Follow-up evaluation of delayed vomiting
Patients were contacted after chemotherapy (day 6 to 10) and reminded to record vomiting
or retching events in the previous 24 hours, remedial treatment, and daily assessment of
nausea using VAS in the patients’ diary. Patients were required to complete HADS and
FLIE questionnaires immediately after logging on day 11.During the study period,
adverse events were graded and recorded according to CTCAE (Version 4.03), and
patients received "remedial treatment" for nausea or vomiting. Patients requiring remedial
therapy were considered to have failed treatment. However, patients receiving remedial
treatment must continue to receive the study drug and complete the log as directed.
10. Termination and exit criteria
The investigator reserves the right to discontinue or withdraw patients from the study at
any time. In addition, patients have the right to withdraw from the study at any time and
for any reason. Reasons for discontinuing the study drug or withdrawing from the study
may include, but are not limited to, the following:
The patient withdraws informed consent at any time.
The researchers determined that there was a medical event that could endanger patient
safety if the study continued. The researchers say early withdrawal from the study would
be of greatest benefit to patients.
Patients did not comply with the study protocol.
Every effort should be made to obtain information on patients dropping out of the study.
The main reasons for withdrawal from the study should be recorded in the CRF table.
Patients should not be followed up for any reason after informed consent is withdrawn.
Patients who drop out of the study should not be replaced by other patients.
11. Statistical analysis
The primary and secondary endpoints of the study were provided in a descriptive and
exploratory manner data.
11.1 Study Population
The intentional-to-treat group (ITT) is a set of subjects based on the principle of
intentionality analysis, which shall mainly include all subjects randomized to be treated

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on the basis of randomization and shall be the primary population used for effectiveness
analysis.
The eligible population (PP) will include all patients who are randomized to receive the
study drug at least once and who strictly follow the study protocol. The reporting analysis
plan excluded patients with severe protocol violations from the PP population. The PP
population provided only a supportive analysis of clinical effectiveness. PP population
analysis is not necessary if PP population reaches 95% or more of ITT population.
The safety cohort (SS) will include all patients enrolled in the randomization who received
the study drug at least once, and if the randomization cohort is inconsistent with the cohort
actually receiving treatment, the safety cohort will be based on the cohort actually
receiving treatment.
11.2 Statistical Analysis
The statistical description and statistical test were determined according to the properties
of the analysis indicators, and the number of cases and incidence of classification
variables were analyzed by the list of classification variables. X2 test, Fisher's exact
probability method or contingency table data statistical analysis were used for the
comparison of classification variables between the two groups. Kaplan-meier method was
used to calculate the time until the first vomiting and curve was drawn.
For the security data statistical analysis plan, all security parameters are described in the
form of tables and summary tables. Adverse events and laboratory parameters were
assessed according to the National Cancer Institute Standard Classification System for
Commonly Used Terminology for Adverse Events (NCI CTC) (V4.03). The safety data
analyzed included the incidence of all reported adverse events and serious adverse events
(regardless of their relevance) and the incidence of all surgery-related adverse events.
11.3 Processing of exit or missing data
In this study, we expected two types of missing data. The first category is "complete
absence"; That is, the patient did not receive any post-treatment evaluation. Post-
treatment was defined as receiving cisplatin on day 1.This may occur in patients who
dropped out of the study early (due to adverse events or lack of efficacy or for other
reasons).The second category is "partial absence", that is, the patient had a post-treatment
evaluation, but data were missing for several days. In the main analysis, category 1
missing data were treated as non-evaluable cases in the full set of analyses. For the
missing data of category 2, the "forward method" is used to fill in the missing data in
each period.
11.4 Analysis Plan

