Conditions: Malignant Neoplasm Nausea Vomiting
Allocation: RANDOMIZED | Intervention model: PARALLEL
Enrollment: 53
Healthy volunteers: no

Brief summary:
This randomized phase II/III trial studies how well netupitant and palonosetron hydrochloride works in preventing chronic nausea and vomiting in patients with cancer. Netupitant and palonosetron hydrochloride may reduce nausea and vomiting.

Detailed description:
PRIMARY OBJECTIVES:

I. To estimate the efficacy (i.e. change in nausea numeric rating scale \[NRS\] from baseline between day 5-15) of fixed dose netupitant and palonosetron hydrochloride (palonosetron) (NEPA) for chronic nausea in cancer patients.

SECONDARY OBJECTIVES:

I. To assess the secondary outcomes (e.g. proportion of patients who achieved their personalized nausea goal, antiemetic use, nausea episodes duration/frequency) for NEPA versus (vs.) placebo.

II. To assess the adverse effects associated with NEPA and placebo.

OUTLINE: Patients are randomized to 1 of 2 groups.

GROUP I: Patients receive netupitant orally (PO) and palonosetron hydrochloride PO on days 1, 6, and 11 in the absence of disease progression or unacceptable toxicity.

GROUP II: Patients receive placebo PO on days 1, 6, and 11.

Arms:
arm 1: Patients receive netupitant orally (PO) and palonosetron hydrochloride PO on days 1, 6, and 11 in the absence of disease progression or unacceptable toxicity. arm 2: Patients receive placebo PO on days 1, 6, and 11.

Interventions: intervention 1: Netupitant intervention 2: Palonosetron intervention 3: Palonosetron Hydrochloride intervention 4: Placebo intervention 5: Questionnaire Administration
Intervention descriptions: intervention 1: Given PO intervention 2: Given PO intervention 3: Given PO intervention 4: Given PO intervention 5: Ancillary studies

Protocol document:
Prot_SAP_000.pdf: 
 
2016-0843 
Rev. August 22, 2018 
Page 1 of 22 
Fixed-Dose Netupitant and Palonosetron for Chronic Nausea and Vomiting in 
Cancer Patients 
 
Principal Investigator: Dr. David Hui 
Co-Principal Investigator: Dr. Eduardo Bruera  
Collaborators: Dr. Sriram Yennu, Dr. Shalini Dalal, Sapna Amin, PharmD, Dr. Colleen 
Gallagher, Dr. Ahmed Kaseb, Dr. Michael Overman, Dr. Milind Javle, Dr. Kanwal P. 
Raghav 
Biostatistics Collaborators: Diane Liu, Minjeong Park 
 
 
Table of Contents 
A. Study Objectives ...............................................................................................2 
B. Background .......................................................................................................2 
C. Pharmaceutical Information…………………………………………………………5 
D. Experimental Approach……………………………………………………………...7 
E. Patient Withdrawal Criteria…………………………………………………….......13 
F. Investigator Communications with Helsinn……………………………………… 15 
G. Serious Adverse Events Reporting…………………………………...…………..16 
H. Statistical Considerations…………………………………………………………..17 
I.  Data Confidentiality Procedures……………………………………………………18 
J. References……………………………………………………………………………19 
 


 
2016-0843 
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Page 2 of 22 
A. Study Objectives 
Primary objective: 
To estimate the efficacy (i.e. change in nausea numeric rating scale [NRS] from 
baseline between day 5-15) of fixed dose netupitant and palonosetron (NEPA) for 
chronic nausea in cancer patients. 
 
Secondary objective: 
1. To assess the secondary outcomes (e.g. proportion of patients who achieved their 
personalized nausea goal, antiemetic use, nausea episodes duration/frequency) for 
NEPA vs. placebo. 
2. To assess the adverse effects associated with NEPA and placebo. 
 
B. Background 
B.1. Significance of Chronic Nausea in Cancer Patients. Nausea is defined as “an 
unpleasant sensory and emotional experience, which may be described in terms of a 
sick feeling with or without a sense of impending vomiting/retching - often associated 
with a perception of epigastric or upper abdominal unpleasantness or awareness”.1 
Chronic nausea is defined as nausea of 1 month or greater.2,3 In one systematic review 
of 39 studies consisting of 24263 patients with incurable cancer, nausea occurred in 
31% (95% confidence interval [CI] 27-35%) of patients, and vomiting in 20% (95% CI 
17-22%).4 In another systematic review of far advanced cancer patients, the prevalence 
of nausea was estimated to be 6-68%.5 Rhondali et al. reported that among 444 cancer 
patients seen at the supportive care clinic at MD Anderson Cancer Center, 112 patients 
had moderate/severe chronic nausea of >=4/10 in intensity.6  68/112 (61%) patients had 
a response (defined as 30% improvement from baseline) to the multimodal therapies 
offered by the palliative care team (e.g. metoclopramide, ondansetron, other anti-
emetics, constipation management, counseling) at the followup visit 2 weeks later. 
   
Nausea is a highly distressing symptom among cancer patients. Acutely, nausea is 
often accompanied by physiologic changes driven by the autonomic nervous system, 
such as tachycardia/bradycardia, hypersecretion of the upper gastrointestinal tract, and 
relaxation of the gastric fundus/cardia, diaphoresis, and skin pallor.7 Chronically, 
nausea is often associated with vomiting, anorexia, cachexia, early satiety, 
compromising oral intake and quality of life.  
 
Patients undergoing cancer treatments are particularly likely to experience nausea and 
vomiting.8 Chemotherapy-induced nausea and vomiting (CINV), radiation-induced 
nausea and vomiting, and post-operative nausea and vomiting are well characterized 
syndromes.9,10 Outside of the cancer treatment setting, some patients may experience 
chronic nausea related to early satiety, constipation, bowel obstruction, and other 
medications such as opioids.11 
 
B.2. Pathophysiology of nausea and vomiting. Much of our understanding of the 
pathophysiology of nausea and vomiting is based on animal studies conducted within 
the framework of chemotherapy-induced nausea and vomiting (CINV).12 Nausea and 
vomiting is mediated by both peripheral and central stimuli.  Peripherally, disturbance in 


 
2016-0843 
Rev. August 22, 2018 
Page 3 of 22 
the gastrointestinal tract results in the release of a variety of mediators by 
enteroendocrine 
cells 
located 
in 
the 
gastrointestinal mucosa, 
such 
as 
5-
hydroxytryptamine (5-HT), substance P, and cholecystokinin. These mediators then 
bind to 5-hydroxytryptamine3 (5-HT3), neurokinin-1, and cholecystokinin-1 receptors at 
the terminal ends of the vagal afferents that terminate in the nucleus tractus solitaries in 
the dorsal brain stem, which subsequently activates the central pattern generator in the 
medulla. Centrally, chemotherapeutic agents, opioids and or humoral stimuli may bind 
to receptors in the chemoreceptor trigger zone in area postrema located at the fourth 
ventricle, directly activating the emetic reflex. Inputs from the limbic system (amygdala), 
vestibular system, cerebellum, glossopharyngeal nerve, and higher cortical centres also 
contribute to modulate the nausea sensation and vomiting response centrally. 
 
