Conditions: Oncology Patients Receiving Chemotherapy
Allocation: RANDOMIZED | Intervention model: SINGLE_GROUP
Enrollment: 34
Healthy volunteers: no

Brief summary:
This study is designed to compare the number of infusion reactions to treatment with an anti-CD20 such as Rituxan® (rituximab) or Taxol® (Paclitaxel) after premedication with intravenous (IV) QUZYTTIR™ cetirizine hydrochloride (HCl) or IV diphenhydramine during first-cycle infusion or re-treatment with an anti-CD20 such as Rituxan® (rituximab) or Paclitaxel. Re-treatment is defined as re-treatment with an anti-CD20 such as Rituxan® (rituximab) or Paclitaxel after 6 months or in patients with persistent infusion reactions while on maintenance or retreatment.

Detailed description:
This will be a randomized, double-blind exploratory study of IV cetirizine HCl 10 mg/mL versus IV diphenhydramine 50 mg/mL in approximately 34 patients who require premedication for hypersensitivity infusion reactions associated with an anti-CD20 such as Rituxan® (rituximab) or Paclitaxel. The objectives and purpose of the study will be described to patients presenting at the participating infusion centers. The patients will be randomized to receive either IV cetirizine HCl or IV diphenhydramine.

Arms:
arm 1: Cetirizine HCl 10 mg/mL: a single 1 mL injection. arm 2: Diphenhydramine 50 mg/mL: a single 1 mL injection.

Interventions: intervention 1: Cetirizine HCl 10 mg/mL intervention 2: Diphenhydramine 50 mg/mL intervention 3: anti-CD20 such as Rituximab or Paclitaxel
Intervention descriptions: intervention 1: Comparison of two injectable products: cetirizine HCl 10 mg/mL and diphenhydramine 50 mg/mL, both administered during a 1 to 2-minute period by IV push using a 1 mL syringe intervention 2: Comparison of two injectable products: cetirizine HCl 10 mg/mL and diphenhydramine 50 mg/mL, both administered during a 1 to 2-minute period by IV push using a 1 mL syringe intervention 3: Compare the number of infusion reactions to treatment with an anti-CD20 such as Rituxan® (Rituximab) or Taxol® (Paclitaxel) after premedication with intravenous (IV) QUZYTTIR™ cetirizine hydrochloride (HCl) or IV diphenhydramine during first-cycle infusion or re-treatment. Re-treatment is defined as re-treatment with Rituxan® (Rituximab) or Paclitaxel after 6 months in patients with persistent infusion reactions while on maintenance or re-treatment.

Protocol document:
Prot_000.pdf: 
 
DISCLOSURE: REDACTED PROTOCOL 
 
Title:   A Phase 2 exploratory study of intravenous QUZYTTIR™ (cetirizine 
hydrochloride injection) versus intravenous diphenhydramine in the prevention of 
hypersensitivity infusion reactions 
 
NCT Number: NCT04189588 
 
Protocol Approval Date:   November 24, 2020 
 
Certain information within this protocol has been redacted (ie, Specific content is 
masked irreversibly from view with a black bar) to protect either personally 
identifiable information or company confidential information. 
 
This may include, but is not limited to, redaction of the following: 
 
• Named persons or organizations associated with the study. 
 
• Proprietary information, such as scales or coding systems, which are 
considered confidential information under prior agreements with license 
holder. 
 
• Other information as needed to protect confidentiality of TerSera or 
partners, personal information, or to otherwise protect the integrity of the 
clinical study. 
 
The information contained in the following document is the property of TerSera 
Therapeutics LLC and should not be shared or used for any purpose other than for 
which it was provided. 
 
 


Confidential and Proprietary 
CLINICAL STUDY PROTOCOL 
A Phase 2 exploratory study of intravenous QUZYTTIRTM (cetirizine 
hydrochloride injection) versus intravenous diphenhydramine in the 
prevention of hypersensitivity infusion reactions 
STUDY TER-QZTR-001 
IND # 107689 
Sponsor: 
TerSera Therapeutics LLC 
Sponsor Contact: 
Version of Protocol: 
Version 4.0 Amendment #3 
Date of Protocol:  
November 24, 2020 
CONFIDENTIAL 
The concepts and information contained in this document or generated during the study are considered 
proprietary and may not be disclosed in whole or in part without the expressed, written consent of TerSera 
Therapeutics LLC. 
The study will be conducted according to the International Council on Harmonization harmonized 
tripartite guideline E6 (R2): Good Clinical Practice, FDA, and EU clinical trial guidelines. 
CCI
CCI
CCI


TerSera Therapeutics LLC 
Cetirizine HCl IV, 10 mg/mL 
Protocol TER-QZTR-001 
Version 4.0 Date: November 24, 2020 
Confidential and Proprietary 
Page 2 of 39 
SIGNATURE PAGE 
The signature below constitutes the approval of this protocol titled, “A Phase 2 exploratory study 
of intravenous QUZYTTIR™ (cetirizine hydrochloride injection) versus intravenous 
diphenhydramine in the prevention of hypersensitivity infusion reactions,” including the 
attachments, and provides the necessary assurances that this study will be conducted according to 
all stipulations of the protocol, including all statements regarding confidentiality, and according 
to local legal and regulatory requirements and applicable US federal regulations and ICH 
guidelines. 
PRINCIPAL INVESTIGATOR: 
Signature 
Date 
Print Name 


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Protocol TER-QZTR-001 
Version 4.0 Date: November 24, 2020 
Confidential and Proprietary 
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TABLE OF CONTENTS 
SIGNATURE PAGE .......................................................................................................................2 
TABLE OF CONTENTS .................................................................................................................3 
LIST OF ABBREVIATIONS ..........................................................................................................6 
1.
SYNOPSIS ...................................................................................................................8 
2.
BACKGROUND AND RATIONALE .......................................................................15 
3.
STUDY OBJECTIVES ..............................................................................................16 
3.1. 
Primary Objectives ......................................................................................................16 
3.2. 
Secondary Objectives .................................................................................................16 
4.
STUDY DESIGN .......................................................................................................17 
5.
STUDY POPULATION .............................................................................................19 
6.
DISCONTINUATIONS .............................................................................................21 
7.
TREATMENT ADMINISTERED .............................................................................21 
7.1. 
Materials and Supplies ................................................................................................22 
7.2. 
Method of Assignment to Treatment ..........................................................................22 
7.3. 
Rationale for the Control Product and Doses of Study Medication ...........................22 
7.3.1. 
Rationale for Using Diphenhydramine as the Control Product ..................................22 
7.3.2. 
Rationale for Selection of the Dose of IV Cetirizine HCl ..........................................23 
7.3.3. 
Study Medication ........................................................................................................23 
7.3.4. 
Maintenance of Study Blind .......................................................................................23 
7.3.5. 
Breaking the Study Blind ............................................................................................24 
7.3.6. 
Concomitant Medications/Rescue Drugs ...................................................................24 
7.4. 
Clinical and Safety Evaluations ..................................................................................24 
8.
CLINICAL OUTCOME AND PROCESS MEASURE .............................................24 
8.1. 
Primary Endpoint ........................................................................................................24 
8.2. 
Secondary Endpoints ..................................................................................................24 
9.
SAFETY EVALUATIONS ........................................................................................26 
9.1. 
Adverse Events ...........................................................................................................26 
9.2. 
Serious Adverse Events ..............................................................................................27 
9.3. 
Pregnancy ...................................................................................................................28 


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9.4. 
Safety Monitoring .......................................................................................................28 
10.
DATA QUALITY ASSURANCE ..............................................................................28 
10.1. 
Data Entry and Computerized Systems ......................................................................29 
10.2. 
Confidentiality of Trial Documents and Patient Records ...........................................29 
10.3. 
Investigator’s Files/Retention of Documents .............................................................29 
11.
SAMPLE SIZE AND STATISTICAL METHODS ...................................................30 
11.1. 
Determination of Sample Size ....................................................................................30 
11.2. 
Statistical and Analytical Plans ..................................................................................30 
11.2.1. 
Analysis Populations ..................................................................................................30 
11.2.2. 
General Considerations ...............................................................................................31 
11.2.3. 
Patient Disposition ......................................................................................................31 
11.2.4. 
Patient Demographic and Baseline Characteristics ....................................................31 
11.2.5. 
Concomitant Therapy .................................................................................................31 
11.2.6. 
Primary Endpoint ........................................................................................................31 
11.2.7. 
Secondary Endpoints ..................................................................................................31 
11.2.8. 
Safety Analyses ..........................................................................................................32 
12.
ETHICS ......................................................................................................................32 
12.1. 
Local Regulations/Declaration of Helsinki ................................................................32 
12.2. 
Ethical Review ............................................................................................................32 
12.3. 
Informed Consent .......................................................................................................33 
12.4. 
Protocol Signatures .....................................................................................................33 
13.
PUBLICATION POLICY ..........................................................................................33 
14.
REFERENCES ...........................................................................................................33 
LIST OF TABLES 
Table 1. 
CTCAE Definition of Graded Infusion Reactions ......................................................18 
LIST OF ATTACHMENTS 
Attachment A. Study Schedule ...................................................................................................35 
Attachment B. Symptom Score ...................................................................................................36 


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Attachment C. 24-Hour Follow-Up Questions ...........................................................................38 
Attachment D. Common P-Glycoprotein Inhibitor (From FDA Drug-Drug Interaction) ..........39 


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LIST OF ABBREVIATIONS 
Abbreviation 
Definition 
AE 
Adverse event 
AUC∞ 
Total area under the plasma-concentration-time-curve 
Cmax 
Maximum observed plasma concentration 
CRF 
Case report form 
CRO 
Contract research organization 
CTCAE 
National Cancer Institute Common Terminology Criteria for Adverse 
Events 
DMID 
Division of Microbiology and Infectious Diseases, NIAID, NIH 
eCRF 
Electronic case report form 
EMR 
Electronic Medical Record 
ESMO 
European Society for Medical Oncology 
EDC 
Electronic data capture 
ETTAU 
Efficacy Trial for the Treatment of Acute Urticaria 
ED 
Emergency department 
FDA 
U.S. Food and Drug Administration 
GCP 
Good Clinical Practice 
H1/H2 
Histamine-1/Histamine-2 
HCl 
Hydrochloride 
HCP 
Health Care Provider 
HIPAA 
Health Insurance Portability and Accountability Act 
IB 
Investigator’s Brochure 
IP 
Investigational product 
ICF 
Informed consent form 
ICH 
International Council on Harmonization 
IEC 
Independent or Institutional Ethics Committee 
IND 
Investigational new drug 
IRB 
Institutional review board 
IV 
Intravenous 
MedDRA 
Medical Dictionary for Regulatory Activities 
MQA 
Medical Quality Assurance 


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Version 4.0 Date: November 24, 2020 
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Abbreviation 
Definition 
NCI 
National Cancer Institute, NIH 
NCCN 
National Comprehensive Cancer Network 
NDA 
New drug application 
NIAID 
National Institute of Allergy and Infectious Diseases, NIH 
NIH 
National Institutes of Health 
ORA 
Office of Regulatory Affairs, DMID, NIAID, NIH 
PHI 
Protected health information 
PI 
Principal investigator 
PK 
Pharmacokinetics 
PP 
Per protocol 
QA 
Quality assurance 
REB 
Research ethics board 
SAE 
Serious adverse event 
SAP 
Statistical Analysis Plan 
SAS 
Safety Analysis Set 
Tmax 
Time to maximum plasma concentration 


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1.
SYNOPSIS
Title of the 
Study 
A Phase 2 exploratory study of intravenous QUZYTTIRTM (cetirizine 
hydrochloride injection) versus intravenous diphenhydramine in the 
prevention of hypersensitivity infusion reactions 
Objectives 
Primary: 
Compare the incidence of infusion reactions (ﬂushing, itching, alterations in 
heart rate and blood pressure, dyspnea, chest discomfort, acute back or 
abdominal pain, fever, shaking chills, nausea, vomiting, diarrhea, skin rashes, 
throat tightening, hypoxia, seizures, dizziness, or syncope) to treatment with 
an anti-CD20, such as Rituxan® (rituximab) or  paclitaxel, after premedication 
with intravenous (IV) QUZYTTIR™ cetirizine hydrochloride (HCl) or IV 
diphenhydramine during the infusion (first-cycle, retreatment after 6 months 
or in patients with persistent infusion reactions while on maintenance or 
retreatment). 
Secondary: 
•
Sedation score at 1 hour and 2 hours post-injection of antihistamine
(IV cetirizine HCl or IV diphenhydramine).
•
Hypersensitivity infusion reactions at 1 hour and 2 hours post-injection
of antihistamine (IV cetirizine HCl or IV diphenhydramine).
•
Document the percentage of patients requiring rescue medication, e.g.,
epinephrine, bronchodilators, or steroids.
•
Describe the reasons for the use of rescue drugs.
•
Statistical calculation to project sample size for future studies.
•
Describe the distribution of the amount of time spent in the treating
center prior to discharge (time from injection to “Readiness for
Discharge”).
•
Document the percentage of patients receiving additional medication,
e.g., epinephrine or steroids after discharge.
•
HCP/Staff satisfaction of amount of time spent during the first 2 hours.
•
HCP/Staff satisfaction with readiness and ease of discharge.
Number of 
Patients 
34 patients 
Duration of 
For each completing patient, approximately 24 hours. The screening period 


