Conditions: COVID-19
Keywords: COVID-19 Coronavirus
Allocation: RANDOMIZED | Intervention model: PARALLEL
Enrollment: 27
Healthy volunteers: no

Brief summary:
The study will evaluate the efficacy and safety of aprepitant injectable emulsion added to standard of care for hospitalized patients with COVID-19.

Detailed description:

Arms:
arm 1: Aprepitant injectable emulsion. arm 2: Saline placebo.

Interventions: intervention 1: Aprepitant injectable emulsion intervention 2: Saline Placebo
Intervention descriptions: intervention 1: Aprepitant injectable emulsion, once daily (QD) for 14 days. intervention 2: Saline Placebo, once daily (QD) for 14 days.

Protocol document:
Prot_000.pdf: 
Document Type:  
Study Protocol 
Official Title:  
A Phase 2 Randomized, Double-Blind, Placebo-Controlled 
Study of Aprepitant Injectable Emulsion in Early Hospitalized 
Adult Patients With COVID-19 
NCT Number:  
NCT04470622 
Document Date:  
11-Dec-2020 
 


Confidentiality Statement 
This document contains confidential information of Heron Therapeutics, Inc. 
Do not copy or distribute without prior written permission of the Sponsor. 
Any unauthorized use, reproduction, publication, or dissemination is strictly prohibited. 
 
 
CLINICAL STUDY PROTOCOL: HTX-019-202 
Protocol Title: 
A Phase 2 Randomized, Double-Blind, Placebo-Controlled 
Study of Aprepitant Injectable Emulsion in Early Hospitalized 
Adult Patients With COVID-19 
Brief Title: 
Aprepitant Injectable Emulsion in Patients With COVID-19 
(GUARDS-1) 
Test Product: 
CINVANTI (aprepitant) injectable emulsion 
Phase of Development: 
2 
Sponsor: 
Heron Therapeutics, Inc. 
4242 Campus Point Court, Suite 200 
San Diego, CA 92121 
USA 
1-858-251-4400 
Medical Monitor: 
 MD 
 
 
Medical Project Leader: 
 PhD, MD  
 
 
Protocol Version: 
Version 5 
11 December 2020 
 
Version 4 
27 August 2020 
 
Version 3 
22 June 2020 
 
Version 2 
16 June 2020 
 
Version 1 
01 June 2020 
 
 


Protocol No: HTX-019-202, Version 5 
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Aprepitant Injectable Emulsion in Patients With COVID-19 (GUARDS-1) 
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2 
SPONSOR SIGNATURE 
 
Protocol Title: 
A Phase 2 Randomized, Double-Blind, Placebo-Controlled Study of 
Aprepitant Injectable Emulsion in Early Hospitalized Adult Patients 
With COVID-19 
Protocol Number: 
HTX-019-202 
 
 
This protocol Version 5 has been reviewed and approved by the Sponsor. 
 
 
The electronic signature is appended. 
 MD 
 
Heron Therapeutics, Inc. 
 
 


Protocol No: HTX-019-202, Version 5 
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INVESTIGATOR AGREEMENT 
CLINICAL STUDY PROTOCOL: HTX-019-202 
TITLE: A Phase 2 Randomized, Double-Blind, Placebo-Controlled Study of Aprepitant 
Injectable Emulsion in Early Hospitalized Adult Patients With COVID-19 
I have read the protocol and agree that it contains all necessary details for carrying out this study. 
I am qualified by education, experience, and training to conduct this clinical research study. I 
will conduct the study as outlined herein. 
I will provide copies of the protocol, the Investigator’s Brochure, and all other information on 
the study drugs that are furnished to me by the Sponsor to all physicians and other study 
personnel responsible to me who participate in this study, and will discuss this material with 
them to ensure that they are fully informed regarding the test product and the conduct of the 
study. 
I agree to keep records on all subject information (ie, medical records, source documents, case 
report forms, and informed consent), study drug shipment and return forms, and all other 
information collected during the study in accordance with local regulations and national Good 
Clinical Practice (GCP) regulations and guidelines. 
 
Principal Investigator: 
 
Address: 
 
Signature: 
 
Date (DD Month YYYY): 
 
 


Protocol No: HTX-019-202, Version 5 
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PROTOCOL SYNOPSIS 
NAME OF SPONSOR: 
Heron Therapeutics, Inc. 
NAME OF TEST PRODUCT: 
Aprepitant injectable emulsion (HTX-019) 
NAME OF ACTIVE INGREDIENT: 
Aprepitant 
PROTOCOL NUMBER: 
HTX-019-202 
PHASE OF DEVELOPMENT: 
2 
PROTOCOL TITLE: A Phase 2 Randomized, Double-Blind, Placebo-Controlled Study of Aprepitant 
Injectable Emulsion in Early Hospitalized Adult Patients With COVID-19 
STUDY SITES: Approximately 10 sites in the United States (US). 
STUDY OBJECTIVES: 
Primary:  
• 
To assess the effect of aprepitant injectable emulsion on the clinical status of coronavirus 
disease (COVID-19) in hospitalized patients with confirmed severe acute respiratory 
syndrome coronavirus 2 (SARS-CoV-2) infection. 
Secondary: 
• 
To evaluate the safety and tolerability of daily administration of aprepitant injectable 
emulsion in hospitalized patients with COVID-19. 
• 
To assess the pharmacokinetics (PK) of aprepitant following daily dosing of aprepitant 
injectable emulsion to hospitalized patients with COVID-19. 
• 
To evaluate the impact of aprepitant injectable emulsion on the inflammatory response 
mediated by cytokines. 
BACKGROUND AND RATIONALE FOR THE STUDY: 
Aprepitant is a selective high-affinity antagonist of neurokinin-1 (NK1) receptors. It has been 
extensively used for almost 20 years for the prevention of chemotherapy-induced nausea and vomiting 
and for 14 years for the prevention of postoperative nausea and vomiting.  
The rationale for the investigation of aprepitant injectable emulsion in COVID-19 is the close 
association between the binding of substance P (SP) to NK1 receptors and the resultant induction of 
inflammatory cytokines, such as interleukin [IL]-6, which are associated with the development of acute 
respiratory distress syndrome (ARDS). NK1 receptors are expressed in human central airways, 
subpleural lung, and postcapillary venules in the upper and lower airways (O'Connor 2004; Quartara 
1998). Stimulation of the NK1 receptors in postcapillary venules leads to capillary leak with 
extravasation of plasma proteins (Quartara 1998). NK1 receptors are also expressed on mast cells, 
neutrophils, eosinophils, monocytes/macrophages, dendritic cells, natural killer cells, B and T cells, 
microglia, and astrocytes (Mashaghi 2016; Suvas 2017). Expression of NK1 receptors is markedly 
increased during infection, especially on lymphocytes and macrophages. Through the binding to NK1 
receptors, SP leads to the production of cytokines with proinflammatory (eg, IL-1), immunomodulatory 
(eg, IL-10), and chemotactic properties (eg, IL-8) (Mashaghi 2016) contributing to the cytokine storm. 
Exposure of a human bronchial epithelial cell line to SP resulted in release of IL-6, IL-8, and tumor 
necrosis factor alpha (TNF-α) (O'Connor 2004). 
The role of SP and inflammatory cytokines (such as IL-6) on lung injury, including ARDS, was 
demonstrated in animal models and in humans (Bhatia 2004; Espiritu 1992; Mao 2016; Puneet 2005; 


Protocol No: HTX-019-202, Version 5 
Heron Therapeutics, Inc. 
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Sio 2010; Wong 2004). In patients with COVID-19, a significant association of increased 
concentrations of IL-6 with more severe disease, ARDS, the need for mechanical ventilation, and death 
was observed (Coomes 2020; Herold 2020). 
The antagonism of NK1 receptors with aprepitant is expected to prevent the cytokine release mediated 
by the binding of SP to NK1 receptors. Reduced concentrations of cytokines following treatment with 
aprepitant were observed in clinical studies in adults infected with HIV (Spitsin 2017; Tebas 2015). It 
is hypothesized that early decrease of cytokine release should limit cytokine 
overactivation/dysregulation potentially preventing or reducing the severity of ARDS. Heron 
hypothesizes that aprepitant injectable emulsion would best be positioned to decrease the 
dysregulation/overactivation of cytokines/chemokines elicited by SP early in the disease process. Once 
the lungs are overwhelmed with the inflammatory response, other mechanisms may increase the 
dysregulation, making NK1 receptor antagonist treatment less effective. Therefore, it would be 
proposed to start treatment with an NK1 receptor antagonist before patients require mechanical 
ventilation. 
In addition, based on published literature, aprepitant may provide direct antiviral activity and could 
reduce cough severity. Using a computational screening approach, aprepitant was found to have the 
ability to form 3 hydrogen bonds to key residues within the binding pocket of the main protease (Mpro) 
of SARS-CoV-2, which is a key enzyme required for replication (Liu 2020). Of note, cough is a 
common symptom of COVID-19 and a recent study has demonstrated that administration of oral 
aprepitant resulted in significantly decreased severity of cough in patients with advanced lung cancer 
(Noronha 2020). 
Aprepitant injectable emulsion is approved in the US as CINVANTI® (aprepitant) injectable emulsion, 
for intravenous (IV) use in combination with other antiemetic agents in adults for the prevention of 
acute and delayed nausea and vomiting associated with initial and repeat courses of highly emetogenic 
cancer chemotherapy (HEC) or moderately emetogenic cancer chemotherapy (MEC) as a single-dose 
regimen or as part of a 3-day regimen on the first day of each chemotherapy cycle. CINVANTI is 
approved for IV administration either by injection over a 2-minute period or by infusion over a 
30-minute period.  
METHODOLOGY: In this randomized, double-blind, placebo-controlled study, approximately 
100 subjects will receive their randomized treatment in addition to Investigator standard of care for the 
treatment of COVID-19. 
Subjects will be screened less than 48 hours of hospitalization to determine eligibility to enter the 
study. Eligible subjects will be randomized in a 1:1 ratio in a parallel manner to receive aprepitant 
injectable emulsion 130 mg or saline placebo administered once daily as a 2-minute IV injection for 
14 days. 
Standard of care will be at the Investigator’s discretion generally following the COVID-19 treatment 
protocol at the institution. 
Subjects will undergo PK, safety, and efficacy assessments. Detailed information regarding laboratory 
assessments, including sample collection procedures for PK and cytokines, will be provided in the 
laboratory manual. Subjects will be followed until death or Day 56, whichever occurs first. If 
discharged, the site will still contact subjects for efficacy and safety follow-up until Day 56. 
Assessments will include the National Institute of Allergy and Infectious Diseases (NIAID) 8-point 
ordinal scale of clinical status, respiratory status, COVID-19 symptoms, and adverse events (AEs). 
An interim review committee (IRC) composed of Sponsor and external representatives will review the 
summary-level unblinded PK, safety, and efficacy data during the conduct of the study and may 
interrupt or stop enrollment, or modify the protocol to enhance subject safety without adapting the 
study design. 
NUMBER OF PLANNED SUBJECTS: Approximately 100 subjects will be randomized. 


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STUDY POPULATION: 
Inclusion Criteria 
Each subject must meet all of the following criteria to be randomized in this study: 
1. Is willing and able to, or has a legally authorized representative who is willing and able to, 
provide written informed consent to participate, and to cooperate with all aspects of the 
protocol. 
2. Is ≥18 years of age at screening. 
3. Is hospitalized for ≤48 hours with SARS-CoV-2 infection prior to randomization. 
4. Has documented SARS-CoV-2 infection diagnostic test (polymerase chain reaction [PCR], 
antigen, or immunoglobulin M [IgM] antibody) prior to randomization. 
5. Has at least 1 of the following: 
a. Radiographic infiltrates by imaging (eg, chest X-ray, computed tomography [CT] scan), 
OR 
b. Oxygen saturation (SpO2) ≤94% by pulse oximetry on room air, OR 
c. Requiring supplemental oxygen. 
6. Is not anticipated to require mechanical ventilation within 48 hours after randomization. 
Exclusion Criteria 
A subject who meets any of the following criteria prior to randomization will be excluded from the 
study: 
1. Is taking high-dose hydroxychloroquine (eg, ≥400 mg twice daily [BID]) or chloroquine 
(eg, ≥500 mg BID) and unwilling to reduce the dose to hydroxychloroquine <400 mg BID or 
chloroquine <500 mg BID prior to receiving study treatment. 
2. Has taken aprepitant or fosaprepitant <24 hours prior to randomization. 
3. Is taking pimozide. 
4. Is taking strong or moderate cytochrome P450 (CYP)3A4 inhibitors (eg, ketoconazole, 
itraconazole, nefazodone, troleandromycin, clarithromycin, ritonavir, nelfinavir, diltiazem) or 
strong CYP3A4 inducers (eg, rifampin, carbamazepine, phenytoin). 
5. Is currently receiving treatment with any of the following: 
a. Janus kinase (JAK) inhibitors, biologic therapies, potent immunosuppressants (including 
azathioprine and cyclosporine) administered with the intent to modify immune response to 
COVID-19 (exception: dexamethasone, methylprednisolone, or equivalent are allowed at a 
50% reduction of standard dose after the start of study drug dosing), or intravenous 
immunoglobulin (IVIg; including convalescent plasma) at the time of consent. 
b. Chemotherapy. 
c. Hemodialysis or peritoneal dialysis. 
6. Has known hypersensitivity to any components of aprepitant injectable emulsion. 
7. Has evidence of ARDS. 
8. Has bilirubin >1.5 × the upper limit of normal (ULN), or aspartate aminotransferase (AST) or 
alanine aminotransferase (ALT) >3 × ULN. 


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9. Has a history of long QT syndrome or a QT interval corrected using Fridericia’s formula 
(QTcF) >500 ms at Screening. 
10. Has a medical condition or clinically significant laboratory abnormality that, in the opinion of 
the Investigator, would prevent participation in this clinical study. 
11. Is currently participating in another study of an investigational drug or therapeutic medical 
device at the time of consent. Emergency Use Authorization of an investigational drug is 
permitted. 
12. Has an expected survival <7 days. 
13. Is using mechanical ventilation via tracheostomy or endotracheal intubation.  
14. Is being treated with oxygen delivered by high-flow nasal cannula (>20 L/minute), 
nonrebreather mask, noninvasive positive pressure ventilation, or extracorporeal membrane 
oxygenation (ECMO).  
15. Is receiving treatment with a vasopressor(s). 
16. Has multiple organ failure. 
17. Has current confirmed Influenza A or B infection. 
18. Has a history of any of the following: 
a. Organ or hematologic transplant. 
b. HIV. 
c. Active hepatitis B or hepatitis C infection. 
19. Female subjects are eligible only if all the following apply: 
a. Not pregnant (female subjects of child-bearing potential must have a negative serum 
pregnancy test at Screening). 
b. Not lactating. 
c. Not planning to become pregnant while participating in the study. 
d. Females must either practice abstinence from heterosexual contact or agree to use an 
acceptable form of birth control from the time of Screening, during the study, and for 
28 days after the last dose of study drug. Acceptable forms of contraception include being 
in a monogamous relationship with a partner who is surgically sterile; practicing 
abstinence; or agreeing to use double-barrier contraception or a nonhormonal intrauterine 
device (eg, copper) in the event of sexual activity. Note: Female subjects in only a 
same-sex relationship do not need to meet this criterion. Hormonal contraceptives are not 
an acceptable form of birth control since the efficacy of hormonal contraceptives may be 
reduced with aprepitant. 
STUDY DRUG: Study drug is defined as aprepitant injectable emulsion (test product) and saline 
placebo (control product). 
TEST PRODUCT, DOSE, AND MODE OF ADMINISTRATION: Aprepitant injectable emulsion 
is a lipid emulsion formulation of aprepitant for IV use. 
Aprepitant injectable emulsion will be supplied by Sponsor in a single-dose, 130-mg vial. 
(Note: aprepitant injectable emulsion to be supplied as the marketed product CINVANTI in the 
commercial container and carton with an additional flag label indicating investigational use.) The 
pharmacist will prepare the product for administration, which includes providing a covering for the 
syringe and infusion line to blind the contents. 


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Aprepitant injectable emulsion 130 mg (18 mL) will be administered once daily as a 2-minute IV 
injection. 
CONTROL PRODUCT, DOSE, AND MODE OF ADMINISTRATION: 
United States Pharmacopeia (USP)-grade normal saline solution (0.9% sodium chloride) will be 
supplied by study sites. Normal saline 18 mL will be administered once daily as a 2-minute IV 
injection. The pharmacist will prepare the product for administration, which includes providing a 
covering for the syringe and infusion line to blind the contents. 
OTHER PROTOCOL-SPECIFIED MEDICATION(S): 
Standard of care will be at the Investigator’s discretion generally following the COVID-19 treatment 
protocol at the institution. 
DURATION OF TREATMENT: All subjects will receive treatment for 14 days, or until discharge or 
death, whichever occurs first, and will be followed through Day 56. The maximum duration of study 
participation for each subject from Screening through the last study visit will be approximately 
62 days. 
The overall duration of the study is anticipated to be approximately 12 months. 
STUDY ASSESSMENTS: 
PK, safety, and efficacy assessments will be performed. 
Pharmacokinetic Assessments 
Time 0 will be the start of study drug administration on Day 4 for PK assessments. 
Blood samples will be collected for measurement of plasma concentrations of aprepitant. Plasma 
samples may also be used to measure concentrations of hydroxychloroquine and chloroquine in 
subjects who experience an adverse event of special interest (AESI) of QTcF prolongation >500 ms 
that may be considered related to hydroxychloroquine or chloroquine use. 
Safety Assessments 
Information from standard-of-care diagnostic and safety laboratory tests will be provided to the 
Sponsor and recorded in the electronic case report form (eCRF). 
• 
AEs, serious adverse events (SAEs), and AESIs. 
• 
Clinical laboratory values (hematology and serum chemistry). 
• 
Vital signs, including SBP and DBP, resting heart rate, and temperature. 
• 
Electrocardiograms (ECGs). 
Efficacy Assessments 
• 
The NIAID 8-point ordinal scale of clinical status: 
1. Death. 
2. Hospitalized, on invasive mechanical ventilation or ECMO. 
3. Hospitalized, on noninvasive ventilation or high-flow oxygen devices. 
4. Hospitalized, requiring low-flow supplemental oxygen. 
5. Hospitalized, not requiring supplemental oxygen, requiring ongoing medical care  
(COVID-19–related or otherwise). 


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6. Hospitalized, not requiring supplemental oxygen, no longer requiring ongoing medical 
care. 
7. Not hospitalized, limitation on activities and/or requiring home oxygen. 
8. Not hospitalized, no limitations on activities. 
• 
Respiratory status: 
− 
Respiratory rate. 
− 
Oxygen supplementation. 
− Room air. 
− Nasal cannula. 
− Face mask. 
− Noninvasive ventilation or high-flow oxygen devices. 
− Mechanical ventilation. 
− ECMO. 
− 
Oxygenation: (SpO2 or partial pressure of oxygen [PaO2]). 
− 
Chest X-ray or CT scan findings (if available). 
• 
Cytokine panel.  
• 
SARS-CoV-2 viral load by quantitative PCR (qPCR). 
• 
COVID-19 symptom assessment (4-point scale, 0=none, 1=mild, 2=moderate, 3=severe) 
− 
Cough. 
− 
Fever. 
− 
Sore throat. 
− 
Loss of taste and/or loss of smell. 
− 
Malaise/fatigue. 
− 
Headaches.  
− 
Myalgia. 
− 
Gastrointestinal symptoms. 
− 
Shortness of breath on exertion. 
− 
Shortness of breath at rest. 
STUDY ENDPOINTS: 
Primary Endpoint 
• 
Proportion of subjects alive and discharged from the hospital at Day 14. 
Secondary Endpoints 
• 
Time to death or respiratory failure defined as any of the following: 


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− 
Endotracheal intubation and mechanical ventilation. 
− 
Oxygen delivered by high-flow nasal cannula (heated, humidified, oxygen delivered 
via reinforced nasal cannula at flow rates >20 L/min). 
− 
Noninvasive positive pressure ventilation. 
− 
ECMO. 
• 
Time to discharge from hospital.  
• 
Incidence of treatment-emergent adverse events. 
• 
Change from Baseline in IL-6 at each specified timepoint. 
PK Endpoints 
• 
PK parameters of aprepitant: maximum concentration (Cmax), and for subjects in whom all 
optional PK samples are collected, area under the concentration-time curve from Time 0 to the 
time of the last quantifiable concentration (AUClast) may be assessed. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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STATISTICAL METHODS: 
Determination of Sample Size 
The sample size was selected empirically without formal statistical hypotheses or assumptions. 
Efficacy Analyses 
The proportion of subjects alive and discharged from the hospital at Day 14 will be analyzed using the 
Fisher’s exact test to compare differences in proportions across treatment arms. Summaries will be 
expressed as the frequency and percentage of subjects meeting the criteria of alive and discharged from 
hospital at Day 14 by treatment arm. Differences in proportions across treatment arms along with 
corresponding exact 95% CIs will also be presented. 
Safety Analyses 
All safety data will be listed and summarized by treatment group; no statistical hypothesis testing will 
be performed. Incidence of AEs, SAEs, adverse reactions, and AESIs will be coded and tabulated by 
System Organ Class and Preferred Term. AESIs are events of anaphylaxis and of QTcF prolongation 
(>500 ms). Associated laboratory parameters such as hepatic profile, renal function, and hematology 
values will be grouped and presented together in summary tables. Individual subject values will be 
listed and values outside of the standard reference range will be flagged. Changes in vital sign 
parameters and ECG parameters will be summarized. 
Pharmacokinetic Analysis 
Plasma PK parameters of aprepitant will be calculated using noncompartmental analysis. 
Interim Analysis 
No formal interim analyses are planned. An IRC will review the data from the study on an ongoing 
basis to enhance subject safety without adapting the study design. 