B.3. The Current Management of Chronic Nausea. A systematic review highlighted 
the paucity of robust studies to inform the management of nausea and/or vomiting 
unrelated to chemotherapy or radiation.  Among the 93 studies on this topic, 14 were 
RCTs. Table 1 includes the key randomized trials on chronic nausea to date. 
Metoclopramide had modest evidence based on randomized controlled trials and 
prospective cohort studies. There were also some evidence to support the use of 
octreotide, dexamethasone and hyoscine butylbromide for nausea related to bowel 
obstruction. The authors concluded that “there are discrepancies between antiemetic 
studies and published antiemetic guidelines, which are largely based on expert opinion. 
Antiemetic recommendations have moderate to weak evidence at best. Prospective 
randomized trials of single antiemetics are needed to properly establish evidence-based 
guidelines.”13  
 
Table 1. Randomized Controlled Trials on Antiemetics for Chronic Nausea and 
Vomiting 
Study 
Patients 
Design 
Interventions 
Outcome 
Bruera et al. Cancer 
1994 22 
N=34 
Advanced cancer  
Nausea >1month 
DB-RCT 
crossover 
Metoclopramide CR 40 mg 
q12h vs. metoclopramide IR 
20 mg q6h x3d then 
crossover 
Nausea VAS on day 3:15 
vs. 8 P=0.047 
Bruera et al. JPSM  
2000 2 
N=26 
Advanced cancer 
Nausea >1month 
DB-RCT 
crossover 
Metoclopramide CR 40 mg 
q12h vs. placebo x4d then 
crossover 
Nausea VAS on day 4:17 
vs. 12 
Bruera et al. JPSM 
2004 23 
N=51 
Nausea >2w 
despite 48h of 
metoclopramide 
DB-RCT  
Metoclopramide 60 mg daily 
+ either dexamethasone 20 
mg daily or placebo x7d  
Nausea NRS on day 3: 4.5 
vs. 2.9 (P=0.16), day 8: 5.9 
vs. 5.9 (P=0.85) 
Corli et al JPSM 
1995 24 
N=30 
Advanced cancer 
DB-RCT, 
crossover 
Levosulpride 75mg daily vs. 
metoclopramide 30 mg daily 
x7d 
Hours with nausea 1.8 vs. 
2.01, nausea VAS 0.75 vs. 
1.42, (P=0.0004) 
Hardy et al. SCC 
2002 25 
N=92 
Opioid induced 
nausea 
DB-RCT 
Ondansetron 24 mg daily, 
metoclopramide 10 mg TID 
vs. placebo x1d 
Complete control of 
nausea: 17%, 36%, 23% 
(P=NS) 
Early termination  
Brown et al. AJHPC 
1992 26 
N=6 
Hospice 
OL-RCT 
Acupressure wrist band, 
placebo wrist band, no wrist 
band 
Not effective 
Mystakidou et al. 
Oncologist 1997 27 
N=120 
Far advanced 
cancer despite 
metoclopramide 
OL-RCT 
Metoclopramide + 
dexamethasone, 
Metoclopramide + 
tropisetron, vs. 
Total control of nausea 
d15: 18%, 74%, 87% 
Total control of vomiting 
24%, 84%, 92% 


 
2016-0843 
Rev. August 22, 2018 
Page 4 of 22 
Metoclopramide + 
dexamethasone + 
tropisetron x15d 
Mystakidou et al. 
Cancer 1998 28 
N=280 
Far advanced 
cancer not bowel 
obstruction 
OL-RCT 
MET + DEX, TRO, MET + 
TRO, MET + DEX + TRO, 
DEX + CHL, TRO + CHL, 
DEX + TRO + CHL x15d 
MET 10mg QID 
DEX 2 mg daily 
TRO 5 mg  OD 
CHL 25 mg BID 
Total control of nausea 
d15: 18%, 66%, 74%, 87%, 
18%, 74%, 85% 
Total control of vomiting 
d15: 24%, 79%, 84%, 92%, 
33%, 85%, 93% 
 
B.4. Novel Agents for Chronic Nausea 
Palonosetron is a selective 5-HT3 receptor antagonist, and exerts its effect by blocking 
serotonin both centrally (i.e. chemoreceptor trigger zone) and peripherally (vagal nerve 
terminals in the periphery).14 It also inhibits the cross-talk between the 5-HT3 and NK1 
receptors. It had an elimination half-life of 48 +/- 19 hours, and Tmax of approximately 5 
hours.  It is available commercially, and can be given either intravenously or orally (oral 
dosage form not current available in the US).   
 
Multiple randomized controlled trials have demonstrated its efficacy in the prevention of 
CINV related to both moderately15,16 and highly emetogenic regimens.17,18  A recent 
meta-analyses showed statistically significant differences in favor of palonosetron 
compared with first-generation 5-HT3 receptor antagonists in the prevention of acute 
CINV, delayed CINV, and overall phase of CINV.19 
 
Netupitant is a selective substance P/neurokinin (NK-1) receptor antagonist.  The NK-1 
receptors are located in the area postrema, the central pattern generator for vomiting 
and/or afferent relay station, and nucleus tractus solitarius. These areas play important 
roles in emesis via NK-1 receptors.14  The absorption of netupitant is 15 minutes to 3 
hours, half-life is 80 +/- 29 hours, and Tmax is approximately 5 hours.20,21 Currently, 
netupitant (parenteral and oral) is not available commercially as a stand-alone product. 
 
Akynzeo (NEPA) is marketed as an oral fixed-dose combination of netupitant 300 mg 
and palonosetron 0.5 mg. Hesketh et al. conducted a double-blind randomized 
controlled trial in 694 patients undergoing cisplatin-based chemotherapy to examine 
NEPA at 3 different doses (100, 200 and 300 mg) versus palonosetron alone; an 
aprepitant/ondansetron group was also included in this study as an exploratory arm. 
The overall complete response rate (i.e. no emesis and no rescue medication 0-120 h) 
was 87.4%, 87.6%, 89.6%, 76.5% and 86.6%, respectively (P<0.05).29 In a second 
study, Aapro et al. conducted a randomized controlled trial involving 1455 patients on 
moderately emetogenic chemotherapy. NEPA was found to be superior to palonosetron 
alone in achieving complete response (76.9% vs. 69.5%; P=0.001) in the delayed 
phase.30 Gralla et al. conducted another double-blind randomized controlled safety 
study involving 413 patients on highly or moderately emetogenic chemotherapy..31 The 
most common adverse effects of NEPA included headache, fatigue, weakness, 
constipation and dyspepsia.  
 


 
2016-0843 
Rev. August 22, 2018 
Page 5 of 22 
Based on the above-mentioned studies, a recent American Society of Clinical Oncology 
guideline update recommended NEPA and dexamethasone as one of the options for 
prophylaxis of CINV among patients undergoing highly emetogenic chemotherapy 
regimens.  Furthermore, palonosetron in combination with a corticosteroid is the 
preferred regimen for patients on moderately emetogenic chemotherapy.32  Of note, 
neither palonosetron nor NEPA have been examined in the chronic nausea and 
vomiting setting. 
 
