Clinical trial NCT03360071
Conditions: Allergic Rhinitis
Sponsor: Johns Hopkins University
Start date: 2016-12-19; Completion date: 2018-11-01
Enrollment: 31 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
This is a randomized, parallel-group, double-blind, phase 2, single center, proof-of-concept study which will evaluate the effect of a preparation of FDA approved allergens (PMA) used as a sub-cutaneously administered immunotherapy for the management of allergic rhinitis (perennial and seasonal).

Detailed description:
This is a randomized, parallel-group, double-blind, phase 2, single center, proof-of-concept study which will evaluate the effect of a proprietory mixed preparation of FDA approved allergens (PMA) used as a sub-cutaneously administered immunotherapy for the management of allergic rhinitis (perennial and seasonal). Participating study subjects will be required to manifest the signs and symptoms of allergic rhinitis and test positive to at least six allergens using a multi aeroallergen screen at the time of study recruitment . All subjects will undergo standard allergen skin prick testing using six Multi-Test® PC skin prick test devices (Lincoln Diagnostics, Decator, IL) or comparable skin testing technique for a total of 48 Skin Prick Test (SPT). Approximately 36 total subjects will be enrolled.

Following a successful screening study visit and two week medication washout period, a 8 week treatment period will be initiated with bi-weekly study visits being undertaken, through to the end of immunotherapy, for assessment of therapeutic response and safety evaluations. Efficacy evaluation will be monitored using validated instruments that assess study subject clinical response, physician global assessment, and medication use. A safety assessment will be undertaken one month following completion of treatment.

At the screening visit (Screening Visit) a potential study subject will be required to fulfill the requirements of the study inclusion and exclusion criteria, will have a clinical evaluation including medical history and physical examination, blood draw and performance of skin testing. The study subject will then abstain from using intranasal steroids and antihistamines for two weeks and then return to the clinic for administration of sub-cutaneous PMA and post-treatment in-clinic safety evaluation. The latter evaluation period will comprise approximately 60 minutes to assess the study subject's response to PMA immunotherapy. Follow up clinic study visits will continue bi-weekly through 8 weeks and at each of these visits the study subject will receive increasing doses of PMA immunotherapy and will be evaluated for safety. Twice weekly clinical evaluation will also be performed. Following the final administration of PMA immunotherapy, a one month follow-up safety and clinical efficacy evaluation will be conducted by telephone or in the clinic. The duration of the study will be approximately 14 weeks.

Arms: arm 1: None arm 2: None
Interventions: intervention 1: Allergen Immunotherapy Extract intervention 2: Allergen Immunotherapy Control
Intervention descriptions: intervention 1: Allergen Immunotherapy treatment mixture to be delivered subcutaneously intervention 2: Allergen Immunotherapy Control Solution to be delivered subcutaneously

Protocol documents:
Prot_SAP_000.pdf: 
NCT: 03360071 
IRB00107909 
PI: Jody R. Tversky, MD 
Document date: 08/07/2018 
Title: A double-blind, prospective, parallel group evaluation of a novel biologic 
therapy for perennial allergic rhinitis 


 
PAGE 
 
PROTOCOL 
 
“A double-blind, prospective, parallel group evaluation of a novel biologic 
therapy for perennial allergic rhinitis” 
 
 
Short Title 
Novel biologic therapy for allergic rhinitis 
 
 
Sponsor: 
Relez Therapeutics, LLC of Maryland 
 
Study Number: 
PMA 001 
 
IND Number: 
 
Not applicable 
 
EudraCT Number: 
 
Not Applicable 
 
Compound: 
 
 
FDA approved antigens in propriatory preparation 
Date: 
August 7, 2018 
Version 6.9.1 
 
 
 
 
 
 
 
 
 


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1.0 
ADMINISTRATIVE INFORMATION  
Contacts  
Contact Type/Role 
USA Contact 
 
 
Serious adverse 
event and 
pregnancy reporting 
Jody R. Tversky, MD 
Johns Hopkins University 
School of Medicine, 
Baltimore, MD 
1-410-550-5949 
 