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TABLE OF CONTENTS 
SPONSOR SIGNATURE ................................................................................................................2 
INVESTIGATOR AGREEMENT...................................................................................................3 
PROTOCOL SYNOPSIS ................................................................................................................4 
SCHEDULE OF EVENTS ............................................................................................................12 
SCHEDULE OF EVENTS POST-DISCHARGE .........................................................................15 
SCHEDULE OF PK BLOOD SAMPLE COLLECTION .............................................................15 
LIST OF ABBREVIATIONS AND DEFINITION OF TERMS ..................................................21 
1. 
INTRODUCTION ......................................................................................................23 
1.1. 
Background Information and Study Rationale ...........................................................23 
1.2. 
Rationale for Study Design, Doses, and Control Groups ...........................................24 
1.3. 
Potential Risks and Benefits .......................................................................................25 
1.3.1. 
Safety ..........................................................................................................................25 
1.3.2. 
Efficacy .......................................................................................................................26 
2. 
STUDY OBJECTIVES ..............................................................................................27 
2.1. 
Primary Objective .......................................................................................................27 
2.2. 
Secondary Objectives .................................................................................................27 
3. 
INVESTIGATIONAL PLAN AND ENDPOINTS ....................................................28 
3.1. 
Description of the Study Design .................................................................................28 
3.2. 
Study Endpoints ..........................................................................................................28 
3.2.1. 
Primary Endpoint ........................................................................................................28 
3.2.2. 
Secondary Endpoints ..................................................................................................28 
3.2.3. 
Pharmacokinetic Endpoints ........................................................................................29 
 
 
3.3. 
Study Duration ............................................................................................................30 
3.4. 
Suspension of the Study..............................................................................................30 
4. 
STUDY ENROLLMENT AND WITHDRAWAL ....................................................31 
4.1. 
Study Population .........................................................................................................31 
4.1.1. 
Inclusion Criteria ........................................................................................................31 
4.1.2. 
Exclusion Criteria .......................................................................................................31 
4.2. 
Method of Assigning Subjects to Treatment Groups .................................................33 
4.2.1. 
Procedures for Handling Randomized Subjects Who Do Not Meet the Study 
Eligibility Criteria .......................................................................................................33 


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4.3. 
Blinding ......................................................................................................................33 
4.3.1. 
Breaking the Blind ......................................................................................................33 
4.4. 
Study Drug Discontinuation and Subject Withdrawal From Study............................34 
4.4.1. 
Study Drug Discontinuation .......................................................................................34 
4.4.2. 
Subject Withdrawal From Study and Subject Replacement .......................................34 
4.5. 
Subject Rehospitalization After Discharge .................................................................34 
5. 
STUDY DRUG ...........................................................................................................35 
5.1. 
Description of Study Drug ..........................................................................................35 
5.1.1. 
Test Product ................................................................................................................35 
5.1.2. 
Control Product ...........................................................................................................35 
5.2. 
Packaging and Labeling ..............................................................................................35 
5.3. 
Storage ........................................................................................................................35 
5.4. 
Preparation ..................................................................................................................35 
5.5. 
Study Drug Administration.........................................................................................35 
5.6. 
Study Drug Compliance .............................................................................................36 
5.7. 
Study Drug Accountability .........................................................................................36 
6. 
STUDY PROCEDURES AND ASSESSMENTS......................................................37 
6.1. 
Comorbidities and Demographics ..............................................................................37 
6.1.1. 
Comorbidities .............................................................................................................37 
6.1.2. 
Demographics .............................................................................................................37 
6.2. 
Prior and Concomitant Therapy ..................................................................................37 
6.2.1. 
Allowed Concomitant Medications ............................................................................37 
6.2.2. 
Prohibited Medications and Treatments .....................................................................37 
6.3. 
Efficacy Assessments .................................................................................................38 
6.3.1. 
8-Point Ordinal Scale of Clinical Status .....................................................................38 
6.3.2. 
Respiratory Status .......................................................................................................38 
6.3.3. 
Cytokine Panel and Other Laboratory Parameters .....................................................39 
6.3.4. 
Viral Load ...................................................................................................................39 
6.3.5. 
COVID-19 Symptoms ................................................................................................40 
6.4. 
Safety Assessments .....................................................................................................40 
6.4.1. 
Adverse Events ...........................................................................................................40 
6.4.2. 
Prospective Assessment of Anaphylaxis ....................................................................41 
6.4.3. 
Physical Examinations ................................................................................................41 


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6.4.4. 
Vital Signs ..................................................................................................................41 
6.4.5. 
12-Lead Electrocardiograms .......................................................................................41 
6.4.6. 
Clinical Laboratory Tests ...........................................................................................41 
6.5. 
Pharmacokinetic Assessments ....................................................................................42 
7. 
GUIDANCE FOR COMPLETING PROCEDURES AND ASSESSMENTS ..........43 
8. 
SAFETY MONITORING AND REPORTING .........................................................44 
8.1. 
Definition of Safety Parameters..................................................................................44 
8.1.1. 
Definition of an Adverse Event ..................................................................................44 
8.1.2. 
Definition of a Serious Adverse Event .......................................................................45 
8.1.3. 
Adverse Events of Special Interest .............................................................................46 
8.1.4. 
Definition of Unanticipated Problems ........................................................................46 
8.2. 
Classification of Adverse Events ................................................................................46 
8.2.1. 
Severity of Adverse Events ........................................................................................46 
8.2.2. 
Relationship to Study Drug ........................................................................................46 
8.3. 
Time Period and Frequency for Event Assessment and Follow Up ...........................47 
8.3.1. 
Adverse Event and Serious Adverse Event Monitoring .............................................47 
8.3.2. 
Follow-Up of Events ...................................................................................................47 
8.4. 
Reporting Procedures ..................................................................................................48 
8.4.1. 
Reporting Serious Adverse Events to the Sponsor .....................................................48 
8.4.2. 
Reporting Unanticipated Problems to the Sponsor .....................................................49 
8.4.3. 
Regulatory Reporting Requirements ..........................................................................49 
8.4.4. 
Pregnancy Reporting ..................................................................................................50 
8.5. 
Safety Oversight .........................................................................................................50 
9. 
OTHER STUDY RESTRICTIONS ...........................................................................51 
9.1. 
Contraception ..............................................................................................................51 
10. 
STATISTICAL CONSIDERATIONS .......................................................................52 
10.1. 
General Considerations ...............................................................................................52 
10.2. 
Determination of Sample Size ....................................................................................52 
10.3. 
Analysis Populations ..................................................................................................52 
10.4. 
Statistical Analysis Methods.......................................................................................52 
10.4.1. 
Disposition and Demographics ...................................................................................52 
10.4.2. 
Efficacy Analyses .......................................................................................................52 
10.4.2.1. 
Primary Efficacy Analysis ..........................................................................................52 


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10.4.2.2. 
Secondary Efficacy Analyses .....................................................................................53 
 
 
10.4.3. 
Handling of Missing Data ...........................................................................................55 
10.4.4. 
Study-Wise Type I Error Control ...............................................................................55 
10.4.5. 
Safety Analyses ..........................................................................................................55 
10.4.6. 
Pharmacokinetic Analysis ..........................................................................................56 
10.5. 
Interim Analysis ..........................................................................................................56 
11. 
QUALITY ASSURANCE AND QUALITY CONTROL .........................................57 
12. 
REGULATORY AND ETHICAL CONSIDERATIONS ..........................................58 
12.1. 
Regulatory Authority Approval ..................................................................................58 
12.2. 
Ethical Conduct of the Study ......................................................................................58 
12.3. 
Ethics Committee Approval .......................................................................................58 
12.4. 
Informed Consent Process ..........................................................................................58 
12.5. 
Confidentiality ............................................................................................................59 
13. 
STUDY ADMINISTRATION ...................................................................................61 
13.1. 
Clinical Monitoring ....................................................................................................61 
13.2. 
Data Monitoring Committees .....................................................................................61 
13.3. 
Source Documents and Record Retention ..................................................................61 
13.4. 
Management of Protocol Amendments and Deviations .............................................61 
13.4.1. 
Protocol Amendments ................................................................................................61 
13.4.2. 
Protocol Deviations ....................................................................................................62 
13.5. 
Financial Disclosure ...................................................................................................62 
13.6. 
Termination of the Study or Closure of a Study Site ..................................................62 
13.6.1. 
Study Termination ......................................................................................................62 
13.6.2. 
Closure of a Study Site ...............................................................................................62 
13.7. 
Publication and Information Disclosure Policy ..........................................................63 
14. 
REFERENCE LIST ....................................................................................................64 
APPENDIX A. CYTOKINE PANELS .......................................................................................66 
APPENDIX B. POST-DISCHARGE ASSESSMENTS .............................................................69 
 


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LIST OF TABLES 
Table 1: 
NIAID 8-Point Ordinal Scale of Clinical Status .........................................................38 
Table 2: 
Clinical Laboratory Analytes ......................................................................................42 
Table 3: 
Cytokine Storm Testing for SARS-CoV-2/COVID-19 ..............................................66 
Table 4: 
Cytokine Limited Panel ..............................................................................................68 
 


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LIST OF ABBREVIATIONS AND DEFINITION OF TERMS 
Abbreviation 
Definition 
AE 
Adverse event 
AESI 
Adverse event of special interest 
ALT 
Alanine aminotransferase 
ARDS 
Acute respiratory distress syndrome 
BA 
Bioanalytical 
BID 
Twice daily 
CFR 
Code of Federal regulations 
CINV 
Chemotherapy-induced nausea and vomiting 
COVID-19 
Coronavirus disease 
CRP 
C-reactive protein 
CT 
Computed tomography 
CYP 
Cytochrome P450 
DBP 
Diastolic blood pressure 
EC 
Ethics committee 
ECG 
Electrocardiogram/electrocardiographic 
ECMO 
Extracorporeal membrane oxygenation 
eCRF 
Electronic case report form 
EDC 
Electronic data capture 
FDA 
Food and Drug Administration 
GCP 
Good Clinical Practice 
IB 
Investigator’s Brochure 
ICF 
Informed consent form 
ICH 
International Council for Harmonisation  
IgM 
Immunoglobulin M 
IL 
Interleukin 
INR 
International Normalized Ratio 
IRC 
Interim review committee 
ITT 
Intent-to-Treat 
IV 
Intravenous(ly) 
IVIg 
Intravenous immunoglobulin  
JAK 
Janus kinase 
NIAID 
National Institute of Allergy and Infectious Diseases 


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Abbreviation 
Definition 
NK1 
Neurokinin-1 
PK 
Pharmacokinetic(s) 
PONV 
Postoperative nausea and vomiting 
PSRMC 
Product Safety and Risk Management Committee  
PT 
Preferred term 
QD 
Once daily 
qPCR 
Quantitative polymerase chain reaction 
QTcF 
QT interval corrected using Fridericia’s formula 
SAE 
Serious adverse event 
SAP 
Statistical analysis plan 
SAR 
Severe adverse reaction 
SARS-CoV-2 
Severe acute respiratory syndrome coronavirus 2 
SBP 
Systolic blood pressure 
SOC 
System Organ Class 
SP 
Substance P 
SpO2 
Oxygen saturation 
TEAE 
Treatment-emergent adverse event 
ULN 
Upper limit of normal 
US 
United States 
WBC 
White blood cell 
Note: Abbreviations defined in the text but not used again in the text are not included in this List of 
Abbreviations. Abbreviations used only in tables or figures are also excluded from this List of Abbreviations; 
they are defined in the table or figure footnotes. 
 


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1. 
INTRODUCTION 
1.1. 
Background Information and Study Rationale 
Heron is investigating the use of aprepitant injectable emulsion for the treatment of adult patients 
with early symptomatic coronavirus disease (COVID-19). COVID-19 is caused by infection with 
the virus designated severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). There is 
currently no approved treatment available for COVID-19. The symptoms of COVID-19 vary 
from asymptomatic disease to pneumonia, acute respiratory distress syndrome (ARDS), 
multisystem organ failure, and death (Rodriguez-Morales 2020; Weiss 2020; Wu 2020). Severe 
complications are more frequent in older patients and patients with preexisting respiratory or 
cardiovascular conditions (Weiss 2020; Wu 2020). Current management of the disease consists 
of supportive care, including invasive and noninvasive oxygen support and treatment with 
antibiotics (Onder 2020; Poston 2020). 
Aprepitant is a selective high-affinity antagonist of human neurokinin-1 (NK1) receptors. It has 
been extensively used for almost 20 years for the prevention of chemotherapy-induced nausea 
and vomiting (CINV) and for 14 years for the prevention of postoperative nausea and vomiting 
(PONV). 
The rationale for the investigation of aprepitant injectable emulsion in COVID-19 is the close 
association between the binding of substance P (SP) to NK1 receptors and the resultant induction 
of inflammatory cytokines, such as interleukin [IL]-6, which are associated with the development 
of ARDS. NK1 receptors are expressed in human central airways, subpleural lung, and 
postcapillary venules in the upper and lower airways (O'Connor 2004; Quartara 1998). 
Stimulation of the NK1 receptors in postcapillary venules leads to capillary leak with 
extravasation of plasma proteins (Quartara 1998). NK1 receptors are also expressed on mast 
cells, neutrophils, eosinophils, monocytes/macrophages, dendritic cells, natural killer cells, B and 
T cells, microglia, and astrocytes (Mashaghi 2016; Suvas 2017). Expression of NK1 receptors is 
markedly increased during infection, especially on lymphocytes and macrophages. Through the 
binding to NK1 receptors, SP leads to the production of cytokines with proinflammatory 
(eg, IL-1), immunomodulatory (eg, IL-10), and chemotactic properties (eg, IL-8) (Mashaghi 
2016) contributing to the cytokine storm. Exposure of a human bronchial epithelial cell line to 
SP resulted in release of IL-6, IL-8, and tumor necrosis factor alpha (TNF-α) (O'Connor 2004). 
The role of SP and inflammatory cytokines (such as IL-6) on lung injury, including ARDS, was 
demonstrated in animal models and in humans (Bhatia 2004; Espiritu 1992; Mao 2016; Puneet 
2005; Sio 2010; Wong 2004). In patients with COVID-19, a significant association of increased 
concentrations of IL-6 with more severe disease, ARDS, the need for mechanical ventilation, and 
death was observed (Coomes 2020; Herold 2020). 
The antagonism of NK1 receptors with aprepitant is expected to prevent the cytokine release 
mediated by the binding of SP to NK1 receptors. Reduced concentrations of cytokines following 
treatment with aprepitant were observed in clinical studies in adults infected with HIV (Spitsin 
2017; Tebas 2015). It is hypothesized that early decrease of cytokine release should limit 
cytokine overactivation/dysregulation potentially preventing or reducing the severity of ARDS. 
Heron hypothesizes that aprepitant injectable emulsion would best be positioned to decrease the 
dysregulation/overactivation of cytokines/chemokines elicited by SP early in the disease process. 
Once the lungs are overwhelmed with the inflammatory response, other mechanisms may 


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increase the dysregulation, making NK1 receptor antagonist treatment less effective. Therefore, 
treatment with an NK1 receptor antagonist before patients require mechanical ventilation is 
proposed. 
In addition, based on published literature, aprepitant may provide direct antiviral activity and 
could reduce cough severity. Using a computational screening approach, aprepitant was found to 
have the ability to form 3 hydrogen bonds to key residues within the binding pocket of the main 
protease (Mpro) of SARS-CoV-2, which is a key enzyme required for replication (Liu 2020). Of 
note, cough is a common symptom of COVID-19 and a recent study has demonstrated that 
administration of oral aprepitant resulted in significantly decreased severity of cough in patients 
with advanced lung cancer (Noronha 2020). 
1.2. 
Rationale for Study Design, Doses, and Control Groups 
This Phase 2 study was designed to compare the efficacy and safety of aprepitant injectable 
emulsion with normal saline placebo control in adult patients with early symptomatic COVID-19 
who are also receiving standard of care for treatment for COVID-19. Pharmacokinetic (PK) 
assessments of aprepitant following daily administration of aprepitant injectable emulsion will be 
performed. The study will employ a randomized and double-blind design to provide the highest 
quality of evidence, and to minimize potential bias in subject selection as well as efficacy and 
safety assessments. 
Aprepitant injectable emulsion is approved in the United States (US) as CINVANTI® 
(aprepitant) injectable emulsion, for intravenous (IV) use in combination with other antiemetic 
agents in adults for the prevention of acute and delayed nausea and vomiting associated with 
initial and repeat courses of highly emetogenic cancer chemotherapy (HEC) or moderately 
emetogenic cancer chemotherapy (MEC) as a single-dose regimen (130 mg) or as part of a 3-day 
regimen (100 mg) on the first day of each chemotherapy cycle. CINVANTI is approved for 
administration IV either by injection over a 2-minute period or by infusion over a 30-minute 
period (CINVANTI USPI October 2019). 
This study will evaluate a regimen of 130 mg once daily (QD) aprepitant injectable emulsion, 
administered for 14 days, compared to saline placebo control. An interim review committee 
(IRC) will review the unblinded PK, safety, and efficacy data. The available nonclinical and 
clinical data and marketing experience for aprepitant injectable emulsion support its safe use in 
adult patients with COVID-19 at a dose level of 130 mg administered as a 2-minute IV injection 
QD for 14 days. 
The nonclinical safety of aprepitant injectable emulsion was adequately characterized at 
appropriate exposures to support its daily administration for up to 28 days. The results of a 
repeated-dose toxicity study of aprepitant injectable emulsion following its QD administration 
for 28 days as a slow IV bolus revealed no safety concerns. The results of a local tolerance study 
of aprepitant injectable emulsion indicated low risk of toxicity due to its accidental extravasation. 
Clinically, the administration of aprepitant injectable emulsion 130 mg as a 2-minute IV 
injection is supported by the results of a Phase 1 study in healthy volunteers (Study 108) and 
from marketing experience with CINVANTI. Administration QD for 14 days is supported by 
reports in the literature regarding the safety of high doses of aprepitant. Refer to the 
Investigator’s Brochure (IB) of Aprepitant Injectable Emulsion for Treatment of Patients With 
COVID-19 for a detailed account of the clinical and nonclinical studies and literature. 


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To measure the effect of aprepitant injectable emulsion on disease progression, the primary 
endpoint will be the proportion of subjects alive and discharged from the hospital at Day 14. This 
endpoint is timed to assess clinically meaningful changes in patient status, treatment, and 
COVID-19 progression. 
To further evaluate disease progression, a secondary endpoint will be time to death or respiratory 
failure, defined as any of the following: endotracheal intubation and mechanical ventilation; 
oxygen delivered by high-flow nasal cannula (heated, humidified, oxygen delivered via 
reinforced nasal cannula at flow rates >20 L/min); noninvasive positive pressure ventilation; or 
extracorporeal membrane oxygenation (ECMO). Other secondary endpoints include the time to 
discharge from hospital; measures of safety; and the effect of study drug on IL-6, a key cytokine. 
In patients with COVID-19, a significant association was observed between increased 
concentrations of IL-6 and more severe disease, ARDS, the need for mechanical ventilation, and 
death (Coomes 2020; Herold 2020). The incidence of adverse events (AEs) and the change from 
Baseline in IL-6 at each timepoint will be assessed. 
 