Summary of NEPA Efficacy in Clinical Trials:  
In the United States, NEPA is approved for prevention of acute and delayed nausea and 
vomiting associated with initial and repeat courses of cancer chemotherapy, including, 
but not limited to, highly emetogenic chemotherapy (HEC). Various Phase 2 and Phase 
3 studies conducted by Helsinn in patients with chemotherapy-induced nausea and 
vomiting have demonstrated that treatment with NEPA provides the following benefits: 
 Shown to prevent of HEC-induced nausea and vomiting 
 Increased response rate to the fixed dose combination in the prevention of CINV 
 Akynzeo given 1 hour prior to chemotherapy is safe, well-tolerated, and 
efficacious as an antiemetic in the prevention of CINV 
 
C. Pharmaceutical Information 
IND Agent: NEPA (300mg Netupitant/0.5mg Palonosetron) Capsule (Refer to 
Investigator’s Brochure for further information)  
 
Chemical Name: 2-[3,5-Bis(trifluoromethyl)phenyl]-N-[6-(4-methylpiperazin-1-yl)-4-o-
tolylpyridin-3-yl]-N-methylisobutyramide 
 
Mode of Action: NEPA is a fixed combination of netupitant, a substance P/neurokinin 1 
(NK) receptor antagonist, and palonosetron, a 
serotonin-3 (5-HT) receptor antagonist 
 
Description: NEPA (300mg netupitant/0.5mg palonosetron) capsules are hard gelatin 
capsules with white body and caramel cap with “HE1” printed on the body. Placebo for 
NEPA will be identical hard gelatin capsules with the “HE1” imprinted on the body. 
 
How Supplied: Helsinn will supply NEPA and Placebo capsules to the site. The 
capsules are packaged as 1 capsule per blister pack/box.  
 
Note: NEPA/Placebo may be repackaged from the supplied bottles and dispensed in 
pharmacy dispensing bottles according to the quantities specified by the investigator.   
  
Storage:  The recommended long term storage condition for NEPA/placebo capsules is 
USP controlled room temperature. Store at 20-25 °C (68-77 °F). Excursions permitted to 
15-30 °C (59-86 °F). 
 
 
Stability:   NEPA/Placebo has a shelf-life of 4 years from date of manufacture. 
 


 
2016-0843 
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Page 6 of 22 
Route(s) of Administration:  Oral 
 
Method of Administration:  It is recommended patients should take NEPA (300mg 
netupitant/0.5mg palonosetron)/Placebo (1 capsule) orally with or without food. 
 
Please refer to the NEPA package insert for safety profile and side effects/drug 
interactions.  
 
Potential Drug Interactions: CYP3A4 Interactions:  
 Akynzeo should be used with caution in patients receiving concomitant 
medications that are primarily metabolized through CYP3A4. The plasma 
concentrations of CYP3A4 substrates can increase when co-administered with 
Akynzeo. The inhibitory effect on CYP3A4 can last for multiple days. Patients on 
these medications will be monitored while on study. 
 
Concomitant and Prohibited Medication 
 Concomitant medications must be recorded in the electronic medical record from 
28 days prior to the first dose of study drug through the last dose of study drug. 
 The use of rescue medications will be allowed (metoclopramide 10 mg q4h PRN 
for breakthrough nausea). 
 As specified within the Exclusion Criteria, scheduled strong or moderate CYP 
3A4 inhibitors (boceprevir, clarithromycin, conivaptan, indinavir, itraconazole, 
ketoconazole, 
lopinavir/ritonavir, 
mibefradil, 
nefazodone, 
nelfinavir, 
posaconazole, ritonavir, saquinavir, telaprevir, telithromycin, voriconazole; 
amprenavir, aprepitant, atazanavir, ciprofloxacin, darunavir/ritonavir, diltiazem, 
erythromycin, fluconazole, fosamprenavir, grapefruit juice, imatinib, verapamil) 
are prohibited within one week of study enrollment. If a patient is required to take 
a strong CYP3A4 inhibitor while enrolled in this trial, they must be discontinued. 
 As specified in the Exclusion Criteria, the administration of scheduled CYP3A4 
substrates with narrow safety range at the time of study enrollment (alfentanil, 
cyclosporine, dihydroergotamine, ergotamine, pimozide, quinidine, sirolimus, 
tacrolimus) are prohibited. If a patient is required to take any of these drugs while 
enrolled in this trial, they must first be discontinued. 
 
Drug Accountability:  
Agent Ordering: 
Helsinn will ship the medication to the Investigational Pharmacy Services. Drug re-
ordering will be via a drug order form or electronic/fax communication with the Helsinn 
representatives.  
 


 
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Rev. August 22, 2018 
Page 7 of 22 
Agent Inventory Records – The investigator, or a responsible party designated by the 
investigator, will maintain a record of the inventory and disposition of all agents received 
from Helsinn. Sites may use their own drug accountability logs per their standard 
procedures. Drug Accountability records will capture Lot numbers dispensed to the 
patient. Unused drug at the remainder of the trial and expired drug may be destroyed on 
site per the site’s drug expiration policy or Helsinn will make arrangements for 
destruction.  
 
Dose: 
Dose 
will 
be 
300mg 
netupitant/0.5mg 
palonosetron. 
NEPA 
(300mg 
netupitant/0.5mg palonosetron)/Placebo capsules will be used in this study. No other 
capsule strengths are available and there are no permitted dose reduction schemes. 
Dosing may be delayed/interrupted at the discretion of the Investigator if needed due to 
an adverse event, and discussed with the patient.  
 
D. Experimental Approach 
D.1. Study Design. This is an 
investigator-initiated study supported 
by Helsinn.  We propose a 2-arm, 
double blind, placebo run-in, parallel 
randomized controlled trial of NEPA 
vs. placebo for cancer patients with 
chronic nausea and vomiting, to be 
followed by an open label extension 
phase (Figure 1).  This is a proof-of-
concept study enrolling 30 evaluable 
patients.  The main goal of this study 
is to determine the effect size for both 
NEPA and placebo arm in order to 
inform a larger, adequately powered 
confirmatory randomized controlled 
trial.  
 
After study consent, eligible patients 
will be asked to try a single dose of 
study medication (placebo) over a 5 
+/-2 day period, in a single-blinded 
fashion.  Those without a significant 
placebo response by Day 5 +/-2 will then be randomized to NEPA or placebo for 10 
days. Study drug will be mailed to study participants. We will also offer an optional open 
label extension for 10 more days after the blinded phase so patients may receive NEPA 
for nausea control if desired. Patients will complete assessments similar to the blinded 
phase (Table 4). We believe this study design is feasible and would not add undue 
burden for patients. Patients will be compensated with a $50 gift card for their time and 
effort. Patients may also be reimbursed for parking charges for study visits at a total of 
up to $45 for all study visits. 
 


