Conditions: Acute Urticaria
Allocation: RANDOMIZED | Intervention model: PARALLEL
Enrollment: 262
Healthy volunteers: no

Brief summary:
This is a multicenter, parallel group, randomized, double-blind, active controlled, Phase III clinical study of cetirizine injection, 10 mg/mL, compared to diphenhydramine injection, 50 mg/mL (Benadryl or generic equivalent) with acute urticaria requiring treatment.

Detailed description:
This was a multi-center, parallel group, randomized, double-blind, active controlled, Phase III clinical trial of cetirizine injection 10 mg/mL versus diphenhydramine injection 50 mg/mL (Benadryl or generic equivalent) in approximately 256 subjects who either presented to Emergency Departments, hospitals, allergy clinics or Urgent Care Centers with acute urticaria, or developed acute urticaria following allergen challenge at an Allergy Clinic.

Patients signed an informed consent and were evaluated for eligibility for inclusion to treat. Eligible subjects were assessed for baseline characteristics, medical and surgical histories, concomitant medications and given a brief physical exam.

Subjects were then randomized, in a 1:1 ratio, to blindly receive either cetirizine 10 mg/mL injection or diphenhydramine 50 mg/mL injection.

Efficacy assessments included patient-rated severity of pruritus, physician assessments of extent of urticaria/erythema, and sedation score. Subjects remained in the treatment center for at least after the 1 hr assessment, after which they may have been discharged at the physician's discretion.

Safety was monitored through the reporting of adverse events for up to 28 days following treatments and by monitoring vital signs at planned intervals from admission into the treating facility until readiness for discharge. After 24 and 48 hrs after discharge, subjects were contacted by phone for follow-up questions regarding recurrence of symptoms, new symptoms, additional medication taken, side effects from medication taken after discharge, relapse requiring a return to treatment center, and return to normal activities.

Arms:
arm 1: JDP-205 Injection, 10 mg/mL, 1 mL arm 2: Diphenhydramine Injection, 50 mg/mL, 1 mL

Interventions: intervention 1: Test Drug (JDP-205) intervention 2: Active Control (Diphenhydramine)
Intervention descriptions: intervention 1: Cetirizine, 10mg/mL; a single 1.0 mL injection via intravenous (IV) push over a period of \~2 minutes intervention 2: Diphenhydramine Injection, 50 mg/mL;a single 1.0 mL injection via intravenous (IV) push over a period of \~2 minutes

Protocol document:
Prot_000.pdf: 
JDP Therapeutics Inc., Cetirizine Injection 
Protocol No: ETTAU-03
DISCLOSURE 
REDACTED PROTOCOL 
The information contained in the following document is the property of JDP Therapeutics Inc. 
and should not be shared or used for any purpose other than which it was provided.  Certain 
information has been redacted from this document pursuant to 42 CFR 11.48(a)(5). 
Confidential Commercial Information (CCI)
 


 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
CONFIDENTIAL 
 


JDP Therapeutics Inc., Cetirizine Injection 
Protocol No: ETTAU-03 
Sponsor: JDP 
Confidential 
ETTAU-03 
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CONFIDENTIAL 
 
 
 
PRINCIPAL INVESTIGATOR’S ACKNOWLEDGEMENT 
5 
1. 
Protocol Summary 
6 
2. 
Background and Rationale 
8 
3. 
Study Objectives 
9 
3.1 
Primary Objectives 
9 
3.2 
Secondary Objectives 
9 
4. 
Study Design 
9 
5. 
Study Population 
11 
5.1 
Inclusion Criteria 
11 
5.2 
Exclusion Criteria 
11 
5.3 
Discontinuations 
12 
6. 
Treatment 
13 
6.1 
Treatments Administered 
13 
6.2 
Materials and Supplies 
13 
6.3 
Method of Assignment to Treatment 
13 
6.4 
Control Product and Study Medication 
14 
6.4.1 
Rationale for Using Diphenhydramine as the Control Product 
14 
6.4.2 
Rationale for Selection of the Dose of cetirizine injection 
14 
6.4.3 
Randomization and Maintenance of Study Blind 
15 
6.4.4 
Breaking the Study Blind 
15 
6.4.5 
Concomitant Medications/Rescue Drugs 
15 
6.5 
Clinical and Safety Evaluations 
16 
7. 
Clinical/Efficacy Outcome and Measures 
16 
7.1 
Primary Clinical Efficacy Measure 
16 
7.2 
Key Secondary Clinical/Efficacy Measures 
16 
7.3 
Other Clinical/Efficacy Measures 
16 
8. 
Safety Evaluations 
17 
8.1 
Adverse Events 
17 
8.2 
Serious Adverse Events 
18 
8.3 
Safety Monitoring 
18 
9. 
Data Quality Assurance 
18 
9.1 
Direct Data Entry and Computerized Systems 
19 
9.2 
Confidentiality of Trial Documents and Subject Records 
19 
9.3 
Investigator’s Files/Retention of Documents 
19 
10. 
Sample Size and Statistical Methods 
19 


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10.1 
Determination of Sample Size 
19 
10.2 
Statistical and Analytical Plans 
20 
10.2.1 Patient/Subject Disposition and Analysis Populations 
20 
10.2.2 Patient/Subject Characteristics 
20 
10.2.3 Medical/Surgical History and Physical Exam Findings 
20 
10.2.4 Concomitant Therapy 
20 
10.2.5 Safety Assessment 
20 
10.2.6 Primary Efficacy Assessment 
21 
10.2.7 Key Secondary Efficacy Analyses 
21 
10.2.8 Other Efficacy Analyses 
21 
11. 
Ethics 
21 
11.1 
Local Regulations/Declaration of Helsinki 
21 
11.2 
Ethical Review 
21 
11.3 
Informed Consent 
21 
11.3.1 Protocol Signatures 
22 
11.3.2 Publication Policy 
22 
12. 
References 
23 
 
ATTACHMETS 
Protocol Attachment A. 
Study Schedule 
Protocol Attachment B. 
Symptom Score and Sedation Score 
Protocol Attachment C. 
24 hour and 48 hour follow-up questions 
Protocol Attachment D. 
Declaration of Helsink 


JDP Therapeutics Inc., Cetirizine Injection 
Protocol No: ETTAU-03 
Confidential 
ETTAU-03 
CONFIDENTIAL 
 
 
 
List of Abbreviations 
 
AE 
Adverse Event/Adverse Experience 
AUCinf 
Extrapolated Area Under the Plasma Concentration Time Curve to  infinity 
CFR 
Code of Federal Regulations 
CI 
Confidence Interval (confidence limits) 
CIOMS 
Council for International Organizations of Medical  Sciences 
CIU 
Chronic Idiopathic Urticaria 
Cmax 
Maximum Observed Plasma Concentration 
CONSORT 
Consolidated Standards of Reporting Trials 
CRF 
Case Report Form 
CRO 
Contract Research Organization 
DCC 
Data Coordinating Center 
DMID 
Division of Microbiology and Infectious Diseases, NIAID,  NIH 
DSMB 
Data Safety and Monitoring Board 
DSMC 
Data Safety and Monitoring Committee 
ETTAU 
Efficacy Trial for the Treatment of Acute Urticaria 
ED 
Emergency Department 
FWA 
Federal-Wide Assurance 
GCP 
Good Clinical Practice 
HIPAA 
Health Insurance Portability and Accountability Act 
IB 
Investigator’s Brochure 
ICF 
Informed Consent Form 
ICH 
International Conference on Harmonization 
IDE 
Investigational Device Exemption 
IEC 
Independent or Institutional Ethics Committee 
IND 
Investigational New Drug 
IRB 
Institutional Review Board 
ISM 
Independent Safety Monitor 
JAMA 
Journal of the American Medical Association 
MedDRA © 
Medical Dictionary for Regulatory Activities 
MOP 
Manual of Procedures 
N 
Number (typically refers to subjects) 
NCI 
National Cancer Institute, NIH 
NDA 
New Drug Application 
NEJM 
New England Journal of Medicine 
NI 
Non-inferiority 
NIAID 
National Institute of Allergy and Infectious Diseases,  NIH 
NIH 
National Institutes of Health 
OCRA 
Office of Clinical Research Affairs, DMID, NIAID,  NIH 
OHRP 
Office for Human Research Protections 
OHSR 
Office for Human Subjects Research 
ORA 
Office of Regulatory Affairs, DMID, NIAID, NIH 
PHI 
Protected Health Information 
PI 
Principal Investigator 
PK 
Pharmacokinetics 
QA 
Quality Assurance 
QC 
Quality Control 
SAP 
Statistical Analysis Plan 
SAE 
Serious Adverse Event/Serious Adverse Experience 
SD 
Standard Deviation 
SMC 
Safety Monitoring Committee 
SOP 
Standard Operating Procedure 
Tmax 
Time of maximum measured plasma concentration; if it occurs at more than one time point, Tmax is defined as 
the first time point with this value 
WHO 
World Health Organization 


JDP Therapeutics Inc., Cetirizine Injection 
Protocol No: ETTAU-03 
Sponsor: JDP 
Confidential 
ETTAU-03 
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CONFIDENTIAL 
 
 
 
 
 
PRINCIPAL  INVESTIGATOR’S ACKNOWLEDGEMENT 
 
I have read and understand this protocol, agree to conduct the study as outlined herein, 
and provide the necessary assurances that this study will be conducted according to all 
stipulations of the protocol, complying with the obligations and requirements of clinical 
investigators and all other requirements listed in 21 CFR part 312 and all applicable local, 
state, and federal regulations and ICH  guidelines. 
 
 
 
 
  
 
 
  
 
 
  
 
 
  
 
Principal  Investigator Signature 
Principal Investigator Name (print) 
Date 
Name of Investigational Site 


JDP Therapeutics Inc., Cetirizine Injection 
Protocol No: ETTAU-03 
Sponsor: JDP 
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1. Protocol Summary 
 
Title: 
A Phase III, multi-center, double blind, randomized, active controlled clinical trial to evaluate the Non-Inferiority 
comparing Cetirizine Injection 10 mg to Diphenhydramine Injection, 50 mg, for the treatment of acute urticaria. 
 
Phase: 
Phase III 
 
Population: 
Males or females aged 18 years and older, with acute urticaria requiring treatment in Emergency Departments, 
hospitals, Urgent Care Centers and Allergy Clinics will be included in this study. 
 
Number of Patients and Number of Sites: 
Approximately 256 patients, and approximately 20 sites 
 
Study Duration: 
Approximately 48 hours. 
 
Study Medications: 
Investigational Product: 
Cetirizine injection, 10 mg/mL – a single 1 mL injection via intravenous slow push (~2 minutes) 
 
Comparator: 
Diphenhydramine injection, 50mg/mL – a single 1 mL injection via intravenous slow push (~2 minutes) 
Objectives: 
Primary Objectives: 
1. The primary objective of this study is to establish the non-inferiority of Cetirizine injection with respect 
to Diphenhydramine injection in reducing patient reported pruritus severity score at 2 hours after 
treatment of acute urticaria. 
 
Secondary Objectives: 
The secondary objectives will assess, for each treatment group, the following parameters: 
1. 
Record the frequency of patient’s return to treatment center after discharge (i.e. 2nd visit within ~24 
hours after discharge) 
2. 
Record and compare sedation scores between treatments 
3. 
Record and compare time-to-discharge between treatments. 
4. 
Record and compare changes in patient reported pruritus severity score at 1 hr post treatment and at 
time of discharge. 
5. 
Record and compare Extent of Urticaria/Erythema scores, and their changes from baseline at various 
time points after treatment. 


JDP Therapeutics Inc., Cetirizine Injection 
Protocol No: ETTAU-03 
Sponsor: JDP 
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6. 
Document the percentage of patients experiencing adverse events (AEs) or serious adverse events 
(SAEs) from the study drugs. 
7. 
Document the percentage of patients requiring rescue medication, e.g. epinephrine, bronchodilators, 
steroids, etc., and the reasons for the use of rescue drugs. 
8. 
Record symptom recurrence rate and additional symptoms occurrence within ~24 hours and/or ~48 
hours after patient discharge from treatment centers. 
9. 
Record the need for medication after discharge. 
 