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Study 
could be up to 14 days prior to randomization/treatment. 
Number of 
Sites 
Approximately up to 10 sites 
Enrollment 
Criteria 
Inclusion Criteria 
Patients are eligible to be included in the study only if they meet all the 
following criteria: 
•
Male or female patients who require treatment premedication with an
antihistamine for hypersensitivity infusion reactions associated with an
anti-CD20, such as Rituxan® (rituximab) or  paclitaxel (first-cycle,
retreatment after 6 months or in patients with persistent infusion
reactions while on maintenance or retreatment).
•
18 years of age or older.
•
Be willing and able to give informed consent.
Exclusion Criteria 
Patients will be excluded from the study if they meet any of the following 
criteria: 
•
Receipt of an investigational drug or device within the past 30 days.
•
Patients at high risk of developing tumor lysis syndrome (TLS):
patients with auto-lyse, Burkitt lymphoma and diffuse large B-cell
lymphoma (DLBCL) with bulky disease (single node 7 or more cm or
3 or more nodal sites with size 3 or more cm)
•
Patients in whom an antihistamine may be contraindicated (e.g.,
narrow angle glaucoma, symptomatic prostatic hypertrophy).
•
Patients who, in the opinion of the investigator, may not tolerate an IV
injection of diphenhydramine 50 mg or cetirizine HCl 10 mg.
•
Receipt of any antihistamine (H1 antagonist) within the past 24 hours
prior to the administration of the study drug regardless of the route of
administration, e.g., diphenhydramine, cetirizine, loratadine,
fexofenadine, levocetirizine, desloratadine. chlorpheniramine,
clemastine and doxylamine.
•
Receipt of an H2 antagonist within the past 4 hours prior to the
administration of the study drug, e.g., ranitidine, cimetidine,
famotidine, nizatidine.
•
Receipt of doxepin within the past 24 hours prior to the administration
of the study drug; doxepin is an antidepressant, but it also has


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Version 4.0 Date: November 24, 2020 
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antihistamine properties. 
•
Receipt of epinephrine (EpiPen® or any other brand) within the past 30
days prior to the administration of the study drug.
•
Has known allergy to hydroxyzine, cetirizine, or levocetirizine, or
diphenhydramine.
•
Pregnant or breastfeeding.
•
Any condition that in the view of the investigator makes the patient
unsuitable for enrollment in this study.
•
Major medical or psychiatric illness, other than diagnosed cancer at the
time of presentation or in the past that in the investigator’s judgement
should not be enrolled in this clinical trial.
•
Inability to provide informed consent.
•
Patients on concomitant P-glycoprotein inhibitors, including
antidepressants, antipsychotics (e.g., olanzapine), and benzodiazepines
(e.g., alprazolam), as they may cause an increase in sedation.
•
Receipt of drugs that cause sedation within the past 24 hours prior to
the administration of the study drug.
Test Product 
Dose and mode of administration: 
Cetirizine HCl 10 mg/mL to be administered as a single 1-mL injection via IV 
push over a period of 1 to 2 minutes. 
Reference 
Therapy 
Dose and mode of administration: 
Diphenhydramine 50 mg/mL to be administered as a single 1-mL injection via 
IV push over a period of 1 to 2 minutes. 
Methodology This will be a parallel-group, randomized, double-blind pilot study of IV 
cetirizine HCl 10 mg/mL versus IV diphenhydramine injection 50 mg/mL in 
approximately 34 patients who will receive premedication for hypersensitivity 
infusion reactions associated with an anti-CD20, such as Rituxan® (rituximab) 
or paclitaxel. 
After the informed consent is received, the study investigator or designee will 
verify all inclusion and exclusion criteria to ensure patient eligibility, and 
capture all baseline data such as vital signs, age, previous medical history, and 
prior medication use, including all medication taken prior to coming to the 
facility. Once these data have been collected, the patient will be randomized to 
receive injection of either cetirizine HCl or diphenhydramine (timing based on 


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Protocol TER-QZTR-001 
Version 4.0 Date: November 24, 2020 
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site pretreatment protocol). 
Prior to the administration of the study medication, the study investigator or 
designee will record the following baseline data: physical examination, vital 
signs, and concomitant medication. 
During the infusion and afterwards, the study investigator or designee will 
record each of the events of an infusion reaction: ﬂushing, itching (pruritus), 
urticaria, alterations in heart rate and blood pressure, dyspnea, chest 
discomfort, acute back or abdominal pain, fever, shaking chills, nausea, 
vomiting, diarrhea, skin rashes, throat tightening, hypoxia, seizures, dizziness, 
or syncope. The study investigator will assess if the event is related to the 
infusion and record the event. 
The infusion reactions will be managed following the Common Terminology 
Criteria for Adverse Events (CTCAE version 5.0) deﬁnitions of graded 
infusion reactions* or clinical site protocol. 
Immune System Disorders 
Adverse 
Event 
Grade 
1 
2 
3 
4 
5 
Infusion 
Reaction 
Mild transient 
reaction: 
infusion 
interruption 
not indicated; 
intervention 
not indicated 
Therapy or 
infusion 
interruption 
indicated but 
responds 
promptly to 
symptomatic 
treatment (e.g., 
antihistamines, 
NSAIDs, 
narcotics, IV 
fluids); 
prophylactic 
medications 
indicated for 
≤ 24 hrs 
Prolonged 
(e.g., not 
rapidly 
responsive to 
symptomatic 
medication 
and/or brief 
interruption of 
infusion); 
recurrence of 
symptoms 
following 
initial 
improvement; 
hospitalization 
indicated for 
clinical 
sequelae 
Life-
threatening 
consequences: 
urgent 
intervention 
indicated 
Death 
Definition: A disorder characterized by an adverse local or general response from exposure to 
an allergen. 
*National Cancer Institute Common Terminology Criteria for Adverse Events (CTCAE).
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Protocol TER-QZTR-001 
Version 4.0 Date: November 24, 2020 
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(Accessed October 8, 2019) 
The same measures will be assessed again at 1 hour and 2 hours after the 
injection of the antihistamine (IV cetirizine HCl or IV diphenhydramine), and 
at the Time of “Readiness for Discharge.” At these same time intervals, 
participating patients will be asked to self-rate (recorded by study staff) any 
symptom and their level of sedation. The patient’s responses will be recorded 
by the investigator/designee on the designated outcome measure form 
(Electronic Medical Record). All rescue medication, e.g., epinephrine, 
bronchodilators, steroids, will be recorded. In addition, Health Care Provider 
(HCP)/Staff will evaluate overall satisfaction with time spent during treatment, 
at 2 hours, and ease of discharge. 
The actual time at which the investigator or designee determines the patient is 
physically and mentally fit to be discharged from the center (Time of 
“Readiness for Discharge”) will be recorded in the source documents. The 
decision to discharge the patient (Time of “Readiness for Discharge”) could be 
made at any time after the 2-hour assessment of study outcome measures 
provided the following criteria are met: 
1. No symptoms of hypersensitivity infusion reaction
2. Patient is alert enough (sedation scores = 0) to understand Discharge
Instructions
3. Based on the investigator’s judgment, the patient is fit to be discharged
Before discharge, patients will be instructed on the procedures they should 
follow when experiencing an adverse event (AE) or serious adverse event 
(SAE). They will be instructed to expect a follow-up phone call from a 
member of the site staff at approximately the same time the following day 
(i.e., 24 hours later) who will ask them a few short questions regarding allergic 
symptoms. 
All AEs and SAEs that are reported after the patient signs an informed consent 
form (ICF) will be recorded in the source documents and captured in the 
electronic case report form (eCRF). Up to 28 days post–IV study drug 
injection, patient self-reported AEs and SAEs will also be included in the 
eCRF. 


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Statistical 
Methods 
A Statistical Analysis Plan (SAP) with analytical details and assumptions will 
be developed and finalized before database lock and unblinding of the study 
data. 
No formal statistical analyses are planned given the exploratory objectives of 
the study.  
Primary Endpoints: 
The primary clinical endpoint is incidence of hypersensitivity infusion 
reactions (ﬂushing, itching, alterations in heart rate and blood pressure, 
dyspnea, chest discomfort, acute back or abdominal pain, fever, shaking chills, 
nausea, vomiting, diarrhea, skin rashes, throat tightening, hypoxia, seizures, 
dizziness, or syncope). 
Secondary Endpoints 
The secondary endpoints will be to document the safety of IV cetirizine HCl 
and to capture additional process-related data, as follows. Sedation score and 
Readiness for Discharge endpoints will be analyzed descriptively by treatment 
group using per protocol (PP) analysis set. All other endpoints will be 
analyzed descriptively by treatment group using the safety analysis set 
population (SAS). 
1. Sedation scores (patient and HCP) at 1 hour and 2 hours post-injection
of antihistamine (IV cetirizine HCl or IV diphenhydramine). The
patient sedation scores are assessed on a scale of 0-4, with 0=None and
4=Extremely Severe (Asleep, Cannot Self-Rate). The HCP sedation
scores are assessed on a scale of 0-4, with 0=None and 4=Extremely
severe.
2. Hypersensitivity infusion reactions at 1 hour and 2 hours post-injection
of antihistamine (IV cetirizine HCl or IV diphenhydramine).
3. Document the percentage of patients requiring rescue medication, e.g.,
epinephrine, bronchodilators, or steroids.
4. Describe the reasons for the use of rescue drugs.
5. Document the AEs and SAEs per study group.
6. Describe the distribution of the amount of time spent in the treatment
center prior to discharge (time from injection to “Readiness for
Discharge”).
7. Document the percentage of patients receiving additional medication,
e.g., epinephrine or steroids after discharge.


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8. Effectively treated based on HCP’s opinion of
9. Analyze subgroup of patients 65 years of age and older.
10. Analyze subgroup of time from Injection to Readiness for Discharge
by chemotherapy received (anti-CD20 or paclitaxel).
Safety: 
Safety analyses will be analyzed descriptively by treatment group using the 
safety analysis set population (SAS). Sedation score will be analyzed 
descriptively by treatment group using per protocol (PP) analysis set. Adverse 
events will be coded using the Medical Dictionary for Regulatory Activities 
(MedDRA) coding dictionary 22.1 and will be summarized by treatment group 
by severity, seriousness, and relationship. Events occurring more than once in 
the same patient will be counted only once. Additional safety analyses include 
summarizing vital signs and physical exam findings descriptively by treatment 
group. 
Sample Size Considerations: 
This is an exploratory clinical study to determine process feasibilities and to 
obtain a baseline clinical response to IV cetirizine HCl and IV 
diphenhydramine on the primary and secondary clinical outcome measures. As 
such, no sample size will be calculated for this study. However, the data 
obtained from this study might be used to calculate the sample size of future 
studies. 
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2.
BACKGROUND AND RATIONALE
Cetirizine, a human metabolite of hydroxyzine, is an antihistamine. Cetirizine hydrochloride 
(HCl) is available as an orally administered over-the-counter product indicated for the treatment 
of acute urticaria in adults and children 6 months of age and older. Cetirizine HCl was originally 
approved in 1995 as a 10-mg oral-dose prescription drug. Over the past 24 years, the safety 
profile with cetirizine HCl used chronically has been well established in both children (6 months 
and older) and adults. 
Intravenous cetirizine HCl 10 mg/mL (QUZYTTIRTM)1 was developed to provide a faster or 
immediate-onset treatment profile over the current 10 mg cetirizine HCl products (Zyrtec®) to 
alleviate acute symptoms such as urticaria, angioedema, and allergic reactions. Cetirizine HCl is 
to be injected IV at a dose of 10 mg in adults. 
A pilot study (ETTAU-02) was conducted in 33 patients and demonstrated that the 
investigational drug, IV cetirizine HCl, was not significantly different (and slightly in favor of 
cetirizine) from the active comparator, diphenhydramine injection, in acute urticaria symptom 
score reductions (composite score and each individual symptom score, such as: pruritus and 
extent of urticaria/erythema) at 1 or 2 hours post-injection and at discharge. There were no 
serious adverse events (SAEs) in either treatment arms. There were no drug-related adverse 
events (AEs) from the cetirizine HCl arm, but several drug-related AEs were recorded in patients 
in the diphenhydramine arm. 
A pivotal Phase 3 study (ETTAU-03) in 262 patients demonstrated similar results as in the pilot 
study (ETTAU-02). The pivotal study demonstrated statistically that IV cetirizine HCl is non-
inferior to IV diphenhydramine on the primary endpoint (2-hour patient-rated pruritus score 
change from baseline), and improvement on two key secondary endpoints (time spent in 
treatment center, and % of patients returned to treatment center). Intravenous cetirizine HCl was 
also better on several other secondary endpoints such as fewer AEs, less sedation, reduced 
rescue-drug usage, and higher rate of effective treatment. 
Pretreatment with antihistamines for drug-induced hypersensitivity is recommended for 
biologics, chemotherapy drugs, and other treatments. Hypersensitivity infusion reactions occur in 
approximately 5% of patients treated with chemotherapy.2  
Some chemotherapy drugs have a greater potential of causing these reactions. For those with 
high potential, pretreatment is recommended with an antihistamine and corticosteroids prior to 
treatment. Severe infusion reactions may require oxygen, epinephrine, and cardiovascular 
support.3  
Currently, the only injectable antihistamine is diphenhydramine; however, it is not indicated for 
pretreatment.4 Management of hypersensitivity infusion reactions have been provided with 
guidelines from the National Comprehensive Cancer Network and the European Society for 
Medical Oncology.5,6 Intravenous cetirizine HCl 10 mg/mL has been shown to treat acute 
urticaria as effectively as diphenhydramine with fewer side effects, and can be used for 
pretreatment for chemotherapy-induced infusion reactions. 