 
 
 
 
1.3. 
Potential Risks and Benefits 
Aprepitant is a highly selective NK1 receptor antagonist first approved in 2003. It is indicated for 
the prevention of CINV and for the prevention of PONV in an oral formulation (EMEND Oral 
USPI November 2019) and for prevention of CINV as an IV formulation of its prodrug, 
fosaprepitant (EMEND IV USPI November 2019). Aprepitant injectable emulsion for IV use 
was US Food and Drug Administration (FDA) approved in November 2017 and has been 
marketed in the US under the brand name CINVANTI for over 2 years. It is approved for the 
prevention of CINV for administration either by injection over a 2-minute period or by infusion 
over a 30-minute period on the first day of each chemotherapy cycle (CINVANTI USPI October 
2019). Aprepitant has not been approved for the treatment of COVID-19. 
1.3.1. 
Safety 
The potential risks associated with the daily administration of aprepitant injectable emulsion in 
patients with COVID-19 are not known. It is expected that AEs following administration of 
aprepitant injectable emulsion to patients with COVID-19 will be similar to those in patients 
with CINV. 
The safety information for aprepitant injectable emulsion presented is based on clinical studies in 
304 healthy volunteers and the cumulative patient marketing experience from CINVANTI in 
cancer patients for prevention of CINV as well as the experience with oral aprepitant and IV 
fosaprepitant. As of 08 November 2019, the cumulative patient exposure to aprepitant injectable 
emulsion was estimated to be 152,323.5 patient-years. The majority of patients exposed to 
aprepitant injectable emulsion received 6 cycles of chemotherapy per year, and aprepitant 
injectable emulsion was administered once per cycle at a dose of 130 mg for most patients (see 


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Section 5.4 of the IB for Aprepitant Injectable Emulsion for Treatment of Patients With 
COVID-19). 
The safety profile of aprepitant injectable emulsion in healthy volunteers was similar when 
administered as either a single 2-minute injection or a 30-minute infusion. Adverse reactions 
(ie, AEs considered by the Investigator to be possibly related to study drug) reported in >2.0% of 
304 healthy subjects who received aprepitant injectable emulsion 130 mg (n=292) or 100 mg 
(n=12) administered IV over 2 to 30 minutes included headache (3.3%) and fatigue (3.0%). 
The most common adverse reactions (≥3%) in adult subjects given oral aprepitant as a 3-day 
regimen for prevention of CINV (125 mg on Day 1 and 80 mg on Days 2 and 3) included 
fatigue, diarrhea, asthenia, dyspepsia, abdominal pain, hiccups, white blood cell count decreased, 
dehydration, and alanine aminotransaminase (ALT) increased. Stevens-Johnson Syndrome has 
been reported in a patient receiving the oral aprepitant regimen with cancer chemotherapy. 
Serious adverse reactions (SARs) reported in non-CINV studies of aprepitant (EMEND IV USPI 
November 2019) include single cases of angioedema and urticaria, constipation, and subileus. 
Hypersensitivity reactions (including anaphylaxis) have been reported in patients receiving 
aprepitant injectable emulsion. Should it occur, discontinue aprepitant injectable emulsion 
immediately, and administer appropriate medical therapy and do not reinitiate treatment with 
aprepitant injectable emulsion. 
Aprepitant is a weak-to-moderate (dose dependent) inhibitor and inducer of cytochrome P450 
(CYP)3A4. Drugs that are substrates of CYP3A4 should be used with caution. Examples include 
hydroxychloroquine/chloroquine, which can possibly increase in toxicity, including prolonged 
QT; dexamethasone, methylprednisolone, or equivalent require a 50% reduction of standard 
dose; pimozide is contraindicated. Strong or moderate CYP3A4 inhibitors (eg, ketoconazole, 
diltiazem) may increase the levels of aprepitant, and strong CYP3A4 inducers (eg, rifampin) may 
decrease its levels; both should be avoided. 
Coadministration with warfarin, a CYP2C9 substrate, may result in a clinically significant 
decrease in the international normalized ratio (INR) of prothrombin time; therefore, it is 
important to monitor the INR in patients on chronic warfarin therapy. 
Upon coadministration with aprepitant injectable emulsion, the efficacy of hormonal 
contraceptives may be reduced during administration of and for 28 days following the last dose 
of aprepitant injectable emulsion. Patients should be advised to use effective alternative or 
back-up methods of non-hormonal contraception for 1 month following the last administration of 
aprepitant injectable emulsion. 
1.3.2. 
Efficacy 
The efficacy of aprepitant injectable emulsion in the treatment of patients with COVID-19 has 
not been evaluated. 
For more information on aprepitant injectable emulsion, refer to the IB for Aprepitant Injectable 
Emulsion for Treatment of Patients With COVID-19 and the CINVANTI prescribing 
information (CINVANTI USPI October 2019). 


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2. 
STUDY OBJECTIVES 
2.1. 
Primary Objective 
• To assess the effect of aprepitant injectable emulsion on the clinical status of 
COVID-19 in hospitalized patients with confirmed SARS-CoV-2 infection. 
2.2. 
Secondary Objectives 
The secondary objectives are as follows: 
• To evaluate the safety and tolerability of daily administration of aprepitant injectable 
emulsion in hospitalized patients with COVID-19. 
• To assess the PK of aprepitant following daily dosing of aprepitant injectable 
emulsion to hospitalized patients with COVID-19. 
• To evaluate the impact of aprepitant injectable emulsion on the inflammatory 
response mediated by cytokines. 


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3. 
INVESTIGATIONAL PLAN AND ENDPOINTS 
3.1. 
Description of the Study Design 
This is a Phase 2 randomized, double-blind, placebo-controlled study in which approximately 
100 subjects will receive their randomized treatment in addition to Investigator standard of care 
for the treatment of COVID-19. 
Subjects will be screened less than 48 hours of hospitalization to determine eligibility to enter the 
study. Eligible subjects will be randomized in a 1:1 ratio in a parallel manner to receive 
aprepitant injectable emulsion or saline placebo administered QD as a 2-minute IV injection for 
14 days. 
Standard of care will be at the Investigator’s discretion generally following the COVID-19 
treatment protocol at the institution. 
Subjects will undergo PK (Section 6.5), safety (Section 6.4), and efficacy (Section 6.3) 
assessments. Safety assessments will include AEs, clinical laboratory values (hematology and 
serum chemistry), vital signs, and electrocardiograms (ECGs). Detailed information regarding 
laboratory assessments, including sample collection procedures for PK and cytokines, will be 
provided in the laboratory manual. Efficacy assessments will include respiratory status, cytokine 
panel, SARS-CoV-2 viral load, COVID-19 symptoms, and the NIAID 8-point ordinal scale of 
clinical status. Subjects will be followed until death or Day 56, whichever occurs first. If 
discharged, the site will still contact subjects for efficacy and safety follow-up until Day 56. 
An IRC will review the unblinded PK, safety, and efficacy data during the conduct of the study 
and may interrupt or stop enrollment, or modify the protocol to enhance subject safety without 
adapting the study design. 
3.2. 
Study Endpoints 
3.2.1. 
Primary Endpoint 
• Proportion of subjects alive and discharged from the hospital at Day 14. 
3.2.2. 
Secondary Endpoints 
• Time to death or respiratory failure defined as any of the following: 
− Endotracheal intubation and mechanical ventilation. 
− Oxygen delivered by high-flow nasal cannula (heated, humidified, oxygen 
delivered via reinforced nasal cannula at flow rates >20 L/min). 
− Noninvasive positive pressure ventilation. 
− ECMO. 
• Time to discharge from hospital. 
• Incidence of treatment-emergent adverse events (TEAEs). 
• Change from Baseline in IL-6 at each specified timepoint. 


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3.2.3. 
Pharmacokinetic Endpoints 
• PK parameters of aprepitant: maximum concentration (Cmax), and for subjects in 
whom all optional PK samples are collected, area under the concentration-time curve 
from Time 0 to the time of the last quantifiable concentration (AUClast) may be 
assessed. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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3.3. 
Study Duration 
The overall duration of the study is anticipated to be approximately 12 months. 
All subjects will receive treatment for 14 days, or until discharge or death, whichever occurs 
first, and will be followed through Day 56. The maximum duration of study participation for 
each subject from Screening through the last study visit will be approximately 62 days. 
For regulatory reporting purposes, the end of the study is defined as the date of the last subject’s 
last visit. 
3.4. 
Suspension of the Study 
Enrollment will be halted when the Sponsor becomes aware of any of the following: 
• If an AE of special interest (AESI) of anaphylaxis (see Section 6.4.2) occurs in at 
least 2 more subjects treated with aprepitant injectable emulsion compared to the 
number of subjects administered saline placebo. 
• If an AESI of prolongation (>500 ms) of QT interval corrected using Fridericia’s 
formula (QTcF) occurs in at least 2 more subjects treated with aprepitant injectable 
emulsion compared to the number of subjects administered saline placebo. 
• If study drug-related mortality occurs in at least 2 more subjects treated with 
aprepitant injectable emulsion compared to the number of subjects administered 
saline placebo. 
Following review of the data, a recommendation will be made by the IRC within 24 hours on 
whether to stop the study, stop future enrollment but continue dosing in subjects where the 
Investigator believes the observed benefit outweighs the potential risk, or modify the protocol to 
enhance subject safety without adapting the study design. 


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4. 
STUDY ENROLLMENT AND WITHDRAWAL 
4.1. 
Study Population 
Approximately 100 subjects will be randomized at approximately 10 study sites in the US. 
4.1.1. 
Inclusion Criteria 
Each subject must meet all of the following criteria to be randomized in this study: 
1. Is willing and able to, or has a legally authorized representative who is willing and able 
to, provide written informed consent to participate, and to cooperate with all aspects of 
the protocol. 
2. Is ≥18 years of age at Screening. 
3. Is hospitalized for ≤48 hours with SARS-CoV-2 infection prior to randomization. 
4. Has documented SARS-CoV-2 infection diagnostic test (polymerase chain reaction 
[PCR], antigen, or immunoglobulin M [IgM] antibody) prior to randomization. 
5. Has at least 1 of the following: 
a. Radiographic infiltrates by imaging (eg, chest X-ray, CT scan), OR 
b. SpO2 ≤94% by pulse oximetry on room air, OR 
c. Requiring supplemental oxygen. 
6. Is not anticipated to require mechanical ventilation within 48 hours after randomization. 
4.1.2. 
Exclusion Criteria 
A subject who meets any of the following criteria prior to randomization will be excluded from 
the study: 
1. Is taking high-dose hydroxychloroquine (eg, ≥400 mg twice daily [BID]) or chloroquine 
(eg, ≥500 mg BID) and unwilling to reduce the dose to hydroxychloroquine <400 mg 
BID or chloroquine <500 mg BID prior to receiving study treatment. 
2. Has taken aprepitant or fosaprepitant <24 hours prior to randomization. 
3. Is taking pimozide. 
4. Is taking strong or moderate CYP3A4 inhibitors (eg, ketoconazole, itraconazole, 
nefazodone, troleandromycin, clarithromycin, ritonavir, nelfinavir, diltiazem) or strong 
CYP3A4 inducers (eg, rifampin, carbamazepine, phenytoin). 
5. Is currently receiving treatment with any of the following: 
a. Janus kinase (JAK) inhibitors, biologic therapies, potent immunosuppressants 
(including azathioprine and cyclosporine) administered with the intent to modify 
immune response to COVID-19 (exception: dexamethasone, methylprednisolone, or 
equivalent are allowed at a 50% reduction of standard dose after the start of study 
drug dosing), or intravenous immunoglobulin (IVIg; including convalescent plasma) 
at the time of consent. 
b. Chemotherapy. 


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c. Hemodialysis or peritoneal dialysis. 
6. Has known hypersensitivity to any components of aprepitant injectable emulsion. 
7. Has evidence of ARDS. 
8. Has bilirubin >1.5 × the upper limit of normal (ULN), or aspartate aminotransferase 
(AST) or ALT >3 × ULN. 
9. Has a history of long QT syndrome or a QTcF >500 ms at Screening. 
10. Has a medical condition or clinically significant laboratory abnormality that, in the 
opinion of the Investigator, would prevent participation in this clinical study. 
11. Is currently participating in another study of an investigational drug or therapeutic 
medical device at the time of consent. Emergency Use Authorization of an investigational 
drug is permitted. 
12. Has an expected survival <7 days. 
13. Is using mechanical ventilation via tracheostomy or endotracheal intubation. 
14. Is being treated with oxygen delivered by high-flow nasal cannula (>20 L/minute), 
nonrebreather mask, noninvasive positive pressure ventilation, or ECMO. 
15. Is receiving treatment with a vasopressor(s). 
16. Has multiple organ failure. 
17. Has current confirmed Influenza A or B infection. 
18. Has a history of any of the following: 
a. Organ or hematologic transplant. 
b. HIV. 
c. Active hepatitis B or hepatitis C infection. 
19. Female subjects are eligible only if all the following apply: 
a. Not pregnant (female subjects of child-bearing potential must have a negative serum 
pregnancy test at Screening). 
b. Not lactating. 
c. Not planning to become pregnant while participating in the study. 
d. Females must either practice abstinence from heterosexual contact or agree to use an 
acceptable form of birth control from the time of Screening, during the study, and for 
28 days after the last dose of study drug. Acceptable forms of contraception include 
being in a monogamous relationship with a partner who is surgically sterile; 
practicing abstinence; or agreeing to use double-barrier contraception or a 
nonhormonal intrauterine device (eg, copper) in the event of sexual activity. 
Note: Female subjects in only a same-sex relationship do not need to meet this 
criterion. Hormonal contraceptives are not an acceptable form of birth control since 
the efficacy of hormonal contraceptives may be reduced with aprepitant. 


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4.2. 
Method of Assigning Subjects to Treatment Groups 
Subjects who meet the Screening eligibility criteria will be randomized. Subjects will be 
randomized using a centralized computer-generated blocked randomization algorithm and 
assigned using an interactive response technology (IRT) system. All randomization information 
will be kept in a secure location accessible only by the randomization personnel, the assigned 
Pharmacist(s) and his/her verifier, and the unblinded clinical monitor. No subject may receive 
study drug prior to randomization. 
4.2.1. 
Procedures for Handling Randomized Subjects Who Do Not Meet the Study 
Eligibility Criteria 
Subjects who fail to meet the eligibility criteria should not, under any circumstances, receive 
study drug. 
In the event a subject does not meet the eligibility criteria, but is randomized and receives study 
drug, the Investigator should inform the Sponsor immediately. The Sponsor’s Medical Monitor 
and the Investigator will discuss whether to allow the subject to continue on study drug. If the 
subject does not continue on study drug, the discharge date will be recorded and the subject will 
undergo study assessments at Days 14, 28, and 56. 
4.3. 
Blinding 
This study will use a double-blind design. Subjects, Investigators, and site staff will be blinded to 
treatment assignment until after database lock. The site’s pharmacy will not be blinded to the 
treatment assignments because aprepitant injectable emulsion is supplied as an opaque, off-white 
to amber emulsion, whereas saline placebo is not. The pharmacy will prepare study drug for 
administration and provide a covering for the syringe and infusion line to blind the contents 
(Section 5.4). The Sponsor’s study team will also be blinded to the treatment assignments with 
the exception of the clinical trial material (CTM) staff, the clinical research associate (CRA) 
performing study drug accountability, the Clinical Operations manager for review of unblinded 
monitoring reports, the bioanalytical (BA) and PK vendors, and the unblinded external 
statistician who will perform the randomization and interim analysis data review, but will 
otherwise not be involved in the conduct of the study. The BA vendor will be unblinded to 
treatment assignment to facilitate generation of BA concentration data from the PK samples, and 
the PK vendor will be unblinded to analyze the BA concentration data. 
The IRC will review the unblinded PK, safety, and efficacy data during the conduct of the study 
and may interrupt or stop enrollment, or modify the protocol to enhance subject safety without 
adapting the study design. The Product Safety and Risk Management Committee (PSRMC) will 
monitor blinded safety data on a periodic basis throughout the study. 
Additional information will be provided in the Study Blinding Plan. 
4.3.1. 
Breaking the Blind 
The study blind should not be broken except in medical emergencies when the appropriate 
management of the subject requires knowledge of the study drug he/she received. An attempt 
should be made to contact the Sponsor before breaking the blind. If the Sponsor cannot be 


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reached and the blind is broken by the Investigator, the reason for unblinding must be 
documented and the Sponsor must be contacted within 24 hours. 
If a study site becomes aware of a potential or actual unblinding event, the site must notify the 
Sponsor within 24 hours of becoming aware of the event. 
All circumstances leading to the premature unblinding will be clearly documented. 
4.4. 
Study Drug Discontinuation and Subject Withdrawal From Study 
4.4.1. 
Study Drug Discontinuation 
Study drug may be discontinued for any of the following reasons: 
• AE. 
• Request by subject. 
• Pregnancy. 
• Investigator’s decision. 
• Disease progression. 
• Sponsor’s decision. 
• Other, specify. 
The date and primary reason for study drug discontinuation will be recorded on the electronic 
case report form (eCRF). 
After study drug discontinuation, every attempt should be made to complete the remaining study 
assessments and follow the subject through Day 56. 
4.4.2. 
Subject Withdrawal From Study and Subject Replacement 
Subjects are free to withdraw from the study at any time without prejudice to further treatment. 
The date and the primary reason for early withdrawal (consent withdrawn or lost to follow-up) 
will be recorded on the eCRF. At the time of withdrawal from the study, complete the Early 
Termination assessments. 
Randomized subjects who withdraw from study will not be replaced. To account for withdrawal 
of subjects who were randomized but not dosed, enrollment will continue until at least 
100 subjects have been randomized and dosed. 
4.5. 
Subject Rehospitalization After Discharge 
For discharged subjects who are readmitted to the hospital prior to Day 56, assessments in the 
Schedule of Events Post-Discharge will be completed. 


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5. 
STUDY DRUG 
Study drug is defined as aprepitant injectable emulsion (test product) and saline placebo (control 
product). 
5.1. 
Description of Study Drug 
5.1.1. 
Test Product 
Aprepitant injectable emulsion is supplied as an opaque, off-white to amber emulsion in a 
single-dose glass vial containing 130 mg/18 mL aprepitant: 
NDC 47426-201-01  
1 single-dose vial per carton. 
Aprepitant injectable emulsion will be supplied by the Sponsor. 
5.1.2. 
Control Product 
United States Pharmacopeia (USP)-grade normal saline solution (0.9% sodium chloride) will be 
supplied by study sites. 
5.2. 
Packaging and Labeling 
Aprepitant injectable emulsion will be packaged and labeled by the Sponsor or designee as the 
marketed product CINVANTI in the commercial container and carton with an additional flag 
label indicating investigational use, and will be packed and dispatched to comply with shipping 
and storage conditions. Aprepitant injectable emulsion for investigational use will be labeled so 
as to not obscure commercial text. Study drug labeling will comply with all applicable national 
and local laws and regulations. 
5.3. 
Storage 
Aprepitant injectable emulsion vials must be refrigerated; store at 2°C to 8°C (36°F to 46°F). 
Aprepitant injectable emulsion vials can remain at room temperature up to 60 days. Do not 
freeze. 
5.4. 
Preparation 
Aprepitant injectable emulsion will be prepared at the study site. For IV injection over a period 
of 2 minutes, aseptically withdraw 18 mL from the vial for the 130 mg dose. Do not dilute. The 
infusion line should be flushed with normal saline before and after administration of aprepitant 
injectable emulsion. Aprepitant injectable emulsion should not be mixed with solutions for 
which physical and chemical compatibility have not been established. 
The pharmacist will prepare test product and control product for administration, which includes 
providing a covering for the syringe and infusion line to blind the contents. Refer to the 
Pharmacy Manual for details on study drug preparation. 
5.5. 
Study Drug Administration 
Eligible subjects will be administered aprepitant injectable emulsion 130 mg (18 mL) or saline 
placebo (18 mL) once daily as a 2-minute IV injection. 