 
Description of Study Design: 
 
This will be a multicenter, parallel group, randomized, double-blind, active controlled, Phase III clinical study of 
cetirizine injection, 10 mg/mL, compared to diphenhydramine injection, 50 mg/mL (Benadryl or generic 
equivalent), in approximately 256 patients (1:1 ratio) with acute urticaria requiring treatment in Emergency 
Departments, hospitals, Urgent Care Centers, Allergy Clinics, and etc. 


JDP Therapeutics Inc., Cetirizine Injection 
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Sponsor: JDP 
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2. Background and Rationale 
 
Urticaria (hives) is a vascular reaction of the skin marked by the transient appearance of smooth, slightly elevated 
patches (wheals) that are erythematous and almost always associated with severe pruritus. Acute urticaria is 
often part of the acute allergic reactions, for examples: about 90% of anaphylaxis patients and most angioedema 
patients have urticaria symptoms at the same time; acute urticaria can also be the only symptom in an acute 
allergic reaction.   Individual lesions usually resolve without scarring in less than 24 hours.  Acute urticaria 
eruption rarely lasts more than several days, but sometimes it may recur over the course of several weeks, but 
less than 6 weeks. [Note: Chronic urticaria is defined as urticaria with recurrent episodes lasting longer than 6 
weeks (1, 2), which is not the patient population of this protocol.] 
 
The development of urticaria is often an isolated event without systemic manifestations. Sometimes, it may be a 
prelude to the development of an anaphylactic reaction. If any features of anaphylaxis (e.g. hypotension, 
respiratory distress, stridor, gastrointestinal distress, swallowing problems, joint swelling, joint pain) develop, 
immediate medical intervention is required. 
 
Acute urticaria, frequently a symptom of acute allergic reactions, is common in hospitals because many 
medications could induce allergic reactions, such as antibiotics, intravenous (i.v.) contrast media, aspirin/NSAIDS, 
anesthetics, blood material, opioids, muscle relaxants, chemotherapy agents, etc. Acute urticaria, frequently a 
symptom of acute allergic reactions, is also common in emergency rooms and allergy clinics, mostly food allergies 
(seafood, nuts, etc.), exercise induced allergy, latex allergy, bee stings, etc. In these conditions, antihistamines 
injections (such as diphenhydramine injection) are usually used together with epinephrine, steroids, or other 
medications for severe cases, or used alone for less severe cases. 
 
In the 2009 US National Hospital Ambulatory Medical Care Survey (3), it was noted that almost 5 million visits 
were made to hospital emergency departments for acute allergic reactions. Acute urticaria is reported to be the 
most common symptom associated with acute allergic reactions treated in the emergency department (ED) (4, 5, 6). 
 
The management of acute urticaria in the ED is usually not dependent on the underlying etiology. Most cases of 
acute urticaria respond to pharmacotherapy, with antihistamines being first-line treatment(7). To provide rapid 
relief of the symptoms and associated pruritus, the parenteral route is preferred, but the only antihistamine 
available for intravenous administration is diphenhydramine injection. Consequently, during the US National 
Hospital Ambulatory Medical Care Survey period between December 2008 and December 2009, 
diphenhydramine was used over 4 million times during patient visits to the ED (3). Unfortunately, 
diphenhydramine (a short acting antihistamine) causes sedation, impairs mental performance, and results in 
unwanted anticholinergic effects (e.g.: urinary retention, dry mouth/eyes, etc.) in a large percentage of patients 
(8, 9, 10, 11) all of which complicate patient management and ED discharge. In contrast, cetirizine, a second 
generation antihistamine, is associated with a lower rate of sedation, a 24-hour duration of action, and is devoid 
of anticholinergic effects (10, 11, 12, 13) and other sides effects associated with diphenhydramine. 
 
Development work for cetirizine injection 10 mg/mL was initiated by JDP in 2009. Several clinical trials have been 
conducted to date: 
 
- 
Relative bioavailability of cetirizine injection has been investigated in the pharmacokinetics & tolerability 
study (study # CTN-P0-741) via IV and IM, against the oral tablet of cetirizine. This study was greatly 
successful. It demonstrated that the AUCs between cetirizine tablet (Zyrtec) and the injection are 
equivalent, and Cmax of the cetirizine injection is about 3.5 times of that of the tablet. In addition, JDP’s 
Cetirizine injection did not cause significant adverse events. 
 
- 
A 2nd relative bioavailability study (Study # CTN-P1-571) on cetirizine injection 10 mg, via IM injection, was 
also successful without any significant adverse events. 


JDP Therapeutics Inc., Cetirizine Injection 
Protocol No: ETTAU-03 
Sponsor: JDP 
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CONFIDENTIAL 
 
 
 
 
- 
A pilot phase III clinical study (ETTUAU-02) with a similar study design as the current study ETTAU-03 was 
conducted as a preparation for the current study to streamline recruiting, IRB process, and IND, etc. ETTAU- 
02 demonstrated a similar efficacy in acute urticaria symptom score reductions while in treatment centers 
between the two treatment groups (Cetirizine injection and diphenhydramine injections), demonstrated an 
earlier patient discharge from treatment centers with the cetirizine group, and also demonstrated a lower 
sedation levels and symptom recurrence rate with the cetirizine group, etc. 
 
Since acute urticaria, frequently a symptom of an acute allergic reaction, is an acute condition and typically seen 
in emergency departments (ED) and urgent care centers, it is not feasible to conduct a placebo controlled clinical 
trial on actual patients. Therefore, non-inferiority clinical trials have been suggested by IRB and regulatory 
agencies. Currently, Diphenhydramine injection is the standard of care for this condition (although not 
specifically indicated for the condition), and is the most commonly used antihistamine injection for acute 
urticaria. It is either used alone for moderate or mild cases, or as an adjunct therapy with other medications for 
severe cases. Therefore, diphenhydramine injection is proposed as an “active comparator” for a phase III clinical 
trial. 
 
The present study will confirm the primary endpoint and secondary endpoints via the multi-center, double blind, 
randomized, active controlled study design to evaluate the efficacy Non-Inferiority comparing Cetirizine Injection 
10 mg to Diphenhydramine Injection, 50 mg, for the treatment of acute urticaria in various clinical settings. 
 
3. Study Objectives 
 
3.1 
Primary Objectives 
The primary objective of this study is to establish the non-inferiority of Cetirizine injection with respect 
to Diphenhydramine injection in reducing patient reported pruritus severity score at 2 hours after 
treatment of acute urticaria. 
 
3.2 
Secondary Objectives 
The secondary objectives will assess, for each treatment group, the following parameters: 
1. 
Record the percent of patients who return to treatment center after discharge (i.e. 2nd visit within ~24 
hours after discharge) 
2. 
Record and compare sedation scores between treatments 
3. 
Record and compare time-to-discharge between treatments. 
4. 
Record and compare changes in patient reported pruritus severity score at 1 hr post treatment and at 
time of discharge. 
5. 
Record and compare Extent of Urticaria/Erythema scores, and their changes from baseline at various 
time points after treatment. 
6. 
Document the percentage of patients experiencing adverse events (AEs) or serious adverse events 
(SAEs) from the study drugs. 
7. 
Document the percentage of patients requiring rescue medication prior to discharge, e.g. epinephrine, 
bronchodilators, steroids, etc., and the reasons for the use of rescue drugs 
8. 
Record symptom recurrence rate and additional symptoms occurrence within ~24-48 hours after patient 
discharge from treatment centers. 
9. 
Record the need for medication after discharge. 
 
4. Study Design 
This is a multi-center, parallel group, randomized, double-blind, active controlled, phase III clinical trial of 


JDP Therapeutics Inc., Cetirizine Injection 
Protocol No: ETTAU-03 
Sponsor: JDP 
Confidential 
ETTAU-03 
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CONFIDENTIAL 
 
 
 
 
cetirizine injection 10 mg/mL versus diphenhydramine injection 50 mg/mL (Benadryl or generic equivalent) in 
approximately 256 patients (1:1 ratio) who either present to Emergency Departments, Hospitals, allergy clinics or 
Urgent Care Centers with acute urticaria, or developed acute urticaria following allergen challenge at an Allergy 
Clinic. 
 
The objectives and purpose of the study will be described to subjects presenting at the participating clinical 
centers. If a subject agrees to participate in the study, an informed consent form (ICF) will be signed by the 
subject according to the process followed by each center for obtaining informed consent. 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 baseline urticarial symptom scores, vital signs, age, previous 
medical history, cause of the symptoms (if known), 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 
cetirizine injection or diphenhydramine injection. The time that the study medication is administered will be 
recorded in the source documents and/or in the eCRF. 
 
Just before the study medication is administered, the study investigator or designee will record the following 
baseline data: vital signs, the extent of urticaria and erythema, the severity of pruritus by patient, and the level of 
sedation by patient. See Attachment B for detailed description of symptom assessment. The same measures will 
be assessed again at 1 hour and/or 2 hours after the injection, and/or at the Time of “Readiness for Discharge” 
which can happen at any time after the 1-hour assessment if the symptom score has reached zero at 1hr. If 
symptom score is not zero prior to 2 hr, patient must be kept at the treatment center for at least 2 hours. At 
these same time intervals, participating patients will be asked to self-rate (recorded by study staff) the severity of 
their pruritus and their level of sedation.  The patient’s responses will be recorded by the investigator/designee 
on the designated Source Document or eCRF) as “patient assessment scores”. The time that the 
investigator/designee determines that patient is physically and mentally fit to be discharged from the center 
(Time of “Readiness for Discharge”), , will be recorded in the source documents. If the Time of “readiness for 
discharge” happens longer than 20 minutes from the previous assessment, then the “readiness for discharge 
assessment” should be done. If the Time of “readiness for discharge” happens within 20 minutes of the previous 
assessment and the symptom score does not change from the previous assessment, then the “readiness for 
discharge” assessment is not needed, because the previous assessment can be treated as the “readiness for 
discharge assessment”. 
 
Site staff should ensure that the patient has appropriate transportation to their destination; under no 
circumstances should a study participant be permitted to drive themselves if the sedation score is at “1” or 
higher.  The time that the patient actually leaves the treatment center is also recorded. 
 
Before discharge, patients will be instructed that a member of the site staff will telephone them at approximately 
the same time or the next convenient time (e.g.: if patient is discharged at 3 am, the site staff will telephone the 
patient at ~8 am) the following day, and the day after (i.e. ~24 hours, and ~48 hours later) to ask them a few 
short questions to follow up on the treatment of their acute urticaria (See attachment C). Patients will be asked 
to provide contact telephone number where they can be reached and also given a telephone number for them to 
call in the event that they are not contacted. Patients will also be instructed to call this number to report any AEs 
or SAEs they may have experienced. 
 
The decision to discharge the patient (Time of “Readiness for Discharge”) can be taken by the 
Investigator/designee provided the following criteria are met: 
 
1) 
Symptoms of the acute allergic reaction have been effectively treated based on investigator/designee’s 
opinion (Note: if rescue drugs are used, patients are deemed not effectively treated by the study drug, 
but effectively treated by rescue drugs.) 
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 


J D P T hera pe utics I nc., Cetirizi ne I njecti o n 
Pr ot oc ol N o: E T T A U -0 3  
S p o n s or: J D P  
C o nfi d e nti al  
E T T A U -0 3  
1 1  of 3 1  
 
C O N FI D E N TI A L  
 
 
 
 
N ot e:  
i) 
If p ati e nt is fit t o b e disc h ar g e d, b ut n ot al ert e n o u g h t o driv e h o m e w h e n t h e s e d ati o n sc or e is at “ 1” or hi g h er, 
h e/s h e m a y b e k e pt f or a m axi m u m of 5 h o urs (t o m a k e it pr actic al f or r es e arc h p ers o n n el). B ut a p pr o pri at e 
arr a n g e m e nt  m ust  b e  d o n e,  s uc h as:  c all f or a t axi, arr a n g e  a fri e n d or  r el ativ e t o h el p  driv e,  or  as k  p ati e nt  t o st a y i n 
t h e w aiti n g  r o o m u ntil  s e d ati o n g o es  a w ay,  etc.  
 
ii) 
St a n d ar d  disc h ar g e  i nstr ucti o n s h o ul d b e  giv e n.  If m e dic ati o ns  ar e  pr escri b e d  at  disc h ar g e,  i nstr uct p ati e nts  t a k e 
t h e m “ as n e e d e d”  
 
iii) I n t h e ev e nt  if t h e s y m pt o ms w er e  n ot  eff ectiv ely  tr e at e d, p ati e nts  will  b e  tr e at e d f oll o wi n g t h e st a n d ar d of  c ar e b y 
att e n di n g  p h ysici a n.  
 
iv) If “ Ti m e of  R e a di n ess  f or Disc h ar g e”  h a p p e ns  pri or  t o t h e 2 h o ur  ass ess m e nt,  t h e “ p ati e nt Pr urit us  Sc or e”  m ust  b e 
Z er o,  ot h er wis e  t h e p ati e nt  h as  t o b e  k e pt  i n t h e tr e at m e nt c e nt er f or at  l e ast 2 h o urs.  
 