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When IV diphenhydramine is unavailable, oral diphenhydramine or other oral antihistamines 
have been used for pretreatment to prevent hypersensitivity infusion reactions.2,7 The use of oral 
antihistamines has limitations; oral cetirizine HCl has a time to maximum concentration (Tmax) of 
1 hour with a delay of Tmax with food to 1.7 hours (Zyrtec PI8).  
There is an unmet medical need for injectable pretreatment antihistamines for use with drugs that 
cause infusion reactions (e.g., biologic chemotherapy). Current literature shows that a second-
generation, less-sedating antihistamine such as IV cetirizine HCl could be a viable and clinically 
meaningful option for patients. Intravenous cetirizine HCl 10 mg/mL has been shown to treat 
acute urticaria as effectively as diphenhydramine with fewer side effects and could be used for 
pretreatment for chemotherapy-induced infusion reactions. 
3.
STUDY OBJECTIVES
3.1. 
Primary Objectives
The primary objective of this study is to compare the incidence of infusion reactions (ﬂushing, 
itching, alterations in heart rate and blood pressure, dyspnea, chest discomfort, acute back or 
abdominal pain, fever, shaking chills, nausea, vomiting, diarrhea, skin rashes, throat tightening, 
hypoxia, seizures, dizziness, or syncope) to treatment with an anti-CD20, such as Rituxan® 
(rituximab) or paclitaxel, after premedication with intravenous (IV) QUZYTTIR™ cetirizine 
hydrochloride (HCl) or IV diphenhydramine during the infusion (first-cycle, retreatment after 6 
months or in patients with persistent infusion reactions while on maintenance or retreatment). 
3.2. 
Secondary Objectives 
•
Sedation score at 1 hour and 2 hours post-injection of antihistamine (IV cetirizine HCl or
IV diphenhydramine).
•
Hypersensitivity infusion reactions at 1 hour and 2 hours post-injection of antihistamine
(IV cetirizine HCl or IV diphenhydramine).
•
Document the percentage of patients requiring rescue medication, e.g., epinephrine,
bronchodilators, or steroids.
•
Describe the reasons for the use of rescue drugs.
•
Statistical calculation to project sample size for future studies.
•
Describe the distribution of the amount of time spent in the treating center prior to
discharge (time from injection to “Readiness for Discharge”).
•
Document the percentage of patients receiving additional medication, e.g., epinephrine or
steroids after discharge.
•
HCP/Staff satisfaction of amount of time spent during the first 2 hours.
•
HCP/Staff satisfaction with readiness and ease of discharge.


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4.
STUDY DESIGN
This will be a parallel-group, randomized, double-blind exploratory study of IV cetirizine HCl 
10 mg/mL versus IV diphenhydramine 50 mg/mL in approximately 34 patients who will receive 
premedication for hypersensitivity infusion reactions associated with an anti-CD20, such as 
Rituxan® (rituximab) or paclitaxel. 
The objectives and purpose of the study will be described to patients presenting at the 
participating infusion centers. If a patient agrees to participate in the study, an informed consent 
form (ICF) will be signed by the patient according to the process followed by each center for 
obtaining informed consent. The screening period could be up to 14 days prior to 
randomization/treatment. After consent is received, the study investigator or designee will verify 
all inclusion and exclusion criteria to ensure patient eligibility and capture all baseline data such 
as vital signs (including temperature), weight, height, age, previous medical history, and prior 
medication use, including all medication taken prior to coming to the facility. Once these data 
have been collected, the patient will be randomized to receive either IV cetirizine HCl or IV 
diphenhydramine. The time that the study medication was administered will be recorded in the 
source documents and in the eCRF. 
During the Baseline/Screening period (Day -14 to Day 0), the study investigator or designee will 
record the following baseline data: medical history, vital signs (including temperature), physical 
examination, and concomitant medication. 
On Antihistamine injection Day (Day 0), before the patient receive randomized antihistamine 
injection (Study drug), the investigator or designee will record the following information: vital 
signs (including temperature), Sedation score, Concomitant medication, and Adverse events - 
Other than infusion reaction.  
During the infusion and afterwards, the study investigator or designee will record each of the 
events of an infusion reaction: ﬂushing, itching (pruritus), urticaria, alterations in heart rate and 
blood pressure, dyspnea, chest discomfort, acute back or abdominal pain, fever, shaking chills, 
nausea, vomiting, diarrhea, skin rashes, throat tightening, hypoxia, seizures, dizziness, syncope, 
or other. The study investigator will assess if the event is related to the Rituxan (rituximab) or 
paclitaxel infusion and record the event. 
The infusion reactions will be managed following the Common Terminology Criteria for 
Adverse Events (CTCAE version 5.0) definition of graded infusion reactions* or clinical site 
protocol. 


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Table 1. 
CTCAE Definition of Graded Infusion Reactions 
Immune System Disorders 
Adverse 
Events 
Grade 
1 
2 
3 
4 
5 
Infusion 
Reactions 
Mild transient 
reaction: 
infusion 
interruption 
not indicated; 
intervention 
not indicated  
Therapy or 
infusion 
interruption 
indicated but 
responds 
promptly to 
symptomatic 
treatment (e.g., 
antihistamines, 
NSAIDs, 
narcotics, IV 
fluids); 
prophylactic 
medications 
indicated for 
≤ 24 hours 
Prolonged 
(e.g., not 
rapidly 
responsive to 
symptomatic 
medication 
and/or brief 
interruption of 
infusion); 
recurrence of 
symptoms 
following 
initial 
improvement; 
hospitalization 
indicated for 
clinical 
sequelae  
Life-
threatening 
consequences: 
urgent 
intervention 
indicated 
Death 
Definition: A disorder characterized by an adverse local or general response from exposure to an allergen. 
*National Cancer Institute Common Terminology Criteria for Adverse Events (CTCAE).
(Accessed October 8, 2019) 
The same measures will be assessed again at 1 hour and 2 hours after the injection of the 
antihistamine (IV cetirizine HCl or IV diphenhydramine) and at the Time of “Readiness for 
Discharge.” At these same time intervals, participating patients will be asked to self-rate 
(recorded by study staff) any symptom and their level of sedation. The patient’s responses will 
be recorded by the investigator/designee on the designated outcome measure form (source 
document). All rescue medication, e.g., epinephrine, bronchodilators, or steroids, will be 
recorded. In addition, site staff will evaluate overall satisfaction with time spent during treatment 
at 2 hours and ease of discharge.  
The actual time at which the investigator or designee determines the patient is physically and 
mentally fit to be discharged from the center (Time of “Readiness for Discharge”) will be 
recorded in the source documents. The decision to discharge the patient (Time of “Readiness for 
Discharge”) could be made at any time after the 2-hour assessment of study outcome measures 
provided the following criteria are met: 
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1. No symptoms of infusion hypersensitivity reaction
2. Patient is alert enough (sedation score = 0) to understand discharge instructions
3. Based on the investigator’s judgment, the patient is fit to be discharged
Note:
i.
If patient is fit to be discharged, but not alert enough to drive home when the
sedation score is at “1” or higher, he/she may be kept in the clinic until sedation
improves. But appropriate arrangement must be done, such as: call for a taxi,
arrange a friend or relative to help drive, or ask patient to stay in the waiting room
until sedation goes away, etc.
ii.
Standard discharge instruction should be given. If medications are prescribed at
discharge, instruct patients take them “as needed.”
iii.
In the event that the symptoms were not effectively treated, patients will be treated
following the standard of care by attending physician or designee.
Before discharge, patients will be instructed on the procedures they have to follow when 
experiencing an AE or SAE. They will be instructed to expect a follow-up phone call at 
approximately the same time the following day (i.e., 24 hours later) from a member of the site 
staff who will ask them a few short questions regarding hypersensitivity infusion reaction 
symptoms. 
All AEs and SAEs that are reported after the patient signs an ICF will be recorded in the source 
documents and captured in the eCRF. Up to 28 days post–IV study drug injection, patient 
self-reported AEs and SAEs will also be included in the eCRF. 
Study procedures and their timing are summarized in the Study Schedule in Attachment A. 
5.
STUDY POPULATION
Patients who meet all the inclusion criteria and none of the exclusion criteria and have signed an 
ICF will be eligible for study participation. 
Inclusion Criteria  
Patients are eligible to be included in the study only if they meet all the following criteria: 
1. Male or female patients who require treatment premedication with an antihistamine for
hypersensitivity infusion reactions associated with an anti-CD20, such as Rituxan®
(rituximab) or  paclitaxel (first-cycle, retreatment after 6 months or in patients with
persistent infusion reactions while on maintenance or retreatment).
2. 18 years of age or older.
3. Be willing and able to give informed consent.


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Exclusion Criteria 
Patients will be excluded from the study if they meet any of the following criteria: 
1. Receipt of an investigational drug or device within the past 30 days.
2. Patients at high risk of developing tumor lysis syndrome (TLS): patients with auto-lyse,
Burkitt lymphoma and diffuse large B-cell lymphoma (DLBCL) with bulky disease
(single node 7 or more cm or 3 or more nodal sites with size 3 or more cm)
3. Patients in whom an antihistamine may be contraindicated (e.g., narrow angle glaucoma,
symptomatic prostatic hypertrophy).
4. Patients who, in the opinion of the investigator, may not tolerate an IV injection of
diphenhydramine 50 mg or cetirizine HCl 10 mg.
5. Receipt of any antihistamine (H1 antagonist) within the past 24 hours prior to the
administration of the study drug regardless of the route of administration, e.g.,
diphenhydramine, cetirizine, loratadine, fexofenadine, levocetirizine, desloratadine.
chlorpheniramine, clemastine and doxylamine.
6. Receipt of an H2 antagonist within the past 4 hours prior to the administration of the
study drug, e.g., ranitidine, cimetidine, famotidine, nizatidine.
7. Receipt of doxepin within the past 24 hours prior to the administration of the study drug;
doxepin is an antidepressant, but it also has antihistamine properties.
8. Receipt of epinephrine (EpiPen® or any other brand) within the past 30 days prior to the
administration of the study drug.
9. Has known allergy to hydroxyzine, cetirizine, or levocetirizine, or diphenhydramine.
10. Pregnant or breastfeeding.
11. Any condition that in the view of the investigator makes the patient unsuitable for
enrollment in this study.
12. Major medical or psychiatric illness, other than diagnosed cancer at the time of
presentation or in the past that in the investigator’s judgement should not be enrolled in
this clinical trial.
13. Inability to provide informed consent.
14. Patients on concomitant P-glycoprotein inhibitors, including antidepressants,
antipsychotic (e.g., olanzapine) and benzodiazepines (e.g., alprazolam), as they may
cause an increase in sedation.9,10,11 (See Attachment D).
15. Receipt of drugs that cause sedation within the past 24 hours prior to administration of
the study drug.