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The start and stop times of study drug dosing will be recorded in the eCRF. 
5.6. 
Study Drug Compliance 
All study drug must be administered in accordance with the treatment assignment. Subject 
compliance monitoring is not necessary because study drug will be administered by trained site 
staff. 
5.7. 
Study Drug Accountability 
Aprepitant injectable emulsion provided for this study will be used only as directed in the study 
protocol. In accordance with Good Clinical Practice (GCP), Investigators are required to 
maintain accurate and up-to-date records of all aprepitant injectable emulsion to permit 
reconciliation. The Investigator or designee must maintain adequate records of distribution, 
including the date received, number and units received, lot numbers, dispensing, and return or 
destruction of all study drug (ie, accountability or dispensing logs). 
All study drug records must be readily available for inspection by the site’s Clinical Monitor 
and/or auditor. The Clinical Monitor is responsible for verifying the accuracy of the aprepitant 
injectable emulsion records at the study site. All returns, disposal, or destruction must be 
approved by the Sponsor in writing. 


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6. 
STUDY PROCEDURES AND ASSESSMENTS 
The following sections describe the study procedures and assessments that will be performed 
during the study. The timing of procedures and assessments is provided in the SCHEDULE OF 
EVENTS, the SCHEDULE OF EVENTS POST-DISCHARGE, and the SCHEDULE OF PK 
BLOOD SAMPLE COLLECTION tables. The assessments to be performed post-discharge are 
described in Appendix B. 
6.1. 
Comorbidities and Demographics 
6.1.1. 
Comorbidities 
Comorbidities will be obtained to ensure that subjects qualify for the study. 
6.1.2. 
Demographics 
Demographic information collected will include age, sex, race, and ethnicity. 
6.2. 
Prior and Concomitant Therapy 
All medications taken by subjects from informed consent form (ICF) signing through the last day 
of study drug administration will be recorded. Medications taken for the treatment of COVID-19 
will be recorded through discharge. 
6.2.1. 
Allowed Concomitant Medications 
All treatments that the Investigator considers necessary for a subject’s welfare may be 
administered at the discretion of the Investigator in keeping with the standard of medical care, 
except for prohibited medications while on study. 
Coadministration of aprepitant injectable emulsion with warfarin, a CYP2C9 substrate, may 
result in a clinically significant decrease in the INR of prothrombin time. Monitor the INR in 
subjects on chronic warfarin therapy in the 2-week period, particularly at 7 to 10 days, following 
initiation of aprepitant injectable emulsion (CINVANTI USPI October 2019). 
If dexamethasone, methylprednisolone, or equivalent, CYP3A4 substrates, are used, the dose 
should be reduced by approximately 50% (CINVANTI USPI October 2019). 
6.2.2. 
Prohibited Medications and Treatments 
Per the exclusion criteria (Section 4.1.2), prohibited medications include high-dose 
hydroxychloroquine (eg, ≥400 mg BID) or chloroquine (eg, ≥500 mg BID), pimozide, JAK 
inhibitors, biologic therapies, potent immunosuppressants (including azathioprine and 
cyclosporine) administered with the intent to modify immune response to COVID-19 (exception: 
dexamethasone, methylprednisolone, or equivalent are allowed at a 50% reduction of standard 
dose after the start of study drug dosing), or IVIg, and chemotherapy. Other forms of aprepitant 
and fosaprepitant are prohibited from 24 hours prior to randomization to Day 14. 
Additionally, strong or moderate CYP3A4 inhibitors (eg, ketoconazole, itraconazole, 
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supplementation for that assessment day’s 24-hour period (from 00:00 to 23:59 hours). For 
example, for Day 21, record the worst status that occurred on Day 21 from 00:00 to 23:59 hours. 
Respiratory Status assessments will include the following: 
• Respiratory rate (record highest). 
• Oxygen supplementation (record highest, listed from lowest to highest). 
− Room air. 
− Nasal cannula. 
− Face mask. 
− Noninvasive ventilation or high-flow oxygen devices. 
− ECMO. 
− Mechanical ventilation. 
• Oxygenation: (record lowest SpO2 at rest or partial pressure of oxygen [PaO2]). 
• Chest X-ray or CT scan findings (if available). 
6.3.3. 
Cytokine Panel and Other Laboratory Parameters 
The markers included in the cytokine storm panel and the cytokine limited panel are presented in 
Appendix A. CRP will be collected independent of the cytokine storm panel per the SCHEDULE 
OF EVENTS. The cytokine storm panel, the cytokine limited panel, CRP, and, if possible, 
Substance P will be performed by a central laboratory. 
Information from the following standard-of-care laboratory tests will be provided to the Sponsor 
and recorded in the eCRF, for the following analytes, if available: 
• D-dimer. 
• Troponin. 
• Brain natriuretic peptide (BNP). 
• Erythrocyte sedimentation rate (ESR). 
• Creatine kinase (CK). 
Detailed instructions on sample collection, processing, and storage are provided in the 
Laboratory Manual. 
6.3.4. 
Viral Load 
SARS-CoV-2 viral RNA load qPCR test will be analyzed by the central laboratory. Heron will 
retain the viral load samples for potential future retrospective analyses. 
The method(s) for collecting samples will be described in the Laboratory Manual. 


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6.3.5. 
COVID-19 Symptoms 
For subjects who are not receiving mechanical ventilation, record each COVID-19 symptom 
from the list below as none, mild, moderate, or severe. For the Baseline status on Day 1, record 
the status at randomization and the symptoms onset time(s). For all other assessment days, record 
the symptoms based on the average severity per subject report during the assessment day’s 
24-hour period (from 00:00 to 23:59 hours). 
None: 
Symptom not present. 
Mild: 
Event is easily tolerated by the subject, causes minimal discomfort, and does not 
interfere with everyday activities. 
Moderate: 
Event results in a low level of inconvenience or concern with the therapeutic 
measures. Moderate events may cause some interference with functioning. 
Severe: 
Event interrupts a participant’s usual daily activity and may require systemic drug 
therapy or other treatment. Severe events are usually potentially life-threatening or 
incapacitating. 
• Cough. 
• Fever. 
• Sore throat. 
• Loss of taste and/or loss of smell. 
• Malaise/Fatigue. 
• Headaches. 
• Myalgia. 
• Gastrointestinal symptoms. 
• Shortness of breath on exertion. 
• Shortness of breath at rest. 
6.4. 
Safety Assessments 
6.4.1. 
Adverse Events 
All AEs, regardless of causality or seriousness, will be recorded from the time the subject or 
legally authorized representative signs the ICF through Day 56. Additional safety monitoring and 
reporting information is provided in Section 8. 
An abnormal finding from any safety assessment that meets the definition of an AE or requires 
medical intervention (eg, medication, intravenous fluids) should be deemed clinically significant 
by the Investigator and must be recorded as AE. 
Any abnormal finding from a safety assessment that is not considered clinically significant 
should not be recorded as an AE. 


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6.4.2. 
Prospective Assessment of Anaphylaxis 
Anaphylaxis events will be prospectively assessed after each study drug administration using 
Sampson’s criteria (Sampson 2006) modified for the COVID-19 study population. 
Anaphylaxis is highly likely when the following criteria are fulfilled: 
• Acute onset of an illness (within minutes to several hours of study drug 
administration) with involvement of the skin, mucosal tissue, or both (eg, generalized 
hives, pruritus or flushing, swollen lips-tongue-uvula). 
AND AT LEAST ONE OF THE FOLLOWING 
a. New or worsening respiratory compromise (eg, dyspnea, wheeze-bronchospasm, 
stridor, reduced peak expiratory flow [PEF], hypoxemia). 
b. New or worsening reduced BP or associated symptoms of end-organ dysfunction 
(eg, hypotonia [collapse], syncope, incontinence). 
If present, anaphylaxis will be recorded as an AE (Section 8.1). 
6.4.3. 
Physical Examinations 
A symptom-directed physical examination should be performed at Screening and when 
appropriate to evaluate an AE. 
Baseline height and weight measurements will be conducted at Screening. 
6.4.4. 
Vital Signs 
Information from standard-of-care vital signs will be provided to the Sponsor and recorded in the 
eCRF. Vital sign measurements will be documented by recording the minimum and maximum 
values during each assessment day’s 24-hour period (from 00:00 to 23:59 hours) for SBP, DBP, 
resting heart rate, and body temperature. 
6.4.5. 
12-Lead Electrocardiograms 
Standard digital 12-lead ECGs will be performed in triplicate at Screening only. The mean of the 
3 ECG recordings will be used as the Baseline result. Subsequently, for subjects receiving 
hydroxychloroquine/chloroquine, if they are not on continuous ECG monitoring, daily single 
ECGs will be performed. For subjects not receiving hydroxychloroquine/chloroquine, record the 
results of a standard-of-care ECG if performed. For all subjects on continuous ECG monitoring, 
record the results of a standard-of-care ECG if performed. 
Any abnormal ECG result deemed clinically significant by the Investigator must be recorded as 
an AE, and the abnormal ECG result must be recorded on an eCRF (scheduled or unscheduled 
assessment eCRF, as applicable). 
6.4.6. 
Clinical Laboratory Tests 
Information from standard-of-care diagnostic and safety laboratory tests will be provided to the 
Sponsor and recorded in the eCRF. 
Blood samples will be collected for diagnostic screening tests and for safety laboratory tests 
(hematology and serum chemistry) at the study site. 




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7. 
GUIDANCE FOR COMPLETING PROCEDURES AND 
ASSESSMENTS 
Study procedures and assessments are described in Section 6. The timing of procedures and 
assessments is provided in the SCHEDULE OF EVENTS, SCHEDULE OF EVENTS POST-
DISCHARGE, and SCHEDULE OF PK BLOOD SAMPLE COLLECTION tables. Time 0 will 
be the start of study drug administration on Day 4 for PK assessments. Unless there is a safety 
concern, every effort should be made to avoid protocol deviations by completing procedures and 
assessments according to the protocol guidance. 
During the Screening period, serum or urine pregnancy tests (female subjects of childbearing 
potential only) should be performed and confirmed as negative prior to performing any 
additional assessments. The definition of childbearing potential is provided in Section 9.1. 
When assessments that involve direct interaction with the subject are scheduled at the same 
timepoint, perform the assessments in the order of least invasive (eg, assessing clinical status) to 
most invasive (eg, blood sample collection), as appropriate. 
Unscheduled assessments should be performed if clinically indicated in the opinion of the 
Investigator to investigate an AE (for example, blood samples to assess drug concentrations or 
for clinical laboratory tests). The results of any unscheduled assessments should be recorded on 
the eCRF. 


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8. 
SAFETY MONITORING AND REPORTING 
Investigators are responsible for the detection, assessment, and documentation of AEs, including 
serious adverse events (SAEs), unanticipated problems, and pregnancies, as detailed in this 
protocol. 
Investigators must review the IB to be aware of the safety-related events that may be anticipated 
with its use. 
8.1. 
Definition of Safety Parameters 
8.1.1. 
Definition of an Adverse Event 
An AE is defined as any untoward medical occurrence associated with the use of a drug in 
humans, whether or not considered drug related. 
An AE may be any unfavorable and unintended sign (including an abnormal laboratory finding), 
symptom, or disease temporally associated with the use of a study drug, whether or not 
considered causally associated with the use of the study drug. Any abnormal physical 
examination finding, laboratory value, vital sign result, or ECG finding deemed clinically 
significant by the Investigator must be reported as an AE. A clinical diagnosis, rather than a 
change in a laboratory analyte or other assessment, should be recorded (eg, anemia rather than 
low hemoglobin value). 
Examples of AEs include the following: 
• Significant or unexpected worsening or exacerbation of the condition or indication 
under study. 
• Exacerbation of a chronic or intermittent pre-existing condition, including either an 
increase in frequency or intensity of the condition (eg, abnormal physical examination 
finding). 
• Signs, symptoms, or clinical sequelae of a suspected interaction. 
• Signs, symptoms, or clinical sequelae of a suspected overdose of the study drug or a 
concurrent medication (overdose per se should not be reported as an AE or SAE, 
unless nonserious or serious sequelae occur). 
• The following abnormal laboratory results: 
− Any laboratory abnormality suggestive of a new disease/organ toxicity or a 
worsening of a pre-existing condition. 
− Any laboratory abnormality that required the subject to have study drug 
interrupted or discontinued. 
− Any laboratory abnormality that required the subject to receive specific treatment 
for the laboratory abnormality. 
− Any laboratory abnormality that required further diagnostic investigation and/or 
follow-up visits (excluding repeat testing to confirm the abnormality). 
The following examples are not considered AEs: 


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• Medical or surgical procedure (eg, endoscopy, appendectomy), although the condition 
that leads to the procedure is an AE. 
• Anticipated day-to-day fluctuations of pre-existing disease(s) or condition(s) 
(including laboratory values) present or detected at the start of the study that do not 
worsen. 
• The disease or disorder being studied; or expected progression, signs, or symptoms of 
the disease or disorder being studied, unless they become more severe or occur with a 
greater frequency than expected for the subject’s condition. 
• Transient paresthesia that is considered to be clinically normal (would be expected to 
occur as a long-acting local anesthetic wears off). 
8.1.2. 
Definition of a Serious Adverse Event 
An AE is considered “serious” if, in the view of either the Investigator or Sponsor, it results in 
any of the following outcomes: 
• Death. 
• A life-threatening AE (ie, an AE that presented an immediate risk of death from the 
event as it occurred. This criterion is not intended to include an AE 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 serious when, based upon appropriate medical 
judgment, they may jeopardize the patient or subject and may require medical or 
surgical intervention to prevent one of the outcomes listed in this definition. 
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. 
The following events do not meet the definition of an SAE: 
• Hospitalization for the following: 
− Elective treatment of a pre-existing condition that does not worsen from baseline. 
− A standard procedure for study drug administration and routine monitoring of the 
studied indication not associated with any deterioration in condition. 
• Social or convenience admission to a hospital. 
• Prolongation of a hospitalization for social or convenience reasons not associated 
with the occurrence of an AE. 


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• Hospitalization or an emergency room visit that lasts less than 24 hours and does not 
meet the criteria of an important medical or a life-threatening event. 
8.1.3. 
Adverse Events of Special Interest 
AESIs are events of anaphylaxis (Section 6.4.2) and of QTcF prolongation (>500 ms). The 
Investigator is responsible for reporting all AESIs within 24 hours of becoming aware of the 
event. 
8.1.4. 
Definition of Unanticipated Problems 
Unanticipated problems are incidents, experiences, or outcomes that meet all of the following 
criteria: 
• Unexpected in terms of nature, severity, or frequency given (a) the research 
procedures that are described in the protocol-related documents, such as the research 
protocol and informed consent document approved by the Ethics Committee (EC; 
includes Institutional Review Boards [IRBs], Independent Ethics Committees [IECs], 
and Research Ethics Boards [REBs]) and (b) the characteristics of the participant 
population being studied. 
• Related or possibly related to participation in the research (“possibly related” means 
there is a reasonable possibility that the incident, experience, or outcome may have 
been caused by the procedures involved in the research). 
• Suggest that the research places subjects or others at a greater risk of harm (including 
physical, psychological, economic, or social harm) than was previously known or 
recognized. 
8.2. 
Classification of Adverse Events 
8.2.1. 
Severity of Adverse Events 
The Investigator will assess the severity of each AE based on his/her clinical judgment using one 
of the following categories: 
• Mild: Event is easily tolerated by the subject, causes minimal discomfort, and does 
not interfere with everyday activities. 
• Moderate: Event results in a low level of inconvenience or concern with the 
therapeutic measures. Moderate events may cause some interference with 
functioning. 
• Severe: Event interrupts a participant’s usual daily activity and may require systemic 
drug therapy or other treatment. Severe events are usually potentially life-threatening 
or incapacitating. 
8.2.2. 
Relationship to Study Drug 
The Investigator will assess the relationship of each AE to study drug (aprepitant injectable 
emulsion and saline placebo) based on his/her clinical judgment. The Investigator’s assessment 
of an AE’s relationship to study drug is part of the documentation process, but it is not a factor in 


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determining what is or is not reported in the study. If there is any doubt as to whether a clinical 
observation is an AE, the event should be reported. 
Relationship to study drug will be assessed according to the following guidelines: 
• Possibly related: The AE is known to occur with the study drug, there is a reasonable 
possibility that the study drug caused the AE, or there is a temporal relationship 
between the study drug and event. Reasonable possibility means that there is evidence 
to suggest a causal relationship between the study drug and the AE. 
• Unlikely related: There is not a reasonable possibility that the administration of the 
study drug caused the event, there is no temporal relationship between the study drug 
and event onset, or an alternate etiology has been established. 
An SAE, including a serious AESI, considered by the Investigator to be possibly related to the 
study drug is a SAR. Even in situations in which minimal information is available for initially 
reporting an SAE, it is important that the Investigator always make an assessment of causality for 
every event when entering the information into the eCRF or completing the SAE reporting form, 
in the event electronic data capture (EDC) is not available. The causality assessment is one of the 
criteria used when determining regulatory reporting requirements. The Investigator may change 
his or her opinion of causality in light of follow-up information and amend the SAE information 
accordingly in the eCRF or the SAE reporting form, as applicable. 
8.3. 
Time Period and Frequency for Event Assessment and Follow Up 
8.3.1. 
Adverse Event and Serious Adverse Event Monitoring 
All AEs will be recorded from the time the subject or legally authorized representative signs the 
ICF through Day 56. 
For subjects who received study drug, if an Investigator becomes aware of an SAE that occurs 
after the subject’s participation in the study ends and the Investigator considers the event to be 
possibly related to the study drug, the Investigator needs to report the SAR to the Sponsor as 
described in Section 8.4.1. 
8.3.2. 
Follow-Up of Events 
After the occurrence of an AE, the Investigator is required to follow each subject proactively and 
provide further information on the subject’s condition. All AEs documented at a previous visit or 
contact and designated as ongoing will be reviewed at subsequent visits or contacts. 
Nonserious AEs will be followed after the last scheduled study visit until the event resolves, the 
condition stabilizes, or until the event is otherwise explained or judged by the Investigator to be 
no longer clinically significant (unless the subject is lost to follow-up or withdraws consent). 
The Investigator will assess the outcome of each AE using the following categories: 
• Recovered/Resolved: The event resolved or the subject recovered without sequelae. 
An event (either serious or nonserious) occurred and had an endpoint, and the subject 
experienced no restrictions. Examples include stent placement for coronary artery 
disease (a device implanted is not a sequela), an appendectomy (a scar is not a 
sequela), a postoperative wound infection, or an upper respiratory tract infection. 