All  A Es  a n d  S A Es  t h at ar e  r e p ort e d aft er  t h e p ati e nt  si g ns a n  I C F will  b e  r ec or d e d i n t h e s o urc e d oc u m e nts  a n d/ or 
c a pt ur e d i n t h e C R F.  
 
St u d y pr oc e d ur es a n d t h eir ti mi n g ar e s u m m ariz e d i n t h e St u d y Sc h e d ul e, Pr ot oc ol Att ac h m e nt A . 
 
5.  St u d y  P o p ul ati o n  
 
S u bj ects w h o m e et all of t h e i ncl usi o n crit eri a a n d n o n e of t h e e xcl usi o n crit eri a a n d h a v e si g n e d a n I C F will b e 
eli gi bl e f or st u d y p artici p ati o n.  
 
5. 1  
I ncl usi o n Crit eri a  
 
P ati e nts ar e eli gi bl e t o b e i ncl u d e d i n t h e st u d y o nl y if t h e y m e et all of t h e f oll o wi n g crit eri a:  
1)  M al e  or  f e m al e p ati e nts  wit h  a di a g n osis  of  ac ut e  urtic ari a  w h o  n e e d  tr e at m e nt wit h  a nti hist a mi n e  t o 
all e vi at e t h eir  s y m pt o ms; 
2)  1 8 y e ars of a g e or  ol d er;  
3)  B e  willi n g  a n d  a bl e  t o giv e  i nf or m e d c o ns e nt;  
4)  P ati e nts  wit h  a P ati e nt  r at e d Pr urit us  S e v erit y  Sc or e  ≥ 1 
 
N ot e : 
 
P ati e nts w h o, i n t h e o pi ni o n of t h e i n v esti g at or, h a v e ac ut e urtic ari a c a us e d b y a r e acti o n t o a 
m e dic ati o n  ( e. g. a nti bi otics,  N S AI Ds,  etc.)  t h at t h e y ar e  c urr e ntl y t a ki n g, b ut  w h o  c a n st o p t h e m e dic ati o n 
aft er  pr es e nti n g  t o t h e sit e m a y  b e  i ncl u d e d i n t h e st u d y. 
 
P ati e nts  o n  r e g ul ar m e dic ati o ns  f or c hr o nic c o n diti o ns m a y  b e  i ncl u d e d i n t h e st u d y. 
 
P ati e nts  pr es e nti n g  wit h  a n gi o e d e m a  i n a d diti o n  t o ac ut e  urtic ari a  ar e  als o  eli gi bl e  t o p artici p at e.  
 
If p ati e nts  pr es e nt  ac ut e  urtic ari a  t o g et h er wit h  a n a p h yl axis,  aft er  a n a p h yl axis  sy m pt o ms h a v e  b e e n 
all e vi at e d,  t h es e p ati e nt  c a n als o  b e  i ncl u d e d i n t h e st u d y as  l o n g as  urtic ari a  still pr es e nts.  
 
A n y  p ati e nts  w h o  m e et  t h e i ncl usi o n/ excl usi o n crit eri a m a y  b e  c o nsi d er e d f or p artici p ati n g  i n t h e st u d y, 
i ncl u di n g h o m el ess  (if c a n b e  r e ac h e d f or f oll o w u p  b y  p h o n e),  h a n dic a p p e d,  etc . 
 
 
5. 2  
E xcl usi o n  Crit eri a  
 
P ati e nts will b e excl u d e d fr o m t h e st u d y if t h e y m e et a n y of t h e f oll o wi n g crit eri a:  
1)  R ec ei pt  of  a n  i n v esti g ati o n al dr u g  or  d e vic e,  wit hi n  t h e p ast  3 0  d a ys;  


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2) Patients in whom an antihistamine may be contraindicated (e.g. narrow angle glaucoma, symptomatic 
prostatic hypertrophy); 
3) Patients who, in the opinion of the investigator, may not tolerate an IV injection of diphenhydramine 50 
mg, or cetirizine 10 mg; 
4) Receipt of any antihistamine (H1 antagonist) within the past 2 hours regardless of the route of 
administration, e.g. diphenhydramine, cetirizine, loratadine, fexofenadine, levocetirizine, desloratadine; 
5) Receipt of an H2 antagonist within the past 2 hours; 
6) Receipt of doxepin within the past 2 hours; doxepin is an antidepressant, but it also has antihistamine 
properties; 
7) Receipt of steroids by the oral, IV, IM, or inhalational routes route within the past 4 hours to manage an 
acute allergic reaction; 
8) Receipt of epinephrine (EpiPen or any other brand) within the past 20 minutes; 
9) Anaphylaxis prior to the acute anaphylactic symptoms having been treated. 
10) Has known allergy to hydroxyzine, cetirizine or levocetirizine, or diphenhydramine; 
11) Pregnancy or breastfeeding; 
12) Patients who have an acute allergic reaction to medication they are taking (e.g. antibiotics, NSAIDs, etc.) 
and who cannot stop the medication; 
13) Patients who, based on their medical history or in the opinion of the investigator, have chronic urticaria, 
hereditary angioedema, urticaria refractory to antihistamines, or dermatological disease that interferes 
with evaluation of a therapeutic response; 
14) Any condition that in the view of the investigator makes the subject unsuitable for enrollment in this 
study; 
15) Major medical or psychiatric illness, other than acute urticaria, at the time of presentation; 
16) Inability to provide informed consent. 
17) Patients on concomitant p-glycoprotein inhibitors 
 
5.3 
Discontinuations 
 
Subjects 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 subjects from the study if he/she feels it is 
the best interest of the subject, or if the subject is uncooperative or non-compliant. The discontinued patients 
will be followed to resolution of any ongoing AEs. 
 
Reasons for discontinuation include: 
• 
Violation of Inclusion or Exclusion criteria found after the study medication has been administered 
• 
The investigator, patient, or the health care professional performing assessments, become un-blinded to 
the study medication for whatever reason; 
• 
The investigator decides that the patient should be withdrawn. If this decision is made because of a 
serious adverse event, the study drug, if any, 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 reasons for the discontinuation; 
• 
The subject may withdraw from the study for any other reason, including withdrawal of consent. 


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An excessive rate of withdrawal can make the study results difficult to interpret. Any patient who discontinues 
for a reason other than the occurrence of an adverse event will be replaced by enrolling an additional patient. 
 
The reason for any discontinuation will be fully documented on the Source Document and/or CRF. 
 
Should a patient decide to withdraw, every effort will be made to complete and report all study observations, 
particularly the 24 hour and/or 48-hour follow-up, as thoroughly as possible. The investigator/designee should 
contact the subject either by telephone, or through a personal visit if necessary, to determine as completely as 
possible the reason for the withdrawal. 
 
Note: 
- 
After discharge, two follow-up phone calls are planned at ~24 hours and ~48 hours. However, sometimes 
patients do not like to answer phone calls. It is possible only one follow-up can be obtained. In this case, this 
patient is not considered as discontinued or as protocol deviation. 
 
- 
If rescue medication is needed very shortly after study drug administration (e.g. within ~10 -15min), this 
indicates that the patient might have or develop into anaphylaxis. This patient should be withdrawn from 
the study, because he/she should have been excluded during screening. 
 
 
6. Treatment 
 
6.1 
Treatments  Administered 
Subjects who fulfill all the inclusion and none of the exclusion criteria will be enrolled into the study. Each subject 
should read and sign an ICF prior to any study procedures being performed. This study involves a comparison of 
two injectable products: cetirizine injection, 10 mg/mL, and diphenhydramine injection, 50 mg/mL, both 
administered during a ~2-minute period by intravenous slow push. The injections can be injected directly or after 
dilution with saline depending on the internal standard procedure at each treatment center related to i.v. 
diphenhydramine. Subjects will receive pre-randomized treatment drugs of one of the following: 
 
• 
Cetirizine, 10mg/mL; a single 1 mL injection via intravenous slow push over a period of ~2 minutes 
• 
Diphenhydramine, 50mg/mL; a single 1 mL injection via intravenous slow push over a period of ~2 
minutes. 
 
6.2 
Materials and Supplies 
Treatment drugs (Investigational drug and Control) will be pre-randomized and blinded before arriving at each 
investigational site.  A drug dispensing log will be kept current and will contain the following information: 
• 
The identification of the subject to whom the drug was dispensed 
• 
The date, quantity, and lot number of the drug dispensed to the subject 
 
Drug inventory and accountability records (Test Article Accountability Log) will be maintained at each site. A 
monitor or designated site staff will reconcile drug inventory and review accountability records. Any unused vials 
of cetirizine will be returned to the sponsor or destructed on site per sponsor request. Study drugs are to be 
stored at room temperature. 
 
6.3 
Method of Assignment to Treatment 
 
Approximately 256 patients will be randomized to either one of two treatment groups in a 1:1 ratio. A 
randomization list in blocks of four will be generated centrally by the sponsor/or CRO for each site. 


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Approximately 13 blocks, i.e. enough study medication for a maximum of 52 patients will be sent to each study 
site prior to patient enrollment. A treatment vial, consisting of one vial of either cetirizine or diphenhydramine, 
based on the treatment assignment of the centralized randomization schedule, will be packaged for each 
randomization number and labeled by the randomization number, using a blinded label to cover the product 
name. A list will contain assignment of sequential numbers to one of the two treatment groups. The original 
randomization list will be kept secured until the study blind is broken. At the investigational site, each 
randomized subject will be assigned a subject identifier number. This identifier number (“Subject Number” or 
“Subject Identification Number”) will be used on all subject documentation. Subject Numbers will be assigned in 
ascending sequential order. The Subject Number will consist of two digits (site number) followed by three digits 
(subject number), e.g. 02-009 (the 9th patient enrolled at site #2). 
The randomization number (Treatment Number) for each subject with its Subject Number will be allocated at 
baseline and entered in the source document or eCRF, after verifying the inclusion and exclusion criteria. 
6.4 
Control Product and Study Medication 
-
Investigational Product: cetirizine injection, a single 1.0 mL injection (10 mg/mL) given by slow
intravenous push (~2 minutes).
-
Control Product: IV diphenhydramine, a single 1.0 mL injection (50 mg/mL) given by slow intravenous
push (~2 minutes).
6.4.1 
Rationale for Using Diphenhydramine as the Control Product 
IV diphenhydramine is the only antihistamine injection available for the treatment of acute urticaria.
The approved indication for IV diphenhydramine is as follows: 
For amelioration 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(14). 
6.4.2 
Rationale for Selection of the Dose of cetirizine injection 
The recommended dose of oral cetirizine is 10 mg (Zyrtec®/Reactine® Prescribing Information). 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 oral dose occurs within one hour in 95% of subjects. 
Although direct comparisons between IV diphenhydramine and IV cetirizine in the medical literature are lacking, 
the generally recommended doses to manage acute allergic reactions are 50 mg and 10 mg, respectively (11). 
Furthermore, cetirizine, 10 mg oral tablet is commonly used to treat acute urticaria by allergists(11,12). Cetirizine 
10 mg is also the Reference Listed Drug (RLD) dose specified by the FDA. 
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JDP conducted its direct comparison study between IV cetirizine 10 mg and IV diphenhydramine 50 mg in a pilot 
phase III clinical trial (ETTUAU-02) with a similar study design as the current study (ETTAU-03) as a preparation for 
the current study to streamline recruiting, IRB process, and IND, etc. ETTAU-02 demonstrated a similar efficacy in 
acute urticaria symptom score reductions while in the treatment centers between the two treatment groups 
(Cetirizine injection 10 mg and diphenhydramine injection), demonstrated an earlier patient discharge time from 
treatment centers with the cetirizine group than the diphenhydramine group, and also demonstrated a lower 
symptom recurrence rate with the cetirizine group within ~24 hours after discharge than with the 
diphenhydramine group, etc.  The 10 mg Cetirizine dosage in an injection form was shown to be similarly 
effective as diphenhydramine injection in the pilot phase III study, and thus was selected for the current study. 
 