 
2016-0843 
Rev. August 22, 2018 
Page 8 of 22 
The placebo run-in period will allow us to (1) evaluate patients prior to exposure to the 
experimental treatment, (2) exclude patients who develop a significant placebo 
response given that our primary outcome is subjective, and (3) select patients who have 
a higher chance of completing the study.  This design has been used in multiple other 
supportive care randomized trials without affecting their internal validity.33-35 The use of 
rescue medications will be allowed (metoclopramide 10 mg q4h PRN for breakthrough 
nausea). 
 
D.2. Eligibility Criteria. The eligibility criteria are shown in Table 2. 
1 according to FDA website 
http://www.fda.gov/Drugs/DevelopmentApprovalProcess/DevelopmentResources/DrugInteractionsLabelin
g/ucm093664.htm 
2  Calculated creatinine clearance can be done within 14 days of study enrollment.  
3 T. bilirubin, albumin, prothrombin time, and serum creatinine tests can be done within 14 days of study 
enrollment (only if not performed in the last 14 days) 
 
Table 2. Study Eligibility Criteria 
Inclusion Criteria 
1. Diagnosis of cancer  
2. Chronic nausea over the past 4 weeks  
3. Average nausea numeric rating scale ≥4/10 over the past 5 days at screening 
4. Outpatient at MD Anderson Cancer Center 
5. Karnofsky performance status >/=50% 
6. Age 18 or older  
7. Able to complete study assessments, including keeping a daily diary 
Exclusion Criteria 
1. Delirium (i.e. Memorial Delirium Rating Scale >13) 
2. Clinical evidence of bowel obstruction at the time of study enrollment 
3. Expected to use other 5HT3 antagonists or NK1 antagonists for prophylaxis during the study 
4. Continuation of over-the-counter therapies for nausea and/or vomiting during the study 
5. On cytotoxic chemotherapy in the high/moderate/low emetogenic risk categories or oral 
antineoplastic agents in the high or moderate emetogenic risk categories according to the latest 
NCCN guideline within 2 weeks of study enrollment 
6. On scheduled potent CYP3A4 inducers at the time of study enrollment (avasimibe, carbamazepine, 
phenytoin, rifampin, efavirenz, nevirapine, barbiturates, systemic glucocorticoids, modafinil, 
oxcarbazine, phenobarbital, pioglitazone, rifabutin, St. John’s wort, troglitazone)1 
7. On  scheduled CYP3A4 substrates with narrow safety range at the time of study enrollment 
(alfentanil, cyclosporine, dihydroergotamine, ergotamine, pimozide, quinidine, sirolimus, tacrolimus) 
8. On scheduled strong or moderate CYP3A4 inhibitors (boceprevir, clarithromycin, conivaptan, 
indinavir, itraconazole, ketoconazole, lopinavir/ritonavir, mibefradil, nefazodone, nelfinavir, 
posaconazole, ritonavir, saquinavir, telaprevir, telithromycin, voriconazole; amprenavir, aprepitant, 
atazanavir, ciprofloxacin, darunavir/ritonavir, diltiazem, erythromycin, fluconazole, fosamprenavir, 
grapefruit juice, imatinib, verapamil) within one week of study enrollment1 
9. Unwilling to provide informed consent 
10. Severe renal impairment (calculated Creatinine clearance <=29 cc/min)2 
11. Severe liver impairment (Child-Pugh Score >9)3 
12. Females who are pregnant, lactating, or intend to become pregnant during the participation of the 
study; childbearing age women who are not on birth control.  Positive pregnancy test for women of 
childbearing potential, as defined by intact uterus and ovaries, and no history of menses within the 
last 12 months.  Pregnancy test to be performed on the day of enrollment. In cases of women with 
elevated b-HCG, these candidates will be eligible to participate so long as the level of b-HCG is not 
consistent with pregnancy and the non-pregnant status is confirmed by a Gynecologic examination.  
 


 
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Page 9 of 22 
Birth Control Information 
Taking part in this study can result in risks to an unborn or breastfeeding baby. Patients 
should not become pregnant, breastfeed a baby, or father a child while on this study.  
Sexually active patients must use birth control during the study. 
 
Birth Control Specifications:  Women who are able to become pregnant must use birth 
control during the study and for 30 days after the last NEPA dose. 
 
Acceptable forms of birth control for men and women include barrier methods (such as 
condom or diaphragm) with spermicide, or abstinence. 
 
Males must tell the doctor right away if their partner becomes pregnant or suspects 
pregnancy. 
 
Pregnant women will not be enrolled on this study. If the patient becomes pregnant or 
suspects that she is pregnant, she must inform her doctor right away. 
Pregnancy may result in removal from this study. 
 
D.3. Study screening. A 2 step consent process will be used.  First, a verbal consent 
will be obtained by the study staff to proceed with screening of potential participants for 
eligibility and to characterize their nausea and vomiting.  Outpatients may be contacted 
by phone within 1 week prior to their scheduled clinic visit to inform them of this study so 
they can make necessary arrangements if interested in participating. Eligible patients 
will then be formally enrolled onto the study after they have signed the informed consent 
indicating a willingness to participate in the trial.  The number of patients screened, 
approached, eligible, and enrolled will be documented.  Reasons for refusal for eligible 
patients will also be captured.   
 
D.4. Randomization. To be eligible for the blinded phase, individuals will need to have 
an average nausea NRS ≥ 4/10 prior to randomization on a day between day 3 and day 
7 (i.e. day 5 +/-2). Patients who report a significant clinical response to placebo (i.e. 
NRS <4/10) during this time on the placebo run-in would not proceed to the double-blind 
phase and will be monitored until day 7 in case their nausea level increased again, in 
which case they will be eligible to proceed and will be randomized. Participants without 
significant clinical response to placebo will be randomized to either NEPA or placebo 
through 
the 
Clinical 
Trial 
Conduct 
website 
( 
https://biostatistics.mdanderson.org/ClinicalTrialConduct/DeskTopDefault.aspx) in a 2:1 
ratio, and stratified by level of nausea NRS (average over past 24 hours, 4-6 vs 7-10) 
obtained prior to randomization. 
 
D.5. Blinding. During placebo run-in, only the patient will be blinded and told that 
he/she will receive one of the two study treatments (Akynzeo or placebo).  During the 
randomized phase, both the patient and the research staff conducting the assessment 
will be blinded to the treatment assignment.  NEPA and identically appearing placebo 
will be dispensed by Dispensing Pharmacy at MD Anderson; only the pharmacy team 
will be aware of the identity of this study agent. Allocation concealment will be 


 
2016-0843 
Rev. August 22, 2018 
Page 10 of 22 
maintained. We will check the blinding from patients and study staff at the end of study 
(Table 4). 
 
Unblinding Procedures: 
1. The Statistician and the investigational pharmacist will have access to the 
codes/assignments. 
2. The codes will be revealed with prior approval from the DSMB and IRB only if there is 
a safety issue and the treating physician needs to be aware of the treatment 
assignment. 
3. The PI should be contacted regarding and give approval for un-blinding 
4. The Investigator/research team must inform the IND Office when un-blinding occurs. 
 