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• Recovered/Resolved with sequelae: The event has at least one secondary outcome 
that may result in permanent disability, functional limitation, or both. Such sequelae 
are usually limited to SAEs. Examples include hip replacement resulting in foot drop 
(foot drop is not the intended outcome but is a risk of surgery), stroke resulting in 
paralysis, or emboli formation after a bacterial infection resulting in a renal infarct 
and loss of renal function. 
• Recovering/Resolving: The event is improving. 
• Not recovered/Not resolved: At the end of the study, a nonserious event either has 
not changed in intensity or may not have recovered to baseline values, and the 
outcome is unknown. Examples include headache, low-grade fever, or nausea. 
• Unknown: The subject has withdrawn from the study prematurely or is lost to 
follow-up, and the status of the event is unknown. 
• Fatal 
SAEs will be followed until the event resolves (ie, when the event no longer meets any of the 
seriousness criteria), the condition stabilizes, or the event is otherwise explained or judged by the 
Investigator to be no longer clinically significant (unless the subject is lost to follow-up or 
withdraws consent). The Investigator will ensure that follow-up information provided to the 
Sponsor includes results of any additional laboratory tests or investigations, histopathologic 
examinations, or consultations with other healthcare professionals that serve to clarify the nature 
of the event, the cause of the event, or both. New or updated information will be recorded as 
outlined in Section 8.4.1. 
8.4. 
Reporting Procedures 
8.4.1. 
Reporting Serious Adverse Events to the Sponsor 
If the Investigator determines that an event that occurs during the course of this study meets the 
protocol definition of an SAE (see Section 8.1.2) due to any cause, regardless of relationship to 
study drug, he/she must notify the Sponsor by entering the SAE information into the eCRF 
within 24 hours of the Investigator becoming aware of the SAE. 
If EDC is not available, the Investigator must complete an SAE reporting form and email it to the 
Sponsor within 24 hours of the Investigator becoming aware of the SAE. The Investigator 
must also enter the SAE information into the eCRF as soon as possible thereafter. 
Email Address: 
Heron_PV@ubc.com 
The following documents are to be forwarded: any laboratory results, diagnostic test results, or 
medical reports relevant to the SAE. 
EDC is the primary method for notification of SAE information. In rare circumstances and in the 
absence of email capacity, notification by fax or telephone is acceptable, with a copy of the SAE 
reporting form sent by overnight mail. Initial notification via telephone does not replace the need 
for the Investigator to complete the SAE information in the eCRF within the time frames 
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If the Investigator does not have all information regarding an SAE, he/she must not wait to 
receive additional information before notifying the Sponsor of the event. The SAE must be 
updated when additional information is received using the same process and timelines as for the 
initial report. 
8.4.2. 
Reporting Unanticipated Problems to the Sponsor 
If the Investigator determines that an event meets the protocol definition of an unanticipated 
problem (see Section 8.1.4), he/she must notify the Sponsor by completing an Unanticipated 
Problem Form and emailing it to the Sponsor within 24 hours of the Investigator becoming 
aware of the problem. 
Email Address: 
Heron_PV@ubc.com 
The following information will be included with unanticipated problem reporting: 
• Protocol identifying information: protocol title, protocol number, and Investigator’s 
name. 
• A detailed description of the event, incident, experience, or outcome. 
• An explanation of the basis for determining that the event, incident, experience, or 
outcome represents an unanticipated problem. 
It is the Investigator’s responsibility to report any unanticipated problem to the Sponsor and their 
EC, as required by local regulations. 
8.4.3. 
Regulatory Reporting Requirements 
The Investigator must promptly report all SAEs to the Sponsor in accordance with the 
procedures detailed in Section 8.4.1. The Sponsor has a legal responsibility to notify, as 
appropriate, both the local regulatory authority and other regulatory agencies about the safety of 
a product under clinical investigation. Prompt notification of SAEs by the Investigator to the 
appropriate project contact for SAE receipt is essential so that serious suspected adverse 
reactions that are either unexpected or observed with increasing occurrence and all serious 
AESIs be reported and legal obligations and ethical responsibilities regarding the safety of other 
subjects are met. 
Mortality or progression to mechanical ventilation or ECMO will not be collected unless 
considered drug-related, because these events are collected and reported as part of the efficacy 
endpoints. The following events will not be notified to regulatory authorities as an expedited 
report: SAEs relating to mortality or mechanical ventilation except when there is evidence 
suggesting a causal relationship between study drug and the event, or an aggregate analysis 
identifies a safety concern. 
The Investigator, or responsible person according to local requirements, must comply with 
requirements related to the reporting of SAEs to the EC. 
The Sponsor is responsible for informing ECs, Investigators, and regulatory authorities of any 
finding that could adversely affect the safety of subjects or affect the conduct of the study. 
Events will be reported to regulatory authorities in accordance with expedited and periodic 


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reporting requirements. Serious AESIs will be reported to regulatory authorities as an expedited 
report. 
Investigator letters are prepared according to Sponsor policy and are forwarded to the 
Investigators as necessary. An Investigator letter is prepared for any suspected adverse reaction 
that is attributable to study drug, serious, and unexpected. The purpose of the Investigator letter 
is to fulfill specific regulatory and GCP requirements regarding the product under investigation. 
8.4.4. 
Pregnancy Reporting 
Pregnancy is not considered to be an AE; however, study drug must be discontinued immediately 
for any subject who becomes pregnant during the study. Female subjects who become pregnant 
within 28 days after receiving study drug should also notify the Investigator. The Investigator 
must attempt to follow the pregnancy to term or termination in order to report on outcome and 
health status of mother and child. 
The Investigator must notify the Sponsor of any pregnancy by completing a Pregnancy Form and 
emailing it to the Sponsor within 24 hours after the Investigator becomes aware of the 
pregnancy. 
Email Address: 
Heron_PV@ubc.com 
8.5. 
Safety Oversight 
Safety oversight will be provided by an IRC, as described in Section 13.2. In addition, the 
PSRMC will monitor blinded safety data on a periodic basis throughout the study. A detailed 
description of safety oversight is provided in the Safety Monitoring Plan for this study. 
The criteria for suspending enrollment for safety issues are provided in Section 3.4 and for 
terminating the study or closing a study site for safety issues in Section 13.6. 


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9. 
OTHER STUDY RESTRICTIONS 
9.1. 
Contraception 
A woman of childbearing potential is defined as a premenopausal female capable of becoming 
pregnant. This includes women on oral, injectable, or mechanical contraception; women who are 
not in a relationship; and women whose partners have been vasectomized or have received or are 
utilizing mechanical contraceptive devices. 
Females must either practice abstinence from heterosexual contact or agree to use an acceptable 
form of birth control from the time of Screening, during the study, and for 28 days after the last 
dose of study drug. Acceptable forms of contraception include being in a monogamous 
relationship with a partner who is surgically sterile; practicing abstinence; or agreeing to use 
double-barrier contraception or a nonhormonal intrauterine device (eg, copper) in the event of 
sexual activity. Note: Female subjects in only a same-sex relationship do not need to meet this 
criterion. Hormonal contraceptives are not an acceptable form of birth control since the efficacy 
of hormonal contraceptives may be reduced with aprepitant injectable emulsion. 


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10. 
STATISTICAL CONSIDERATIONS 
10.1. 
General Considerations 
All efficacy and safety data will be listed by subject. Unless otherwise specified, Baseline is 
defined as the last observed measurement, whether scheduled or unscheduled, prior to first dose 
of study drug. All safety and efficacy endpoints will be summarized by treatment group. 
Continuous variables will be summarized using the number of subjects with data (n), mean, SD, 
median, minimum, and maximum. Selected continuous variable summaries will also include the 
SE. Categorical variables will be summarized using frequency and percentages. For time to event 
analyses, follow-up time starts when subjects are randomized. Additional statistical details will 
be described in the statistical analysis plan (SAP). 
10.2. 
Determination of Sample Size 
The sample size was selected empirically without formal statistical hypotheses or assumptions. 
10.3. 
Analysis Populations 
Intent-to-Treat (ITT) Population: All subjects who are randomized will be included in the ITT 
Population. This population will be used as the primary analysis population for all efficacy 
endpoints. The randomized treatment assignment will be used for analysis in this population. 
Safety Population: All subjects who receive study drug will be included in the Safety Population. 
This population will be used for all summaries of safety data. The actual treatment received will 
be used for analysis in this population. 
PK Population: All subjects who receive 1 dose of study drug on Day 4 and have sufficient data 
to calculate PK parameters and do not have protocol deviations thought to significantly affect the 
PK of aprepitant will be included in the PK population. 
10.4. 
Statistical Analysis Methods 
10.4.1. 
Disposition and Demographics 
The number and percentage of subjects in each analysis population will be summarized. Subject 
disposition, including the number of subjects screened, randomized, dosed, completing the 
14-day treatment period, completing the Day 56 Visit, and not completing the Day 56 Visit by 
reason for withdrawal will be summarized. Subject demographics and baseline characteristics 
will be summarized for the ITT Population and the Safety Population and will include age, 
age category, sex, race, ethnicity, height, weight, and BMI. 
10.4.2. 
Efficacy Analyses 
10.4.2.1. Primary Efficacy Analysis 
The proportion of subjects alive and discharged from the hospital at Day 14 will be analyzed 
using Fisher’s exact test to compare differences in proportions across treatment arms. Summaries 
will be expressed as the frequency and percentage of subjects meeting the criteria of alive and 


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discharged from hospital at Day 14 by treatment arm. Differences in proportions across treatment 
arms along with corresponding exact 95% CIs will also be presented. 
10.4.2.2. Secondary Efficacy Analyses 
Time to death or respiratory failure will be analyzed using Kaplan-Meier methods. Kaplan-Meier 
plots will be presented by treatment arm and the log-rank test will be used to make pairwise 
comparisons between treatment arms. Median time to death or respiratory failure, 95% CIs, and 
p-values will be summarized. Events will be defined as either time when the subject first meets 
any of the 4 criteria of respiratory failure or dies, whichever comes first. Subjects who never 
meet the criteria for respiratory failure and who are alive at the end of the study will be censored 
at the time of last assessment of respiratory status. Follow-up time starts when subjects are 
randomized. 
The analysis of time to discharge from hospital will be based on Kaplan-Meier methods. Deaths 
will be censored at the longest observed follow-up time across the two arms in the analysis. 
Kaplan-Meier plots will be presented by treatment arm and the log-rank test will be used to make 
pairwise comparisons between treatment arms. Median time to discharge, 95% CIs, and p-values 
will be summarized. Follow-up time starts when subjects are randomized. Subjects who are not 
discharged and are alive at the end of the study will be censored at the time of last contact. 
Individual and group changes from Baseline in IL-6 will be assessed across timepoints by 
treatment arm using both graphical and/or tabular presentations. Change from Baseline and 
percentage change from Baseline will be presented in graphical profiles across timepoints in 
spaghetti plots. Tabular summaries of change from Baseline and percentage change from 
Baseline will include descriptive statistics by post-Baseline timepoints. Tabular presentations 
will include summary statistics (mean, median, min, max) presented at each scheduled timepoint, 
for minimum and maximum post-Baseline values, and for last post-Baseline value. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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10.4.3. 
Handling of Missing Data 
The SAP will describe the handling of missing data for the various study endpoints. 
10.4.4. 
Study-Wise Type I Error Control 
Unless otherwise specified, all statistical hypothesis testing will be 2-sided using α level= 0.05. 
Analyses of pairwise comparisons will not be adjusted for multiple comparisons. Details will be 
provided in the SAP. 
10.4.5. 
Safety Analyses 
Safety data will be presented both separately and pooled. 
All safety data will be listed and summarized by treatment group; no statistical hypothesis testing 
will be performed. Incidence of AEs, SAEs, adverse reactions, and AESIs will be coded and 
tabulated by System Organ Class (SOC) and Preferred Term (PT). AESIs are events of 
anaphylaxis and of QTcF prolongation (>500 ms). 
AEs that occur between the time the subject or legally authorized representative signs the ICF 
and the start of study drug administration will be considered as non-treatment emergent AEs. 
AEs that start during or after study drug administration, or AEs with an onset prior to study drug 
administration that worsen after study drug administration will be considered TEAEs. 
Incidence of TEAEs will be summarized by SOC and PT across treatment arms. 
TEAEs leading to study drug discontinuation, if any, will be listed separately. 
Associated laboratory parameters such as hepatic profile, renal function, and hematology values 
will be grouped and presented together in summary tables. Individual subject values will be 
listed and values outside of the standard reference range will be flagged. Shift tables will be 
produced showing the frequency of shifts from baseline to the minimum and maximum 
post-Baseline value, last post-Baseline value, and by visit. Laboratory parameters will also be 
summarized by visit. Changes in vital sign parameters and ECG parameters will be summarized. 


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10.4.6. 
Pharmacokinetic Analysis 
Plasma aprepitant concentrations will be determined using a validated liquid chromatography 
tandem-mass spectrometry assay. Concentrations will be calculated by interpolation from a 
calibration curve. PK parameters will be calculated using noncompartmental analysis. 
Concentrations of hydroxychloroquine and chloroquine may also be determined using a 
validated liquid chromatography tandem-mass spectrometry assay. Concentrations will be 
calculated by interpolation from a calibration curve. 
Additional details will be provided in the PK Analysis Plan. 
10.5. 
Interim Analysis 
No formal interim analyses are planned. An IRC will review the summary-level unblinded PK, 
safety, and efficacy data during the conduct of the study and may interrupt or stop enrollment, or 
modify the protocol to enhance subject safety without adapting the study design. The IRC will be 
composed of Sponsor representatives from each of the Clinical Research, Biometrics, 
Pharmacovigilance, Regulatory, and Pharmaceutical and Translational Sciences functions, and 
an external expert in critical care medicine. The IRC will operate under a written, detailed IRC 
Charter. 


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11. 
QUALITY ASSURANCE AND QUALITY CONTROL 
Quality assurance and quality control systems will be implemented and maintained by the 
Sponsor and its designee(s), as appropriate, following Standard Operating Procedures to ensure 
that the clinical study is conducted and the data are generated, documented (recorded), and 
reported in compliance with the protocol, International Council for Harmonisation (ICH) E6 
GCP guidelines, and applicable regulatory requirements. The accuracy, completeness, and 
reliability of the study data presented to the Sponsor, however, are the responsibility of the 
Investigator. The Investigator or designee must record all required data using the prespecified 
data collection method defined by the Sponsor or its designee. 
The study will be monitored regularly by the Sponsor (Section 13.1) and may be audited by the 
Sponsor (or designee) or inspected by a regulatory authority at any time during the study or after 
study completion. In the event of an audit or inspection, the Investigator agrees to allow the 
Sponsor, representatives of the Sponsor, the competent authority, or other regulatory authority 
direct access to all study records. The Investigator will immediately notify the Sponsor of all 
audits or inspections scheduled by any regulatory authority and promptly forward to the Sponsor 
copies of any inspection reports received. 


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12. 
REGULATORY AND ETHICAL CONSIDERATIONS 
12.1. 
Regulatory Authority Approval 
The Sponsor will obtain approval to conduct the study from the appropriate regulatory agency in 
accordance with any applicable country-specific regulatory requirements before any site may 
initiate the study in that country. 
12.2. 
Ethical Conduct of the Study 
This study will be conducted in compliance with the protocol and all applicable regulatory 
requirements in accordance with ICH/GCP and in general conformity with the most recent 
version of the Declaration of Helsinki. 
12.3. 
Ethics Committee Approval 
The Investigator or the Sponsor is responsible for submitting the following documents to the ECs 
for review and, if applicable, approval: study protocol, ICF(s), IB, recruitment materials, 
information about study compensation to subjects, and any information for presentation to 
potential subjects. 
The Investigator is responsible for providing the Sponsor with the written EC approval prior to 
commencing the study (ie, before shipment of study drug to the site). All amendments to the 
protocol require review and approval by the EC before the changes to the study are implemented. 
All changes to the ICF will be approved by the EC; a determination will be made regarding 
whether previously consented participants need to be re-consented. If any other information 
previously approved by the EC for presentation to potential subjects is amended during the 
study, the Investigator is also responsible for ensuring EC review and re-approval. 
Study sites must adhere to all requirements stipulated by their respective ECs. This may include, 
but not be limited to, notifying the EC of serious and unexpected AEs or other local safety 
reporting requirements, submitting a final status report, or providing a synopsis of the study 
report upon study completion. 
12.4. 
Informed Consent Process 
Note: All references to “subject” in this section refer to the study subject or his/her legally 
authorized representative. 
The Sponsor (or its designee) will provide Investigators with an ICF for this study. Investigators 
may adapt the information to suit the needs of their institution, if necessary (although it must 
reflect the required elements of informed consent specified in 21 Code of Federal Regulations 
[CFR] Part 50.25). The final ICF must be accepted by the Sponsor and approved by the EC. 
Investigators must provide the Sponsor with an unsigned copy of the final ICF before and after it 
is approved by the EC. If any new information becomes available that might affect subjects’ 
willingness to participate in the study, or if any amendments to the protocol require changes to 
the ICF, the Sponsor will provide Investigators with a revised ICF. 
Prior to participating in any study-related procedure, each subject must sign and date an 
EC-approved ICF written in a language the subject can understand. The ICF should be as 


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nontechnical as practical and understandable to the subject. The ICF must provide the subject 
with all the information necessary to make an informed decision about their participation in the 
study, including the nature and intended purpose of the study, possible benefits, possible risks, 
and disclosures of the subject’s personal and personal health information for purposes of 
conducting the study. The ICF details the requirements of the participant and the fact that he/she 
is free to withdraw at any time without giving a reason and without prejudice to his/her further 
medical care. The ICF should also include a statement educating subjects about the continued 
scientific importance of their data if they discontinue study treatment early or withdraw from the 
study. Before informed consent is obtained, the subject should be given ample time and 
opportunity to inquire about the details of the study. All questions must be answered to the 
satisfaction of the subject. 
Once signed, the original ICF will be stored in the Investigator’s site file and made available for 
review by the Sponsor. Documentation of the informed consent discussion must be noted in the 
subject’s case history. All subjects will receive a copy of their signed and dated ICF. 
If the ICF is revised during the study and requires the subject to be re-consented, informed 
consent will be obtained in the same manner as for the original ICF. 
12.5. 
Confidentiality 
All information provided by Heron Therapeutics, Inc. and all data and information generated by 
the site as part of the study (other than a subject’s medical records) will be kept confidential by 
the Investigator and site staff. This information and data will not be used by the Investigator or 
other site personnel for any purpose other than conducting the study and will not be released to 
any unauthorized third party without prior written approval of the Sponsor. These restrictions do 
not apply to the following: 1) information that becomes publicly available through no fault of the 
Investigator or site staff, 2) information that must be disclosed in confidence to an EC solely for 
the evaluation of the study results, 3) information that must be disclosed in order to provide 
appropriate medical care to a study subject, or 4) study results that may be published as 
described in Section 13.7. If a written contract for the conduct of the study is executed and that 
contract includes confidentiality provisions inconsistent with this statement, that contract’s 
confidentiality provisions shall apply rather than this statement; provided, however, that the 
confidentiality provisions in any written contract shall not be less restrictive than this statement. 
The Investigator agrees to comply with all applicable national, state, and local laws and 
regulations relating to the privacy of a subject’s health information. The Investigator shall ensure 
that study subjects authorize the use and disclosure of protected health information in accordance 
with the privacy regulations of the Health Insurance Portability and Accountability Act (HIPAA) 
and in a form satisfactory to the Sponsor. 
The subject’s contact information will be securely stored at each clinical site for internal use 
during the study. Throughout the study, a subject’s source data will only be linked to the 
Sponsor’s clinical study database or documentation via a unique identification number. Copies of 
any subject source documents that are provided to the Sponsor must have certain personally 
identifiable information removed (ie, subject name, address, and other identifier fields not 
collected in the subject’s eCRF). At the end of the study, all records will continue to be kept in a 
secure location for as long a period as dictated by the EC and institutional regulations. 


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To comply with ICH guidelines for GCP and to verify compliance with this protocol, the 
Sponsor requires that the Investigator permit its monitor or designee’s monitor, representatives 
from any regulatory authority, the Sponsor’s designated auditors, and the appropriate ECs to 
review the subject’s original medical records (source data or documents), including, but not 
limited to, clinical laboratory test result reports, ECG reports, admission and discharge 
summaries for hospital admissions occurring during a subject’s study participation, and autopsy 
reports. Access to a subject’s original medical records requires the specific authorization by the 
subject as part of the informed consent process (Section 12.4). 