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6.
DISCONTINUATIONS
Patients have the right to withdraw from the study at any time for any reason without 
compromising their clinical management. The investigator also has the right to withdraw patients 
from the study if he/she feels it is in the best interest of the patient, or if the patient is 
uncooperative or non-compliant. 
Reasons for discontinuation include: 
•
Violation of inclusion or exclusion criteria found after the study medication has been
administered.
•
The investigator, patient, or the healthcare professional performing assessments become
unblinded to the study medication for whatever reason.
•
The investigator decides that the patient should be withdrawn. If this decision is made
because of an SAE, the study drug is to be discontinued and appropriate measures are to
be taken. The investigator will notify the Sponsor immediately.
•
Administrative decision by the Sponsor or Regulatory Authorities. All patients will be
discontinued from the protocol and notified of the reason for the discontinuation.
•
The patient may withdraw from the study for any other reason, including withdrawal of
consent.
An excessive rate of withdrawal can make the study results difficult to interpret. 
The reason for any discontinuation will be fully documented on the source document and eCRF. 
Should a patient decide to withdraw, every effort will be made to complete and report all study 
observations, particularly the 24-hour follow-up, as thoroughly as possible (Attachment C). The 
investigator/designee should contact the patient by telephone to determine as completely as 
possible the reason for the withdrawal. 
7.
TREATMENT ADMINISTERED
Patients who fulfill all the inclusion and none of the exclusion criteria will be enrolled into the 
study. Each patient should read and sign an ICF prior to any study procedures being performed. 
This study involves a comparison of two injectable products: cetirizine HCl 10 mg/mL and 
diphenhydramine 50 mg/mL, both administered during a 1- to 2-minute period by IV push using 
a 1-mL syringe and flush with normal saline as needed. Patients will be randomly assigned to 
either: 
•
Cetirizine HCl 10 mg/mL: a single 1-mL injection via IV push over a period of 1 to
2 minutes.
•
Diphenhydramine 50 mg/mL: a single 1-mL injection via IV push over a period of 1 to
2 minutes.


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Timing to administer the study drug or other pretreatment mediation before starting the 
chemotherapy will be based on the site’s chemotherapy treatment procedure. 
7.1. 
Materials and Supplies 
A drug dispensing log will be kept current and will contain the following information: 
•
The identification of the patient to whom the drug was dispensed.
•
The date, quantity, and lot number of the drug dispensed to the patient.
Drug inventory and accountability records (Test Article Accountability Log) will be maintained 
at the site. A monitor will reconcile drug inventory and review accountability records. Any 
unused vials of study drug will be collected by the Monitor and returned to the sponsor. Study 
drugs may be stored at room temperature. 
7.2. 
Method of Assignment to Treatment 
Approximately 34 patients will be randomized to 1 of 2 treatment groups in a 1:1 ratio. Specifics 
for the randomization scheme and blinding plan will be described in the Statistical Analysis Plan 
(SAP) for the study. Study medication/Investigational Product (IP will be sent to each study site 
depending on the recruiting capabilities of each site. At the investigational site, each subject will 
be entered in EDC with a subject ID in the format of ##-###, where the first 2 digits represent 
site number and the last 3 digits represent a sequential patient number (i.e., 02-009 represents the 
ninth patient consented at site two).  
Upon verification that all eligibility criteria are met the subject can be randomized within EDC. 
The site will be provided with a blinded treatment code that corresponds to appropriate drug 
label.  
7.3. 
Rationale for the Control Product and Doses of Study Medication 
Investigational Product: IV cetirizine HCl, a single 1-mL injection (10 mg/mL) given by IV push 
over a period of 1 to 2 minutes. 
Control Product: IV diphenhydramine, a single 1-mL injection (50 mg/mL) given by IV push 
over a period of 1 to 2 minutes. 
7.3.1. 
Rationale for Using Diphenhydramine as the Control Product 
Intravenous diphenhydramine is the only antihistamine injection available currently for the 
treatment of reducing the incidence of infusion induced reaction. 
 The approved indication for IV diphenhydramine is as follows: 
For amelioration (improvement) of allergic reactions to blood or plasma, in anaphylaxis as an 
adjunct to epinephrine and other standard measures after the acute symptoms have been 
controlled, and for other uncomplicated allergic conditions of the immediate type when oral 
therapy is impossible or contraindicated.3 
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7.3.2. 
Rationale for Selection of the Dose of IV Cetirizine HCl  
The recommended dose of oral cetirizine HCl is 10 mg (Zyrtec). This dose has been shown to 
strongly inhibit the wheal and flare caused by the intradermal injection of histamine. The onset 
of this activity after a single 10 mg dose occurs within 20 minutes in 50% of patients and within 
one hour in 95% of patients. 
Intravenous cetirizine HCl was demonstrated to be non-inferior to diphenhydramine injection for 
acute urticaria while in a treatment center, but was demonstrated to be better in the benefits of: 
less sedation, less rescue-drug usage, shorter time spent in the treatment center, longer duration 
of action, lower return rate to the treatment centers, less symptom recurrence post-discharge, 
fewer AEs, lack of anticholinergic effect, and no significant drug-drug interactions. 
7.3.3. 
Study Medication 
Intravenous cetirizine HCl 10 mg/mL has been shown to treat acute urticaria as effectively as 
diphenhydramine with fewer side effects and could be used for pretreatment of chemotherapy-
induced infusion reactions. Pretreatment for infusion reactions includes antihistamines where IV 
diphenhydramine is given as currently the only available injectable antihistamine. IV Cetirizine 
HCl, a second-generation injectable antihistamine, provides a new option for patients.  
7.3.4. 
Maintenance of Study Blind 
This will be a double-blind study; the investigator, the patient, and any healthcare professional 
involved in patient management or outcome assessment will remain blinded. Both IV cetirizine 
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HCl and IV diphenhydramine are presented as a clear aqueous solution in 2-mL amber vials 
containing 1 mL of medication and having the same physical appearance. A blinded and 
randomized label created for the study conceals the product label of each vial (for both the test 
drug cetirizine HCl or the comparator diphenhydramine). In the event of an emergency, patient 
and site may be unblinded. 
7.3.5. 
Breaking the Study Blind 
In order to preserve the blinding of the study, site personnel will not have access to the 
randomization list and treatment assignments before database lock. Study blinding may only be 
broken if the identity of the study drug is considered vital for the clinical management or to 
ensure safety of the patients. 
7.3.6. 
Concomitant Medications/Rescue Drugs 
To ensure optimal patient management, additional medications, e.g., epinephrine or steroids, 
may be given at any time during the study if deemed necessary by the investigator. However, if 
without medical complication, all effort should be made to have the patient complete at least the 
1-hour assessments prior to administration of the rescue medication.
The product label of the rescue drugs should be followed to determine the appropriate dose.
The identity, dose, frequency, and route of administration of all medications being taken prior to 
study enrollment will be recorded, as well as all concomitant medications administered during 
the study. 
7.4. 
Clinical and Safety Evaluations 
Study procedures and their timing are summarized in the Study Schedule in Attachment A and 
Symptom Score Assessment in Attachment B.
All patients who received at least 1 dose of study medication will be included in the PP and SAS 
analyses and safety evaluations. 
8.
CLINICAL OUTCOME AND PROCESS MEASURE
8.1. 
Primary Endpoint
The primary clinical endpoint is incidence of hypersensitivity infusion reactions (ﬂushing, 
itching, alterations in heart rate and blood pressure, dyspnea, chest discomfort, acute back or 
abdominal pain, fever, shaking chills, nausea, vomiting, diarrhea, skin rashes, throat tightening, 
hypoxia, seizures, dizziness, or syncope). 
8.2. 
Secondary Endpoints 
The secondary endpoints will be to document the safety of IV cetirizine HCl and to 
capture additional process-related data, as follows.  


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Sedation score and Readiness for Discharge endpoints will be analyzed descriptively by 
treatment group using per protocol analysis set. All other endpoints will be analyzed 
descriptively by treatment group using the safety analysis set population (SAS). 
1. Sedation scores (patient and HCP) at 1 hour and 2 hours post-injection of antihistamine
(IV cetirizine HCl or IV diphenhydramine). The patient sedation scores are assessed on a
scale of 0-4, with 0=None and 4=Extremely Severe (Asleep, Cannot Self-Rate). The HCP
sedation scores are assessed on a scale of 0-4, with 0=None and 4=Extremely severe.
“How drowsy do you feel at the moment?” 
•
Patient Sedation Score
0 = None (Not drowsy at all)
1 = Mild (Slightly drowsy)
2 = Moderate (Quite drowsy)
3 = Severe (Extremely drowsy)
4 = Extremely Severe (Asleep, cannot self-rate)
•
HCP Sedation Score
0 = None (Patient is completely alert. Does not look tired at all.)
1 = Mild (Patient sitting/lying comfortably, and looks tired)
2 = Moderate (Drowsy, with occasional eyes closing)
3 = Severe (Asleep, with eyes closed but responds to minor motor stimulation)
4 = Extremely Severe (Asleep; does not respond to minor motor stimulation)
2. Hypersensitivity infusion reactions at 1 hour and 2 hours post-injection of antihistamine
(IV cetirizine HCl or IV diphenhydramine).
3. Percentage of patients requiring rescue medication, e.g., epinephrine, bronchodilators, or
steroids.
4. Describe the reasons for the use of rescue drugs.
5. Document the AEs and SAEs per study group.
6. Describe the distribution of the amount of time spent in the treatment center prior to
discharge (time from injection to “Readiness for Discharge”).
7. Document the percentage of patients receiving additional medication, e.g., epinephrine or
steroids after discharge.
8. Effectively treated based on HCP’s opinion of
9. Analyze subgroup of patients 65 years of age and older.
10. Analyze subgroup of Time from Injection to Readiness for Discharge by chemotherapy
received (anti-CD20 or paclitaxel).
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9.
SAFETY EVALUATIONS
The safety population is defined as all patients who received study medication. Investigators are 
responsible for monitoring the safety of patients who are participating in this study and for 
alerting the Sponsor of any event that seems unusual, even if this event may be considered as an 
unanticipated benefit to the patient. The investigator is responsible for the appropriate medical 
care of patients during the study. 
All AEs and SAEs that are reported after the patient signs an ICF will be recorded in the source 
documents and captured in the eCRF. Up to 28 days post–IV study drug injection, patient 
self-reported AEs and SAEs will also be included in the eCRF. 
The investigator remains responsible for following, through an appropriate healthcare option, 
AEs or SAEs that caused the patient to discontinue before completing the study. The patient 
should be followed until the event is resolved or explained. Frequency of follow-up is left to the 
discretion of the investigator. 
9.1. 
Adverse Events 
An AE is any untoward medical occurrence in a patient administered a pharmaceutical product, 
without regard to the possibility of a causal relationship to the treatment. Lack of drug effect is 
not an AE in clinical trials because the purpose of the clinical trial is to establish a drug effect 
Prior to enrollment, study site personnel will note the occurrence and nature of each patient’s 
medical condition(s) in the appropriate section of the source document or eCRF (Medical 
History). 
If a patient experiences an AE (including a change in documented baseline medical conditions) 
after the informed consent document is signed, the event will be recorded as an AE in the source 
document and electronic case report form (eCRF). All AEs will additionally include severity and 
causality assessments. 
The severity of the event will be classified according to CTCAE v 5.0 toxicity grading: 
•
Grade 1 Mild: asymptomatic or mild symptoms; clinical or diagnostic observations
only; intervention not indicated.
•
Grade 2 Moderate: minimal, local or noninvasive intervention indicated; limiting age
appropriate instrumental ADL.
•
Grade 3 Severe: Severe or medically significant but not immediately life-threatening;
hospitalization or prolongation of hospitalization indicated; disabling; limiting self-care
ADL.
•
Grade 4 Life-Threatening: Life-threatening consequences; urgent intervention
indicated.
•
Grade 5 Death: Death related to AE.
The causality will be classified as: 