 
 
 
 
 
Responsible 
Medical Officer  
(carries overall 
responsibility for 
the conduct of the 
study) 
Jody R. Tversky, MD 
Johns Hopkins University 
School of Medicine, 
Baltimore, MD 
1-410-550-5949 
 
 
 


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1.1 
Approval  
 
REPRESENTATIVES OF JOHNS HOPKINS UNIVERSITY SCHOOL OF MEDICINES 
This study will be conducted with the highest respect for the individual participants in accordance 
with the requirements of this clinical study protocol and also in accordance with the following: 
 The ethical principles that have their origin in the Declaration of Helsinki. 
 International Conference on Harmonisation E6 Good Clinical Practice: Consolidated 
Guideline. 
 All applicable laws and regulations, including, without limitation, data privacy laws, clinical 
trial disclosure laws, and regulations. 
 
SIGNATURES  
The signatures of the responsible Johns Hopkins University School of Medicine Co-ordinating 
Investigator and the study Principal and Co-Principal Investigators can be found on this signature 
page. 
 
Jody R. Tversky, M.D. 
Principal Investigator 
Assistant Professor of Medicine 
Division of Allergy & Clinical Immunology 
Johns Hopkins University School of Medicine 
Date Antoine E. Azar, MD 
Co-Principal Investigator 
Assistant Professor of Medicine 
Division of Allergy & Clinical Immunology 
Johns Hopkins University School of Medicine 
Date 


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INVESTIGATOR AGREEMENT  
I confirm that I have read and that I understand this protocol and any other product information 
provided by the sponsor. I agree to conduct this study in accordance with the requirements of this 
protocol and also to protect the rights, safety, privacy, and well-being of study subjects in 
accordance with the following: 
 The ethical principles that have their origin in the Declaration of Helsinki. 
 International Conference on Harmonisation, E6 Good Clinical Practice: Consolidated 
Guideline. 
 All applicable laws and regulations, including, without limitation, data privacy laws and 
regulations. 
 Regulatory requirements for reporting serious adverse events defined in Section 9.2 of this 
protocol. 
 Terms outlined in the Clinical Study Site Agreement. 
 Appendix B – Responsibilities of the Investigator. 
 


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_____________________________________________________ 
Signature of Investigator                                                            Date 
______________________________________________________ 
Signature of Co-Investigator                                                     Date  
________________________
Investigator Name (print or type) 
Co-Investigator Name (print or type) 
Johns Hopkins Bayview Medical Center, Baltimore, MD, USA 
Location of Facility  
USA 
Country 
 


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TABLE OF CONTENTS 
1.0 
ADMINISTRATIVE INFORMATION .............................................................................. 2 
1.1 Approval ...................................................................................................................... 3 
1.2 Abstract and Study Design: ......................................................................................... 11 
2.0 
STUDY REFERENCE INFORMATION ......................................................................... 15 
2.1 Endpoints ................................................................................................................... 15 
2.1.1 Primary Endpoints ............................................................................................. 15 
2.1.2 Secondary Endpoint ........................................................................................... 15 
2.2 Primary Investigator ................................................................................................... 15 
2.3 List of Abbreviations .................................................................................................. 16 
3.0 
INTRODUCTION ............................................................................................................ 18 
3.1 Background ................................................................................................................ 18 
3.2 Rationale for the Proposed Study ................................................................................ 19 
4.0 
STUDY OBJECTIVES AND ENDPOINTS ..................................................................... 21 
4.1.1 Primary Objective .............................................................................................. 21 
4.1.2 Secondary Objective .......................................................................................... 21 
5.0 
STUDY DESIGN AND METHODS ................................................................................ 22 
5.1 Study Design .............................................................................................................. 22 
5.2 Justification for Study Design, Dose, and Endpoints ................................................... 23 
5.3 Premature Termination or Suspension of Study or Investigational Site ........................ 24 
5.3.1 Criteria for Premature Termination or Suspension of the Study .......................... 24 
5.3.2 Criteria for Premature Termination or Suspension of the Investigational Site ..... 24 
5.3.3 Procedures for Premature Termination or Suspension of the Study or the 
Participation of the Investigational Site .............................................................. 24 
6.0 
SELECTION AND DISCONTINUATION/WITHDRAWAL OF SUBJECTS ................. 25 
6.1 Inclusion Criteria ........................................................................................................ 25 
6.2 Exclusion Criteria ....................................................................................................... 25 
6.3 Excluded Medications................................................................................................. 26 
6.4 Criteria for Discontinuation or Withdrawal of a Subject .............................................. 26 
7.0 
CLINICAL TRIAL MATERIAL MANAGEMENT ......................................................... 28 
7.1 Drugs / Substances / Devices ...................................................................................... 28 
7.1.1 Dosage Form, Preparation and Labeling ............................................................. 28 
7.1.1.1 Investigational immunotherapy .................................................................... 30 