 
6.4.3 
Randomization and Maintenance of Study Blind 
 
This will be a double-blind study; the investigator, the patient, and any health care professional involved in 
patient management or outcome assessment will remain blinded. Both cetirizine injection and IV 
diphenhydramine are presented as a clear aqueous solution in 2 mL amber vials containing 1.0 mL of medication, 
and having similar physical appearance. A blinded and randomized label created for the study conceals the 
product label of each vial for both the Investigational drug cetirizine and the comparator diphenhydramine. To 
further maintain blinding, the randomized medication can be drawn up into a syringe for administration by a staff 
member who is not involved in patient management or outcome assessment. The healthcare professional 
involved in patient management and outcome assessment is completely blinded. 
 
Treatment drugs (Investigational drug and Control) will be pre-randomized and blinded at 1:1 ratio by the 
Sponsor or CRO, according to the randomization schedule (see Section 6.3), prior to being delivered to each 
investigational site. At the investigational site, the trial randomization code will remain secure at all times, but 
may be accessed in the event of an emergency. 
 
6.4.4 
Breaking the Study Blind 
In order to preserve the blinding of the study, site personnel will not have access to the randomization code and 
treatment assignments before data base lock. Study blinding may only be broken if the identity of the study drug 
is considered vital for the clinical management of the subject. 
 
Since this is an acute care study it is impractical to notify the Sponsor and Medical Monitor prior to breaking the 
blind for a patient should it be necessary. However, all emergency code breaks must be reported to the Sponsor, 
CRO, the Medical Monitor and/or the Project Manager in a timely fashion. The time, date, the reason and who 
broke the blind, must be documented in the source documents and/or will be captured in the eCRF. 
 
If the investigator, patient, or health care professional performing the assessments, is unblinded for whatever 
reason, the patient will be included in all analyses of the study results, but a replacement patient will be recruited 
by the center. No assigned Subject ID Numbers will be reused for any subjects. 
 
6.4.5 
Concomitant Medications/Rescue Drugs 
To ensure optimal patient management, additional medications, e.g. epinephrine, steroids, or etc., may be given 
during the study if deemed necessary by the investigator/designee. 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. If rescue medication is needed very shortly after study drug administration (e.g. within 
~10 -15min), this indicates that the patient might have anaphylaxis. This patient should be withdrawn from the 
study, because he/she should have been excluded during screening. 
 
 
The product label of the rescue drugs should be followed to determine the appropriate dose. 


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The identity, dose, frequency and route of administration of all medications being taken prior to study enrolment 
will be recorded, as well as all concomitant medications administered during the study (rescue drug). 
 
6.5 
Clinical and Safety Evaluations 
 
Study procedures and their timing are summarized in the Study Schedule, Protocol Attachment A. All subjects who 
received at least one dose of study medication will be included in all analyses and safety analyses. 
 
7. Clinical/Efficacy Outcome and Measures 
 
7.1 
Primary Clinical Efficacy Measure 
 
The primary clinical efficacy outcome measure is the 2-hour patient rated Pruritus Severity Score 
Reduction/Change from Baseline (D2) as defined under Attachment B, comparing between the two treatment 
groups. 
 
7.2 
Key Secondary Clinical/Efficacy Measures 
 
The following key secondary clinical or efficacy measures will be assessed for each patient: 
1) The need to return to treatment center after study discharge (i.e. 2nd visit within approximately ~24 
hours after discharge) 
 
2) Time spent at the treating center (time from treatment administration to Readiness for discharge) 
 
7.3 
Other Clinical/Efficacy Measures 
The following other clinical or efficacy measures will be assessed for each patient: 
1) Pruritus treatment success (% of patients), defined as a patient who had the Pruritus Severity Score 
Reduction of at least 1 unit for the 2-hour patient rated Pruritus Severity score from Baseline (D2) as 
defined under Attachment B, comparing between the two treatment groups. 
2) Patient rated pruritus severity scores reduction/change from baseline (D1 & D3) at 1 hour and at “time 
of discharge” 
3) Sedation Scores, at baseline, 1hr, and/or 2hr, and/or Readiness for Discharge (B2) 
4) Physician rated Extent of Urticaria/Erythema Scores and their reduction/change from baseline at 1 hour, 
2 hours and “time of discharge” (C1, C2, C3). 
 
5) Use of rescue medication, e.g. epinephrine, bronchodilators, steroids, etc., and the reasons for the use 
of rescue drugs 
 
6) “Effectively treated” based on investigator’s opinion of Yes or No. 
 
7) Symptom recurrence and additional symptom occurrence within ~24 - 48 hours after patient discharge 
from treatment centers. 
 
8) The need for prescribed medication within ~24-48 hours after discharge. 
 
9) The need for additional medication, including any over-the-counter medications, within ~24 -48 hours 
after discharge. 


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10) Ability of returning to normal activity after discharge 
 
 
8. 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. 
The investigator remains responsible for following through an appropriate health care option for adverse events 
that are serious or 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. 
In this study, safety will be evaluated by recording any adverse events for up to 28 days following treatments and 
by monitoring vital signs at planned intervals from admission into the treating facility until readiness for 
discharge. 
 
8.1 
Adverse Events 
 
An adverse event (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. Cases of pregnancy should be reported 
for tracking purposes. Lack of drug effect is not an adverse event 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 CRF (Medical History). 
If a patient experiences an adverse event after the informed consent document is signed, the event will be 
recorded as an adverse event in the Source Document and/or CRF. All AEs encountered will be described in the 
source documents and/or in the CRF. 
The severity of the event will be classified according to the following terms: 
• 
Mild: symptom is manifest but is tolerated. 
• 
Moderate: normal activity affected. 
• 
Severe: severe effect or inability to work or necessary to discontinue the study medication 
The causality will be classified as: 
• 
Not related: Any adverse event which is not related to the product being studied. 
• 
Possible: Any adverse event which 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 which can be caused by the use of 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 subject is discontinued as a result of an adverse event, study site personnel must clearly document the 
circumstances leading to any such discontinuation of treatment, in the source document and/or on the CRF. 


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Events leading to a clinical outcome will be included as part of the safety and efficacy analyses for this study, and 
will not be recorded as AE unless the investigator believes the event may have been caused by the study drug. 
8.2 
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 adverse event from this study that results in one of the following outcomes, or is significant for any other 
reason: 
•
death
•
initial or prolonged inpatient hospitalization
•
a life-threatening experience (that is, immediate risk of dying)
•
persistent or significant disability/incapacity
•
congenital anomaly/birth defect
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 can be made by fax or email to: 
The Investigator/designee must provide the following information, as a minimum: the subject 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. 
An SAE occurring after a subject is discontinued from the study will be reported regardless of causality to the 
study medication or a protocol procedure. Should an investigator be made aware of any SAE occurring any time 
after the active reporting period, it must be promptly reported to the Sponsor or designate. 
8.3 
Safety Monitoring 
The Medical Monitor will review safety data, including vital signs, adverse events, and serious adverse events on 
an ongoing basis. 
Vital signs, which include sitting systolic and diastolic blood pressures, heart rate, temperature and respiration 
rate, will be collected on each subject at arrival at the treatment center, at baseline (just prior to treatment 
administration) at 1 hr and/or 2 hrs post treatment and at the time of discharge. 
9.
Data Quality Assurance
To ensure accurate, complete, and reliable data, the Sponsor or CRO will do the following: 
•
Provide instructional material to the study sites, as appropriate.
•
Sponsor an Investigator/coordinator training session to instruct the investigators and study
coordinators. This session will give instruction on the protocol, the completion of the source
document, CRFs, and study procedures.
o
Make periodic visits to the study site.
o
Be available for consultation and stay in contact with the study site personnel by mail,
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email, telephone, and/or fax. 
o
Review and evaluate the source document and/or CRF data and use standard computer
edits to detect errors in data collection.
o
Conduct a quality review of the database.
•
Verify the quality of the data.
In addition, the Sponsor representative will periodically check a sample of 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. 
9.1 
Direct Data Entry and Computerized Systems 
An electronic data capture system may be used in this trial. Some or all of a patient’s data may be directly 
entered into the system on an eCRF at the time that the information is obtained. In instances where eCRF is not 
feasible, data may be recorded manually directly to the Source Document first; then later transferred to the 
eCRF. Monitored and verified data will subsequently be transferred to the sponsor. 
9.2 
Confidentiality of Trial Documents and Subject Records 
The investigator must assure that the subjects’ anonymity will be maintained and that their identities are 
protected from unauthorized parties. On the source document, CRFs or other documents submitted to the 
Sponsor, subjects should not be identified by their names, but by an identification code. The Investigator should 
keep a subject enrolment log reconciling subject codes and subject names. The Investigator should maintain all 
subject related documents in strict confidence. 
9.3 
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 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 the duration required by local 
regulation, after completion or discontinuation of the study. After that period of time the documents may be 
destroyed, in accordance with local regulations. 
10. Sample Size and Statistical Methods
10.1 
Determination of Sample Size 
Assuming the diphenhydramine treated group responds similar to ETTAU-02 results, the common standard 
deviation is expected to be around 
A minimum sample size of 
 subjects per arm is needed to provide 
90% coverage probability (90% power) that the width of the 95% confidence interval of the treatment differences 
will remain within 
 if cetirizine is to be non-inferior to diphenhydramine. 
 the sample size of 
per treatment arm is recommended for a total 
enrollment of 
subjects to ensure sufficient numbers of completers at 2 hrs. The sample size estimation was 
performed using 
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10.2 
Statistical and Analytical Plans 
 
10.2.1 
Patient/Subject Disposition and Analysis Populations 
The disposition of all subjects, including those who discontinued, will be summarized by group, using counts and 
frequencies in each population. Subjects will be categorized into the following analysis populations: 
 
• 
Intent-To-Treat (ITT) Population: Includes any subject who was randomized and given a Subject ID 
Number with intent to treat with one of the blinded study drugs. All efficacy and non-inferiority 
analyses will be performed on the ITT population with subjects grouped by the treatment they were 
randomized to receive. 
 
• 
Safety Population (SAF): Includes any subjects in the ITT population who actually receives a blinded 
study drug, regardless whether or not they complete all assessments, withdraw or are discontinued by 
the investigator. All safety summaries will be performed on the SAF population with subjects grouped by 
the treatment they actually received. 
• 
Per Protocol Population (PP): Includes subjects in the SAF population who complete all necessary 
assessments without any incidence that would potentially affect the ability to objectively assess 
treatment response (e.g. discontinuation, protocol deviation, use of rescue medication, etc.). 
 
10.2.2 
Patient/Subject  Characteristics 
 
Descriptive statistics will be used to summarize participant demographics and baseline characteristics by 
treatment group. Characteristics such as weight, height and/or age will be summarized as continuous variables 
with means, SD, medians, minimums and maximums. Demographics, such as ethnicity and/or race will be 
summarized as counts and frequencies. The ITT population will be used to summarize baseline characteristics 
and demographics by treatment group. 
 
10.2.3 
Medical/Surgical History and Physical Exam Findings 
Upon arrival subjects will be asked about their medical/medication and surgical histories, and allergy history. 
This information will be used in the event that it may help to explain any adverse reactions or other unexpected 
outcomes. The findings will be provided in data listings, but will not be tabulated and summarized by treatment 
group. 
 