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•
Not related: Any adverse event that is not related to the product being studied.
•
Possible: Any adverse event that can be caused by the use of the product being studied,
but for which another explanation can be found – for example, the existence of a
concomitant treatment or concurrent disease(s) – or for which the relation in time is not
obvious.
•
Probable: Any adverse event that can be caused using the product being studied. The
relationship in time is suggestive (for example, if the event disappears when the treatment
is interrupted). Another explanation is less probable – for example, the existence of a
concomitant treatment or concurrent disease(s).
•
Not assessable: It is impossible to attribute the event to any of the categories above,
because the information obtained is insufficient, incomplete, or contradictory. Additional
information is necessary to determine the causal relationship with the product being
studied.
If a patient is discontinued as a result of an AE, study site personnel must clearly document the 
circumstances leading to any such discontinuation of treatment, in the source document and on 
the eCRF.  
Events leading to a study endpoint will be included as part of the safety and efficacy analyses for 
this study and will not be recorded as AE or SAE unless the investigator believes the event may 
have been caused by the study drug. The primary endpoint is the incidence of hypersensitivity 
infusion reactions (ﬂushing, itching, alterations in heart rate and blood pressure, dyspnea, chest 
discomfort, acute back or abdominal pain, fever, shaking chills, nausea, vomiting, diarrhea, skin 
rashes, throat tightening, hypoxia, seizures, dizziness, or syncope) and the secondary endpoint is 
sedation. 
9.2. 
Serious Adverse Events 
A serious adverse event (SAE) is any experience that suggests a significant hazard, 
contradiction, side effect, or precaution. Study site personnel must report immediately to the 
Sponsor by the designated transmission method any AE from this study that results in one of the 
following outcomes, or is significant for any other reason: 
•
Death
•
Medically significant
•
Initial or prolonged inpatient hospitalization
•
A life-threatening experience (that is, immediate risk of dying)
•
Persistent or significant disability/incapacity
•
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All SAEs must be reported to the Sponsor (or to the Sponsor’s designated person) within 
24 hours of the Investigator’s knowledge of the event. Notification will be made through the 
EDC program and sent by email to: 
The clinical sites need to follow the same processes for SAEs as documented above for AEs in 
Section 9.1. The Investigator must provide the following information, at a minimum: the patient 
number in the study, the nature of the event, the date of onset of the event, and the relationship 
with the study treatment according to the information available at the time of reporting. 
9.3. 
Pregnancy 
Should a patient report a pregnancy during the course of the study, it should be recorded in the 
source documents and electronic case report form (eCRF). The sponsor will follow the 
pregnancy outcome upon patient consent. 
9.4. 
Safety Monitoring 
The Medical Monitor will provide medical expertise in the safety oversight and review of safety 
information including but not limited to AE, SAE, and other safety listings.  
10.
DATA QUALITY ASSURANCE
To ensure accurate, complete, and reliable data, the Sponsor or their representative will do the 
following: 
•
Provide instructional material to the study sites, as appropriate.
•
Host a training session to instruct the investigators and study coordinators on the
protocol, the completion of the source document, eCRFs, and study procedures.
•
Make periodic monitoring visits to the study site.
•
Be available for consultation and stay in contact with the study site personnel by mail,
email, telephone, and/or fax.
•
Review and evaluate the source document and eCRF data and use standard computer edit
checks to detect errors in data collection.
•
Conduct a quality review of the database.
•
Verify the quality of the data.
In addition, the Sponsor representative will periodically check the patient data recorded against 
source documents at the study site. The study may be audited by Medical Quality Assurance 
(MQA) and/or regulatory agencies at any time. Investigators will be given notice before an MQA 
audit occurs. 
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10.1. 
Data Entry and Computerized Systems 
Relevant study data will be collected on each subject and entered an Electronic Data Capture 
(EDC) system. The URL for the EDC system is 
 Supported operating 
systems are Microsoft Windows XP, Microsoft Windows 2000, Microsoft Windows 7 and 8, 
Microsoft Vista, and Mac OS X. Microsoft Internet Explorer (version 9 and later), Firefox 
(version 27 and later), Chrome (version 30 and later), and Safari (version 9.0 and later) are 
acceptable web browsers. 
Medrio software supports compliance with regulations such as 21 CFR Part 11, Annex 11, EU 
Safe Harbor, Good Clinical Practice, and HIPAA. Procedural controls include electronic audit 
trails of all changes to study data, electronic signatures, data encryption, and access restrictions 
to Protected Health Information (PHI). Access to the Medrio EDC system will only be granted to 
study personnel after training is conducted. User accounts are permission based which grants 
limited access and functionalities dependent upon permissions granted by study administrator.  
All data that goes into and out of the server is encrypted using 128-bit Secure Sockets Layer 
(SSL) and 1024-bit RSA public keys. The servers, hosted by Medrio, are housed in a fully 
redundant N+1 data center with redundant power, cooling, and network connectivity. All servers 
reside behind Cisco firewalls and advanced intrusion detection/prevention systems. Medrio 
performs nightly backups to locations both on-site and off-site and maintains redundant 
hardware.  
Data collection will begin at the signing of informed consent. All data (other than SAEs) should 
be submitted within 72 working hours of the visit in which data was collected. Edit checks (often 
called queries) will fire in real time as data is being entered to ensure quality data is provided. In 
addition to edit checks, manual queries will be generated by Data Managers and Monitors. Sites 
will have 10 working days to address all edit checks and manually created queries. Source Data 
Verification (SDV), Data Management Review and electronic signature by site PI will all take 
place prior to locking data.  
10.2. 
Confidentiality of Trial Documents and Patient Records 
The investigator must assure that the patients’ anonymity will be maintained and that their 
identities are protected from unauthorized parties. On the source document, eCRFs, or other 
documents submitted to the Sponsor, patients should not be identified by their names, but by an 
identification code. The investigator should keep a patient enrollment log reconciling patient 
codes and patient names. The investigator should maintain all patient-related documents in strict 
confidence. If a patient record such as a discharge report is needed for the study file all names 
and specific identifiers except for what is used for the study must be redacted.  
10.3. 
Investigator’s Files/Retention of Documents 
The Investigator must maintain adequate and accurate records to enable the conduct of the study 
to be fully documented and the study data to be subsequently verified. These documents should 
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Protocol TER-QZTR-001 
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Confidential and Proprietary 
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be classified into two different separate categories, namely Investigator Study File and Patient 
Clinical Source Documents. 
The investigator must keep these two categories of documents on file for at least 2 years after 
completion or discontinuation of the study. After that period of time, the documents may be 
destroyed, in accordance with local regulations. 
11.
SAMPLE SIZE AND STATISTICAL METHODS
11.1. 
Determination of Sample Size
This is a pilot clinical study to determine process feasibilities and to obtain a baseline clinical 
response (drug reaction to Rituxan) with pre-treatment of cetirizine HCl injection and 
diphenhydramine injection on the primary and secondary clinical outcome measures. As such, no 
sample size was calculated for this study. However, the data obtained from this study may be 
used to calculate the sample size of future studies.  
11.2. 
Statistical and Analytical Plans 
A Statistical Analysis Plan (SAP) with analytical details and assumptions will be developed and 
finalized before database lock and unblinding of the study data. 
11.2.1. 
Analysis Populations 
Patients with baseline Sedation Score greater than 0 may have taken a sedating concomitant or 
other medication. It may be impossible to confirm that patients did not take a sedating 
medication prior to receiving treatment. Sedation Score greater than 0 would be a confounding 
factor and may invalidate the results of endpoints of Sedation score and Readiness for Discharge. 
Therefore, these two endpoints will only be analyzed by the PP population defined as patients 
with Baseline Sedation score of 0. 
The following analysis populations will be identified for this study: 
•
Full Analysis Set (FAS): The FAS consists of all randomized patients. Patients will be
analyzed according to the randomized treatment.
•
Safety Analysis Set (SAS): The SAS consists of all patients who received at least 1 dose
of study medication. Patients will be analyzed according to the treatment actually
received.
•
Per Protocol Analysis Set (PP): The PP consists of patients with a Baseline Sedation
score of 0 and who received at least 1 dose of study medication. Patients will be analyzed
according to the treatment actually received.


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Protocol TER-QZTR-001 
Version 4.0 Date: November 24, 2020 
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11.2.2. 
General Considerations 
All presentations and analyses will be conducted using SAS version 9.4 or higher, unless 
otherwise specified. For continuous data, the number of observations (n), mean, median, 
minimum, and maximum, and standard deviation (SD) values will be presented. For categorical 
data, the frequency counts and percentages will be presented.  
11.2.3. 
Patient Disposition 
Patient disposition (e.g., the number of patients signing the informed consent, randomized, 
completed, and discontinued) along with the number of patients in each of the analysis 
populations will be summarized descriptively by treatment group.  
11.2.4. 
Patient Demographic and Baseline Characteristics 
Descriptive statistics will be used to summarize patient demographics and baseline 
characteristics such as medical and surgical history by treatment group. Additionally, 
demographics will be presented for screen failure subjects. 
11.2.5. 
Concomitant Therapy 
The frequency of medications taken prior to study enrollment and while enrolled in the study 
(concomitant medications) will be summarized using descriptive statistics by treatment group. 
11.2.6. 
Primary Endpoint 
The primary endpoint is the incidence of hypersensitivity infusion reactions (ﬂushing, itching, 
alterations in heart rate and blood pressure, dyspnea, chest discomfort, acute back or abdominal 
pain, fever, shaking chills, nausea, vomiting, diarrhea, skin rashes, throat tightening, hypoxia, 
seizures, dizziness, or syncope). 
The number and percent of patients experiencing hypersensitivity infusion reactions will be 
summarized by reaction and treatment group using descriptive statistics. This analysis will be 
performed using the FAS population.  
11.2.7. 
Secondary Endpoints 
The secondary endpoints will be to document the safety of IV cetirizine HCl and to capture 
additional process-related data, as follows. Sedation score and Readiness for Discharge 
endpoints will be analyzed descriptively by treatment group using the per protocol analysis set. 
All other endpoints will be analyzed descriptively by treatment group using the safety analysis 
set population (SAS). 
1. Sedation scores (patient and HCP) at 1 hour and 2 hours post-injection of antihistamine
(IV cetirizine HCl or IV diphenhydramine). The patient sedation scores are assessed on a
scale of 0-4, with 0=None and 4=Extremely Severe (Asleep, Cannot Self-Rate). The HCP
sedation scores are assessed on a scale of 0-4, with 0=None and 4=Extremely severe.