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7.1.1.2 Storage ......................................................................................................... 30 
7.1.2 Immunotherapy Dose and Regimen .................................................................... 30 
7.1.3 Overdose ............................................................................................................ 31 
7.2 Investigational drug Assignment and Dispensing Procedures ...................................... 31 
7.3 Unblinding Procedure ................................................................................................. 32 
7.4 Accountability and Destruction of Sponsor-Supplied Drugs ........................................ 32 
8.0 
STUDY PLAN ................................................................................................................. 34 
8.1 Study Procedures ........................................................................................................ 34 
8.1.1 Informed Consent Procedure .............................................................................. 34 
8.1.2 Demographics, Medical History, and Medication History Procedure .................. 34 
8.1.3 Physical Examination Procedure ........................................................................ 34 
8.1.4 Weight, Height ................................................................................................... 34 
8.1.5 Vital Sign Procedure .......................................................................................... 34 
8.1.6 Primary Efficacy Measurement .......................................................................... 35 
8.1.7 Documentation of Concomitant Medications ...................................................... 35 
8.1.8 Documentation of Concurrent Medical Conditions ............................................. 35 
8.1.9 Procedures for Clinical Laboratory Samples ....................................................... 35 
8.1.10 Pregnancy .......................................................................................................... 35 
8.1.11 Documentation of Screen Failure ....................................................................... 36 
8.1.12 Documentation of Study Randomization ............................................................ 36 
8.1.13 Allergen Skin Prick Testing Procedures ............................................................. 36 
8.2 Monitoring Subject Treatment Compliance ................................................................. 36 
8.3 Schedule of Observations and Procedures ................................................................... 37 
8.3.1 Screening ........................................................................................................... 37 
8.3.2 Study Entrance Randomization .......................................................................... 37 
8.3.3 Treatment Phase ................................................................................................. 38 
8.3.4 Final Visit or Early Termination ......................................................................... 38 
8.3.5 Follow-up .......................................................................................................... 38 
8.3.6 Post Study Care .................................................................................................. 38 
9.0 
PRETREATMENT EVENTS AND ADVERSE EVENTS ............................................... 39 
9.1 Definitions .................................................................................................................. 39 
9.1.1 PTEs .................................................................................................................. 39 
9.1.2 AEs .................................................................................................................... 39 