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13. 
STUDY ADMINISTRATION 
13.1. 
Clinical Monitoring 
The Sponsor (or its designee) is responsible for ensuring the proper conduct of the study. This 
includes ensuring the subjects’ rights and well-being are protected, the conduct of the study is 
within compliance of an approved protocol and GCPs, and the integrity of the data are accurate, 
complete, and verifiable from source documentation. During the study, the Sponsor’s study 
monitors will contact the study site via site visits or remote monitoring (eg, telephone calls, 
emails, and letters) in order to review study progress and the eCRF completion and to address 
any concerns or questions regarding the study conduct. During monitoring visits, the following 
aspects of study conduct will be carefully reviewed: subjects’ informed consent process and 
documents, the site’s essential documents, subject recruitment procedures, subjects’ compliance 
with the study procedures, source-data verification, drug accountability, use of concomitant 
therapy by subjects, AE and SAE documentation and reporting, and the quality of data. 
13.2. 
Data Monitoring Committees 
An IRC will review the summary-level unblinded PK, safety, and efficacy data during the 
conduct of the study and may interrupt or stop enrollment, or modify the protocol to enhance 
subject safety without adapting the study design. The IRC will be composed of Sponsor 
representatives from the Clinical Research, Biometrics, Pharmacovigilance, Regulatory, and 
Pharmaceutical and Translational Sciences functions, and an external expert in critical care 
medicine. The IRC will operate under a written, detailed IRC Charter. 
13.3. 
Source Documents and Record Retention 
Each study site will maintain study documents and records as specified in ICH E6, Section 8 
(Essential Documents for the Conduct of a Clinical Trial) and as required by regulatory 
authorities and institutional requirements. These include, but are not limited to the following: the 
study protocol, eCRF, delegation of authority log, pharmacy dispensing records, drug 
accountability logs, AE reports, subject source data (original or certified copies), correspondence 
with regulatory authorities and ECs, ICFs, monitoring visit logs and records, laboratory 
certification or quality control procedures, and laboratory reference ranges and reports. Access to 
study documents and records will be strictly controlled (Section 12.5). 
Study documents and records must be retained for at least 2 years after the last approval of a 
marketing application in the US and until there are no pending or contemplated marketing 
applications in the US or until at least 2 years have elapsed since the formal discontinuation of 
clinical development of the test product. However, these documents must be retained for a longer 
period if required by applicable regulatory requirements or if agreed to in the Clinical Trial 
Agreement. It is the responsibility of the Sponsor to inform the site as to when these documents 
no longer need to be retained. 
13.4. 
Management of Protocol Amendments and Deviations 
13.4.1. 
Protocol Amendments 
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13.4.2. 
Protocol Deviations 
A protocol deviation is a change, divergence, or departure from the study design or procedures 
defined in this protocol. The Investigator will notify the EC of any protocol deviations as 
required by EC guidelines and site requirements. Protocol deviations will be documented at the 
site and in the Sponsor files. 
13.5. 
Financial Disclosure 
The Sponsor will determine whether the study is a Covered Clinical Study and is subject to 
21 CFR Part 54, Financial Disclosure by Clinical Investigators. 
For a Covered Clinical Study, Investigators are required to inform the Sponsor of all disclosable 
financial interests or arrangements (including those of their spouse and dependent children), 
prior to study initiation at the site, at study completion, and any changes after 1 year after study 
completion in accordance with 21 CFR Part 54. In addition, the Investigator or subinvestigators 
must promptly notify the Sponsor if there are any reportable changes that occur during the above 
described period. 
Disclosable financial interests or arrangements, or the absence thereof will be recorded on the 
Financial Disclosure for Clinical Investigators Form. 
Any Investigator(s) added as investigational staff to the FDA 1572 form must complete the 
Financial Disclosure for Clinical Investigators Form at the start of his/her participation in the 
study. 
13.6. 
Termination of the Study or Closure of a Study Site 
If the Sponsor, Investigator, or officials from regulatory agencies discover conditions arising 
during the study that indicate that the study should be halted or that a study site should be closed, 
this action may be taken after appropriate consultation between the Sponsor and Investigator(s). 
13.6.1. 
Study Termination 
If the study is terminated early by the Sponsor, written notification documenting the reason for 
study termination will be provided to the Investigator and regulatory authorities. The Investigator 
will promptly inform the EC and provide the reason(s) for study termination. 
13.6.2. 
Closure of a Study Site 
If the Sponsor, Investigator, or officials from regulatory agencies discover conditions arising 
during the study that indicate that a study site should be closed, this action may be taken after 
appropriate consultation between the Sponsor and Investigator(s). Reasons for closing a site 
include, but are not limited to, the following: 
• Failure of the Principal Investigator to comply with the protocol, GCP regulations and 
guidelines, or local requirements. 
• Insufficient adherence to protocol requirements or an unacceptably high rate of 
missing, erroneous, or improperly collected data. 
• Insufficiently complete and/or evaluable data. 


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• Inadequate recruitment of subjects by the Investigator. 
• Sponsor decision. 
If a study site is closed by the Sponsor, written notification documenting the reason for study site 
closure will be provided to the Investigator and regulatory authorities. The Investigator will 
promptly inform the EC and provide the reason(s) for study site closure. 
13.7. 
Publication and Information Disclosure Policy 
All information provided by the Sponsor and all data and information generated by the site as 
part of the study (other than a subject’s medical records) are the sole property of Heron 
Therapeutics, Inc. 
For clinical interventional studies in patients, Heron will post study results on websites such as 
https://clinicaltrials.gov/ and https://eudract.ema.europa.eu/ in accordance with FDA and 
European Union reporting rules. Regardless of study outcome, Heron commits to submit for 
publication results of its interventional clinical studies according to the prespecified plans for 
data analysis. Wherever possible, Heron also plans to submit for publication the results of any 
nonclinical or technology studies while protecting any proprietary information. 
Any publication or presentation of the results of this study may only be made in compliance with 
the provisions outlined in the executed Clinical Trial Agreement. Heron has developed a policy 
for the publication of scientific and clinical data that follows the recommendations of the 
International Committee of Medical Journal Editors (ICMJE), the Consolidated Standards of 
Reporting Trials (CONSORT) group, and Good Publication Practice (GPP). A copy of this 
policy will be made available to the Investigator upon request. 
When the study is completed or prematurely terminated, the Sponsor or designee will ensure a 
Clinical Study Report is written in compliance with ICH E3 (Structure and Content of Clinical 
Study Reports) and submitted to the regulatory authorities, as required by the applicable 
regulatory requirement(s). Where required by applicable regulatory requirements, the 
Investigator signatory will be identified for the approval of the Clinical Study Report. The 
Investigator will be provided reasonable access to statistical tables, listings, and figures, as well 
as relevant reports, and will have the opportunity to review the complete study results. 
 


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14. 
REFERENCE LIST 
Bhatia M, Moochhala S. Role of inflammatory mediators in the pathophysiology of acute 
respiratory distress syndrome. J Pathol 2004;202(2):145-156. 
CINVANTI USPI. CINVANTI (aprepitant) injectable emulsion, for intravenour use. San Diego, 
CA: Heron Therapeutics, Inc; October 2019. 
Coomes EA, Haghbayan H. Interleukin-6 in COVID-19: A systematic review and meta-analysis.  
2020. 
EMEND IV USPI. EMEND (fosaprepitant) for injection, for intravenous use. Whitehouse 
Station, NJ: Merk and CO., Inc.; November 2019. 
EMEND Oral USPI. EMEND (aprepitant) capsules, for oral use; EMEND (aprepitant) for oral 
suspension. Whitehouse Station, NJ: Merck and Co., Inc; November 2019. 
Espiritu RF, Pittet JF, Matthay MA, Goetzl EJ. Neuropeptides in pulmonary edema fluid of adult 
respiratory distress syndrome. Inflammation 1992;16(5):509-517. 
Herold T, Jurinovic V, Arnreich C, et al. Level of IL-6 predicts respiratory failure in hospitalized 
symptomatic COVID-19 patients.  2020. 
Liu X, Wang XJ. Potential inhibitors against 2019-nCoV coronavirus M protease from clinically 
approved medicines. J Genet Genomics 2020;47(2):119-121. 
Mao S, Li C, Sun H. Aprepitant, a NK1 receptor antagonist, improves both airway inflammation 
and depressive-like behaviors in a rat model with asthma and depression. Int J Clin Exp Med 
2016;9(6):9504-9512. 
Mashaghi A, Marmalidou A, Tehrani M, Grace PM, Pothoulakis C, Dana R. Neuropeptide 
substance P and the immune response. Cell Mol Life Sci 2016;73(22):4249-4264. 
Noronha V, Bhattacharjee A, Patil VM, et al. Aprepitant for Cough Suppression in Advanced 
Lung Cancer: A Randomized Trial. Chest 2020. 
O'Connor TM, O'Connell J, O'Brien DI, Goode T, Bredin CP, Shanahan F. The role of substance 
P in inflammatory disease. J Cell Physiol 2004;201(2):167-180. 
Onder G, Rezza G, Brusaferro S. Case-Fatality Rate and Characteristics of Patients Dying in 
Relation to COVID-19 in Italy. JAMA 2020. 
Poston JT, Patel BK, Davis AM. Management of Critically Ill Adults With COVID-19. JAMA 
2020. 
Puneet P, Moochhala S, Bhatia M. Chemokines in acute respiratory distress syndrome. Am J 
Physiol Lung Cell Mol Physiol 2005;288(1):L3-15. 


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Quartara L, Maggi CA. The tachykinin NK1 receptor. Part II: Distribution and 
pathophysiological roles. Neuropeptides 1998;32(1):1-49. 
Rodriguez-Morales AJ, Cardona-Ospina JA, Gutierrez-Ocampo E, et al. Clinical, laboratory and 
imaging features of COVID-19: A systematic review and meta-analysis. Travel Med Infect Dis 
2020:101623. 
Sampson HA, Munoz-Furlong A, Campbell RL, et al. Second symposium on the definition and 
management of anaphylaxis: summary report--Second National Institute of Allergy and 
Infectious Disease/Food Allergy and Anaphylaxis Network symposium. J Allergy Clin Immunol 
2006;117(2):391-397. 
Sio SW, Ang SF, Lu J, Moochhala S, Bhatia M. Substance P upregulates cyclooxygenase-2 and 
prostaglandin E metabolite by activating ERK1/2 and NF-kappaB in a mouse model of burn-
induced remote acute lung injury. J Immunol 2010;185(10):6265-6276. 
Spitsin S, Tebas P, Barrett JS, et al. Antiinflammatory effects of aprepitant coadministration with 
cART regimen containing ritonavir in HIV-infected adults. JCI Insight 2017;2(19). 
Suvas S. Role of Substance P Neuropeptide in Inflammation, Wound Healing, and Tissue 
Homeostasis. J Immunol 2017;199(5):1543-1552. 
Tebas P, Spitsin S, Barrett JS, et al. Reduction of soluble CD163, substance P, programmed 
death 1 and inflammatory markers: phase 1B trial of aprepitant in HIV-1-infected adults. AIDS 
2015;29(8):931-939. 
Weiss P, Murdoch DR. Clinical course and mortality risk of severe COVID-19. Lancet 
2020;395(10229):1014-1015. 
Wong SS, Sun NN, Lantz RC, Witten ML. Substance P and neutral endopeptidase in 
development of acute respiratory distress syndrome following fire smoke inhalation. Am J 
Physiol Lung Cell Mol Physiol 2004;287(4):L859-866. 
Wu C, Chen X, Cai Y, et al. Risk Factors Associated With Acute Respiratory Distress Syndrome 
and Death in Patients With Coronavirus Disease 2019 Pneumonia in Wuhan, China. JAMA 
Intern Med 2020. 
 


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APPENDIX A. CYTOKINE PANELS 
Table 3: 
Cytokine Storm Testing for SARS-CoV-2/COVID-19 
Test/Abbreviation 
Full name 
A2Macro 
Alpha-2-macroglobulin 
AAT 
α1-antitrypsin 
Adiponectin 
Adiponectin 
B2M 
β2 microglobulin 
BDNF 
Brain-derived neurotrophic factor  
C3 
Complement component 3 
CRP 
C-reactive protein 
EN-RAGE 
Extracellular newly identified RAGE binding protein 
Eotaxin-1 
Eotaxin-1 
Ferritin 
Ferritin 
Fibrinogen 
Fibrinogen 
Gm-CSF 
Granulocyte-macrophage colony-stimulating factor 
Haptoglobin 
Haptoglobin 
ICAM-1 
Intercellular adhesion molecule 1 
IFN-gamma 
Interferon 
IgA 
Immunoglobulin A 
IgM 
Immunoglobulin M 
IL-1 alpha 
Interleukin 1 alpha 
IL-1 beta 
Interleukin -1 beta 
IL-10 
Interleukin -10 
IL-12p40 
Interleukin -12p40 
IL-12p70 
Interleukin -12p70 
IL-18 
Interleukin -18 
IL-18 
Interleukin -18 
IL-1ra 
Interleukin -1ra 
IL-2 
Interleukin -2 
IL-23 
Interleukin -23 
IL-3 
Interleukin -3 
IL-4 
Interleukin -4 
IL-5 
Interleukin -5 
IL-6 
Interleukin -6 
IL-7 
Interleukin -7 


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Test/Abbreviation 
Full name 
IL-8 
Interleukin -8 
Lp(a) 
Lipoprotein (a) 
MCP-1 
Monocyte chemoattractant protein-1 
MIP-1 alpha 
Macrophage inflammatory protein-1 
MIP-1 beta 
Macrophage inflammatory protein-1 
MMP-3 
Matrix metalloproteinase 3 
MMP-9 
Matrix metalloproteinase 3 
Myoglobin 
Myoglobin 
PAI-1 
Plasminogen activator inhibitor 1  
PARC 
Pulmonary and activation-regulated chemokine  
RANTES 
Regulated on activation normal T cell expressed and secreted 
SAP 
SLAM-associated protein 
SCF 
Stem cell factor  
TBG 
Thyroxine-binding globulin 
TIMP-1 
Metallopeptidase inhibitor 1 
TNF-alpha 
Tumor necrosis factor alpha 
TNF-beta 
Tumor necrosis factor beta 
TNFRS 
Tumor necrosis factor receptors 
VCAM-1 
Vascular cell adhesion molecule-1 
VDBP 
Vitamin D-binding protein 
VEGF 
Vascular endothelial growth factor 
vWF 
von Willebrand factor 
 




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APPENDIX B. POST-DISCHARGE ASSESSMENTS 
The subject will be contacted on Days 15, 22, 29, and 57 to collect information for the Days 14, 
21, 28, and 56 assessments, respectively. 
NIAID 8-Point Ordinal Scale of Clinical Status 
Record the worst (ie, lowest ordinal) score for that assessment day’s 24-hour period (from 00:00 
to 23:59 hours). For example, for Day 21, record the worst (ie, lowest ordinal) score that 
occurred on Day 21 from 00:00 to 23:59 hours. 
1. Death. 
2. Hospitalized, on invasive mechanical ventilation or extracorporeal membrane 
oxygenation (ECMO). 
3. Hospitalized, on noninvasive ventilation or high-flow oxygen devices. 
4. Hospitalized, requiring low-flow supplemental oxygen. 
5. Hospitalized, not requiring supplemental oxygen, requiring ongoing medical care 
(COVID-19–related or otherwise). 
6. Hospitalized, not requiring supplemental oxygen, no longer requiring ongoing medical 
care). 
7. Not hospitalized, limitation on activities and/or requiring home oxygen. 
8. Not hospitalized, no limitations on activities. 
Respiratory Status 
Record the worst respiratory status regarding oxygen supplementation (listed from lowest to 
highest, or worst, oxygen supplementation status) for that assessment day’s 24-hour period (from 
00:00 to 23:59 hours). For example, for Day 21, record the worst status that occurred on Day 21 
from 00:00 to 23:59 hours. 
• Room air. 
• Nasal cannula. 
• Face mask. 
• Noninvasive ventilation or high-flow oxygen devices.  
• ECMO. 
• Mechanical ventilation. 
 
 


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COVID-19 Symptoms 
Record each COVID-19 symptom from the list below as none, mild, moderate, or severe based 
on the average severity per subject report during the assessment day’s 24-hour period (from 
00:00 to 23:59 hours).  
None: 
Symptom not present. 
Mild: 
Event is easily tolerated by the subject, causes minimal discomfort, and does not 
interfere with everyday activities. 
Moderate: 
Event results in a low level of inconvenience or concern with the therapeutic 
measures. Moderate events may cause some interference with functioning. 
Severe: 
Event interrupts a participant’s usual daily activity and may require systemic drug 
therapy or other treatment. Severe events are usually potentially life-threatening or 
incapacitating. 
• Cough. 
• Fever. 
• Sore throat. 
• Loss of taste and/or loss of smell. 
• Malaise/Fatigue. 
• Headaches. 
• Myalgia. 
• Gastrointestinal symptoms. 
• Shortness of breath on exertion. 
• Shortness of breath at rest. 
Adverse Events 
Record any AEs since the last assessment. 


Signature Page for VV-CLIN-004590 v2.0
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Approval
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SAP_001.pdf: 
Document Type:  
Statistical Analysis Plan 
Official Title:  
A Phase 2 Randomized, Double-Blind, Placebo-Controlled 
Study of Aprepitant Injectable Emulsion in Early Hospitalized 
Adult Patients With COVID-19 
NCT Number:  
NCT04470622 
Document Date:  
22-Jun-2021 
 


Confidentiality Statement 
This document contains confidential information of Heron Therapeutics, Inc. 
Do not copy or distribute without written permission of the Sponsor. 
Any unauthorized use, reproduction, publication, or dissemination is strictly prohibited. 
STUDY HTX-019-202 
 
A Phase 2 Randomized, Double-Blind, Placebo-Controlled Study of Aprepitant 
Injectable Emulsion in Early Hospitalized Adult Patients With COVID-19 
 
22 June 2021 
 
Statistical Analysis Plan 
 
Version 1.0 
 
Prepared by: 
 
 PhD 
Heron Therapeutics, Inc. 
4242 Campus Point Court, Suite 200 
San Diego, CA 92121 
USA 
 
 
Upon review of this document, the undersigned approves the statistical analysis plan. The 
analysis methods are acceptable, and the table, listing, and figure shell production can begin. 
 
 
 
 
Approved by: 
 
 
 
Date:   
 
 
 PhD 
 
 
Heron Therapeutics, Inc. 
 
 
  
 
Approved by: 
 
 
 
 
Date: 
  
 
 
 MD 
 
Heron Therapeutics, Inc. 
 
 
  
 
 
 


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TABLE OF CONTENTS 
LIST OF ABBREVIATIONS AND DEFINITION OF TERMS ................................ 5 
1. 
ADMINISTRATIVE STRUCTURE ........................................................ 7 
1.1. 
Sponsor and Oversight .............................................................................. 7 
1.2. 
Data Quality Assurance ............................................................................ 7 
2. 
INTRODUCTION .................................................................................... 7 
3. 
OBJECTIVES ........................................................................................... 7 
4. 
INVESTIGATIONAL PLAN ................................................................... 8 
4.1. 
Overall Study Design and Plan ................................................................. 8 
4.2. 
Assessments .............................................................................................. 8 
4.3. 
Study Endpoints ...................................................................................... 10 
4.3.1. 
Primary Endpoint .................................................................................... 10 
4.3.2. 
Secondary Endpoints .............................................................................. 10 
 
 
5. 
GENERAL STATISTICAL CONSIDERATIONS ................................ 11 
5.1. 
Sample Size ............................................................................................ 12 
5.2. 
Randomization, Stratification, and Blinding .......................................... 12 
5.3. 
Analysis Populations .............................................................................. 13 
5.4. 
Layout of Summaries .............................................................................. 13 
5.5. 
Other Important Considerations ............................................................. 13 
5.5.1. 
Definition of Baseline ............................................................................. 13 
5.5.2. 
Calculation of Change and Percent Change from Baseline .................... 13 
5.5.3. 
Study Day Calculation for Reporting Purposes ...................................... 14 
5.5.4. 
Visit Windows ........................................................................................ 14 
5.5.5. 
Handling of Missing and Partial Data .................................................... 14 
5.5.6. 
Study-Wise Type I Error Control ........................................................... 14 
6. 
SUBJECT DISPOSITION ...................................................................... 14 
7. 
DEMOGRAPHICS, CHARACTERISTICS, AND MEDICAL 
HISTORY ............................................................................................... 15 
7.1. 
Demographics and Baseline Characteristics ........................................... 15 
7.2. 
Medical History ...................................................................................... 15 
7.3. 
Protocol Deviations ................................................................................ 15 
8. 
TREATMENTS AND MEDICATIONS ................................................ 16 


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8.1. 
Prior and Concomitant Medications ....................................................... 16 
8.2. 
Study Treatment ...................................................................................... 16 
9. 
EFFICACY ANALYSIS ........................................................................ 16 
9.1. 
Primary Endpoint .................................................................................... 16 
9.1.1. 
Proportion of Subjects Alive and Discharged From the Hospital at Day 
14 ............................................................................................................ 16 
9.2. 
Secondary Endpoints .............................................................................. 17 
9.2.1. 
Time to Death or Respiratory Failure ..................................................... 17 
9.2.2. 
Time to Discharge From Hospital .......................................................... 18 
9.2.3. 
Change From Baseline in Interleukin 6 at Each Specified Timepoint ... 18 
 
 
9.3.1. 
Proportion of Subjects Alive and Free of Respiratory Filure at Days 14, 
21, 28, and 56 .......................................................................................... 19 
9.3.2. 
Proportion of Subjects Alive and Discharged Fom the Hospital at Days 
21, 28, and 56 .......................................................................................... 19 
9.3.3. 
Proportion of Subjects Alive and Free of Invasive Mechanical 
Ventilation at Days 14, 21, 28, and 56 ................................................... 20 
9.3.4. 
Clinical Status Based on an 8-Point Ordinal Scale on Days 14, 21, 28, 
and 56 ...................................................................................................... 20 
9.3.5. 
Change from Baseline for CRP, Cytokines, Substance P, 
WBCs/Lymphocytes, and SARS-CoV-2 Viral Load ............................. 21 
9.3.6. 
Proportion of Subjects With Normalization of Fever and Oxygen 
Saturation ................................................................................................ 21 
9.3.7. 
Change From Screening in Chest X-Ray or CT Scan Results on Day 14
 ................................................................................................................ 22 
9.3.8. 
Time to Recovery ................................................................................... 22 
9.3.9. 
Overall Survival ...................................................................................... 23 
9.3.10. 
All-Cause Mortality Rate at Days 14, 21, 28, and 56 ............................. 23 
9.3.11. 
Proportion of Subjects Free of COVID-19 Symptoms at Days 14, 21, 28, 
and 56 ...................................................................................................... 23 
9.3.12. 
Proportion of Discharged Subjects With No New or Worsening COVID-
19 Symptoms After Discharge, at Any Time, and at Day 28 and Day 56
 ................................................................................................................ 24 
10. 
SAFETY ANALYSIS ............................................................................ 24 
10.1. 
Adverse Events ....................................................................................... 25 
10.1.1. 
Secondary Endpoint ................................................................................ 25 