TerSera Therapeutics LLC 
Cetirizine HCl IV, 10 mg/mL 
Protocol TER-QZTR-001 
Version 4.0 Date: November 24, 2020 
Confidential and Proprietary 
Page 32 of 39 
2. Hypersensitivity infusion reactions at 1 hour and 2 hours post-injection of antihistamine
(IV cetirizine HCl or IV diphenhydramine).
3. Percentage of patients requiring rescue medication, e.g., epinephrine, bronchodilators, or
steroids.
4. Describe the reasons for the use of rescue drugs.
5. Document the AEs and SAEs per study group.
6. Describe the distribution of the amount of time spent in the treatment center prior to
discharge (time from injection to “Readiness for Discharge”).
7. Document the percentage of patients receiving additional medication, e.g., epinephrine or
steroids after discharge.
8. Effectively treated based on HCP’s opinion of
9. Analyze subgroup of patients 65 years of age and older.
10. Analyze subgroup of Time from Injection to Readiness for Discharge by
chemotherapy received (anti-CD20 or paclitaxel).
11.2.8. 
Safety Analyses 
Safety analysis will be analyzed descriptively by treatment group using the safety analysis set 
population (SAS). Sedation score will be analyzed descriptively by treatment group using per 
protocol analysis set. Adverse events will be coded using the Medical Dictionary for Regulatory 
Activities (MedDRA) coding dictionary 22.1 and will be summarized by treatment group by 
severity, seriousness, and relationship. Events occurring more than once in the same patient will 
be counted only once. Additional safety analyses include summarizing vital signs and physical 
exam findings descriptively by treatment group. 
12.
ETHICS
12.1. 
Local Regulations/Declaration of Helsinki
This study will be conducted in accordance with the ethical principles that have their origin in 
the Declaration of Helsinki and that are consistent with “Good Clinical Practice” ICH Tripartite 
Guideline and the applicable laws and regulations of the country in which the research is 
conducted, whichever affords the greater protection to the individual. 
12.2. 
Ethical Review 
It is the understanding of the Sponsor that this protocol (and any amendment), as well as 
appropriate consent procedures, will be reviewed and approved by a research ethics 
board/institutional review board (REB/IRB). This board must operate in accordance with the 
current federal regulations. A letter or certification of approval will be sent by the investigator to 
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Cetirizine HCl IV, 10 mg/mL 
Protocol TER-QZTR-001 
Version 4.0 Date: November 24, 2020 
Confidential and Proprietary 
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the Sponsor prior to initiation of the study, and whenever subsequent modifications to the 
protocol are made. 
12.3. 
Informed Consent 
It is the responsibility of the investigator, or a person designated by the investigator (if 
acceptable by local regulation), to obtain written informed consent from each individual 
participating in this study after adequate explanation of the aims, methods, objectives, and 
potential hazards of the study. It must also be explained to the patients that they are completely 
free to refuse to enter the study or to withdraw from it at any time for any reason. Appropriate 
forms for obtaining written informed consent will be provided by the Sponsor to the investigator 
to use to obtain consent from the patient. 
The eCRFs for this study contain a section for documenting informed patient consent, and this 
must be completed appropriately. If new safety information results in significant changes in the 
risk/benefit assessment, the consent form should be reviewed and updated if necessary. All 
patients (including those already being treated) should be informed of the new information, given 
a copy of the revised form, and asked to give their consent to continue in the study. 
12.4. 
Protocol Signatures 
After reading the protocol, each investigator will sign two protocol signature pages and return 
one of the signed pages to the Sponsor or Sponsor’s designee (e.g., CRO). 
13.
PUBLICATION POLICY
The Publication Policy will be addressed in the Research and Financial agreement, and all details 
outlined in the agreement will apply to this protocol. 
14.
REFERENCES
1. QUZYTTIR™ (cetirizine hydrochloride injection) for intravenous use [prescribing
information]. TerSera Therapeutics LLC. Lake Forest, IL. 2019.
2. Gobel BH. Chemotherapy-induced hypersensitivity reactions. Oncol Nurs Forum.
2005;32(5):1027-1034.
3. Joerger M. Prevention and handling of acute allergic and infusion reactions in oncology.
Ann Oncol 2012;23(suppl 10): x313–x319.
4. Diphenhydramine hydrochloride injection [prescribing information]. BD Rx Inc. Franklin
Lakes, NJ. Available from:
 Accessed October 8, 2019.
5. NCCN Guidelines Version 1.2019 Management of Immunotherapy-Related Toxicities.
Version1. 2019 11/14/2018 National Comprehensive Cancer Network© (NCCN)©
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Protocol TER-QZTR-001 
Version 4.0 Date: November 24, 2020 
Confidential and Proprietary 
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6. Roselló S, Blasco I, García Fabregat L, Cervantes A, Jordan K, on behalf of the ESMO
Guidelines Committee. Management of infusion reactions to systemic anticancer therapy:
ESMO Clinical Practice Guidelines. Ann Oncol 2017;28(Suppl 4): iv100-iv118.
7. Durham CG, Thotakura D, Sager L, Foster J, Herrington JD. Cetirizine versus
diphenhydramine in the prevention of chemotherapy-related hypersensitivity reactions.
J Oncol Pharm Practice 2019;25(6):1396-1401.
8. Zyrtec® (cetirizine hydrochloride) for oral use [package insert]. UCB Pharma. Smyrna,
GA. Available from:
 Accessed October 8, 2019. 
9. Polli JW, Baughman TM, Humphreys JE, Jordan KH, Mote AL, Salisbury JA, Tippin
TK, Serabjit-Singh CJ. P-glycoprotein influences the brain concentrations of cetirizine
(Zyrtec), a second-generation non-sedating antihistamine. J Pharm Sci. 2003
Oct;92(10):2082-9.
10. Wang JS, Zhu HJ, Markowitz JS, Donovan JL, DeVane L. Evaluation of antipsychotic
drugs as inhibitors of multi drug resistance transporter P-glycoprotein.
Psychopharmacology (Berl) 2006;187:415-23.
11. Lima SA, Tavares J, Gameiro P, de Castro B, Cordeiro-da-Silva A. Flurazepam inhibits
the P-glycoprotein transport function: an insight to revert multidrug-resistance phenotype.
Eur J Pharmacol. 2008 Feb 26;581(1-2):30-6.
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Protocol TER-QZTR-001 
Version 4.0 Date: November 24, 2020 
Confidential and Proprietary 
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Attachment A. 
Study Schedule 
Assessments 
Baseline 
Screening 
(Day -14 to 
Day 0)1 
 Antihistamine 
injection Day 
(Day 0) 
During 
Infusion 
1 hr post- 
antihistamine 
injection 
2 hr post- 
antihistamine 
injection 
Discharge 24 hr 
Up to 28 
days 
Post- 
24 hr 
FU Call 
Informed consent 
X 
Demographics 
X 
Inclusion/exclusion 
criteria 
X 
Medical and surgical 
history 
X 
Vital signs 
X 
X 
X 
X 
X 
Physical examination 
X 
Randomization 
X 
Study medication 
administration 
X 
Infusion reaction 
events 
X 
X 
X 
X 
Rescue medication, 
e.g., epinephrine,
bronchodilators,
steroids
X 
X 
X 
X 
X 
Sedation score 
X 
X 
X 
X 
HCP/Staff satisfaction 
of time spent 
X 
HCP/Site staff 
assessment of ease and 
readiness for discharge 
X 
Time of discharge 
X 
Concomitant 
medication 
X 
X 
X 
X 
X 
X 
Adverse events - Other 
than infusion reaction 2 
X 
X 
X 
X 
X 
X 
X 
Follow-up Q&A Sheet 
X 
Record patient self-
reported AEs 
X 
AE = adverse event; FU = follow-up; Q&A = question and answer 
1 The Screening period is up to 14 days prior to randomization/treatment to allow procedure to be completed. However, 
screening and randomization/treatment can occur on the same day. 
2  All AEs and SAEs reported after the patient signs an ICF will be recorded in the source documents and captured in the eCRF. 
Up to 28 days post–IV study drug injection, patient self-reported AEs and SAEs will also be included in the eCRF. 


TerSera Therapeutics LLC 
Cetirizine HCl IV, 10 mg/mL 
Protocol TER-QZTR-001 
Version 4.0 Date: November 24, 2020 
Confidential and Proprietary 
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Attachment B. 
Symptom Score 
A. HCP Assessments
a.
Physician/Designee
b. Nurse
c.
Other (specify)
1. HCP Sedation Score (baseline, 1 hr post- antihistamine injection, 2 hr post- antihistamine
injection and discharge)
0 = None (Patient is completely alert. Does not look tired at all.)  
1 = Mild (Patient sitting/lying comfortably, and look tired) 
2 =Moderate (Drowsy, with occasional eyes closing) 
3 = Severe (Asleep, with eyes closed but responds to minor motor stimulation) 
4 = Extremely Severe (Asleep; does not respond to minor motor stimulation) 
2. HCP/Infusion staff overall satisfaction based on antihistamine used for pretreatment
Amount of time spent during the first 2 hours 
1 = Very satisfied 
2 = Somewhat satisfied 
3 = Somewhat dissatisfied 
4 = not at all satisfied 
How satisfied are you with readiness and ease of discharge? 
1 = Very satisfied 
2 = Somewhat satisfied 
3 = Somewhat dissatisfied 
4 = not at all satisfied 


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Protocol TER-QZTR-001 
Version 4.0 Date: November 24, 2020 
Confidential and Proprietary 
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B. Patient Self-Rated Assessments (baseline, 1 hr post- antihistamine injection, 2 hr post- 
antihistamine injection and discharge)
Patient Sedation Score
Ask the patient “How drowsy do you feel at the moment?” 
0 = None (Not drowsy at all)  
1 = Mild (Slightly drowsy) 
2 = Moderate (Quite drowsy) 
3 = Severe (Extremely drowsy) 
4 = Extremely Severe (Asleep, cannot self-rate) 
C. HCP Readiness for Discharge
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Attachment C. 
24-Hour Follow-Up Questions 
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Protocol TER-QZTR-001 
Version 4.0 Date: November 24, 2020 
Confidential and Proprietary 
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Attachment D. 
Common P-Glycoprotein Inhibitor (From FDA Drug-Drug Interaction) 
1. Examples of in vitro inhibitors for transporters (9/26/2016)
Transporter 
Gene 
Inhibitor 
P-gp
ABCB1 
Cyclosporine 
Elacridar (GF120918) 
Ketoconazole 
Quinidine 
Reserpine 
Ritonavir 
Tacrolimus 
Valspodar (PSC833) 
Verapamil 
Zosuquidar (LY335979) 
2. Examples of clinical inhibitors for transporters (for use in clinical DDI studies and drug
labeling) (9/26/2016)
Transporter 
Gene 
Inhibitor 
P-gp(a)
ABCB1 
amiodarone, carvedilol, clarithromycin, dronedarone, 
itraconazole, lapatinib, lopinavir and ritonavir, propafenone, 
quinidine, ranolazine, ritonavir, saquinavir and ritonavir, 
telaprevir, tipranavir and ritonavir, verapamil 
a Strong inhibitor of CYP1A2 and CYP2C19, and moderate inhibitor of CYP2D6 and CYP3A 
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SAP_001.pdf: 
 
DISCLOSURE: REDACTED STATISTICAL ANALYSIS PLAN 
 
Title:   A Phase 2 exploratory study of intravenous QUZYTTIR™ (cetirizine 
hydrochloride injection) versus intravenous diphenhydramine in the prevention of 
hypersensitivity infusion reactions 
 
NCT Number: NCT04189588 
 
Statistical Analysis Approval Date: November 25, 2020 
 
Certain information within this protocol has been redacted (ie, Specific content is 
masked irreversibly from view with a black bar) to protect either personally 
identifiable information or company confidential information. 
 
This may include, but is not limited to, redaction of the following: 
 
• Named persons or organizations associated with the study. 
 
• Proprietary information, such as scales or coding systems, which are 
considered confidential information under prior agreements with license 
holder. 
 
• Other information as needed to protect confidentiality of TerSera or 
partners, personal information, or to otherwise protect the integrity of the 
clinical study. 
 
The information contained in the following document is the property of TerSera 
Therapeutics LLC and should not be shared or used for any purpose other than for 
which it was provided. 
 
 


Protocol TER-QZTR-001, SAP Rev. B 
Page 1 of 15 
Statistical Analysis Plan 
Protocol No.: TER-QZTR-001 
Protocol Title: 
A Phase 2 exploratory study of intravenous QUZYTTIRTM (cetirizine hydrochloride 
injection) versus intravenous diphenhydramine in the prevention of hypersensitivity infusion 
reactions 
Author: 
Technical Approver: 
________________________________             
      _______________ 
            Date of Approval 
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Protocol TER-QZTR-001, SAP Rev. B 
Page 2 of 15 
Table of Contents 
TABLE OF CONTENTS ............................................................................................................................................ 2 
1.
PREFACE ............................................................................................................................................................ 4 
2.
STUDY OBJECTIVES AND ENDPOINTS ...................................................................................................... 4 
3.
STUDY DESIGN ................................................................................................................................................. 5 
4.
SAMPLE SIZE CONSIDERATIONS ............................................................................................................... 7 
5.
ANALYSIS POPULATIONS ............................................................................................................................. 7 
6.
INTERIM ANALYSIS ........................................................................................................................................ 8 
7.
GENERAL CONSIDERATIONS FOR DATA ANALYSES........................................................................... 9 
7.1 
Imputed and Missing Data ......................................................................................................................... 9 
7.2 
Hypothesis Testing ..................................................................................................................................... 9 
7.3 
Adjustments for Multiplicity ....................................................................................................................... 9 
7.4 
Covariates .................................................................................................................................................. 9 
7.5 
Examination of Subgroups ......................................................................................................................... 9 
7.6 
Premature Discontinuation and Missing Data ........................................................................................ 10 
7.7 
Study Centers ........................................................................................................................................... 10 
7.8 
Data Review ............................................................................................................................................. 10 
7.9 
Derived Data ........................................................................................................................................... 10 
7.10 
Transformed Data .................................................................................................................................... 10 
7.11 
Changes from Protocol Planned Analysis ............................................................................................... 10 
8.
STUDY POPULATION .................................................................................................................................... 10 
8.1 
Patient Accountability.............................................................................................................................. 10 
8.2 
Demographics .......................................................................................................................................... 10 
8.3 
Medical/Surgical History ......................................................................................................................... 10 
8.4 
Physical Examination .............................................................................................................................. 10 
8.5 
Protocol Deviations ................................................................................................................................. 10 
9.
EFFICACY ANALYSIS ................................................................................................................................... 10 
10.
SAFETY ANALYSIS .................................................................................................................................... 10 
10.1 
Sedation score at baseline, 1 hour and 2 hours post-injection of antihistamine, and at discharge ......... 10 
10.2 
Hypersensitivity infusion reactions at 1 hour and 2 hours post-injection of antihistamine and at 
discharge (IV cetirizine HCl or IV diphenhydramine) ......................................................................................... 11 
10.3 
Percentage of patients requiring rescue medication, e.g., epinephrine, bronchodilators, or steroids ..... 11 
10.4 
Reasons for the use of rescue drugs ......................................................................................................... 11 
10.5 
Adverse Events ......................................................................................................................................... 11 
10.5.1 
Summary for Serious TEAEs ........................................................................................................................... 11 
10.5.2 
Deaths ............................................................................................................................................................... 11 
10.6 
The distribution of the amount of time spent in the treatment center prior to discharge (time from 
injection to “Readiness for Discharge”) ............................................................................................................. 12 
10.7 
Percentage of patients receiving additional medication, e.g., epinephrine or steroids after discharge..12 
10.8 
Vital Signs ................................................................................................................................................ 12 
10.9 
Other Analyses ......................................................................................................................................... 13 
10.9.1 
Percentage of effectively treated based on HCP’s opinion of 
 ......................................................... 13 
10.9.2 
Percentage HCP/Staff satisfaction of amount of time spent during the first 2 hours ........................................ 13 
10.9.3 
HCP/Staff satisfaction with readiness and ease of discharge ............................................................................ 13 
10.9.4 
Prior and Concomitant Medications ................................................................................................................. 13 
10.9.5 
Concomitant Procedures ................................................................................................................................... 13 
10.9.6 
24 Hr Follow-Up Questionnaire ....................................................................................................................... 13 
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Protocol TER-QZTR-001, SAP Rev. B 
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11.
REPORTING CONVENTIONS ................................................................................................................... 13 