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The analysis was planned after the last patient completed study treatment and
observation, and the main analysis parameters were primary end points and secondary
end points.
12. Adverse event reporting and recording
12.1 Definition
Adverse Event (AE): The term adverse event covers the appearance or worsening of any
syndrome, symptom, syndrome, or disease that occurs during the observation period of
a clinical study and affects the health of the subject. The term also includes clinically
relevant conditions discovered during laboratory or other diagnostic procedures, such as
the need for unplanned treatment, or lead to withdrawal from the trial. Adverse events
may be new disease, treatment status, worsening of symptoms or signs, or
accompanying disease progression, the role of control drugs, or combination of one or
more factors unrelated to participation in a trial. So the term "adverse event" does not
imply a causal relationship with the experimental drug.
The protocol stipulates that any unexpected medical event that occurs outside the
follow-up period is not an adverse event.
Pre-existing diseases, symptoms (such as cancer or other diseases) or medically
significant abnormalities confirmed by laboratory tests or instruments (such as
electrocardiograms) should not be considered as adverse events. However, the
emergence of new symptoms and exacerbations of pre-existing conditions should be
considered as adverse events. In addition, if an emerging abnormality confirmed by
laboratory tests or instrumentation has clinical implications for the patient, it may
reduce the use of the investigational drug.
It should be considered an adverse event if the dose, delay treatment or discontinue
treatment, or cause a serious adverse event (SAE) as defined below.
Serious adverse event (SAE): an adverse event occurring at any dose of the experimental
drug or at any time during observation:
A) Resulting in death;
B) Immediate life-threatening, that is, in the investigator's opinion, the occurrence
of an event that poses a risk of death to the patient (excluding an event in
which a hypothetical exacerbation of the illness would result in death);
C) Requiring hospitalization or prolonged hospitalization;

25
D) Disability refers to an event clinically determined to result in permanent or
severe disability/disability. Disability refers to a person's apparent loss of
ability to live a normal life;
E) Birth defects (defects in the child after birth due to the use of medical products
before fertilization or during pregnancy;
F) Medically significant (meaning an event that does not immediately endanger
life or cause death or require hospitalization, but may endanger patients or
require measures to prevent one of the consequences defined above); Medical
treatment is required to prevent permanent loss or damage. Such events include
allergic bronchospasm that requires emergency room or home care,
hemodystrophy or convulsions that do not require hospitalization.
12.2 Expected range of adverse events
Common adverse reactions:
Digestive system: anorexia, hiccups, constipation, diarrhea, nausea and vomiting,
duodenal ulcer perforation, etc. Nervous system: muscle weakness, disorientation, anxiety,
etc.
Skin: rash, Stevens-Johnson syndrome, etc.
Others: such as flushed face, weakness, fatigue, upper respiratory tract infection,
tachycardia, pelvic pain, bone pain, myalgia, hypokalemia, bradycardia, etc.
12.3 Indicators related to the judgment of causality between adverse events and drugs
The related indexes for judging the causal relationship between adverse events and drugs:
①Whether there is a reasonable sequential relationship between the start time of
medication and the occurrence time of suspected adverse reactions.②Whether the
suspected adverse reactions are consistent with the known adverse reaction types of the
drug.②Whether the suspected adverse reactions can be explained by the patient's
pathological status, drug combination, combined therapy, and previous therapy.④Stop
the drug or reduce the dosage, whether the suspected adverse reactions can be alleviated
and disappear.⑤Whether the same reaction occurs again after exposure to the same
drug.
Judgment of causality between adverse events and drugs: According to the above five
indicators, the analysis of causality is positive, probable, possible, suspicious and
unlikely (level 5.)