10.2.4 
Concomitant Therapy 
 
The medications taken by each group, prior to study enrollment and during the treatment period, will be coded 
using the latest WHO-Drug Coding Dictionary for anatomical therapeutic class (ATC) and preferred medication 
names and summarized by incidence as counts and frequencies within ATC and preferred names for each 
treatment group. The SAF population (safety population) will be used to summarize all concomitant therapies by 
treatment group. 
 
10.2.5 
Safety Assessment 
 
Safety parameters include assessment of adverse events (AEs) throughout the study. The safety analysis set will 
include all patients who received the study medication. All safety data will be displayed and analyzed ‘as 
randomized’ using descriptive statistical methods such as incidence rates. Events occurring more than once in the 
same patient will be counted only once. No formal inferential analysis is planned for safety comparisons. 
 
AEs will be coded for system organ class (SOC) and preferred terminology using the latest MedDRA coding 
dictionary. Incidences of AEs will be summarized as counts and frequencies within the SOC and preferred terms 
for each treatment group. The SAF population will be used to summarize all AEs by treatment group. 


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Vital signs will be summarized as continuous data with means, SD, medians, minimums and maximums for each 
vital sign for each assessment time, by treatment group. 
10.2.6 
Primary Efficacy Assessment 
All patients who received the study medication will be included in the full set analyses (FAS) the analyses. 
The primary clinical outcome measures of D2 as defined under Attachment B, will be summarized for each study 
group in cross classified tables for the 2-hour assessment. 
The hypothesis is defined as: the D2 score for the investigational drug is not worse than the comparator at the 2- 
hour time point, based on 95% confidence interval 
. See the statistical analysis 
plan for details. 
10.2.7 
Key Secondary Efficacy Analyses 
Key secondary clinical outcomes as detailed under Section 7.2 will be summarized using descriptive statistics 
(frequencies, proportions, means, standard deviation, median and/or range, etc.). Inferential treatment 
comparisons will be performed for each outcome with adjustments made for multiplicity as described in the 
statistical analysis plan. 
10.2.8 
Other Efficacy Analyses 
Other clinical outcomes as detailed under Section 7.3 will be summarized using descriptive statistics (frequencies, 
proportions, means, standard deviation, median and/or range, etc.).  No inferential treatment comparisons will 
be made on these outcomes. 
11. Ethics
11.1 
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 (1996) and that are consistent with “Good Clinical Practice” ICH Tripartite Guideline (January 1997) and 
the applicable laws and regulations of the country in which the research is conducted, whichever affords the 
greater protection to the individual. 
11.2 
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 (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 the Sponsor prior to initiation of the study, and also whenever subsequent modifications to the 
protocol are made. 
11.3 
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 
subjects 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 consent the patient. 
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The CRFs for this study contain a section for documenting informed subject consent, and this must be completed 
appropriately. If new safety information results in significant changes in the risk/benefice assessment, the 
consent form should be reviewed and updated if necessary. All subjects (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. 
 
11.3.1 
Protocol Signatures 
 
After reading the protocol, each investigator will sign two protocol signature pages and return one of the signed 
pages to the Sponsor (Page 5 of the Protocol). 
 
11.3.2 
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. 


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12. References 
 
1. Kaplan AP, Greaves, M. Pathogenesis of chronic urticaria. Clin Exp Allergy; 2009 ;39: 777-787 
2. Frigas E, Park M.A. Acute urticaria and angioedema: diagnostic and treatment considerations. Am J Clin 
Dermatology; 2009; 10: 239-250 
3. National Hospital Ambulatory Medical Care Survey: 2009 Emergency Department Summary 
Tablesa=v&q=cache:gvyu34jAfOIJ:www.cdc.gov/nchs/data/ahcd/nhamcs_emergency/2009_ed_web_tables. 
pdf+national+hospital+ambulatory+medical+care+survey+2009+emergency+department+summary&hl=en& 
gl=ca&pid=bl&srcid=ADGEESgDP5OTVY6CDN_XqvW3m32WMkQhnPbh5dJh8u0quP3uRI05tZHuQrPlgsrqidvB 
H_jNLUclR_7WuBAIIBJy4yY33xcg3NchuXWUOnKcgkEDGQds8-She91S59w0j-DL- 
NzStOGq&sig=AHIEtbQW7x57INfnud0QvmmimCyBJTSguQ Accessed October 28th 2012 
4. Simonart,T et al. Particularities of urticaria seen in the emergency department. Eur J Emerg Med 1994; 1; 80- 
82 
5. Gupta R, et al. Increasing hospital admissions for systemic allergic disorders in England: analysis of national 
admissions data. BMJ: 2003; 327, 1142-1143 
6. Champion, R.H et al. Urticaria and Angio-Edema a Review of 554 patients. Br. J. Derm: 1969, 81, 588-597 
7. Zuberbier,T et al. EAACI/GALEN/EDF/WAO Guideline: definition, classification and diagnosis of urticaria. 
Allergy 2009; 64: 1417–1426 
8. Gengo, F, et al. The pharmacodynamics of diphenhydramine-induced drowsiness and changes in mental 
performance. Clin Pharmacol Ther 1989;45:1 5-21 
9. Kay, G et al. Initial and Steady-State Effects of Diphenhydramine and Loratadine on edation, Cognition, 
Mood, and Psychomotor Performance. Arch Intern Med. 1997;157:2350-2356 
10. Kay, G. The effects of antihistamines on cognition and performance. J Allergy Clin Immunol 2000; 105:S622-7 
11. Banerji, A, et al. Diphenhydramine versus nonsedating antihistamines for acute allergic reactions: A literature 
review. Allergy Asthma Proc 2007 28:418 –426 
12. Park, J. et al. Comparison of cetirizine and diphenhydramine in the treatment of acute food-induced allergic 
reactions. J Allergy Clin Immunol: 128; 1127-1128 
13. JDP Therapeutics Inc., Clinical Study Report No CTN-P0-741. Date of Report: 2011/09/11. Protocol Title: 
Single Dose Crossover Pharmacokinetics Study of Cetrizine Injection at 5 mg and 10 mg Intravenous doses 
and 10 mg Intramuscular dose compared to oral Cetrizine 10 mg tablets in healthy male and female 
volunteers. Fasting state 
14. JDP Therapeutics Inc., Clinical Study Report No CTN-P4-427 (ETTAU-02). Date of Report: 2015/02/06. 
Protocol Title: Multicenter pilot study to assess the feasibility of conduction phase III trial comparing i.v. 
administration of cetirizine injection 10 mg, to i.v. injection of diphenhydramine injection 50 mg, for the 
treatment of acute urticaria associated with an acute allergic reaction. 
15. Benadryl® (Diphenhydramine Hydrochloride Injection, USP) 2006 Product Information Sheet. 


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Protocol Attachment A 
Study Schedule 
Assessments 
Arrival at 
the site 
Baseline 
0 Hr 
1 Hr 
2 Hrs 
Time of 
Discharge 
24 Hr 
Follow 
Up 
p To 28 
days post 
4 Hr FU 
Informed consent 
X 
Inclusion/exclusion  criteria 
X 
Demographics 
X 
Medical and Surgical History 
X 
Vital signs 
X 
X 
X 
X 
X 
Study Medication 
Administration 
X 
Extent of urticaria/erythema)1
X 
X 
X 
X 
Pruritus Severity Score2
X 
X 
X 
X 
Sedation Score2
X 
X 
X 
X 
Time of Discharge 
X 
Concomitant  medication 
X 
X 
X 
X 
X 
X 
Adverse events 
X 
X 
X 
X 
X 
X 
Follow-up Q&A Sheet 
X 
Record patient self-reported 
AEs 
X 
1 Assessed only by the doctor 
2 Assessed by the doctor and the patient 


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Symptom Scores 
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Protocol Attachment D 
Declaration of Helsinki 
WORLD MEDICAL ASSOCIATION DECLARATION OF HELSINKI 
Ethical Principles for Medical Research Involving Human Subjects 
Adopted by the 18th WMA General Assembly, Helsinki, Finland, June 1964, and amended by the: 
29th WMA General Assembly, Tokyo, Japan, October 1975 
35th WMA General Assembly, Venice, Italy, October 1983 
41st WMA General Assembly, Hong Kong, September 1989 
48th WMA General Assembly, Somerset West, Republic of South Africa, October 1996 
52nd WMA General Assembly, Edinburgh, Scotland, October 2000 
53rd WMA General Assembly, Washington 2002 (Note of Clarification on paragraph 29 added) 
55th WMA General Assembly, Tokyo 2004 (Note of Clarification on Paragraph 30 added) 
59th WMA General Assembly, Seoul, October 2008 
A.
INTRODUCTION
1.
The World Medical Association (WMA) has developed the Declaration of Helsinki as a statement of ethical
principles for medical research involving human subjects, including research on identifiable human material and
data. 
The Declaration is intended to be read as a whole and each of its constituent paragraphs should not be
applied without consideration of all other relevant paragraphs.
2.
Although the Declaration is addressed primarily to physicians, the WMA encourages other participants in medical
research involving human subjects to adopt these principles.
3.
It is the duty of the physician to promote and safeguard the health of patients, including those who are involved
in medical research. The physician's knowledge and conscience are dedicated to the fulfilment of this duty. 
4.
The Declaration of Geneva of the WMA binds the physician with the words, “The health of my patient will be my
first consideration,” and the International Code of Medical Ethics declares that, “A physician shall act in the
patient's best interest when providing medical care.”
5.
Medical progress is based on research that ultimately must include studies involving human subjects. Populations
that are underrepresented in medical research should be provided appropriate access to participation in research.
6.
In medical research involving human subjects, the well-being of the individual research subject must take
precedence over all other interests. 
7.
The primary purpose of medical research involving human subjects is to understand the causes, development and
effects of diseases and improve preventive, diagnostic and therapeutic interventions (methods, procedures and
treatments). Even the best current interventions must be evaluated continually through research for their safety,
effectiveness, efficiency, accessibility and quality.
8.
In medical practice and in medical research, most interventions involve risks and burdens.
9.
Medical research is subject to ethical standards that promote respect for all human subjects and protect their
health and rights. Some research populations are particularly vulnerable and need special protection. These
include those who cannot give or refuse consent for themselves and those who may be vulnerable to coercion or
undue influence.


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10. 
Physicians should consider the ethical, legal and regulatory norms and standards for research involving human 
subjects in their own countries as well as applicable international norms and standards. No national or 
international ethical, legal or regulatory requirement should reduce or eliminate any of the protections for 
research subjects set forth in this Declaration. 
 
B. PRINCIPLES FOR ALL MEDICAL RESEARCH 
 
11. 
It is the duty of physicians who participate in medical research to protect the life, health, dignity, integrity, right to 
self-determination, privacy, and confidentiality of personal information of research subjects. 
 
12. 
Medical research involving human subjects must conform to generally accepted scientific principles, be based on  
a thorough knowledge of the scientific literature, other relevant sources of information, and adequate laboratory 
and, as appropriate, animal experimentation. The welfare of animals used for research must be respected. 
 
13. 
Appropriate caution must be exercised in the conduct of medical research that may harm the environment. 
 
14. 
The design and performance of each research study involving human subjects must be clearly described in a 
research protocol. The protocol should contain a statement of the ethical considerations involved and should 
indicate how the principles in this Declaration have been addressed. The protocol should include information 
regarding funding, sponsors, institutional affiliations, and other potential conflicts of interest, incentives for 
subjects and provisions for treating and/or compensating subjects who are harmed as a consequence of 
participation in the research study. The protocol should describe arrangements for post-study access by study 
subjects to interventions identified as beneficial in the study or access to other appropriate care or benefits. 
 
15. 
The research protocol must be submitted for consideration, comment, guidance and approval to a research ethics 
committee before the study begins. This committee must be independent of the researcher, the sponsor and any 
other undue influence. It must take into consideration the laws and regulations of the country or countries in 
which the research is to be performed as well as applicable international norms and standards but these must not 
be allowed to reduce or eliminate any of the protections for research subjects set forth in this Declaration. The 
committee must have the right to monitor ongoing studies. The researcher must provide monitoring information 
to the committee, especially information about any serious adverse events. No change to the protocol may be 
made without consideration and approval by the committee. 
 