D.6. Research staff. An orientation will be held with research staff involved in this study 
to introduce them with the study design and to standardize the provision of each 
intervention. 
 
D.7. Study Interventions. The supply of study medication (both NEPA and placebo) 
will be provided by Helsinn. NEPA is a fixed dosed capsule consisting of 300 mg 
netupitant and 0.5 mg palonosetron.  It was approved by the US Food and Drug 
Administration (NDA 205718) in October 2014 for “for the prevention of acute and 
delayed nausea and vomiting associated with initial and repeat courses of cancer 
chemotherapy, including, but not limited to, highly emetogenic chemotherapy. Oral 
palonosetron prevents nausea and vomiting during the acute phase and netupitant 
prevents nausea and vomiting during both the acute and delayed phase after cancer 
chemotherapy.” During the double-blinded phase, patients will be asked to take NEPA 
or placebo orally on day 6 and on day 11 of the double-blind treatment period, and on 
day 16 and on day 21 of the open-label extension phase. Each dose lasts for 5 days. 
The capsule can be taken with or without food. The study medication will be stored 
below 30°C (86°F), not refrigerated, in a secure area with limited access and protected 
from light. 
 
In the control arm, patients will be using metoclopramide on an as needed basis (see 
section D.8), which represents standard of care.   
 
Previous studies of NEPA only used a single dose per cycle because CINV is mostly 
confined to the first 5 days.  However, chronic nausea is present for longer periods of 
time thus one additional dose is proposed to alleviate nausea. Previous trials examining 
the use of NEPA for repeated cycles of chemotherapy (duration between cycles not 
specified) found that NEPA was well tolerated.31 The most frequent NEPA-related side 
effects were constipation (3.6%) and headache (1%) and the investigators found no 
indication of increased adverse events over multiple cycles.31 Thus, we propose to 
study NEPA with one repeat dose given the clinical need, its low side effect profile and 
the close monitoring of adverse events during this study. 
 
D.8. Medication use during study. This information will be recorded in the patient 
diary.  Patients will be allowed to use metoclopramide 10 mg PO on an as needed 


 
2016-0843 
Rev. August 22, 2018 
Page 11 of 22 
basis.  They will be asked not to take other anti-emetics (e.g. haloperidol, olanzapine, 
corticosteroids, antihistamines, anticholinergics) unless (1) they have already been 
using them on a scheduled basis for an indication other than nausea or (2) if 
metoclopramide is ineffective or intolerable, in which case they may use them as 
prescribed previously for rescue purposes. Metoclopramide will be provided free of 
charge to patients requiring rescue medication. All antiemetic medications during the 
study will be documented.   
 
To minimize constipation, all patients will be advised to take a laxative regimen (e.g. 
senna 1-4 tablets BID, PEG 17 g PO BID PRN) prophylactically if they are on opioids 
and/or report any constipation symptoms.  
 
D.9. Stopping rules. Patients who had a significant placebo response (see Section 
D.4) by day 4(+/-1) will not continue. Patients may also withdraw from study anytime 
and pursue standard of care. Patient dropouts prior to the administration of drug or 
placebo will be replaced. 
 
D.10. Study assessments. See Table 4 for a detailed description of all study 
assessments. 
 
Nausea numeric rating scale (primary outcome): To evaluate the efficacy of 
NEPA/placebo, each patient will complete a diary daily from time of enrollment through 
the end of study documenting the average intensity of nausea over the preceding 24 h 
and over the past 5 days at Baseline and on or about Days 5, 10, 15, 20, and 25 using a 
0-10 NRS (where 0=no nausea and 10=worst possible.  This scale has been used in 
multiple studies.6,23 The primary efficacy endpoint is change in nausea intensity from 
day 5 to day 15. The minimal clinically important difference is 1 point.36 
 
Secondary endpoints:  
 Worst intensity of nausea—highest score over the preceding 24 h using a 0-10 NRS 
(where 0=no nausea and 10=worst possible). 
 Number of doses of rescue antiemetic (i.e. metoclopramide) and total dose over the 
past 24 hours. 
 Index of nausea and vomiting and retching (INV-R)—this validated questionnaire 
consists of 8 items asking about the patient’s experience regarding nausea and 
vomiting over the past 12 hours.  Each item includes a 5-point Likert scale (0-4 
points) with descriptive words.  The concurrent validity is 0.83-0.87, and Cronbach’s 
alpha was 0.89-0.97.37-39 The total score ranges from 0 to 32 points, with a higher 
score indicating more nausea/vomiting. 
 Proportion of patients with complete response—defined as no significant nausea 
(average NRS≤2), no rescue medication for nausea/vomiting and no emesis. A 
vomiting episode is defined as a single vomiting episode (defined as expulsion of 
stomach contents), a single retching (defined as an effort to vomit without expulsion 
of stomach contents) or any retching combined with vomiting.27-29,31 
 Global symptom evaluation – we will assess impression of change by asking them 
about their nausea and vomiting (worse, about the same, or better; If better, how 


 
2016-0843 
Rev. August 22, 2018 
Page 12 of 22 
much better? Hardly any better, a little better, somewhat better, moderately better, a 
good deal better, a great deal better, a very great deal better; If worse, how much 
worse? Hardly any worse, a little worse, somewhat worse, moderately worse, a good 
deal worse, a great deal worse, a very great deal worse) comparing between the 
level of nausea and vomiting days 1-5 vs. days 6-15. Study satisfaction will be 
assessed with the following questions, “Was it worthwhile for you to participate in 
this research study?”, “If you had to do it over, would you participate in this research 
study again?”, “Would you recommend participating in this research study to 
others?”, “Did your quality of life get better by participating in this research study?”, 
“Did your quality of life get worse by participating in this research study?”  Blinding 
will be assessed by asking patients and study staff which group assignment they 
believe they received: “NEPA”, “placebo”, or “do not know”. 
 Personalized Nausea Goal—we will assess personalized nausea goal by asking “At 
what level of intensity would you feel comfortable? 0-10 where 0=no nausea and 
10=worst possible”. Personalized nausea response is defined as nausea NRS ≤ 
personalized nausea goal.  To assess stability of personalized nausea goal, we will 
be asking participants to provide this on day 152 as well. 
 Functional Living Index Emesis (FLIE)—a questionnaire validated to assesses the 
impact of chemotherapy-induced nausea and vomiting on patient's function and 
quality of life over the past 5-days. It consists of 18 items, with 9 items on nausea 
and 9 items on vomiting.  The questions include how much nausea/vomiting, and 
impact of these symptoms on recreation or leisure activities, make meal/do tasks, 
ability to enjoy meal, enjoy drinking fluids, see family/ friends, daily functioning, 
personal hardship, and hardship on others.  Each question was rated using a 
numeric rating scale from 1-7. The total score range from 18 to 126, where a higher 
score indicates higher quality of life.43-46 
 
D.11 Feasibility data. In addition to clinical outcomes, we will also collect feasibility 
data in this study, including the following: 
 Rates of recruitment and retention (% of subjects able to complete the study) 
 Reasons for refusal and dropout 
 Participant satisfaction—participants will provide an opinion regarding their 
satisfaction with study overall 
 
D.12. Patient Safety, Monitoring, and Confidentiality. Regulatory monitoring will be 
provided by the principal investigator, Institutional Review Board (IRB), and the Data 
Safety Monitoring Board (DSMB). Patient confidentiality will be ensured by use of study 
numbers, secure storage of clinical data, and anonymous reporting. 
 