Protocol TER-QZTR-001, SAP Rev. B 
Page 4 of 15 
1.
PREFACE
This Statistical Analysis Plan (SAP) describes the planned statistical analyses to be performed 
for data from Protocol TER-QZTR-001, “A Phase 2 exploratory study of intravenous 
QUZYTTIRTM (cetirizine hydrochloride injection) versus intravenous diphenhydramine in the 
prevention of hypersensitivity infusion reactions”. This SAP was created using Clinical Protocol 
TER-QZTR-001 Version 4.0 Amendment #3 dated 24NOV2020. Any post-hoc or unplanned 
analyses not identified in this SAP will be clearly identified in the CSR. 
The table and listing shells will be provided in separate files as attachments to this SAP. 
2.
STUDY OBJECTIVES AND ENDPOINTS
This is a parallel-group, randomized, double-blind exploratory study of IV cetirizine HCl 10 
mg/mL versus IV diphenhydramine 50 mg/mL in approximately 34 patients aged 18 or older, at 
up to 10 sites. The duration of study is approximately 24 hours for each completing patient. 
The objectives of this study are: 
The primary objective of this study is to compare the incidence of infusion reactions (flushing, 
itching, alterations in heart rate and blood pressure, dyspnea, chest discomfort, acute back or 
abdominal pain, fever, shaking chills, nausea, vomiting, diarrhea, skin rashes, throat tightening, 
hypoxia, seizures, dizziness, syncope, or other) to treatment with an anti-CD20 such as Rituxan® 
(rituximab) or paclitaxel, after premedication with intravenous (IV) QUZYTTIR™ cetirizine 
hydrochloride (HCl) or IV diphenhydramine during the infusion (first-cycle, retreatment after 6 
months or in patients with persistent infusion reactions while on maintenance or retreatment). 
The secondary objectives are to document the safety of IV cetirizine HCl and to capture 
additional process-related data, as follows: 
•
Sedation score (Patient and HCP) at 1 hour and 2 hours post-injection of
antihistamine (IV cetirizine HCl or IV diphenhydramine).
•
Hypersensitivity infusion reactions at 1 hour and 2 hours post-injection of
antihistamine (IV cetirizine HCl or IV diphenhydramine).
•
Document the percentage of patients requiring rescue medication, e.g., epinephrine,
bronchodilators, or steroids.
•
Describe the reasons for the use of rescue drugs.
•
Document the AEs and SAEs per study group.
•
Statistical calculation to project sample size for future studies.
•
Describe the distribution of the amount of time spent in the treating center prior to
discharge (time from injection to “Readiness for Discharge”).
•
Document the percentage of patients receiving additional medication, e.g.,
epinephrine or steroids after discharge.


Protocol TER-QZTR-001, SAP Rev. B 
Page 5 of 15 
•
HCP/Staff satisfaction of amount of time spent during the first 2 hours.
•
HCP/Staff satisfaction with readiness and ease of discharge.
•
HCP/Staff opinion of effectively treated.
The endpoints of this study are: 
The primary endpoint of this study is the incidence of hypersensitivity infusion reactions 
(flushing, itching, alterations in heart rate and blood pressure, dyspnea, chest discomfort, acute 
back or abdominal pain, fever, shaking chills, nausea, vomiting, diarrhea, skin rashes, throat 
tightening, hypoxia, seizures, dizziness, syncope, or other). 
The secondary endpoints will be to document the safety of IV cetirizine HCl and to capture 
additional process-related data, as follows. Sedation score and Readiness for Discharge endpoints 
will be analyzed descriptively by treatment group using per protocol (PP) analysis set. All other 
endpoints will be analyzed descriptively by treatment group using the safety analysis set 
population (SAS).  
•
Sedation score at 1 hour and 2 hours post-injection of antihistamine (IV cetirizine
HCl or IV diphenhydramine).
•
Hypersensitivity infusion reactions at 1 hour and 2 hours post-injection of
antihistamine (IV cetirizine HCl or IV diphenhydramine).
•
Percentage of patients requiring rescue medication, e.g., epinephrine, bronchodilators,
or steroids.
•
Reasons for the use of rescue drugs.
•
AEs and SAEs per study group.
•
The distribution of the amount of time spent in the treatment center prior to discharge
(time from injection to “Readiness for Discharge”).
•
Percentage of patients receiving additional medication, e.g., epinephrine or steroids
after discharge.
•
Percentage of effectively treated based on HCP’s opinion of
•
Analyze subgroup of patients 65 years of age and older.
•
Analyze subgroup of Time from Injection to Readiness for Discharge by chemotherapy
received (anti-CD20 or paclitaxel.
3.
STUDY DESIGN
This will be a parallel-group, randomized, double-blind exploratory study of IV cetirizine HCl 
10 mg/mL versus IV diphenhydramine 50 mg/mL in approximately 34 patients who will receive 
premedication for hypersensitivity infusion reactions associated with an anti-CD20, such as 
Rituxan® (rituximab) or paclitaxel. 
The objectives and purpose of the study will be described to patients presenting at the 
participating infusion centers. If a patient agrees to participate in the study, an informed consent 
form (ICF) will be signed by the patient according to the process followed by each center for 
obtaining informed consent. The screening period could be up to 14 days prior to 
randomization/treatment. After consent is received, the study investigator or designee will verify 
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Protocol TER-QZTR-001, SAP Rev. B 
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all inclusion and exclusion criteria to ensure patient eligibility and capture all baseline data such 
as vital signs (including temperature), weight, height, age, previous medical history, and prior 
medication use, including all medication taken prior to coming to the facility. Once these data 


Protocol TER-QZTR-001, SAP Rev. B 
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have been collected, the patient will be randomized to receive either IV cetirizine HCl or IV 
diphenhydramine. The time that the study medication was administered will be recorded in the 
source documents and in the eCRF. 
During the Baseline/Screening period (Day -14 to Day 0), the study investigator or designee will 
record the following baseline data: medical/surgical history, vital signs (including temperature), 
physical examination, and concomitant medication. 
On Antihistamine injection Day (Day 0), before the patient receives randomized antihistamine 
injection (Study drug or control), the investigator or designee will record the following 
information: vital signs (including temperature), Sedation score, Concomitant medication, and 
Adverse events - Other than infusion reaction. Patients are randomized in a 1:1 ratio to either 
cetirizine HCl or IV diphenhydramine in a blinded fashion. 
During the infusion and afterwards, the study investigator or designee will record each of the 
events of an infusion reaction: flushing, itching (pruritus), urticaria, alterations in heart rate and 
blood pressure, dyspnea, chest discomfort, acute back or abdominal pain, fever, shaking chills, 
nausea, vomiting, diarrhea, skin rashes, throat tightening, hypoxia, seizures, dizziness, syncope, or 
other. The study investigator will assess if the event is related to the Rituxan (rituximab) or 
paclitaxel infusion and record the event. 
The infusion reactions will be managed following the Common Terminology Criteria for Adverse 
Events (CTCAE version 5.0) definition of graded infusion reactions or clinical site protocol. 
The same measures will be assessed again at 1 hour and 2 hours after the injection of the 
antihistamine (IV cetirizine HCl or IV diphenhydramine) and at the Time of “Readiness for 
Discharge.” At these same time intervals, participating patients will be asked to self-rate (recorded 
by study staff) any symptom and their level of sedation. The patient’s responses will be recorded 
by the investigator/designee on the designated outcome measure form (source document). All 
rescue medication, e.g., epinephrine, bronchodilators, or steroids, will be recorded. In addition, 
site staff will evaluate overall satisfaction with time spent during treatment at 2 hours and ease of 
discharge. 
The actual time at which the investigator or designee determines the patient is physically and 
mentally fit to be discharged from the center (Time of “Readiness for Discharge”) will be recorded 
in the source documents. The decision to discharge the patient (Time of “Readiness for 
Discharge”) could be made at any time after the 2-hour assessment of study outcome measures 
provided the following criteria are met: 
Note: 
1. No symptoms of infusion hypersensitivity reaction
2. Patient is alert enough (sedation score = 0) to understand discharge instructions
3. Based on the investigator’s judgment, the patient is fit to be discharged


Protocol TER-QZTR-001, SAP Rev. B 
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i. If patient is fit to be discharged, but not alert enough to drive home when the sedation
score is at “1” or higher, he/she may be kept in the clinic until sedation improves. But
appropriate arrangement must be done, such as: call for a taxi, arrange a friend or relative
to help drive, or ask patient to stay in the waiting room until sedation goes away, etc.
ii. Standard discharge instruction should be given. If medications are prescribed at
discharge, instruct patients take them “as needed.”
iii. In the event that the symptoms were not effectively treated, patients will be treated
following the standard of care by attending physician.
Before discharge, patients will be instructed on the procedures they have to follow when 
experiencing an AE or SAE. They will be instructed to expect a follow-up phone call at 
approximately the same time the following day (i.e., 24 hours later) from a member of the site staff 
who will ask them a few short questions regarding hypersensitivity infusion reaction symptoms. 
All AEs and SAEs that are reported after the patient signs an ICF will be recorded in the source 
documents and captured in the eCRF. Up to 28 days post–IV study drug injection, patient self- 
reported AEs and SAEs will also be included in the eCRF. 
Please refer to the Protocol, Attachment A, for the schedule of study evaluations. 
4.
SAMPLE SIZE CONSIDERATIONS
This is a pilot clinical study to determine process feasibilities and to obtain a baseline clinical 
response (drug reaction to Rituxan or Paclitaxel) with pre-treatment of cetirizine HCl injection and 
diphenhydramine injection on the primary and secondary clinical outcome measures. As such, no 
sample size was calculated for this study. However, the data obtained from this study may be used 
to calculate the sample size of future studies. 
5.
ANALYSIS POPULATIONS
Patients with baseline Sedation Score greater than 0 may have taken a sedating concomitant or other 
medication. It may be impossible to confirm that patients did not take a sedating medication prior to 
receiving treatment. Sedation Score greater than 0 would be a confounding factor and may invalidate the 
results of endpoints of Sedation score and Readiness for Discharge. Therefore, these two endpoints will 
only be analyzed by the PP population, defined as patients with both a Patient and Health Care Provider 
(HCP) assessed Baseline Sedation score of 0. 
Patients will be categorized into the following analysis populations: 
Full Analysis Set (FAS): The FAS consists of all randomized patients. Analysis will be done according to 
the treatment patients were randomized to. 
Safety Analysis Set (SAS): The SAS consists of all patients who received at least 1 dose of study 
medication. Analysis will be done according to the actual treatment patients received.  
Per Protocol Analysis Set (PP): The PP consists of patients with both a Patient and HCP assessed 
Baseline Sedation score of 0, and who received at least 1 dose of study medication. Patients will be 
analyzed according to the treatment actually received. 


Protocol TER-QZTR-001, SAP Rev. B 
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6.
INTERIM ANALYSIS
No interim analyses are planned. 