16. 
Medical research involving human subjects must be conducted only by individuals with the appropriate scientific 
training and qualifications. Research on patients or healthy volunteers requires the supervision of a competent 
and appropriately qualified physician or other health care professional. The responsibility for the protection of 
research subjects must always rest with the physician or other health care professional and never the research 
subjects, even though they have given consent. 
 
17. 
Medical research involving a disadvantaged or vulnerable population or community is only justified if the research 
is responsive to the health needs and priorities of this population or community and if there is a reasonable 
likelihood that this population or community stands to benefit from the results of the research. 
 
18. 
Every medical research study involving human subjects must be preceded by careful assessment of predictable 
risks and burdens to the individuals and communities involved in the research in comparison with foreseeable 
benefits to them and to other individuals or communities affected by the condition under investigation. 
 
19. 
Every clinical trial must be registered in a publicly accessible database before recruitment of the first subject. 
 
20. 
Physicians may not participate in a research study involving human subjects unless they are confident that the 
risks involved have been adequately assessed and can be satisfactorily managed. Physicians must immediately 
stop a study when the risks are found to outweigh the potential benefits or when there is conclusive proof of 
positive and beneficial results. 


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21. 
Medical research involving human subjects may only be conducted if the importance of the objective outweighs 
the inherent risks and burdens to the research subjects. 
 
22. 
Participation by competent individuals as subjects in medical research must be voluntary. Although it may be 
appropriate to consult family members or community leaders, no competent individual may be enrolled in a 
research study unless he or she freely agrees. 
 
23. 
Every precaution must be taken to protect the privacy of research subjects and the confidentiality of their 
personal information and to minimize the impact of the study on their physical, mental and social integrity. 
 
24. 
In medical research involving competent human subjects, each potential subject must be adequately informed of 
the aims, methods, sources of funding, any possible conflicts of interest, institutional affiliations of the researcher, 
the anticipated benefits and potential risks of the study and the discomfort it may entail, and any other relevant 
aspects of the study. The potential subject must be informed of the right to refuse to participate in the study or to 
withdraw consent to participate at any time without reprisal. Special attention should be given to the specific 
information needs of individual potential subjects as well as to the methods used to deliver the information. After 
ensuring that the potential subject has understood the information, the physician or another appropriately 
qualified individual must then seek the potential subject’s freely-given informed consent, preferably in writing. If 
the consent cannot be expressed in writing, the non-written consent must be formally documented and 
witnessed. 
 
25. 
For medical research using identifiable human material or data, physicians must normally seek consent for the 
collection, analysis, storage and/or reuse. There may be situations where consent would be impossible or 
impractical to obtain for such research or would pose a threat to the validity of the research. In such situations 
the research may be done only after consideration and approval of a research ethics committee. 
 
26. 
When seeking informed consent for participation in a research study the physician should be particularly cautious 
if the potential subject is in a dependent relationship with the physician or may consent under duress. In such 
situations the informed consent should be sought by an appropriately qualified individual who is completely 
independent of this relationship. 
 
27. 
For a potential research subject who is incompetent, the physician must seek informed consent from the legally 
authorized representative. These individuals must not be included in a research study that has no likelihood of 
benefit for them unless it is intended to promote the health of the population represented by the potential 
subject, the research cannot instead be performed with competent persons, and the research entails  only 
minimal risk and minimal burden. 
 
28. 
When a potential research subject who is deemed incompetent is able to give assent to decisions about 
participation in research, the physician must seek that assent in addition to the consent of the legally authorized 
representative. The potential subject’s dissent should be respected. 
 
29. 
Research involving subjects who are physically or mentally incapable of giving consent, for example, unconscious 
patients, may be done only if the physical or mental condition that prevents giving informed consent is  a 
necessary characteristic of the research population. In such circumstances the physician should seek informed 
consent from the legally authorized representative. If no such representative is available and if the research 
cannot be delayed, the study may proceed without informed consent provided that the specific reasons for 
involving subjects with a condition that renders them unable to give informed consent have been stated in the 
research protocol and the study has been approved by a research ethics committee. Consent to remain in the 
research should be obtained as soon as possible from the subject or a legally authorized representative. 
 
30. 
Authors, editors and publishers all have ethical obligations with regard to the publication of the results of 
research. Authors have a duty to make publicly available the results of their research on human subjects and are 
accountable for the completeness and accuracy of their reports. They should adhere to accepted guidelines for 
ethical reporting. Negative and inconclusive as well as positive results should be published or otherwise made 
publicly available. Sources of funding, institutional affiliations and conflicts of interest should be declared in the 


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publication. Reports of research not in accordance with the principles of this Declaration should not be accepted 
for publication. 
 
C. 
ADDITIONAL PRINCIPLES FOR MEDICAL RESEARCH COMBINED WITH MEDICAL CARE 
 
31. 
The physician may combine medical research with medical care only to the extent that the research is justified by 
its potential preventive, diagnostic or therapeutic value and if the physician has good reason to believe that 
participation in the research study will not adversely affect the health of the patients who serve as research 
subjects. 
 
32. 
The benefits, risks, burdens and effectiveness of a new intervention must be tested against those of the best 
current proven intervention, except in the following circumstances: 
• 
The use of placebo, or no treatment, is acceptable in studies where no current proven intervention 
exists; or 
• 
Where for compelling and scientifically sound methodological reasons the use of placebo is necessary to 
determine the efficacy or safety of an intervention and the patients who receive placebo or no 
treatment will not be subject to any risk of serious or irreversible harm. Extreme care must be taken to 
avoid abuse of this option. 
 
33. 
At the conclusion of the study, patients entered into the study are entitled to be informed about the outcome of 
the study and to share any benefits that result from it, for example, access to interventions identified as beneficial 
in the study or to other appropriate care or benefits. 
 
34. 
The physician must fully inform the patient which aspects of the care are related to the research. The refusal of a 
patient to participate in a study or the patient’s decision to withdraw from the study must never interfere with 
the patient-physician relationship. 
 
35. 
In the treatment of a patient, where proven interventions do not exist or have been ineffective, the physician, 
after seeking expert advice, with informed consent from the patient or a legally authorized representative, may 
use an unproven intervention if in the physician's judgement it offers hope of saving life, re-establishing health or 
alleviating suffering. Where possible, this intervention should be made the object of research, designed to 
evaluate its safety and efficacy. In all cases, new information should be recorded and, where appropriate, made 
publicly available. 

SAP_001.pdf: 
JDP Therapeutics Inc., Cetirizine Injection 
Protocol No: ETTAU-03 
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DISCLOSURE 
REDACTED STATISTICAL ANALYSIS PLAN 
The information contained in the following document is the property of JDP Therapeutics Inc. 
and should not be shared or used for any purpose other than which it was  provided.  Certain 
information has been redacted from this document pursuant to 42 CFR 11.48(a)(5). 
Confidential Commercial Information (CCI)


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Statistical Analysis Plan 
 
 
 
Protocol No.: ETTAU-03 
Protocol Title: 
A Phase III, multi-center, double blind, randomized, active controlled clinical trial 
to evaluate the Non-Inferiority comparing Cetirizine Injection 10 mg to 
Diphenhydramine Injection, 50 mg, for the treatment of acute urticaria. 
 
 
 
 
 
 
 
 
 
Author:  Susan E. Spruill, Applied Statistics and Consulting 
 
 
Technical Approver: 
 
 
 
 
08May2018 
 
 
Jie Du, Ph.D. 
Date of Approval 
Chief Scientific Officer, JDP Therapeutics, Inc. 


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TABLE OF CONTENTS 
 
Page 
 
1. 
Preface ..................................................................................................................................... 5 
2. 
Study Objectives and Endpoints .............................................................................................. 5 
3. 
Study Design ............................................................................................................................. 7 
4. 
Sequence of Planned Analyses ................................................................................................. 8 
5. 
Defining Non-Inferiority margin ............................................................................................... 9 
6. 
Sample Size Considerations ..................................................................................................... 9 
7. 
Analysis Populations ................................................................................................................ 9 
8. 
Interim Analyses ..................................................................................................................... 10 
9. 
General considerations for data analyses .............................................................................. 10 
9.1. 
Imputed and Missing Data ........................................................................................... 10 
9.2. 
Hypothesis Testing ....................................................................................................... 11 
9.3. 
Adjustments for Multiplicity ........................................................................................ 12 
9.4. 
Covariates 12 
9.5. 
Examination of Subgroups ........................................................................................... 12 
9.6. 
Premature Discontinuation and Missing Data ............................................................. 12 
9.7. 
Study Centers ............................................................................................................... 12 
9.8. 
Data Review ................................................................................................................. 13 
9.9. 
Derived Data ................................................................................................................ 13 
9.10. Transformed Data ........................................................................................................ 14 
9.11. Changes from Protocol Planned Analysis .................................................................... 14 
10. Study population .................................................................................................................... 14 
10.1. Subject Accountability ................................................................................................. 14 
10.2. Protocol Deviations ...................................................................................................... 14 
10.3. Treatment Compliance ................................................................................................ 15 
10.4. Other Descriptions of Study Population ...................................................................... 15 
10.4.1. 
Medical/Surgical History and Physical Exam Findings ............................... 15 
10.4.2. 
Prior and Concomitant Therapy ................................................................. 15 
11. Efficacy Analyses .................................................................................................................... 15 
11.1. Primary Endpoint ......................................................................................................... 15 
11.2. Key Secondary Efficacy Analyses ................................................................................. 16 
11.3. Other Efficacy Analyses ............................................................................................... 17 
12. Safety Analyses ...................................................................................................................... 17 
12.1. Vital Signs 18 
12.2. Adverse Events ............................................................................................................ 18 


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13. Reporting conventions ........................................................................................................... 18 
14. References.............................................................................................................................. 19 


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Abbreviations and Definitions: 
 
AE 
Adverse Event/Adverse Experience 
CI 
Confidence Interval (confidence limits) 
ETTAU 
Efficacy Trial for the Treatment of Acute Urticaria 
ED 
Emergency Department 
MedDRA © 
Medical Dictionary for Regulatory Activities 
N 
Number (typically refers to subjects) 
NI 
Non-inferiority 
SAP 
Statistical Analysis Plan 
SAE 
Serious Adverse Event 
SD 
Standard Deviation 
WHO 
World Health Organization 


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1. 
PREFACE 
 
This document describes in detail the statistical methods that will be used to summarize and analyze the 
background, safety, and efficacy data from protocol ETTAU-03 entitled “A Phase III, multi-center, double 
blind, randomized, active controlled clinical trial to evaluate the non-inferiority comparing Cetirizine 
injection 10 mg, to Diphenhydramine injection 50 mg, for the treatment of acute urticaria.” (dated April 
10, 2017). 
 
2. 
STUDY OBJECTIVES AND ENDPOINTS 
 
This will be a multicenter, parallel group, randomized, double-blind, active controlled, Phase III clinical 
study of cetirizine injection, 10 mg/mL, compared to diphenhydramine injection, 50 mg/mL (Benadryl or 
generic equivalent), in approximately 254 subjects with acute urticaria requiring treatment in 
Emergency Departments (ED), hospitals, Urgent Care Centers, or Allergy Clinics. 
 
The objectives of this study are: 
 
The primary objective of this study is to establish the non-inferiority of Cetirizine injection with respect 
to Diphenhydramine injection in reducing patient reported pruritus severity score at 2 hours after 
treatment of acute urticaria. The secondary objectives are as follows: 
 
1. Record the percentage of subjects who return to treatment center after discharge (i.e. 2nd visit 
within 24 hours after discharge) 
 
2. Record and compare sedation scores between treatments 
3. Record and compare time-to-discharge between treatments 
4. Record and compare changes in patient reported pruritus severity score at 1 hr post treatment 
and at time of discharge. 
5. Record and compare extent of urticaria/erythema scores, and their changes from baseline at 
various time points after treatment. 
6. Document the percentage of subjects experiencing adverse events (AEs) or serious adverse 
events (SAEs) from the both study drugs. 
 
7. Document the percentage of subjects requiring rescue medication prior to discharge, e.g. 
epinephrine, bronchodilators, steroids, etc., 
 
8. Record symptom recurrence rate and additional symptoms occurrence within 24-48 hours after 
subject discharge from treatment centers. 
 