 
Table 4. Summary of Study Assessments 
Assessments 
Day of 
enrollment 
Days 1-25 
Day  
52 
Day 
102 
Day 152 
 
Days  
202 
2521 
Screening procedures (eligibility criteria)/ 
Pregnancy Test/Calculated creatinine 
clearance, T. bilirubin, albumin, 
prothrombin time, serum creatinine 
 
Pregnancy 
test within 
7 days of 
 
 
 
 
 


 
2016-0843 
Rev. August 22, 2018 
Page 13 of 22 
signing 
consent 
Baseline characteristics2 (Appendix A) 
 
 
 
 
 
 
Medication history3 (Appendix A) 
 
 
 
 
 
 
Nausea Diary including nausea numeric 
rating scale (primary outcome), rescue 
medications and Index of nausea and 
vomiting and retching4 (Appendix B) 
 
* 
 
 
 
 
Edmonton Symptom Assessment Scale5 
(Appendix C) 
 
 
 
* 
* 
* 
Personalized nausea goal6 (Appendix D) 
 
 
 
 
* 
 
Functional Living Index Emesis7 (Appendix 
E) 
 
 
 
* 
* 
* 
Global assessment (Appendix F), study 
satisfaction (Appendix H) and blinding 
(Appendix G)8  
 
 
 
 
* 
 
Nausea Numeric Rating Scale past 5 days 
(Appendix U)9 
 
 
* 
* 
* 
* 
 
*   Assessments may be done over the phone or in person from day 1 to day 152, and on day 
202 and 252. For the other days starting day 16 (open label phase), patients will continue to 
complete assessments in the diary on their own until the end of study. 
1 Optional extension phase  
2 patient initials, medical record number, date of birth, sex, race, education, marital status, cancer 
diagnosis, stage, co-morbidities, cause(s) of nausea, date of last cancer treatment, Karnofsky 
Performance status, Memorial Delirium Assessment Scale (MDAS).41 
3 all scheduled and as needed medications that could be used to treat nausea, such as 
metoclopramide, haloperidol, olanzapine, corticosteroids, 5HT3 antagonists, antihistamines, 
anticholinergics will be documented. 
4 To evaluate the efficacy of NEPA/placebo, each patient will complete a diary from time of 
enrollment through the end of study documenting the average intensity of nausea over the 
preceding 24 h using a 0-10 NRS (where 0=no nausea and 10=worst possible), the worst 
intensity of nausea over the preceding 24 h using the same 0-10 NRS (where 0=no nausea and 
10=worst possible), the number of doses of rescue antiemetic (i.e. metoclopramide) and total 
dose over the past 24 hours, and the Index of nausea and vomiting and retching (see Section 
D.10). 
5 validated questionnaire that measures 9 other common symptoms in the past 24 hours (pain, 
fatigue, nausea, depression, anxiety, drowsiness, shortness of breath, appetite, sleep, and 
feeling of well-being) using numeric rating scales.42 
6 we will assess personalized nausea goal by asking “At what level of intensity would you feel 
comfortable? 0-10 where 0=no nausea and 10=worst possible” 40. Personalized nausea response 
is defined as nausea NRS  personalized nausea goal.  To assess stability of personalized 
nausea goal, we will be asking participants to provide this on day 152 as well. 
7 Functional Living Index Emesis (FLIE) is a questionnaire validated to assess the impact 
of chemotherapy-induced nausea and vomiting on patient's function and quality of life over the 
past 5-days. It consists of 18 items, with 9 items on nausea and 9 items on vomiting.  The 
questions include how much nausea/vomiting, and impact of these symptoms on recreation or 
leisure activities, make meal/do tasks, ability to enjoy meal, enjoy drinking fluids, see family/ 
friends, daily functioning, personal hardship, and hardship on others.  Each question was rated 
using a numeric rating scale from 1-7. The total score range from 18 to 126, where a higher score 
indicates higher quality of life.43-46 
8 Patient Global Impression of Change will be assessed by asking them about their nausea and 
vomiting (worse, about the same, or better; If better, how much better? Hardly any better, a little 
better, somewhat better, moderately better, a good deal better, a great deal better, a very great 
deal better; If worse, how much worse? Hardly any worse, a little worse, somewhat worse, 
moderately worse, a good deal worse, a great deal worse, a very great deal worse) comparing 


 
2016-0843 
Rev. August 22, 2018 
Page 14 of 22 
between the level of nausea and vomiting days 1-5 vs. days 6-15.47,48  Study satisfaction will be 
assessed with the following questions, “Was it worthwhile for you to participate in this research 
study?”, “If you had to do it over, would you participate in this research study again?”, “Would you 
recommend participating in this research study to others?”, “Did your quality of life get better by 
participating in this research study?”, “Did your quality of life get worse by participating in this 
research study?”  Blinding will be assessed by asking patients and study staff which group 
assignment they believe they received: “NEPA”, “placebo”, or “do not know”. 
9 Average nausea NRS over the past 5 days at baseline and on days 52, 102, 152, 202, and 
252 
 
D.13.Source Documentation. The medical record and questionnaire responses will be 
considered source data.  
The Investigator or physician designee is responsible for providing source 
documentation and assigning attribution for all AEs.  
 
D.14. Subject Compliance. Site personnel will assess treatment compliance at each 
visit during the treatment period using the patient’s diary and by the patient returning the 
unused study medication and/or empty study medication bottle.  
 
E. Patient Withdrawal Criteria 
Patients may withdraw their consent at any time and discontinue the study. Patients 
may also be discontinued from the study at any time for the following reasons:  
 Adverse event requiring cessation of study drug (adverse event(s) that, in the 
judgment of the Investigator, may cause severe or permanent harm or which rule 
out continuation of study drug)  
 Major protocol violation (patient lost to follow-up, hospitalization resulting from 
major side effects, lack of consent, lack of safety laboratory tests) 
 Lost to follow-up (We will make every effort to follow all randomized patients 
including contact of family members and/or other medical facilities to avoid losing 
patients to study follow-up) 
 Death 
 For patients who experience an adverse event requiring cessation of study drug, 
they will be followed until the event resolves, until they begin another clinical trial, 
or until the end of the study. However, certain adverse events (e.g., a 
cerebrovascular accident, worsening hypertension) will not be expected to 
resolve completely; in these cases, the date and time should be recorded when 
the event reaches its new, stable equilibrium and any remaining residual of the 
event should be documented. 
 Suspected pregnancy 
 We will add replacement patients to account for withdrawals until we reach 30 
total patients.  
Classifications for adverse event assessment 
All AEs will be assessed and documented by the investigator according to the categories 
detailed below. 
 