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10.2. 
Clinical Laboratory Evaluations ............................................................. 27 
10.2.1. 
Hematology ............................................................................................. 28 
10.2.2. 
Serum Chemistry .................................................................................... 28 
10.2.3. 
Other Laboratory Parameters .................................................................. 29 
10.3. 
Vital Sign Measurements ........................................................................ 29 
10.4. 
Electrocardiogram ................................................................................... 30 
10.5. 
Physical Examination ............................................................................. 30 
11. 
INTERIM ANALYSIS ........................................................................... 30 
11.1. 
Data Safety Monitoring Board ................................................................ 31 
12. 
REFERENCES ....................................................................................... 31 
APPENDIX A. IMPUTATION OF PARTIAL AND MISSING DATES ............. 32 
APPENDIX B. DOCUMENT REVISION HISTORY ........................................... 33 


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LIST OF ABBREVIATIONS AND DEFINITION OF TERMS 
Abbreviation 
Definition 
AE 
Adverse event 
AESI 
Adverse event of special interest 
ALT 
Alanine aminotransferase 
ARDS 
Acute respiratory distress syndrome 
BID 
Twice daily 
CFR 
Code of Federal regulations 
CINV 
Chemotherapy-induced nausea and vomiting 
COVID-19 
Coronavirus disease 
CRP 
C-reactive protein 
CT 
Computed tomography 
CYP 
Cytochrome P450 
DBP 
Diastolic blood pressure 
EC 
Ethics committee 
ECG 
Electrocardiogram/electrocardiographic 
ECMO 
Extracorporeal membrane oxygenation 
eCRF 
Electronic case report form 
EDC 
Electronic data capture 
FDA 
Food and Drug Administration 
GCP 
Good Clinical Practice 
IB 
Investigator’s Brochure 
ICH 
International Council for Harmonisation  
IL 
Interleukin 
INR 
International Normalized Ratio 
IRC 
Interim review committee 
ITT 
Intent-to-Treat 
IV 
Intravenous(ly) 
IVIg 
Intravenous immunoglobulin  
JAK 
Janus kinase 
KM 
Kaplan-Meier 
NIAID 
National Institute of Allergy and Infectious Diseases 
NK1 
Neurokinin-1 
PK 
Pharmacokinetic(s) 


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Abbreviation 
Definition 
PONV 
Postoperative nausea and vomiting 
PSRMC 
Product Safety and Risk Management Committee  
PT 
Preferred term 
QD 
Once daily 
qPCR 
Quantitative polymerase chain reaction 
QTcF 
QT interval corrected using Fridericia’s formula 
SAE 
Serious adverse event 
SAP 
Statistical analysis plan 
SAR 
Severe adverse reaction 
SARS-CoV-2 
Severe acute respiratory syndrome coronavirus 2 
SBP 
Systolic blood pressure 
SOC 
System Organ Class 
SP 
Substance P 
SpO2 
Oxygen saturation 
TEAE 
Treatment-emergent adverse event 
ULN 
Upper limit of normal 
US 
United States 
WBC 
White blood cell 
Note: Abbreviations defined in the text but not used again in the text are not included in this List of 
Abbreviations. Abbreviations used only in tables or figures are also excluded from this List of 
Abbreviations; they are defined in the table or figure footnotes. 
 


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1. 
ADMINISTRATIVE STRUCTURE 
1.1. 
Sponsor and Oversight 
This study is being conducted under the sponsorship of Heron Therapeutics, Inc. (Heron). 
Data management (DM) will be performed by Heron and the statistical analyses will be 
performed under contract with 
, with oversight from 
Heron. 
. 
1.2. 
Data Quality Assurance 
The Clinical Operations and Biostatistics departments will collaborate to ensure that the data 
collected and analyzed for this study are of the highest quality possible and meet the data 
standards set for the study. This will be accomplished in part through programmed edit 
checks, which will be reviewed by the data managers, statisticians, programmers, and other 
team members on an ongoing basis to evaluate whether any checks need to be added or any 
existing checks need to be modified. In addition, periodic reviews of listings of accumulating 
data, assessment of data query trends, and resulting retraining of study site personnel will be 
performed to further ensure data quality.  
2. 
INTRODUCTION  
This statistical analysis plan (SAP) presents a detailed plan of the statistical methods to be 
used during the reporting and analysis of efficacy and safety data collected in this Phase 2 
study. This SAP does not include the planned analysis and reporting of pharmacokinetics 
(PK) assessments in the study. Planned PK analysis will be presented in a separate PK 
analysis plan. 
This SAP was prepared prior to data analysis to provide full details of analyses to be 
presented in the clinical study report (CSR), including a technical and detailed elaboration of 
the statistical analysis methods presented in the protocol. Revisions can be made to this SAP 
while the study is ongoing; however, it must be finalized prior to database lock. Any 
deviations from the analysis plan provided in the SAP will be fully documented in the final 
CSR. 
This SAP should be read in conjunction with the study protocol and the electronic case report 
forms (eCRFs). Methods described in the SAP supersede any methods or analyses described 
in the study protocol.   
3. 
OBJECTIVES 
Primary Objective: 


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• To assess the effect of aprepitant injectable emulsion on the clinical status of 
coronavirus disease (COVID-19) in hospitalized patients with confirmed severe 
acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection. 
Secondary Objectives: 
• To evaluate the safety and tolerability of daily administration of aprepitant 
injectable emulsion in hospitalized patients with COVID-19. 
• To assess the pharmacokinetics (PK) of aprepitant following daily dosing of 
aprepitant injectable emulsion to hospitalized patients with COVID-19. 
• To evaluate the impact of aprepitant injectable emulsion on the inflammatory 
response mediated by cytokines. 
4. 
INVESTIGATIONAL PLAN 
4.1. 
Overall Study Design and Plan 
This is a Phase 2 randomized, double-blind, placebo-controlled study in which approximately 
100 subjects will receive their randomized treatment in addition to Investigator standard of 
care for the treatment of COVID-19. 
Subjects will be screened less than 48 hours of hospitalization to determine eligibility to enter 
the study. Eligible subjects will be randomized in a 1:1 ratio in a parallel manner to receive 
aprepitant injectable emulsion or saline placebo administered once daily (QD) as a 2-minute 
IV injection for 14 days. 
Standard of care will be at the Investigator’s discretion generally following the COVID-19 
treatment protocol at the institution. 
Subjects will undergo PK, safety, and efficacy assessments. Safety assessments will include 
adverse events (AEs), clinical laboratory values (hematology and serum chemistry), vital 
signs, and electrocardiograms (ECGs). Detailed information regarding laboratory 
assessments, including sample collection procedures for PK and cytokines, will be provided 
in the laboratory manual. Efficacy assessments will include respiratory status, cytokine panel, 
SARS-CoV-2 viral load, COVID-19 symptoms, and the National Institute of Allergy and 
Infectious Diseases (NIAID) 8-point ordinal scale of clinical status. Subjects will be followed 
until death or Day 56, whichever occurs first. If discharged, the site will still contact subjects 
for efficacy and safety follow-up until Day 56. 
An interim review committee (IRC) will review the unblinded PK, safety, and efficacy data 
during the conduct of the study and may interrupt or stop enrollment, or modify the protocol 
to enhance subject safety without adapting the study design. 
4.2. 
Assessments 
Safety and efficacy assessments will be performed. 
Safety assessments will include the following: 
• AEs, serious adverse events (SAEs), and AEs of special interest (AESIs). 


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• Clinical laboratory values (hematology and serum chemistry).  
• Vital signs, including systolic blood pressure (SBP) and diastolic blood pressure 
(DBP), resting heart rate (HR), and temperature. 
• Electrocardiograms (ECGs). 
Information from standard-of-care diagnostic and safety laboratory tests will be provided to 
the Sponsor and recorded in the electronic case report form (eCRF). 
Efficacy assessments will include: 
• The NIAID 8-point ordinal scale of clinical status: 
1. Death. 
2. Hospitalized, on invasive mechanical ventilation or extracorporeal membrane 
oxygenation (ECMO). 
3. Hospitalized, on noninvasive ventilation or high-flow oxygen devices. 
4. Hospitalized, requiring low-flow supplemental oxygen. 
5. Hospitalized, not requiring supplemental oxygen, requiring ongoing medical 
care (COVID-19–related or otherwise). 
6. Hospitalized, not requiring supplemental oxygen, no longer requiring ongoing 
medical care. 
7. Not hospitalized, limitation on activities and/or requiring home oxygen. 
8. Not hospitalized, no limitations on activities. 
• Respiratory status: 
o Respiratory rate. 
o Oxygen supplementation. 
- Room air. 
- Nasal cannula. 
- Face mask. 
- Noninvasive ventilation or high-flow oxygen 
devices.  
- Mechanical ventilation. 
- ECMO. 
o Oxygenation: (oxygen saturation (SpO2) at rest or partial pressure 
of oxygen [PaO2]). 
o Chest X-ray or computed tomography(CT) scan findings (if 
available). 
• Cytokine panel.  


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• SARS-CoV-2 viral load by quantitative PCR (qPCR). 
• COVID-19 symptom assessment (4-point scale, 0=none, 1=mild, 2=moderate, 
3=severe): 
− Cough. 
− Fever. 
− Sore throat. 
− Loss of taste and/or loss of smell. 
− Malaise/fatigue. 
− Headaches.  
− Myalgia. 
− Gastrointestinal symptoms. 
− Shortness of breath on exertion. 
− Shortness of breath at rest. 
4.3. 
Study Endpoints 
4.3.1. 
Primary Endpoint 
• Proportion of subjects alive and discharged from the hospital at Day 14. 
4.3.2. 
Secondary Endpoints 
• Time to death or respiratory failure, whichever comes first. Respiratory failure is 
defined as any of the following: 
− Endotracheal intubation and mechanical ventilation. 
− Oxygen delivered by high-flow nasal cannula (heated, humidified, oxygen 
delivered via reinforced nasal cannula at flow rates >20 L/min). 
− Noninvasive positive pressure ventilation. 
− ECMO. 
• Time to discharge from hospital.  
• Incidence of treatment-emergent adverse events (TEAEs). 
• Change from Baseline in IL-6 at each specified timepoint. 
 
 
 
 
 
 
 


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5. 
GENERAL STATISTICAL CONSIDERATIONS 
Continuous data will be presented using descriptive statistics: number of subjects (n), mean, 
standard deviation (SD), median, minimum, and maximum. Descriptive statistics on efficacy 
measures will also include the standard error (SE). Categorical data will be summarized by 
the frequency and percent of subjects. Data will be displayed in all listings sorted by 
treatment group, subject number, and visit/study day. When count data are presented, the 
percent will be suppressed when the count is zero in order to draw attention to the non-zero 
counts. A row denoted “Missing” will be included in count tabulations where necessary to 
account for dropouts and missing values. The denominator for all percentages will be the 
number of subjects in that treatment group within the population of interest, unless otherwise 


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stated. Non-zero percentages will be rounded to one decimal place, except 100% will be 
displayed without any decimal places. Additional rounding rules are as follows: 
• If the original value has 0 decimal places: mean, and median will have one 
decimal place and SD and SE will have 2 decimal places. 
• If the original value has 1 decimal place: mean, and median will have 2 decimal 
places and SD and SE will have 3 decimal places. 
• If the original value has 2 or more decimal places: mean, median, SD, and SE will 
all have 3 decimal places. 
Minimum and maximum will always have the same decimal places as the original measure, 
up to a maximum of 3 decimal places. The above rounding rules will not be applied to 
original measures displayed in listings. 
All p-values will be rounded to 4 decimal places. If a p-value is less than 0.0001, it will be 
reported as “<0.0001”.   
Values that are collected with “<” or “>” signs will be analyzed as the numerical value 
without the sign in tables and figures. In listings, these data will be reported as collected with 
the sign. 
All efficacy and safety data will be collected electronically. Datasets will be created using the 
Study Data Tabulation Model (SDTM) v. 1.4 or higher, conforming to the SDTM 
Implementation Guide (SDTMIG) v. 3.2 or higher. Datasets, tables, listings, and figures will 
be programmed using SAS® v. 9.4 or higher.   
5.1. 
Sample Size 
The sample size was selected empirically without formal statistical hypotheses or 
assumptions. 
5.2. 
Randomization, Stratification, and Blinding 
Subjects who meet the Screening eligibility criteria will be randomized in a 1:1 ratio in a 
parallel manner to receive aprepitant injectable emulsion 130 mg or saline placebo 
administered once daily as a 2-minute IV injection for 14 days. Subjects will be randomized 
using a centralized computer-generated blocked randomization algorithm and assigned using 
an interactive response technology (IRT) system. All randomization information will be kept 
in a secure location accessible only by the randomization personnel, the assigned 
Pharmacist(s) and his/her verifier, and the unblinded clinical monitor. No subject may 
receive study drug prior to randomization. 
This study will use a double-blind design. Subjects, Investigators, and site staff will be 
blinded to treatment assignment until after database lock. The site’s pharmacy will not be 
blinded to the treatment assignments because aprepitant injectable emulsion is supplied as an 
opaque, off-white to amber emulsion, whereas saline placebo is not. The pharmacy will 
prepare study drug for administration and provide a covering for the syringe and infusion line 
to blind the contents. 


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The study blind should not be broken except in medical emergencies when the appropriate 
management of the subject requires knowledge of the study drug he/she received. 
5.3. 
Analysis Populations 
Intent-to-Treat (ITT) Population: All subjects who are randomized will be included in the 
ITT Population. This population will be used as the primary analysis population for all 
efficacy endpoints. The randomized treatment assignment will be used for analysis in this 
population. 
Safety Population: All subjects who receive study drug will be included in the Safety 
Population. This population will be used for all summaries of safety data. The actual 
treatment received will be used for analysis in this population. 
5.4. 
Layout of Summaries 
Table 1 displays the planned treatment groups being studied. 
Table 1. Layout of Treatment Groups 
Study Phase 
Treatment Group 
Planned 
Sample Size 
2 
Aprepitant injectable emulsion 130 mg/18 mL  
50 
 
Saline placebo  
50 
 
Unless otherwise specified, efficacy and safety analyses will be summarized by treatment 
group (Table 2). 
Table 2. Layout of Summary 
Aprepitant 130 mg (18 mL) 
Saline placebo  
  
  
  
  
  
  
  
 
5.5. 
Other Important Considerations 
5.5.1. 
Definition of Baseline 
Baseline data are defined as the last observed measurement collected, whether scheduled or 
unscheduled, prior to the start of study drug administration.   
5.5.2. 
Calculation of Change and Percent Change from Baseline 
Change from Baseline to any timepoint t (Ct) is calculated as follows: 
 
Ct = Mt – MB, where: 
• Mt is the measurement of interest at timepoint t. 


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• MB is the measurement of interest at Baseline. 
Percent change from Baseline to any timepoint (Pt) is calculated as follows: 
 
Pt = 100*(Ct/MB). 
5.5.3. 
Study Day Calculation for Reporting Purposes 
The following convention will be used to calculate study day for reporting purposes: 
• The study day of start of study drug administration is Study Day 1. 
• For measurements that are on or after the date of start of study drug 
administration:  
o Study Day = date of measurement – date of start of study drug 
administration + 1. 
• For measurements that are prior to the date of start of study drug administration: 
o Study Day = date of measurement – date of start of study drug 
administration. 
5.5.4. 
Visit Windows 
Unless otherwise specified, analyses and summaries by visit will use nominal visits. No 
programmatically defined visit windows will be applied to map unscheduled or early 
termination visits to nominal scheduled visits. 
5.5.5. 
Handling of Missing and Partial Data 
Methods for missing data will be described for each efficacy endpoint in Section 9.   
No imputation of missing safety data will be performed except in the case of partial AE and 
concomitant medication onset dates (Appendix A). 
5.5.6. 
Study-Wise Type I Error Control 
Unless otherwise specified, all statistical hypothesis testing will be 2-sided using α = 0.05.   
6. 
SUBJECT DISPOSITION 
The number and percentage of subjects in each analysis population will be summarized. 
Subject disposition, including the number of subjects enrolled (signed the Informed Consent 
Form), subjects who failed screening with reason for screening failure, subjects in the ITT 
Population, subjects in the Safety Population, subjects completing scheduled treatment prior 
to discharge, primary reason for discontinuation from study drug, subjects completing the 
study (completing through Day 56 Visit or death), and subjects not completing the study by 
reason for withdrawal will be summarized.   


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7. 
DEMOGRAPHICS, CHARACTERISTICS, AND MEDICAL 
HISTORY 
7.1. 
Demographics and Baseline Characteristics 
Subject demographics and baseline characteristics will be summarized for the ITT 
Population, and the Safety Population (if different from the ITT Population) and will include 
age, age category, sex, race, ethnicity, height, weight, and body mass index (BMI). Chest 
imaging results will also be summarized if available. Baseline height and weight 
measurements will be conducted at Screening and BMI will be derived based on BMI = 
(Weight in kilograms [kg])/(height in meters [m])2. A subject’s age in years is calculated 
using the integer part of the difference in number of days between the date that informed 
consent is signed and date of birth divided by 365.25, or is recorded directly on the eCRF. 
The number and percentage of subjects in the following age categories will be presented: 18-
44, 45-54, 55-64, 65-74, 75-84, and ≥85. Demographics will also be presented for all subjects 
enrolled who fail screening. 
7.2. 
Medical History 
Medical history comorbidities will be summarized based on confirmation of comorbidity for 
each comorbidity by frequency and percentage of subjects for the safety population.   
7.3. 
Protocol Deviations 
Deviations from the protocol will be recorded. Protocol deviations will be classified into, but 
not necessarily limited to, the following categories: 
• Informed Consent Form procedures. 
• Eligibility criteria. 
• Prohibited concomitant medication/therapy. 
• Study procedures not done. 
• Safety reporting. 
• Study drug dosing/administration. 
• Out of window procedure. 
• Other. 
Classification of deviations as major protocol deviations will be decided on a case-by-case 
basis. All protocol deviations and major protocol deviations will be presented in a summary 
table by protocol deviation category for the ITT Population and the Safety Population (if 
different from the ITT Population). All protocol deviations will also be listed. 