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9.1.3 Additional Points to Consider for PTEs and AEs ................................................ 39 
9.1.4 SAEs .................................................................................................................. 41 
9.1.5 Severity of PTEs and AEs .................................................................................. 42 
9.1.6 Causality of AEs ................................................................................................ 42 
9.1.7 Relationship to Study Procedures ....................................................................... 43 
9.1.8 Start Date ........................................................................................................... 43 
9.1.9 Stop Date ........................................................................................................... 43 
9.1.10 Frequency .......................................................................................................... 43 
9.1.11 Action Concerning Study Medication ................................................................. 43 
9.1.12 Outcome ............................................................................................................ 43 
9.2 Procedures .................................................................................................................. 44 
9.2.1 Collection and Reporting of AEs ........................................................................ 44 
9.2.1.1 PTE and AE Collection Period ..................................................................... 44 
9.2.1.2 PTE and AE Reporting ................................................................................. 44 
9.2.2 Collection and Reporting of SAEs ...................................................................... 45 
9.3 Follow-up of SAEs ..................................................................................................... 46 
9.3.1 Safety Reporting to the Johns Hopkins IRB and Regulatory Authorities ............. 46 
10.0 
STUDY-SPECIFIC COMMITTEES .............................................................................. 47 
11.0 
DATA HANDLING AND RECORDKEEPING ............................................................. 48 
11.1 CRFs (Paper) ............................................................................................................ 48 
11.2 Record Retention ...................................................................................................... 48 
12.0 
STATISTICAL METHODS ........................................................................................... 50 
12.1 Statistical and Analytical Plans ................................................................................. 50 
12.1.1 Analysis Sets...................................................................................................... 50 
12.1.2 Analysis of Demographics and Other Baseline Characteristics ........................... 50 
12.1.3 Efficacy Analysis ............................................................................................... 50 
12.1.4 Safety Analysis .................................................................................................. 52 
12.2 Interim Analysis and Criteria for Early Termination ................................................. 52 
12.3 Determination of Sample Size ................................................................................... 52 
13.0 
QUALITY CONTROL AND QUALITY ASSURANCE ............................................... 53 
13.1 Study-Site Monitoring Visits .................................................................................... 53 
13.2 Protocol Deviations .................................................................................................. 53 
14.0 
ETHICAL ASPECTS OF THE STUDY ......................................................................... 54 


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14.1 IRB Approval ........................................................................................................... 54 
14.2 Risks......................................................................................................................... 54 
14.3 Benefits .................................................................................................................... 55 
14.4 Subject Information, Informed Consent, and Subject Authorization .......................... 56 
14.5 Subject Confidentiality ............................................................................................. 57 
14.6 Publication, Disclosure, and Clinical Trial Registration Policy .................................. 57 
14.6.1 Publication and Disclosure ................................................................................. 57 
14.6.2 Clinical Trial Registration .................................................................................. 58 
14.6.3 Clinical Trial Results Disclosure ........................................................................ 58 
14.7 Insurance and Compensation for Injury ..................................................................... 58 
 
LIST OF IN-TEXT TABLES 
Table 10.a Sponsor’s Medically Significant AE List ............................................................... 41 
 
LIST OF IN-TEXT FIGURES 
Figure 5.a Schematic of Study Design .................................................................................... 23 
 
LIST OF APPENDICES 
Appendix A Schedule of Study Procedures ............................................................................ 60 
Appendix B Responsibilities of the Investigator ..................................................................... 61 
Appendix C Elements of the Subject Informed Consent ......................................................... 63 
Appendix D    Allergen Skin Prick Testing interpretation methodology ..................................... 66 
Appendix E 
FDA approved Allergens Used For Treatment .................................................... 67 
Appendix F  Immunotherapy efficacy assessement instruments .............................................. 78 
Appendix G  Allergens used for skin prick testing................................................................... 79 
Appendix H  Immunotherapy injection schedule ..................................................................... 81 
Appendix I 
Allergy Rescue Medication Action Plan ............................................................. 82 
Appendix J 
Clinical Visit Summary ...................................................................................... 83 
Appendix K  Symptom and Medication Card .......................................................................... 84 
 


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STUDY SUMMARY 
Name of Sponsor: 
Relez Therapeutics, LLC 
Compound: 
FDA approved antigens in propriatory 
preparation 
Title of Protocol:  
“A double-blind, prospective, parallel group 
evaluation of a novel novel biologic therapy for 
perennial allergic rhinitis” 
 
IND No.:  
Not Applicable 
EudraCT No.: 
Not Applicable 
Study Number: PMA 001 
Phase: 2 Proof of Concept 