9. Record the need for medication after discharge. 
 
The primary demonstration of efficacy will be non-inferiority of cetirizine to diphenhydramine with 
regards to the change from baseline in patient rated pruritus severity at 2 hours post-treatment. 
 
The following outcomes that will provide key support to the primary efficacy claim: 


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• 
Return to Treatment Center: During the 24 and 48 hr follow up questions, subjects will be asked if 
they had to return to a treatment facility for their urticaria. Subjects will be flagged as either YES or 
NO. 
 
• 
Time Spent at Treatment Center: This will be defined as the difference between the time of 
treatment administration and of Readiness for Discharge. If a patient is admitted to hospital (not to 
go home), or stayed in ED observation overnight, the time to “Readiness for Discharge” is not 
recorded.  These subjects will not be included in the summary analyses. 
 
In addition, the following outcomes will be assessed by treatment as supportive information for the 
application: 
 
1) Pruritus Treatment Success: A subject will be defined as having treatment success if the patient 
rated pruritus severity score at 2 hrs is at least 1 unit less than at baseline. 
 
2) Patient Rated Pruritus Severity Scores change at other time points: The scores change/reduction 
from baseline at other assessment times (i.e.:  1 hr and at discharge) 
 
3) Sedation Score: Subjects will be asked to rate their sedation at baseline, 1 hr, 2 hr and discharge. 
 
4) Physician Rated Extent of Urticaria/Erythema Scores: Physicians will rate the percentage of body 
area affected and the intensity of redness on scales from 0 (none) to 3(severe) at baseline, 1 hr, 2 hr 
and discharge. The average of body area and intensity scores at each assessment time will be the 
Extent of Urticaria/Erythema score for that assessment time. This outcome will have the range from 
0 to 3 with increments of 0.5 units. 
 
5) Proportion of Subjects Needing Rescue Medication: A subject will be defined as needing rescue, if at 
any time after study drug and prior to readiness for discharge, the subject requires other 
medications for the symptoms of urticaria. 
 
6) Effectively Treated: The investigator’s judgment of a subject’s effective treatment of symptoms 
(Yes/No). 
 
7) Symptom Recurrence: Subjects will be followed up after 24 and 48 hours after discharge and asked if 
they have had any recurrence of symptoms since discharge. 
 
8) Need for Prescription Medications: During the 24 and 48 hr follow up questions, subjects will be 
asked if they took any medications prescribed at discharge since discharge. 
 
9) Need for Additional Medications: During the 24 and 48 hr follow up questions, subjects will be asked 
if they took any additional medications since discharge. 
 
10) Return to Normal Activity: During the 24 and 48 hr follow up questions, subjects will be asked if they 
had returned to their normal activities. 
 
See Section 10.4 for detail on the specific analyses to be performed for each outcome. 


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3. 
STUDY DESIGN 
 
This is a multi-center, parallel group, randomized, double-blind, active controlled, phase III clinical trial 
of cetirizine injection 10 mg/mL versus diphenhydramine injection 50 mg/mL (Benadryl or generic 
equivalent) in approximately 254 subjects who either present to Emergency Departments, hospitals, 
allergy clinics or Urgent Care Centers with acute urticaria, or developed acute urticaria following 
allergen challenge at an Allergy Clinic. 
 
Subjects, or their guardians, will sign an informed consent and will be evaluated for eligibility for 
inclusion to treat. Eligible subjects will be assessed for baseline characteristics, medical and surgical 
histories, concomitant medications and given a brief physical exam. Then subjects will be randomized, 
in a 1:1 ratio, to blindly receive either cetirizine 10 mg/mL injection or diphenhydramine 50 mg/mL 
injection. At randomization, the subjects will be given a Subject ID Number that corresponds to the 
randomization schedule and administered study medication based on the kit contents. Neither the 
subjects, nor study personnel will know which study drug is given. 
 
Efficacy assessments will include patient rated severity of pruritus, and physician assessments of Extent 
Urticaria/Erythema, etc. Subjects will remain in the treatment center for at least after the 1 hr 
assessment, after which they may be discharged at the physician’s discretion. 
 
Safety will be monitored through the reporting of adverse events for up to 28 days following treatments 
and by monitoring vital signs at planned intervals from admission into the treating facility until readiness 
for discharge. After 24 and 48 hours after discharge, subjects will be contacted by phone for follow up 
questions regarding recurrence of symptoms, new symptoms, additional medication taken, side effects 
from medication taken after discharge, relapse requiring a return to treatment center and return to 
normal activities.  The schedule of assessments is outlined in Table 1. 


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Table 1 Schedule of Assessments 
 
 
Assessments 
Arrival 
at the 
site 
Baselin 
e 
0 Hr 
1 Hr 
2 Hrs 
Time of 
Discharge 
24 Hr 
Follow 
Up 
Up To 
28 days 
post 24 
Hr FU 
Informed consent 
X 
Inclusion/exclusion 
criteria 
X 
Demographics 
X 
Medical and Surgical 
History 
X 
Vital signs 
X 
X 
X 
X 
X 
Physical examination 
X 
Study Medication 
Administration 
X 
Extent of 
urticaria/erythema)1 
X 
X 
X 
X 
Pruritus Severity 
Score2 
X 
X 
X 
X 
Sedation Score2 
X 
X 
X 
X 
Time of Discharge 
X 
Concomitant 
medication 
X 
X 
X 
X 
X 
X 
Adverse events 
X 
X 
X 
X 
X 
X 
Follow-up Q&A Sheet 
X 
Record subject self- 
reported AEs 
X 
 
 
4. 
SEQUENCE OF PLANNED ANALYSES 
 
All analyses outlined in this document will be carried out after: 
 
• 
The study database has been authorized by the Sponsor Clinical team as complete and final. 
• 
Protocol deviations have been identified. 
• 
The study is officially unblinded to treatment assignments 


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5.
DEFINING NON-INFERIORITY MARGIN
The effect of diphenhydramine injection based on patient recorded pruritus scores in comparison to 
placebo is unknown. Given the length of time (usually several hours) subjects indicated that urticaria 
started prior to ED/clinic admission or started while in ED for other diseases, it is reasonable to assume 
that if left untreated, there would be no spontaneous resolution within 2 hours of ED/clinic admission. 
6.
SAMPLE SIZE CONSIDERATIONS
Assuming the diphenhydramine treated group respond similar to ETTAU-02 results, the common 
standard deviation is expected to be around 
. A sample size of 
 subjects per arm (total
 is 
needed to provide 90% statistical power to determine that Cetirizine will be non-inferior to 
diphenhydramine. The sample size was calculated based on the 
 as the non- 
inferiority limit of the difference, using 1-sided test at alpha
 
. 
Sample size estimation was performed using
two-group t-test of equivalence in means (MTE0-1). 
7.
ANALYSIS POPULATIONS
The disposition of all subjects, including those who discontinued, will be summarized by group, using 
counts and frequencies in each population. Subjects will be categorized into the following analysis 
populations: 
Intent-To-Treat (ITT) Population: Includes any subject who was randomized and given a Subject ID 
Number with intent to treat with one of the blinded study drugs. All efficacy and non-inferiority 
analyses will be performed on the ITT population with subjects grouped by the treatment they were 
randomized to receive. 
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Safety Population (SAF): Includes any subjects in the ITT population who actually receives a blinded 
study drug, regardless whether or not they complete all assessments, withdraw or are discontinued by 
the investigator. All safety summaries will be performed on the SAF population with subjects grouped by 
the treatment they actually received. 
Per Protocol Population (PP): Includes subjects in the SAF population who complete all necessary 
assessments without any incidence that would potentially affect the ability to objectively assess 
treatment response (e.g. discontinuation, protocol deviation, use of rescue medication, etc.). 
8.
INTERIM ANALYSES
No interim analyses are planned for this study. 
9.
GENERAL CONSIDERATIONS FOR DATA ANALYSES
All statistical analyses and summaries will be performed using SAS for PC, version 9.4 (SAS Institute, 
Cary, NC). Continuous and quantitative, variable summaries will include the number of patients (N) 
assessed (with non-missing values/valid cases), mean, standard deviation, minimum. 
Categorical and qualitative variable summaries will include the frequency and percentage of subjects 
who are in the particular category. The denominator for each percentage will be the number of subjects 
within the population of the treatment arm (unless otherwise specified). 
The assumed overall type I error rate/significance level for the primary efficacy outcome is 5%, two- 
sided, unless otherwise specified. Two-sided confidence limits will be evaluated at 95%, p-values from 
inferential tests comparing specific cohorts or subgroups will be compared to 5%. 
9.1. 
Imputed and Missing Data 
The primary efficacy analysis will be performed on the ITT population. Subjects may be discharged at 
any time after 1 hr post-treatment assessment, which would result in missing data at the 2 hr post- 
treatment assessment time. Therefore, assessments of pruritus, extent of urticaria, and sedation for 
subjects discharged prior to the 2 hr assessment will be carried forward from the last recorded score to 
2 hrs and beyond. 
In addition, subjects may receive rescue medication at any time post-study drug and prior to Readiness 
for Discharge if the attending physician deems it necessary. Any assessment of pruritus, extent of 
urticaria and sedation after administering rescue medication will be confounded with the response to 
rescue medication. If a subject is given one or more rescue medications prior to the 2 hr assessment, the 
last pre-rescue assessments will be carried forward to the 2 hr assessment and to any post-rescue 
assessments. 
Since the use of rescue would always occur prior to readiness for discharge, the use of rescue will always 
supersede early discharge with regards to carrying the last observation forward.  As long as rescue drug 


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is used, the pre-rescue score will be carried forward to all subsequent assessment including the 1hr, 2hr, 
and readiness-for-discharge-assessment. 
Examples: 
i)
If the earliest rescue is used at 30 minutes after study drug, and the patient’s readiness-for- 
discharge is at 1.5hr, the baseline scores (the last pre-rescue score) will be carried forward to the
1hr, 2hr and discharge assessments, regardless of the existing assessments at 1hr and 1.5hr (the
discharge assessment).
ii)
If the earliest rescue is used at 30 minutes after study drug, and the patient is ready for discharge at
2.5hr post study drug, the baseline scores (the last pre-rescue-score) will be carried forward to the
1hr, 2hr and discharge assessments, regardless of the existing assessments at 1hr, 2hr and 2.5hr (the
discharge assessment).
iii) If the earliest rescue is used at 3hrs after study drug, and the patient’s readiness-for-discharge is at
4hrs, the 2hr scores (the last pre-rescue-scores) will be carried forward to the discharge assessment
regardless the existing 4hr assessment (the discharge assessment).
iv) For a patient without rescue drug, if readiness-for-discharge occurs at 1.5hr, the discharge
assessment (1.5hr, the last obtained score) will be carried forward to 2hr.
v)
For a patient without rescue drug, if readiness-for-discharge occurs at the same time as the 1hr
assessment, the 1hr assessment (the last obtained score) will be carried forward to 2hr and to the
discharge assessment.
vi) For a patient without rescue drug, if readiness-for-discharge occurs at the same time as the 2hr
assessment, the 2hr assessment will be carried forward to the readiness-for-discharge assessment.
9.2. 
Hypothesis Testing 
The purpose of this study is to determine if the effectiveness of cetirizine 10 mg/mL injection is non- 
inferior to the effectiveness of diphenhydramine 50 mg/mL. The non-inferiority margin will be set at 
  See Section 5 for the rationale. 
The null hypothesis is that cetirizine is inferior to diphenhydramine if the difference is 
with 95% confidence.  The null hypothesis is stated as: 
H0: 
where D2 is the change from baseline of the 2 hr patient rated severity of pruritus for each treatment. 
The alternative hypothesis to be tested is: 
H1: 
If the null hypothesis is rejected in favor of the alternative (e.g., cetirizine is not inferior to 
diphenhydramine) and if the treatment difference 
 then the alternative 
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hypothesis will be further refined in a stepwise manner to test for superiority of cetirizine over 
diphenhydramine: 
H2: 
This stepwise process of testing for superiority only after rejecting the null for non-inferiority will spare 
type I error.  Details of the methods to be used are provided in Section 10.1, 
9.3. 
Adjustments for Multiplicity 
There is only one primary endpoint being tested to determine efficacy of cetirizine 10 mg/mL injection 
on 2hr patient rated pruritus severity. Key secondary endpoints will be used to support the claims of the 
primary efficacy outcome. There are 2 outcome measures that are key in supporting the efficacy claim: 
the need to return to treatment center after study discharge and time spent at the treatment center 
(time from treatment administration to readiness for discharge).  Family-wise error rate will be 
controlled using Holm-Bonferroni method of rejecting individual hypotheses (Holm, 1979). 
Although nominal p-values will be reported for treatment differences, none of the other secondary 
endpoints will be used to evaluate for superiority or non-inferiority of cetirizine compared to 
diphenhydramine, therefore no adjustments for multiplicity are planned. 
9.4. 
Covariates 
No covariates are planned. However, in the event there are some treatment disparities in baseline 
characteristics (e.g., age or weight), covariates may be added to the analysis of the primary endpoint as 
part of the per protocol analysis. 
9.5. 
Examination of Subgroups 
No subgroup analyses are planned. 
9.6. 
Premature Discontinuation and Missing Data 
For any subject who withdraws prematurely from the study, all available data up to the time of 
discontinuation will be included in analyses. 
9.7. 
Study Centers 
A total of 22 study centers will be used in this protocol. The likelihood that all centers enroll an equal 
number of subjects is small. No center will be allowed to enroll more than 20% of the entire study 
population (N=87). In the event there is a discrepancy of more than 10% between the largest enrolling 
center and smallest, centers will be pooled from the ranked extremes until the pooled centers are 
within of each other (e.g. the smallest center will be pooled with the largest, and so forth). Study 
centers will be added to the analysis of variance model for the primary endpoint. See Section 10.1 for 
details of methods. 
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9.8. 
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. 
9.9. 
Derived Data 
The following data will be derived from collected data: 
•
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9.10. 
Transformed Data 
 