 Seriousness 


 
2016-0843 
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Page 15 of 22 
For each AE, the seriousness must be determined according to the criteria given in 
Section F below 
 
 Intensity 
The intensity of the AE is classified according to the CTCAEv4.0.  Grade refers to 
the severity (intensity) of the AE: 
CTCAEv4 Grade 1: mild; asymptomatic or mild symptoms; clinical or diagnostic 
observations only; intervention is not indicated. 
CTCAEv4 Grade 2: moderate; minimal, local, or noninvasive intervention is 
indicated; limiting to age-appropriate instrumental activities of daily living (ADL; 
instrumental ADL refers to preparing meals, shopping for groceries or clothes, 
using the telephone, managing money, etc). 
CTCAEv4 Grade 3: Severe or medically significant but not immediately life 
threatening; hospitalization or prolongation of hospitalization is indicated; 
disabling; limiting to self care ADL (self care ADL refers to bathing, dressing and 
undressing, feeding self, using the toilet, taking medications, and not bedridden). 
CTCAEv4 Grade 4: life-threatening consequences; urgent intervention is indicated. 
CTCAEv4 Grade 5: death due to an AE. 
 
Expected adverse events such as headache, fatigue, nausea, diarrhea, and AEs 
assessed as Grades 1 and 2 will not require reporting to Helsinn. Adverse events will be 
tracked and submitted during annual review to the IRB. Adverse events (including event 
name, grade, start/stop date and attribution) will be entered into Prometheus. The 
Principal Investigator or physician designee will verify the attribution assigned in 
Prometheus by signing the Prometheus adverse events printout at the end of protocol 
treatment.  Prometheus will be utilized as the electronic case report form for this study. 
 
Causal relationship  
The assessment of the causal relationship between an AE and the administration of 
treatment is a clinical decision based on all available information. 
The causality assessment should be done separately for each study treatment. 
The assessment is based on the question whether there was a “reasonable causal 
relationship” to the study treatment in question. 
Possible answers are “yes” or “no”. An assessment of “no” would include: 
1. The existence of a clear alternative explanation, e.g. mechanical bleeding at 
surgical site. 
or 
2. Non-plausibility, e.g. the subject is struck by an automobile when there is no 
indication that the drug caused disorientation that may have caused the event; 
cancer developing a few days after the first drug administration. 


 
2016-0843 
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Page 16 of 22 
An assessment of “yes” indicates that there is a reasonable suspicion that the AE is 
associated with the use of the study treatment. 
Factors to be considered in assessing the relationship of the AE to study treatment 
include: 
- The temporal sequence from drug administration:  The event should occur after the 
drug is given.  The length of time from drug exposure to event should be evaluated 
in the clinical context of the event. 
- Underlying, concomitant, intercurrent diseases:   
Each event should be evaluated in the context of the natural history and course of 
the disease being treated and any other disease the subject may have. 
- Concomitant medication or treatment:  
The other drugs the subject is taking or the treatment the subject receives should be 
examined to determine whether any of them may be suspected to cause the event 
in question. 
- The pharmacology and pharmacokinetics of the study treatment:  
The pharmacokinetic properties (absorption, distribution, metabolism and excretion) 
of the study treatment, coupled with the individual subject’s pharmacodynamics 
should be considered. 
 
F. Investigator Communications with Helsinn 
 
As stipulated in 2.6 of the Strategic Collaboration Agreement, MD Anderson is 
the sponsor and assumes all obligations regarding the preparation and submission of 
individual and aggregate safety reports to FDA, Ethic Committee, and other relevant 
persons to the extent required by and as per the applicable US laws, regulations, and 
guidelines. The Principal Investigator will forward to Helsinn any serious adverse 
reaction (i.e. for which it is judged there is a reasonable causal relationship between the 
study drug and the adverse event) on the MedWatch Form, regardless of its 
expectedness, within 24 hours from first awareness, including follow-ups. 
The Principal Investigator shall provide Helsinn with relevant safety data 
including study and IND safety reports (prior to their finalization) and any safety signal 
or risk (with the rationale) originating from the study. The e-mail address for exchanging 
all the above mentioned safety information is: drug-safety@helsinn.com. 
 
Recommended Adverse Event Recording Guidelines 
 
Attribution 
Grade 1 
Grade 2 
Grade 3 
Grade 4 
Grade 5 
Unrelated 
Phase I 
Phase I 
Phase I 
Phase II   
 
Phase I 
Phase II   
Phase III 
Phase I  
Phase II   
Phase III 
Unlikely 
Phase I 
Phase I 
Phase I  
Phase II   
Phase I 
Phase II   
Phase III 
Phase I 
Phase II   
Phase III 
Possible 
Phase I 
Phase II   
Phase I 
Phase II   
Phase III 
Phase I 
Phase II   
Phase III 
Phase I 
Phase II   
Phase III 
Phase I 
Phase II   
Phase III 
Probable 
Phase I 
Phase I 
Phase I 
Phase I 
Phase I 


 
2016-0843 
Rev. August 22, 2018 
Page 17 of 22 
Phase II  
 
Phase II   
Phase III 
Phase II   
Phase III 
Phase II   
Phase III 
Phase II   
Phase III 
Definitive 
Phase I 
Phase II  
  
Phase I 
Phase II   
Phase III 
Phase I 
Phase II   
Phase III 
Phase I 
Phase II  
Phase III  
Phase I 
Phase II   
Phase III 
 
Adverse events will be captured according to the recommended AE recording 
guidelines for a Phase II protocol. 
 
G. Serious Adverse Event Reporting 
An adverse event or suspected adverse reaction is considered “serious” if, in the view of 
either the investigator or the sponsor, it results in any of the following outcomes: 
 
 Death 
 A life-threatening adverse drug experience – any adverse experience that places the 
patient, in the view of the initial reporter, at immediate risk of death from the adverse 
experience as it occurred. It does not include an adverse experience that, had it 
occurred in a more severe form, might have caused death. 
 Inpatient hospitalization or prolongation of existing hospitalization 
 A persistent or significant incapacity or substantial disruption of the ability to conduct 
normal life functions. 
 A congenital anomaly/birth defect. 
 
Important medical events that may not result in death, be life-threatening, or require 
hospitalization may be considered a serious adverse drug experience when, based 
upon appropriate medical judgment, they may jeopardize the patient or subject and may 
require medical or surgical intervention to prevent one of the outcomes listed in this 
definition. Examples of such medical events include allergic bronchospasm requiring 
intensive treatment in an emergency room or at home, blood dyscrasias or convulsions 
that do not result in inpatient hospitalization, or the development of drug dependency or 
drug abuse (21 CFR 312.32). 
 