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8. 
TREATMENTS AND MEDICATIONS 
8.1. 
Prior and Concomitant Medications 
Prior medications are defined as medications with a stop date occurring before Day 1. 
Concomitant medications are defined as medications that are ongoing on Day 1 or with a 
start date occurring on or after Day 1. Medications with start and stop dates which bracket 
Day 1, or for which missing start and/or stop dates make it impossible to determine the prior 
or concomitant status, will be summarized as concomitant medications. 
All medications will be coded with the World Health Organization Drug Dictionary Global 
B3 Format (WHODrug Global B3), March 2020. 
Prior and concomitant medications will be summarized separately by drug class and generic 
drug name. At each level of summarization, a subject is counted once if that subject reports 1 
or more medications at that level. Drug class will correspond to the Anatomical Therapeutic 
Classification (ATC) Level 2 term. 
All prior and concomitant medications will be summarized for the Safety Population.   
8.2. 
Study Treatment 
Eligible subjects will be administered aprepitant injectable emulsion 130 mg (18 mL) or 
saline placebo (18 mL) once daily as a 2-minute IV injection. 
Drug compliance will be calculated for each subject by taking into account whether a subject 
takes all doses of randomized drug as planned. The overall investigational drug compliance 
rate will be calculated as (the total number of doses administered/the total number of doses 
planned) *100. The number of planned doses is defined as the number of days through 
discharge (-1 day) or Day 14, whichever is less. Basic descriptive statistics will be 
summarized for drug compliance. In addition, the following summaries will be provided: 
• Total number of doses administered (n, mean, med, min, max). 
• Total number of doses planned (n, mean, med, min, max). 
• Total Number of full doses received (n, mean, med, min, max). 
• Subjects with full dose not administered by reason (n (%)). 
• Subjects with doses prolonged or interrupted by reason (n (%)). 
9. 
EFFICACY ANALYSIS 
For efficacy analyses, the date of randomization is considered as Day 1. 
9.1. 
Primary Endpoint 
9.1.1. 
Proportion of Subjects Alive and Discharged From the Hospital at Day 14 
The proportion of subjects alive and discharged from the hospital at Day 14 will be 
calculated as the number of subjects who are documented as being discharged alive from the 


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hospital, and have not subsequently died, on or before study Day 14, with day of 
randomization equal to Day 1, divided by the number of subjects randomized. The numerator 
is the number of subjects who are discharged alive, and have not subsequently died, on or 
before study Day 14 and who have a non-missing discharge date that is less than or equal to 
the date of randomization + 13 days.   
Subjects who are rehospitalized due to COVID-19 or COVID-19 sequelae and remain in 
hospital before Day 14 will not be considered as being discharged at Day 14. For example, if 
a subject was initially discharged on Day 8 and rehospitalized on Day 10 and was discharged 
a second time on Day 20, this subject is not considered to have met the primary endpoint 
criterion of discharged at Day 14. Subjects who are rehospitalized before Day 14 due to 
non-COVID-19 reasons will retain the original discharge date and will be considered to have 
met the primary endpoint criterion of discharged at Day 14.   
Subjects who are transferred from one hospital to another hospital will be considered as 
having a single uninterrupted hospitalization. The date of discharge will be from the second 
hospital. 
Fisher’s exact test will be used to compare differences in proportions across treatment arms. 
Summaries will be expressed as the frequency and percentage of subjects meeting the criteria 
of alive and discharged from hospital at Day 14 by treatment arm. Differences in proportions 
across treatment arms along with corresponding exact 95% CIs will also be presented. 
9.2. 
Secondary Endpoints 
9.2.1. 
Time to Death or Respiratory Failure 
Time to death or respiratory failure will be analyzed using Kaplan-Meier (KM) methods. KM 
plots will be presented by treatment arm and the log-rank test will be used to make 
comparisons between treatment arms. Median time to death or respiratory failure (if it can be 
estimated), 95% CIs, and p-values will be reported. Events will be defined as either time 
when the subject first meets any of the 4 criteria of respiratory failure or dies, whichever 
comes first. Subjects who never meet the criteria for respiratory failure and who are alive at 
the end of the study will be censored at the time of last assessment of respiratory status. 
Follow-up time starts when subjects are randomized. 
Respiratory failure is defined as:  
• Having an oxygen supplementation status of “Oxygen delivered by high-flow 
nasal cannula,” “Noninvasive positive pressure ventilation”, “ECMO”, or 
“Endotracheal intubation and mechanical ventilation”. 
For subjects who have an event (respiratory failure or death), the time to event will be 
calculated as: 
• Date of first occurrence of event – date of randomization + 1. 
For subjects who are censored, the time to event will be calculated as: 
• Date of last assessment of respiratory status – date of randomization + 1. 


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9.2.2. 
Time to Discharge From Hospital 
The analysis of time to discharge from hospital will be based on KM methods. KM plots will 
be presented by treatment arm and the log-rank test will be used to make comparisons 
between treatment arms. Number of events and number at risk will be presented in KM plots. 
Median time to discharge, 95% CIs, and p-values will be summarized. Subjects who are not 
discharged and are alive at the end of the study will be censored at the time of last contact. 
Follow-up time starts when subjects are randomized. 
Subjects who are rehospitalized due to COVID-19 or COVID-19 sequelae and remained in 
hospital will not be considered as being discharged. For example, if a subject was initially 
discharged on Day 8 and rehospitalized on Day 10 due to COVID-19 or COVID-19 sequelae 
and stays in the hospital, this subject is not considered to have a discharge event on Day 8. 
However, if this subject is discharged a second time on Day 20, the subject’s discharge date 
will be updated to Day 20. However, subjects who are rehospitalized due to non-COVID-19 
reasons will retain their original discharge date.   
Subjects who are transferred from one hospital to another hospital will be considered as 
having a single uninterrupted hospitalization. The date of discharge will be from the second 
hospital. 
Deaths that occur prior to being discharged alive from the hospital will be censored at the 
longest observed follow-up time across the 2 arms in the analysis. Censoring time for deaths 
should be set to the longest follow-up time among all subjects. The follow-up time includes 
the following 3 types:   
• For subjects who are discharged alive, set followup time as from date of 
randomization to date of discharge.  
• For subjects alive but not discharged, set followup time as from date of 
randomization to the end of study date, if available, or date of their last 
observation (including scheduled/unscheduled visits as well as log forms, such as 
AE/CM), if the end of study date is not available.  
• For subjects who died prior to being discharged, set followup time as from date of 
randomization to date of their death. 
For subjects who are discharged alive from the hospital, the time to discharge will be 
calculated as: 
• Date of discharge – date of randomization + 1. 
For subjects who are censored, the time to event will be calculated as: 
• Date of censoring – date of randomization + 1. 
9.2.3. 
Change From Baseline in Interleukin 6 at Each Specified Timepoint 
Individual and group changes from Baseline in interleukin (IL)-6 will be assessed across 
timepoints by treatment arm using both graphical and/or tabular presentations. Change from 
Baseline and percentage change from Baseline will be presented in graphical profiles across 
timepoints in spaghetti plots. Tabular summaries of change from Baseline and percentage 
change from Baseline will include descriptive statistics by post-Baseline timepoints. Tabular 


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presentations will include summary statistics (mean, median, min, max) presented at each 
scheduled timepoint, for minimum and maximum post-Baseline values, and for last post-
Baseline value. Analysis will be based on observed data. 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
   
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
   
 
 
 


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10. 
SAFETY ANALYSIS 
All analyses of safety data will be conducted using the Safety Population. Statistical 
hypothesis testing will not be performed on any safety results. No imputation of missing 
safety data will be performed except in the case of partial AE and concomitant medication 
onset dates (Appendix A). 
For safety analyses, the study day of start of study drug administration is Study Day 1. 


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10.1. 
Adverse Events 
An AE is defined as any untoward medical occurrence associated with the use of a drug in 
humans, whether or not considered drug related. A TEAE is any AE which occurs any time 
during or after study drug administration, or any AE with an onset prior to study drug 
administration that worsens during or after study drug administration. An AE may be any 
unfavorable and unintended sign (including an abnormal laboratory finding), symptom, or 
disease temporally associated with the use of a study drug, whether or not considered 
causally associated with the use of the study drug. Any abnormal laboratory value, vital sign 
result, or ECG finding deemed clinically significant by the Investigator, regardless of causal 
relationship, must be reported as an AE.  
For an event to be a TEAE, it must meet 1 of the following conditions: 
• Begins on Study Day 1, during or after administration of study drug. 
• Begins after Study Day 1. 
• Begins before Study Day 1 and worsens in severity during or after the Study 
Day 1 administration of study drug. 
AEs with unknown onset dates or unknown end dates will be counted as TEAEs unless it is 
known that the event resolves before study drug administration on Study Day 1.   
AEs will be coded using MedDRA version 23.0. Only TEAEs will be presented in AE tables, 
according to the SOC and PT. Any AEs that occur and resolve prior to Study Day 1 or are 
ongoing but do not worsen on or after Study Day 1 will be considered pretreatment AEs and 
will appear in the AE listing but not in TEAE tables. 
10.1.1. 
Secondary Endpoint 
10.1.1.1. Incidence of Treatment Emergent Adverse Events 
The incidence of TEAEs table will include only 1 occurrence of a PT per subject. If a subject 
reports the same PT multiple times, then that PT will only be incremented by 1 since subject 
counts will be presented. As with the PT, if a subject reports multiple TEAEs within the same 
SOC, then that SOC will only be incremented by 1 since subject counts will be presented. 
For tables showing incidence by SOC and PT, SOCs will be sorted by the internationally 
agreed order and PTs will be sorted within SOC in descending order of incidence for 
aprepitant. For tables showing incidence by PT only, the PTs will be sorted in descending 
order of incidence for aprepitant.   
An overall summary of TEAEs will be presented, and will include the following: 
• Number of TEAEs. 
• Number of subjects with at least 1 TEAE. 
• Number of subjects with at least 1 TEAE possibly related to study drug.  
• Number of subjects with at least 1 severe TEAE: 
o Number of subjects with at least 1 severe TEAE by severity. 


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• Number of subjects with at least 1 TEAE leading to discontinuation of study drug. 
• Number of subjects with at least 1 TEAE leading to study withdrawal. 
• Number of subjects with TEAEs that are AESIs. 
• Number of treatment-emergent SAEs (TESAEs): 
o Number of subjects with at least 1 TESAE by severity. 
• Number of subjects with at least 1 TESAE. 
• Number of subjects with fatal TEAEs. 
• Number of subjects with at least 1 TESAE possibly related to study drug. 
The incidence of all TEAEs will be presented by SOC and PT and separately by PT only.   
10.1.1.1.1. Relationship of Adverse Events to Study Drug 
The incidence of TEAEs possibly related to study drug will be presented in a table by SOC 
and PT.   
10.1.1.1.2. Severity of Adverse Event 
The incidence of severe TEAEs will be presented in a table by SOC and PT.     
10.1.1.1.3. Serious Adverse Events 
The seriousness of a TEAE should be assessed by the Investigator independently from the 
severity of the TEAE. An SAE is an AE occurrence that results in death, is life-threatening, 
requires inpatient hospitalization or prolongation of existing inpatient hospitalization, results 
in persistent or significant disability/incapacity, or is a congenital abnormality/birth defect. 
Important medical events that may not be immediately life-threatening or result in death, or 
require hospitalization may be considered SAEs when, based upon medical judgment, they 
may jeopardize the subject or may require intervention to prevent one of the outcomes listed 
above. 
Incidence of TESAEs will be presented in a table by SOC and PT. All SAEs will also be 
listed separately. 
Incidence of TESAEs related to study drug will also be summarized by SOC and PT. 
10.1.1.1.4. Death 
Any subject deaths during this study will be collected and presented in a listing. The 
information that is presented will include date of death, days on study, cause of death, and 
relationship of death to study drug. 
10.1.1.1.5. Adverse Events of Special Interest 
Incidence of AESIs will be presented by PT. Prespecified AEs that may be AESIs include the 
following: 
• Anaphylaxis. 


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• QT prolongation (>500 ms). 
AESIs will be ascertained from the Adverse Event Details form on the eCRF. If “Yes” was 
selected for “Was this an Anaphylaxis event?” or “Is this event a QT prolongation (QTcF) 
greater than 500 ms?” the AE would be considered an AESI. 
10.1.1.1.6. Adverse Events Leading to Study Withdrawal 
All TEAEs reported with “Withdrawal from study” checked on the eCRF will be presented in 
a listing. 
10.1.1.1.7. Adverse Events Leading to Discontinuation of Study drug 
All TEAEs reported with “Drug withdrawn” checked on the eCRF will be presented in a 
listing. The incidence of TEAEs leading to discontinuation of study drug will be presented in 
a table by SOC and PT. 
10.2. 
Clinical Laboratory Evaluations 
Laboratory assessments will be performed by a local laboratory (hematology, serum 
chemistry, and urine pregnancy test) and all summaries of local laboratory data will be based 
on the standard international (SI) units provided by the local lab. Sites will record the worst 
hematology and serum chemistry results from a daily 24-hour period. Associated laboratory 
parameters such as hepatic profile, renal function, and hematology values will be grouped 
and presented together.   
Summary tables for hematology and chemistry including actual values and change from 
Baseline values will be presented for clinical laboratory tests with numeric values. These 
tables will include at each scheduled visit (Screening, Day 1, Derived Baseline, at each day 
from Day 2 through Day 14, Day 21, Day 28, Day 35, Day 42, Day 49, Day 56, at Discharge) 
the highest postdose value, lowest postdose value, and the last postdose value. 
Laboratory data will also be summarized using shift tables where appropriate. Each subject’s 
hematology and serum chemistry values will be flagged as “low”, “normal”, or “high” 
relative to the normal ranges of the local laboratory. Shift tables will be produced showing 
the frequency of shifts from baseline to the minimum and maximum post-Baseline value, last 
post-Baseline value, and by visit. Laboratory parameters will also be summarized by visit. 
Laboratory data collected at unscheduled and early termination (if applicable) visits will be 
included in listings and will contribute to tables of shifts from Baseline and in tables showing 
changes from Baseline to highest value, lowest value, and last value. Unscheduled or early 
termination laboratory results will not be windowed for the purposes of assigning a nominal 
visit. 
Listings of laboratory values will include flags for values outside the local laboratory normal 
ranges that indicate how far out of the normal range a value is. For example, a value that is 
≥3 ×the upper limit of normal (ULN) but below 4 × ULN will have a “3H” flag. Flag 
multipliers will show values that are 1, 2, 3, 4, 5, and 10 times relative to the ULN, if high.  
Values that are below the lower limit of normal (LLN) will be flagged simply with “L”.   


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Listings of out-of-range values for hematology and chemistry will be presented separately in 
addition to listings of all laboratory values.  
10.2.1. 
Hematology 
The following laboratory tests will be included in hematology summary tables: hematocrit, 
hemoglobin, platelet count, absolute neutrophils, absolute lymphocytes, and total and 
differential WBC count (basophils, eosinophils, lymphocytes, monocytes, and neutrophils). 
In addition, change from Baseline in WBC count and lymphocytes will be analyzed using 
spaghetti plots showing individual subject data over time. Also, the number and percentage 
of subjects with a maximum lymphocyte count less than 0.82 × 103/L and greater than or 
equal to 0.82 × 103/L will be tabulated by treatment group. The maximum value for each 
subject will be based on all samples taken after the first dose of study drug. 
10.2.2. 
Serum Chemistry 
The following laboratory tests will be included in the serum chemistry summary tables: 
alanine aminotransferase (ALT), aspartate aminotransferase (AST), alkaline phosphatase 
(ALP), creatinine, glucose, total bilirubin, sodium, potassium, bicarbonate, total protein, 
albumin. 
Evaluation of drug-induced serious hepatotoxicity (eDISH) scatterplots of the highest 
postdose ALT within the 24 hour period vs. total bilirubin observed during the same 24 hour 
period as the highest postdose ALT value, and of the highest postdose AST within the 
24 hour period vs. total bilirubin observed during the same 24 hour period as the highest 
postdose AST value, will be produced. 
The incidence of subjects with out-of-range liver function values will be summarized at each 
visit for the following categories. Subjects with out-of-range liver function values will be 
presented in data listing as well. 
• ALT or AST: 
o >1 × ULN.  
o ≥2 × ULN. 
o ≥3 × ULN. 
o ≥4 × ULN. 
o ≥5 × ULN.  
• Total bilirubin ≥2 × ULN. 
• ALP: 
o ≥1.5 × ULN. 
o ≥2 × ULN. 
• ALT ≥3 × ULN and AST ≥3 × ULN (from same 24 hour period). 
• ALT ≥3 × ULN and total bilirubin ≥2 × ULN (from same 24 hour period). 
• AST ≥3 × ULN and total bilirubin ≥2 × ULN (from same 24 hour period). 




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Abbreviations: bpm, beats per minute; DBP, diastolic blood pressure; HR, heart rate; SBP, systolic blood 
pressure. 
10.4. 
Electrocardiogram 
The 12-lead ECGs will be performed at Screening and at each day from Day 2 to Day 14, 
Day 21, Day 28, Day 35, Day 42, Day 49, and Day 56. ECG parameters include HR 
(beats/min), PR interval (ms), RR interval (ms), QRS interval (ms), QT interval (ms), and QT 
interval corrected using Fridericia’s formula (QTcF) (ms). Overall interpretations of ECG 
results are also included.  
QTcF will be calculated and used in tabular summaries, according to,  
QTcF = QT interval / (RR interval)1/3.   
Site reported ECG parameters and calculated QTcF will be provided in listings. 
ECG assessments will be performed in triplicate only at Screening, where the mean value of 
the observed triplicates will be used for each ECG parameter. Only 12-lead ECGs, if 
performed, will be summarized. Summary statistics of ECG parameters and change from 
Baseline in ECG parameters will be presented using descriptive statistics at each scheduled 
visit by treatment group. Shift from Baseline of overall ECG interpretation at each 
postoperative timepoint will also be provided.  
The frequency and percentage of subjects with the following clinically relevant abnormalities 
will be presented in summary tables and data listings at each timepoint: 
• QTcF values >450 ms, >480 ms, and >500 ms. 
• Change from Baseline in QTcF values >30 ms and >60 ms. 
Clinically relevant abnormalities will be summarized overall at any timepoint and by 
timepoint. Reasons for why 12-lead ECGs were not performed will be summarized using 
frequency and percentages. 
10.5. 
Physical Examination 
A symptom-directed physical examination will be performed at Screening and when 
appropriate to evaluate an AE. Physical examination data will only be listed. 
11. 
INTERIM ANALYSIS 
No formal interim analyses are planned. An IRC will review the summary-level unblinded 
PK, safety, and efficacy data during the conduct of the study and may interrupt or stop 
enrollment, or modify the protocol to enhance subject safety without adapting the study 
design. The IRC will be composed of Sponsor representatives from each of the Clinical 
Research, Biometrics, Pharmacovigilance, Regulatory, and Pharmaceutical and Translational 
Sciences functions, and an external expert in critical care medicine. The IRC will operate 
under a written, detailed IRC Charter. 


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11.1. 
Data Safety Monitoring Board 
An independent Data Safety Monitoring Board (DSMB) will not be involved with the 
conduct of this study. The internal IRC and Product Safety and Risk Management Committee 
(PSRMC) will monitor safety data on a periodic basis throughout the study, including regular 
review of AEs (including SAEs), laboratory results, and other safety assessments.   
12. 
REFERENCES 
Dong G, Qiu J, Wang D, Vandemeulebroecke M (2018). “The stratified win ratio.” Journal 
of Biopharmaceutical Statistics 28(4): 778-796. 


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APPENDIX A. IMPUTATION OF PARTIAL AND MISSING DATES 
Incomplete Dates of Adverse Event start 
All AE onset dates must be entered on the eCRF as complete dates. In the rare case that all or 
part of an AE onset date is missing but an AE resolution date is present and after study drug 
administration then the AE onset date will be imputed as follows: 
Year of onset 
Month of onset 
Day of onset 
Onset date to be imputed as 
Missing 
Missing 
Missing 
Date of SDA 
year = year of SDA 
Missing 
Nonmissing 
Date of SDA 
year = year of SDA 
Missing 
Missing 
Set month and day to those of SDA 
year < year of SDA 
Missing 
Nonmissing 
set month to December 
year < year of SDA 
Missing 
Missing 
set month and day to December 31 
year > year of SDA 
Missing 
Nonmissing 
set month to January 
year > year of SDA 
Missing 
Missing 
set month and day to January 1 
year = year of SDA 
Month = month of SDA 
Missing 
Set day as day of SDA 
year = year of SDA 
Month < month of SDA 
Missing 
Set day as last day of onset month 
year = year of SDA 
Month > month of SDA 
Missing 
Set day as first day of onset month 
year < year of SDA 
Nonmissing 
Missing 
Set day as last day of onset month 
year > year of SDA 
Nonmissing 
Missing 
Set day as first day of onset month 
Abbreviation: SDA, study drug administration. 
If AE resolution date is present and prior to study drug administration, no need to impute 
incomplete AE start date, as the AE is not treatment emergent and the event should be in the 
medical history. 
Concomitant Medications 
• If year and month are present and day is missing, then set day to first day of 
month for start date, and set day to last day of month for end date. 
• If year and day are present and month is missing, then set month to January for 
start date, and set month to December for end date. 
• If year is present and month and day are missing, then set month and day to 
January 1 for start date, and set month and day to December 31 for end date. 
• Completely missing dates will not be imputed. 
If start date is completely missing and end date is not prior to study drug administration, then 
the medication will be classified as concomitant; if the end date is missing, then the 
medication will be classified as ongoing. Medications, for which the start and end dates are 
completely missing, will be classified as concomitant. 


Heron Therapeutics, Inc. 
Statistical Analysis Plan, V1.0 
Protocol HTX-019-202 
22JUN2021
 
Confidential  
33 
APPENDIX B. DOCUMENT REVISION HISTORY 
Version 
Date 
Notes/Revisions 
Version 1.0 
22JUN2021 
Version 1.0, based on protocol version 5 (11 
December 2020) 
 
 
 


Signature Page for VV-CLIN-004744 v1.0
Signature Page for VV-CLIN-004744 v1.0
Approval Task
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