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1.2 
Abstract and Study Design: 
This is a randomized, parallel-group, double-blind,  phase 2, single center, proof–of-concept 
study which will evaluate the effect of a propriatory mixed preparation of FDA approved allergens 
(PMA) used as a sub-cutaneously administered immunotherapy for the management of allergic 
rhinitis (perennial and seasonal). Participating study subjects will be required to manifest the signs 
and symptoms of allergic rhinitis and test positive to at least six allergens using a multi  
aeroallergen screen at the time of study recruitment . All subjects will undergo standard allergen 
skin prick testing using six Multi-Test® PC skin prick test devices  (Lincoln Diagnostics, Decator, 
IL) or comparable skin testing technique for a total of 48 SPT. Approximately 36 total subjects 
will be enrolled.    
Following a successful screening study visit and two week medication washout period, a 8 
week treatment period will be initiated with bi-weekly study visits being undertaken, through to 
the end of immunotherapy, for assessment of therapeutic response and safety evaluations. Efficacy 
evaluation will be monitored using validated instruments that assess study subject clinical 
response, physician global assessment, and medication use. A safety assessment will be 
undertaken one month following completion of treatment.  
At the screening visit (Screening Visit) a potential study subject will be required to fulfill the 
requirements of the study inclusion and exclusion criteria, will have a clinical evaluation including 
medical history and physical examination, blood draw and performance of skin testing. The study 
subject will then abstain from using intranasal steroids and antihistamines for two weeks and then 
return to the clinic for administration of sub-cutaneous PMA and post-treatment in-clinic safety 
evaluation. The latter evaluation period will comprise approximately 60 minutes to assess the 
study subject’s response to PMA immunotherapy. Follow up clinic study visits will continue 
bi-weekly through 8 weeks and at each of these visits the study subject will receive increasing 
doses of PMA immunotherapy and will be evaluated for safety. Twice weekly clinical evaluation 
will also be performed. Following the final administration of PMA immunotherapy, a one month 
follow-up safety and clinical efficacy evaluation will be conducted by telephone or in the clinic. 
The duration of the study will be approximately 14 weeks. 
Primary Objectives: 
To evaluate whether there is a difference in the signs and symptoms of moderate to severe 
allergic rhinitis when treated with a propriatory mixed preparation of FDA approved allergens, 
administered sub-cutaneously over a 8-week period, versus the response to placebo and standard 
of care.  
Secondary Objectives: 
The secondary objectives of this study are to quantify allergy medication use and adverse 
events. Serum will also be stored to evaluate changes in IgE and IgG subclasses.  


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Subject Population: Adult male and female subjects aged 18-65 with moderate to severe allergic 
rhinitis. 
Number of Subjects: 
Approximately 36 total study subjects will be 
recruited 
Subjects will be equally divided between active 
treatment and placebo administration.   
Number of Sites:  
Single site 
Dose Level(s): 
All subjects will be started on the same dilution of 
PMA  
Route of Administration: 
PMA – sub-cutaneous 
Placebo – sub-cutaneous  
Duration of Treatment: 
8 weeks 
Period of Evaluation: 
14 weeks 
Main Criteria for Inclusion: 
1. In the opinion of the investigator, the subject is capable of understanding and complying with 
protocol requirements. 
2. The subject signs and dates a written, informed consent form and any required privacy 
authorization prior to the initiation of any study procedures.  
3. The subject is a male or a non-pregnant, non-lactating female between the ages of 18 and 65. 
4. The subject is actively manifesting symptoms and signs of moderate to severe allergic PAR 
with or without SAR component defined as score of at least 28 on the RQLQ and 6 on the 
TNSS scale. Scores will be determined on the first and second visit (after the 14 day 
medication washout period). Both scores exceeding their threshold on either day will qualify. 
5. Skin test strongly positive (wheal at least 5mm diameter and 2mm greater than negative 
control) to at least 6 of 48 allergy skin prick tests including at least one species of dust mite.  
1.3 
Exclusion Criteria 
Any subject who meets any of the following criteria will not qualify for entry into the study:  
1. The subject has received any investigational compound within 30 days prior to screening. 
2. The subject has received allergen immunotherapy or SLIT in a previous clinical study or as a 
therapeutic agent within the past two years.  
3. The subject has a history or clinical manifestations of significant medical conditions 
(cardiovascular, hepatic, infectious or renal disease, etc.) which in the opinion of the 