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12.4 Management of adverse events
12.4.1 Record of adverse events
Adverse events
Researchers should explain and require patients to truthfully report the changes in their
condition after medication. Doctors should avoid leading questions. Any adverse events
that occur during the study, including abnormal laboratory tests, must be carefully
questioned and followed up. All adverse events must be determined in terms of their
nature, severity and relevance to the drug. Investigators should follow up to observe and
record the outcome of all adverse events, and follow up patients who dropped out of the
trial due to adverse events until the adverse events were resolved. For each event, the
following information is recorded in the Adverse Events (AE) section of the Case Report
Form (CRF):
1. Definitely
relevant
Events follow a reasonable chronological sequence from the time
of administration. The event resolved when treatment was
discontinued. Adverse events (AE) have been shown to recur with
repeated administration (re-excitation).
2. Probably
related
Events occurred in a reasonable chronological sequence from the
time the experimental drug was administered. The event resolved
when treatment was discontinued. The event cannot reasonably be
interpreted as a known symptom of the patient's clinical state or as
an event triggered by another drug/treatment.
3. It may be
relevant
Events occurred in a reasonable chronological sequence from the
time the experimental drug was administered. The event was
consistent with a known response to the investigational drug, but
could have been caused by the patient's clinical status or other
drug/treatment.
4. Probably not
Events did not follow a reasonable chronological sequence from the
time the experimental drug was administered. Events may be
caused by documented pre-existing conditions, concomitant
treatment, or the patient's clinical status.
5. Definitely
not
The event must be caused by the patient's
clinical status or other medications/treatments.

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Severity: Adverse events are classified as major adverse events or non-
major adverse events.
AE: Whenever possible, the specific diagnosis of the event should be recorded. If
diagnosis is not possible, record each sign or symptom separately, e.g., nausea and
vomiting as two adverse events. If an event occurs more than once, and there is an
appropriate time interval to indicate symptoms that could be considered for recurrence,
each adverse event should be recorded separately on the case report form.
Start date: Records the start date of the event. If an abnormal change in laboratory tests
is reported as an adverse event (AE), the date of collection of the first laboratory sample
indicating a change in the condition is recorded as the start date of the event. The
commencement date of a serious adverse event was defined as the date on which the
event began to meet the criteria for a serious adverse event.
End Date: Record the end date of the event. If abnormal changes in laboratory tests are
reported as an adverse event, the date of collection of the first sample after the event, on
which the test would indicate a return to the pre-event state or a return to normal levels,
is recorded as the event stop date.
Relationship with the experimental drug
Therapeutic intervention: Record any therapeutic intervention necessary in the
concomitant care section of the CASE Report Form (CRF) and indicate whether it is
pharmacological or non-pharmacological.
Outcomes:
(1) Event remission without sequelae -- the patient recovers from an adverse
event without observing any sequelae.
(2) Event remission with sequelae -- patients recovered from the adverse event,
but with some sequelae (described in the AE section of CRF)
(3) The event is not alleviated -- the event still exists. Patients should be followed
until definitive results are available. Follow-up information was recorded in the AE
section of the CRF when follow-up data were collected. If the incident is serious, fill
out the follow-up SAE report.)

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(4) Death -- The patient died of adverse events. (List the main causes of death
in the AE section of the case report form and, if feasible, attach an autopsy report to
the case report form)
Actions taken in relation to the test drug:
(1) None -- No actions taken in relation to the test drug.
(2) Discontinuation/adjustment -- suspend the trial drug and resume it
when the patient's symptoms are relieved.
(3) Discontinue -- permanently discontinue the use of the
investigational drug.
12.4.2 Report of serious adverse events
Serious adverse event (SAE) should be actively treated or rescued, and should be notified
by telephone/fax within 24 hours, and fill out a report on the "serious adverse events," a
book Geared to the needs of the local pharmaceutical supervisory and administrative
department, the state drug administration at the provincial level, clinical research and
ethics committee report. The sponsor and its client CRO will immediately inform the
participating hospitals and ensure that all legal and regulatory requirements of the
reporting procedures are met.
Organization
Contact
Phone
Sun Yat-sen University
Cancer Center
Xin An
Yanxia Shi
+862087343801
Drug Clinical Trial Ethics
Committee, Cancer Center,
Sun Yat-sen University
+862087343565

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Contact information for serious adverse event reporting is as follows:
When a death occurs, the investigator should write a comprehensive description of
the death on the SAE form, and Keep an SAE report at the base with CRF. If an
autopsy is performed, the investigator should voluntarily obtain a copy of the autopsy
report and keep a copy of the autopsy report at the site with the CRF.
State Food and Drug
Administration
Drug Research and
Supervision Department,
Safety Supervision
Department
（010）68313344-1013

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