Protocol TER-QZTR-001, SAP Rev. B 
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7.
GENERAL CONSIDERATIONS FOR DATA ANALYSES
All statistical analyses will be performed using SAS® Version 9.4, unless otherwise noted. Data 
will be summarized using descriptive statistics only. Number of patients (n), mean, median, 
standard deviation, minimum, and maximum will be summarized for continuous variables. 
Categorical variables will be summarized using frequencies and percentages. The number of 
patients in the population of interest will be used as the denominator. Percentages will be rounded 
to one decimal place, and thus may not always add up to exactly 100%. Time to event variables 
will be summarized using median, Q1 (25th percentile) and Q3 (75th percentile) from the Kaplan- 
Meier (KM) estimate of survival. Presentations will be by treatment group (IV cetirizine HCl 10 
mg/mL, and IV diphenhydramine 50 mg/mL) and overall, unless otherwise noted. 
In general, all summary tables will be supported by a relevant patient data listing including all 
patients who are randomized. The listings will include all data collected, and will be sorted by 
patient ID, and actual visit date, as applicable, unless otherwise noted. 
Concomitant medications will be coded using the WHO Drug Dictionary and adverse events and 
medical history will be coded using the Medical Dictionary for Regulatory Activities (MedDRA). 
The dictionary versions will be documented in the Data Management Plan for the study. 
Study day 1 is the day of antihistamine injection.  Study day is the day relative to the study day 1. 
Baseline is the last non-missing valid value prior to antihistamine injection. If a patient is not 
dosed, baseline will be set to the Screening/Baseline visit value. 
7.1 
Imputed and Missing Data 
No formal imputation of missing data will be performed. 
7.2 
Hypothesis Testing 
This is an exploratory study and no hypothesis testing will be performed. 
7.3 
Adjustments for Multiplicity 
No adjustments for multiplicity will be performed. 
7.4 
Covariates 
No covariates are planned. 
7.5 
Examination of Subgroups 
Subgroup of patients 65 years of age and older will be analyzed. 
Time from injection to Readiness for Discharge by chemotherapy received (anti-CD20 or 
paclitaxel) will be analyzed for this subgroup.  


Protocol TER-QZTR-001, SAP Rev. B 
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7.6 
Premature Discontinuation and Missing Data 
For any patient who withdraws prematurely from the study, all available data up to the time of 
discontinuation will be included in analyses. 
7.7 
Study Centers 
Up to 10 study centers will be used in this study. 
7.8 
Data Review 
Prior to unblinding of the study database, the data will be reviewed by the Clinical Project 
Manager. The investigational centers will be queried about any discrepancies or unclear data 
and, if necessary, these will be corrected in the database. 
7.9 
Derived Data 
The following data will be derived from collected data: 
7.10 
Transformed Data 
No data transformations are planned. 
7.11 
Changes from Protocol Planned Analysis 
No changes from protocol planned analysis are planned. 
8.
STUDY POPULATION
8.1 
Patient Accountability
All patients who signed the informed consent will be accounted for in Subject Disposition. The 
following disposition information will be summarized by the number and percentage of patients, 
by treatment group and overall: 
•
Patients who signed the informed consent, and who comprise the FAS, PP and
SAS populations
•
Patients receiving Rituxan (or anti-CD20 medication) vs Paclitaxel
•
Patients who complete the treatment or withdraw prematurely along with the reason
for discontinuation
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Protocol TER-QZTR-001, SAP Rev. B. 
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8.2 
Demographics 
Sex, age (in years), race, and ethnicity will be summarized by treatment group and overall, for all 
screened patients. 
8.3 
Medical/Surgical History 
The number and percentage of patients in the FAS population with any medical/surgical history 
will be tabulated by system organ class (SOC) and preferred terms (PT) using the MedDRA 
dictionary. Medical/surgical history will be counted only once for a patient within each PT and 
SOC; thus, since a patient may have more than one PT within a SOC, percentages of PT may not 
sum to the percentages in the SOC. 
8.4 
Physical Examination 
The number and percentage of patients with any clinically significant abnormal findings will be 
summarized by treatment group and overall, for the FAS population. 
8.5 
Protocol Deviations 
Data on protocol deviations will not be summarized but will be provided as a listing. 
9.
EFFICACY ANALYSIS
The primary endpoint is the incidence of hypersensitivity infusion reactions. The efficacy analysis 
will be summarized for the FAS population by treatment group and overall. The number and 
percentage of patients experiencing any infusion reaction events during the study, and the number 
and percentage of patients experienced each symptom by CTCAE grade (flushing, itching, 
alterations in heart rate and blood pressure, dyspnea, chest discomfort, acute back or abdominal 
pain, fever, shaking chills, nausea, vomiting, diarrhea, skin rashes, throat tightening, hypoxia, 
seizures, dizziness, syncope, or other) will be summarized. 
10.
SAFETY ANALYSIS
Safety analysis will be summarized for the SAS population by treatment group and overall. Sedation 
score endpoint will be summarized for the PP population by treatment group and overall. 
10.1 
Sedation score at baseline, 1 hour and 2 hours post-injection of 
antihistamine, and at discharge 
The patient sedation score and HCP sedation score will be summarized at baseline, 1 hour and 2 
hours post-injection of antihistamine, and at discharge. Change from baseline at each scheduled 
post-baseline time point will also be summarized. A listing of sedation score, including all time 
points, will be presented. 


Protocol TER-QZTR-001, SAP Rev. B. 
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10.2 
Hypersensitivity infusion reactions at 1 hour and 2 hours post-injection of 
antihistamine and at discharge (IV cetirizine HCl or IV diphenhydramine) 
The number of patients experiencing any infusion reaction events, and the number and percentage 
of patients experiencing each symptom (flushing, itching, alterations in heart rate and blood 
pressure, dyspnea, chest discomfort, acute back or abdominal pain, fever, shaking chills, nausea, 
vomiting, diarrhea, skin rashes, throat tightening, hypoxia, seizures, dizziness, syncope, or other) 
by CTCAE grade, will be summarized at during infusion, 1 hour and 2 hours post-injection of 
antihistamine, and at discharge. 
10.3 
Percentage of patients requiring rescue medication, e.g., epinephrine, 
bronchodilators, or steroids. 
The number and percentage of patients requiring rescue medication 
will be 
summarized, and a listing provided. 
10.4 
Reasons for the use of rescue drugs. 
Rescue drugs, if any, will be provided in a listing including the reasons for the use of rescue 
drugs. 
10.5 
Adverse Events 
All adverse events will be reported and listed, but only treatment emergent adverse events (TEAEs) 
will be summarized in the tables. A treatment emergent adverse event is defined as an AE that 
occurs on or after the date of the first study treatment. Safety evaluations will include patient self- 
reported adverse events and serious adverse events up to 28 days post IV study drug injection. 
A summary of all TEAEs by the number and percentages of patients who experienced any of the 
following will be provided: 
•
Any TEAE, including CTCAE toxicity grade (Mild, Moderate, Severe, Life-
Threatening and Fatal), relationship to study treatment (Not Related, Possible,
Probable, Not Assessable), AEs leading to discontinuation of study participation,
AEs leading to discontinuation of study treatment.
•
Any serious TEAE, including CTCAE toxicity grade (Mild, Moderate, Severe,
Life-Threatening and Fatal), relationship to study treatment (Not Related, Possible,
Probable, Not Assessable), AEs leading to discontinuation of study participation,
AEs leading to discontinuation of study treatment.
•
Any fatal TEAEs, including relationship to study treatment (Not Related, Possible,
Probable, Not Assessable)
Additionally, the number and percentage of unique patients reporting any TEAE will be 
summarized by system organ class (SOC) and preferred terms (PT). The number and percent of 
unique patients reporting any TEAE will also be summarized by SOC, PT, and worst CTCAE 
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Protocol TER-QZTR-001, SAP Rev. B. 
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toxicity grade and closest relationship to study treatment. For all AE summaries, patients will be 
counted once for each SOC or PT, at highest grade of event or closest relationship. 
A Listing of all AEs will be provided. This listing will include a flag identifying if an AE is a 
TEAE and a flag indicating if this AE is patient self-reported. 
10.5.1 
Summary for Serious TEAEs 
For all serious TEAEs the following will be summarized: 
•
Overall summary of any serious TEAEs by worst CTCAE toxicity presented
by SOC/PT
•
Overall summary of any serious TEAEs by closest relationship to study
treatment presented by SOC/PT
A Listing of all serious AEs will be provided. This listing will include a flag identifying if an AE 
is a TEAE. 
10.5.2 
Deaths 
Deaths, if any, will be provided in a listing only. 
10.6 
The distribution of the amount of time spent in the treatment center prior to 
discharge (time from injection to “Readiness for Discharge”) 
The KM estimate of survival will be used to summarize the time (in hours) to discharge by 
treatment group 
A KM survival curve stratified by treatment group will be provided. A listing of time of discharge 
will also be provided. 
10.7 
Percentage of patients receiving additional medication, e.g., epinephrine or 
steroids after discharge 
The number and percentage of patients receiving additional medication 
 will be 
summarized. 
10.8 
Vital Signs 
Vital signs, including blood pressure (mmHg), heart rate (beats/min), respiratory rate 
(breaths/min), and body temperature (C), will be summarized.  Observed values will be tabulated 
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Protocol TER-QZTR-001, SAP Rev. B. 
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at baseline, and at each scheduled post-baseline time point. Change from baseline at each 
scheduled post-baseline time point will also be summarized. Observed values at the screening visit 
may be presented if the screening visit is not the baseline. 
10.9 
Other Analyses 
10.9.1 
Percentage of effectively treated based on HCP’s opinion of 
The number and percentage of patients who are effectively treated will be summarized. A listing 
of the HCP’s opinion on effective treatment will also be provided. 
10.9.2 
Percentage HCP/Staff satisfaction of amount of time spent during the first 2 
hours 
10.9.3 
HCP/Staff satisfaction with readiness and ease of discharge. 
10.9.4 
Prior and Concomitant Medications 
Concomitant Medications are defined as medications taken during the trial. The number and 
percentage of patients taking any prior and concomitant medications will be summarized by WHO 
classification for therapeutic class (ATC level 3 terms) and preferred medication names. If an ATC 
level 3 term is not available, the next available level term should be used for the summary. If a 
patient is taking a medication before the first study treatment and continues during the trial, the 
medication will be included in both the prior and concomitant medication summary tables. 
10.9.5 
Concomitant Procedures 
A listing of concomitant procedures will be provided. 
10.9.6 
24 Hr Follow-Up Questionnaire 
A listing of 24-hour follow-up questionnaire responses will be provided. 
11.
REPORTING CONVENTIONS
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Protocol TER-QZTR-001, SAP Rev. B. 
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The following specifications will be used in the production of tables and listings. 
1. Page Setup
Unless otherwise noted, tables and listings will use landscape orientation. Margins will be at
least 3/4 of an inch on the left side of page, at least 3/4 of an inch at the top, and 3/8 of an
inch on the other sides.
The following header information should be included:
•
Upper left:  Sponsor name and protocol number
•
Center: CONFIDENTIAL; Database Download Date: ddmmmyy
•
Upper right: Page number shown as Page n of N. Page numbers should be sequential
within a table or listing.
The footer should include: 
•
Left: the name of the SAS program used to generate the output
•
Center: run date/time and the words “by CTDS”.
•
Right:  output file name.
2. Footnotes
Unless otherwise specified, footnotes should appear on all pages within the table.
3. Font
Font will be 9-point Arial, or smaller if needed for space constraints. If possible, small tables
should appear on one page. If tables continue on to multiple pages, there should be a page
break after an assessment so that all the statistics for an assessment appear on the same page.
4. Tables
Table titles should reflect the content of the table. Under the main title, in parentheses, the
name of the analysis population being summarized should appear.
4.1 Summary Statistics - Continuous Data 
Unless otherwise noted, the mean and median and confidence interval (CI) of a set of 
values should be printed out to one decimal place more than the original value. The 
standard deviation should be printed out to 2 decimal places more than the original 
value.   The number of patients on whom the parameter is assessed should appear. 
Minimum and maximum should be consistent with the original value. 
4.2 Summary Statistics - Categorical Data 
Numbers of patients are reported as whole numbers. Null counts are represented as 0. 
Table percentages should be reported to one decimal unless otherwise noted. Null 
percentages should be reported as 0.0. For all categories, the total number of patients 
with data will be presented as N. 
5. Patients Included in Listings


Protocol TER-QZTR-001, SAP Rev. B. 
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In general, patient data listings should include all patients who are randomized.  The 
population flag (FAS/ SAS) should be included in all listings as a column to indicate which 
population(s) a patient belongs to. If a listing includes a subset of patients who meet a certain 
condition (eg, patients with SAEs) then this should be clear from the title of the listing. If there 
is no record for a listing, then a statement, such as There is no serious adverse event in any of 
the treatment groups, will be presented.