 Important medical events as defined above, may also be considered serious 
adverse events. Any important medical event can and should be reported as an SAE 
if deemed appropriate by the Principal Investigator or the IND Sponsor, IND Office. 
 All events occurring during the conduct of a protocol and meeting the definition of a 
SAE must be reported to the IRB in accordance with the timeframes and procedures 
outlined in “The University of Texas M. D. Anderson Cancer Center Institutional 
Review Board Policy for Investigators on Reporting Serious Unanticipated Adverse 
Events for Drugs and Devices”.  Unless stated otherwise in the protocol, all SAEs, 
expected or unexpected, must be reported to the IND Office, regardless of attribution 
(within 5 working days of knowledge of the event). 
 All life-threatening or fatal events, that are unexpected, and related to the study 
drug, must have a written report submitted within 24 hours (next working day) of 
knowledge of the event to the Safety Project Manager in the IND Office.   
 Unless otherwise noted, the electronic SAE application (eSAE) will be utilized for 
safety reporting to the IND Office and MDACC IRB.  


 
2016-0843 
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Page 18 of 22 
 Serious adverse events will be captured from the time of the first protocol-specific 
intervention, until 30 days after the last dose of drug, unless the participant 
withdraws consent. Serious adverse events must be followed until clinical recovery 
is complete and laboratory tests have returned to baseline, progression of the event 
has stabilized, or there has been acceptable resolution of the event. 
 Additionally, any serious adverse events that occur after the 30 day time period that 
are related to the study treatment must be reported to the IND Office. This may 
include the development of a secondary malignancy. 
 
Reporting to FDA: 
 
Serious adverse events will be forwarded to FDA by the IND Sponsor (Safety 
Project Manager IND Office) according to 21 CFR 312.32. 
 
It is the responsibility of the PI and the research team to ensure serious 
adverse events are reported according to the Code of Federal Regulations, 
Good Clinical Practices, the protocol guidelines, the sponsor’s guidelines, and 
Institutional Review Board policy. 
 
H. Statistical Considerations 
The primary objective of this phase II study is to estimate the effect of NEPA on the 
nausea numeric rating scale (i.e. change between day 5 and day 15).  The target 
accrual is 30 evaluable patients who complete the study with a randomization ratio of 
2:1 (NEPA vs Placebo), but accrual will range from 41-50, given an attrition rate of 30-
40%. With 20 patients in the NEPA arm, we would have a 92% power to detect a 
difference of 2 points with a standard deviation of 2.5 (effect size of 0.8) using two-sided 
paired t-test with a significance level of 0.05. 
 
Descriptive statistics, including mean, standard deviation, 95% confidence intervals, 
median, range, frequency and percentage will be summarized for all variables of 
interest such as patients’ demographics, clinical characteristics, personalized nausea 
goal, NRS and adverse effects, whichever appropriate.  
 
We will focus on estimating the magnitude of change in NRS between day 5 and day 
15. We will use a mixed model to examine the change in nausea overtime in both the 
NEPA arm and placebo arm. 
 
We will estimate the proportion (with 95% confidence interval) of patients who achieve 
their personalized nausea goal for NEPA and placebo as a secondary outcome.  
Adverse effects associated with NEPA and placebo will be collected and frequency will 
be summarized. 
 
A comparison between NEPA and placebo is not the objective of this study. However, 
Chi-squared test or Fisher’s exact test, whichever the most appropriate, will be used to 
test for association between categorical variables, such as CTCAE adverse effects, 
global assessment, and blinding. Wilcoxon rank sum test or Kruskal-Wallis test will be 
used to test for difference of continuous variables, such as ESAS and FLIE. General 


 
2016-0843 
Rev. August 22, 2018 
Page 19 of 22 
linear model may be considered to examine the effect of potential important factors on 
NRS. 
 
A Response/Toxicity Summary will be submitted to the IND Office Medical Monitor, after 
the first ten evaluable patients complete study treatment, and every 10 evaluable 
patients thereafter. 
 
 
I. Data Confidentiality Procedures 
This study will be monitored by the MD Anderson IND Office and a protocol-specific 
monitoring plan will be followed. 
 
All records identifying the subject will be kept confidential and, to the extent permitted by 
the applicable laws and/or regulations, will not be made publicly available. 
 
During the study, trained research staff will be performing study assessments and 
monitoring the patient carefully throughout the study period. Regulatory monitoring will 
be provided by the principal investigator and the IND office. Patient confidentiality will be 
maintained by use of unique study numbers, secure storage of clinical data, and 
anonymous reporting. 
 
Collection of identifiers: We will collect and securely store patients' identifiers 
(including name and medical record number).  Each patient will be assigned a study 
number that will be the only identifier to figure in the analytical file and personal data will 
not be disclosed in any form. The key linking these numbers will be retained in a 
securely locked file by the investigator. 
 
Data Storage: Protection of electronic and paper records will be maintained to the best 
of our ability. All electronic records will be stored on password-protected institution 
computers behind the institution firewall.  Any paper records will be classified and stored 
in locked files inside a locked office. 
 
Training of personnel: Only MDACC personnel trained in maintaining confidentiality, 
the principal investigators, co-investigators, and the research team will have access to 
study records. 
 
Data sharing: Study data will not be shared with any individuals or entities outside of 
the MD Anderson Research Group and Supporter without an IRB-approved protocol. 
The data will be kept by the principal investigator in a locked file cabinet and password-
protected database. 
 
Final disposition of study records: These data will be used only for this research 
study. Entities outside of the MD Anderson Research Group and Supporter will not be 
allowed access to the data without an IRB-approved protocol. PHI may be maintained 
indefinitely, aggregated in the future, and used for future research studies.  
 
J. References  


 
2016-0843 
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Page 20 of 22 
 
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2. 
Bruera E, Belzile M, Neumann C, et al: A double-blind, crossover study of 
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3. 
Bruera E, Seifert L, Watanabe S, et al: Chronic nausea in advanced 
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4. 
Teunissen SC, Wesker W, Kruitwagen C, et al: Symptom prevalence in 
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Solano JP, Gomes B, Higginson IJ: A comparison of symptom prevalence 
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Roila F, Hesketh PJ, Herrstedt J: Prevention of chemotherapy- and 
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10. 
Feyer P, Jahn F, Jordan K: Prophylactic Management of Radiation-
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Smith HS, Laufer A: Opioid induced nausea and vomiting. Eur J 
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Hesketh PJ: Chemotherapy-induced nausea and vomiting. The New 
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13. 
Davis MP, Hallerberg G: A systematic review of the treatment of nausea 
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14. 
Rojas C, Slusher BS: Mechanisms and latest clinical studies of new NK1 
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Gralla R, Lichinitser M, Van Der Vegt S, et al: Palonosetron improves 
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Eisenberg P, Figueroa-Vadillo J, Zamora R, et al: Improved prevention of 
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17. 
Eisenberg P, MacKintosh FR, Ritch P, et al: Efficacy, safety and 
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Aapro MS, Grunberg SM, Manikhas GM, et al: A phase III, double-blind, 
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Likun Z, Xiang J, Yi B, et al: A systematic review and meta-analysis of 
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Keating GM: Netupitant/Palonosetron: A Review in the Prevention of 
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Natale JJ, Spinelli T, Calcagnile S, et al: Drug-drug interaction profile of 
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