No data transformations are planned. 
 
 
 
9.11. 
Changes from Protocol Planned Analysis 
 
The protocol included collecting information on the reason for use of rescue drugs (secondary objective 
#7), however, it was determined at the time of CRF development that capturing such data would not 
add to the determination that a rescue medication was given.  Therefore, this was not captured. 
 
The sample size justification in the protocol was not updated to match the final methodology used. 
While both the protocol and the SAP sample size justifications results in the need for 127 subjects per 
treatment arm, the assumptions in this SAP are more indicative of the actual assumptions and 
methodology used to arrive at this sample size. 
 
The protocol did not make provisions for subjects who needed to be hospitalized or kept in the ED 
overnight for observations. The SAP covers the needs to treat the time spent at the treatment center to 
“missing” for these subjects. 
 
 
 
10. 
STUDY POPULATION 
 
10.1. 
Subject Accountability 
 
The disposition of all subjects, including those who discontinued, will be summarized by treatment 
group, using frequencies and percentages in each population. Subjects will be categorized into ITT, SAF, 
and PP populations.  Screen failures and excluded-prior-to-enrollment will not be summarized. 
 
10.2. 
Protocol Deviations 
 
All randomized subjects will be included in the ITT and SAF populations. If a violation hinders the ability 
to assess an efficacy outcome, the following approaches can be taken: 
 
Examples: 
 
i) If patient does not have the disease intended to treat, the outcome for the 2 hr assessment will be set 
to the baseline values and the subjects will be considered a treatment failure. In this example, the 
“readiness for discharge” time will be missing, since the discharge time is confounded by the wrong 
disease. 
 
ii) if a subject receives an antihistamine within 2 hrs prior to baseline (not meeting exclusion #4), that 
subject will be considered a failure with change from baseline to 2 hr pruritus score and with change 
from baseline to 2 hr extent of urticaria score set to zero (0). In this example, sedation score will be 
missing since sedation is confounded by the antihistamine prior to baseline. 


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Inclusion of subjects in other efficacy endpoints will be dependent on availability of data for each 
assessment times point. Subject data will be reviewed for major protocol violations by a qualified 
clinical reviewer prior to database lock and unblinding. Subjects with any major protocol violations will 
be identified and excluded from the Per Protocol Population. A summary list of the individual subjects 
excluded, will be provided, sorted by treatment group with description of their protocol 
violation/deviation. 
10.3. 
Treatment Compliance 
All subjects will receive their treatment in the treatment center; therefore, there will be no need to 
confirm treatment compliance. 
10.4. 
Other Descriptions of Study Population 
Descriptive statistics will be used to summarize participant demographics and baseline characteristics by 
treatment group. Characteristics such as weight, height and age will be summarized as continuous 
variables with means, SD, medians, minimums and maximums.  Demographics, such as ethnicity and 
race will be summarized as counts and frequencies. The ITT population will be used to summarize 
baseline characteristics and demographics by treatment group. 
10.4.1. Medical/Surgical History and Physical Exam Findings 
Medical and surgical history and physical examination findings will be used in the event that it may help 
to explain any adverse reactions or other unexpected outcomes. The findings will be provided in data 
listings for the ITT population, but will not be tabulated and summarized by treatment group. 
10.4.2. Prior and Concomitant Therapy 
The medications taken by each group, prior to study enrollment and during the treatment period, will be 
coded using the latest WHO-Drug Coding Dictionary for anatomical therapeutic class (ATC) and 
preferred medication names. Concomitant medications will be summarized by incidence as counts and 
percentages within ATC and preferred names for each treatment group.   The SAF population will be 
used to summarize all concomitant therapies by treatment group. 
11.
EFFICACY ANALYSES
11.1. 
Primary Endpoint
The primary clinical outcome measure is patient rated severity of pruritus at 2 hr post-treatment. The 
primary analysis will test for the non-inferiority of cetirizine to the active comparator, diphenhydramine, 
for the mean change from baseline in patient rated pruritus at 2 hours. See Section 9.9 for derivation of 
this endpoint. Using the notation of Gupta, 2011, the NI margin of -0.50 will be used to test the 
hypothesis: 
H0: 
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Computationally, if the lower bound of the 95% CI of 
 then cetirizine is non-inferior 
to diphenhydramine and if lower bound of the 95% CI > 0 and the p-value ≤ 0.05 for treatment 
difference, then cetirizine will be determined to be superior to diphenhydramine. 
The point estimate of the treatment differences of D2 and the 95% CI will be calculated using 2-side t- 
test from a generalized linear mixed-effects model 
 adjust for site and site by 
treatment interactions. If there are treatment disparities in baseline characteristics, such as age or 
gender, these may be added as covariates (See Section 9.4). An example of 
 code that 
may be used to perform this analysis follows: 
The primary analysis will be performed on the ITT population with LOCF used to impute 2 hr scores if 
subjects are discharged prior. If different from ITT, the primary analysis will also be performed on the PP 
population as a test of sensitivity to protocol deviations and discontinuations. 
In the event that a rescue medication is used prior to the 1 hr assessment, D1 will be set to zero (0) for 
that subject. Otherwise, if rescue drug is given, then the last observation prior to rescue will be carried 
forward (LOCF) for subsequent calculations of change. 
11.2. 
Key Secondary Efficacy Analyses 
The following key secondary efficacy analyses are intended to support the primary analysis findings. 
1.
Return to Treatment Center: The number and proportion of subjects who returned to a treatment
center for additional treatment of their urticaria will be summarized by response (YES, NO, UNK) for
each follow up time and by treatment group. The difference in treatments will be tested using
Fisher’s 2-sided Exact test of frequencies of returns.
2.
Time Spent at Treatment Center: The time spent in a treatment center (for the initial treatment) will
be summarized by treatment group for the number of subjects in each group, the mean, SD,
median, minimum and maximum. The average time in treatment center will be tested for treatment
differences using the same model as proposed for the primary endpoint.
Rejection of the null-hypothesis that Pcet = Pdiph will be adjusted based on the order of p-values from all 
key secondary tests, using the Holm-Bonferroni method (Holm, 1979). 
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11.3. 
Other Efficacy Analyses 
1.
Pruritus Treatment Success: The number and proportion of success in each treatment group will be
summarized.
2.
Patient Rated Pruritus Severity Scores Change (D1, D3): The scores and change from baseline at each
assessment time (baseline, 1 hr and discharge) will be summarized by treatment group for the
number of subjects in each group, the mean, SD, median, minimum and maximum.
3.
Sedation Score Change (E1, E2, E3): The patient reported Sedation Scores Change at each
assessment time will be summarized by treatment group for the number of subjects in each group,
the mean, SD, median, minimum and maximum.
4.
Physician Rated Extent of Urticaria/Erythema Scores Change (C1, C2, C3): See Section 9.9 for details
of how this endpoint is derived. Physician scores will be summarized by treatment group and
assessment time for the number of subjects in each group, the mean, SD, median, minimum and
maximum.
5.
Proportion of Subjects Needing Rescue Medication: The number and proportion of subjects who
needed rescue while in the treatment center will be summarized by treatment group.
6.
Effectively Treated: The number and proportion of effectively treated subjects in each treatment
group will be summarized.
7.
Symptom Recurrence: The number and proportion of subjects with symptom recurrence or a new
symptom will be summarized by response (YES, NO, UNK) for each follow up times and by treatment
group.
8.
Need for Prescription Medications: The number and proportion of subjects who needed to take a
prescription medication after discharge will be summarized by response (YES, NO, N/A, UNK) for
each follow up time and by treatment group.
9.
Need for Additional Medications: The number and proportion of subjects who needed additional
medications (not prescription) will be summarized by response (YES, NO, UNK) for each follow up
time and by treatment group.
10. Return to Normal Activity: The number and proportion of subjects who returned to their normal
activity will be summarized by response (YES, NO, UNK) for each follow up time and by treatment
group.
12.
SAFETY ANALYSES
Safety assessments include reporting of adverse events (AEs) throughout the study as well as monitoring 
of vital signed at specified intervals within the treatment period. Safety assessments will be summarized 
by treatment group, but no inferential analyses of treatment differences will be performed. In the event 
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used on categorical variables. All tests will be two-sided at α= 0.05. All safety summaries will be 
performed on the SAF population. 
 
12.1. 
Vital Signs 
 
Vital signs will be summarized as continuous data with means, SD, medians, minimums and maximums 
for each vital sign for each assessment time, by treatment group. The vital signs to be summarized 
include systolic and diastolic blood pressure (mmHg), heart rate (bpm), respiration rate (bpm), and body 
temperature (C). 
 
12.2. 
Adverse Events 
 
Adverse events with onset after the start of study drug will be summarized and grouped by MedDRA 
System Organ Class (SOC) and specific adverse event. Results will be displayed in order of decreasing 
frequency, both across SOC and within each SOC term. 
 
For presentation, adverse event verbatim text will be coded into a MedDRA term, and classified by SOC 
and preferred term. A cross reference listing, which will relate SOC, preferred term, and verbatim text 
will be provided. 
 
In addition, summaries may be provided by gender, severity (mild, moderate, severe), and by 
relationship to study drug (Related, Unrelated). "Possibly Related", "Probably Related" and "Almost 
Certain" will be grouped as 'Related'.  "Not Likely to be Related" will be grouped with "Unrelated". 
 
Serious adverse events and adverse events leading to discontinuation will be summarized by treatment 
group and listed. 
 
 
 
13. 
REPORTING CONVENTIONS 
 
Reporting conventions will adhere when possible to the International Conference on Harmonization (ICH) 
Guidance document E3, “Structure and Content of Clinical Study Reports”. Some specific conventions are 
outlined below: 
 
1. 
All tables and listings will be in landscape format. 
2. 
All SAS output for tables and listings will be distributed in PDF files. 


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14.
REFERENCES
International Conference on Harmonization, Guidance E3. (www.ich.org) 
NQuery Advisor. Statistical Solutions, Ltd (www.statsol.com) 
SAS Institute, Inc. (www.SAS.com) 
Gupta, Sandeep (2011) “Non-inferiority clinical trials: Practical issues and current regulatory 
perspective” Indian J Pharmacol. 2011 Jul-Aug; 43(4): 371–374. doi:10.4103/0253-7613.83103 
Holm, S. (1979). “A simple sequentially rejective multiple test procedure”. Scandinavian Journal of 
Statistics 6 (2): 65-70.