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investigator renders them unacceptable study subjects.  
4. The subject has a history of drug abuse (defined as any chronic illicit drug use) or a history of 
alcohol abuse within 5 years prior to the screening visit.    
5. The subject is required to take excluded medications listed in Section 6.3. 
6. If female, the subject is pregnant or lactating or intending to become pregnant before, during, 
or within 1 month after participating in this study; or intending to donate ova during such time 
period. 
7. Subjects found to have on physical exam significant nasal polyps, septal deviation or 
infectious sinusitis.  
8. The subject has a history of allergic rhinitis but is not currently manifesting active signs and 
symptoms of the disorder. 
9. Subject has a history of cancer, other than squamous cell or basal cell carcinoma of the skin 
that has not been in full remission for at least 5 years prior to Screening. (A history of treated 
CIN I, II, or CIN III [cervical intraepithelial neoplasia] is allowed.)  
Main Criteria for Evaluation and Analyses: 
Primary efficacy endpoint 
The primary efficacy endpoint for this study is the quantitative comparison of the study subject 
clinical response of active PMA immunotherapy compared to the placebo treatment. The total 
combined symptom and medication score (DCS) will be used as a validated assessment.  
Secondary efficacy endpoints 
The secondary efficacy endpoints for this study are mini-Rhinitis Quality of Life Questionaire 
(RQLQ) and safety assessment. Serum will also be stored to evaluate changes in IgE and IgG 
subclasses.  
Safety Analysis 
Safety outcomes will be assessed by adverse event reporting in active and placebo treated 
study subjects. 
Overall safety and tolerability will be assessed by evaluating the incidence of treatment 
emergent adverse events (TEAE), vital signs, and other safety variables. Treatment-emergent AEs 
will be defined as any AEs, regardless of relationship to study drug, which occurs on or after the 
first double blind dose date and up to 30 days after the last dose date of the double-blind study drug. 
Treatment-emergent adverse events (treatment at time of event) will be summarized using the 
Medical Dictionary for Regulatory Agencies (MedDRA) coding dictionary.  
 
Statistical Considerations: 


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Efficacy Analyses 
The intent-to-treat approach will be used. Baseline characteristics (those collected prior to 
randomization) will be described using mean and standard deviation for continuous variables and 
medians and ranges for discrete variables. 
The primary efficacy variable is the change in symptoms at the end of the periods of PMA or 
placebo study drug administration. The p-value, least square (LS) treatment means, difference 
between the LS treatment means, and 95% confidence intervals for the treatment differences will 
be presented. 
The secondary efficacy variables are rescue medication requirement and adverse events. These 
changes will be analyzed similarly to that of the primary efficacy variable.  
The percentage of subjects stopping PMA or placebo administration due to intolerance or lack 
of efficacy will be summarized by treatment group, and the groups will be compared using 
Fisher’s exact test. 
Sample Size Justification:  
The study sample size is based upon the results of prior immunotherapy investigations 
undertaken by the Investigators of this study and their colleagues in the Division of Allergy & 
Clinical Immunology, Johns Hopkins University School of Medicine. Efficacy for immunotherapy 
was estimated to be 80% for treatmet group and 30% for placebo. Using an error rate () of 0.05 
and 80% Power we calculate a total sample size needed of 28 subjects. To account for drop off we 
will recruit up to 36 subjects. 
  
 


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2.0 
STUDY REFERENCE INFORMATION 
2.1 
Endpoints  
2.1.1 Primary Endpoints  
The primary endpoint is to quantify and compare the clinical difference in signs and symptoms and 
medication usage that may be apparent when subjects with active perennial allergic rhinitis (PAR) 
with or without seasonal symptoms (SAR) are treated in a double-blind, prospective, controlled 
eight weeks study with a PMA versus placebo.   
 
2.1.2 Secondary Endpoint 
The secondary endpoints include the global RQLQ index and adverse events profile (AE). Serum 
will also be stored for measurement of immunoglobulins at a later date.  
2.2 
Primary Investigator  
The sponsor has selected a Signatory Primary Investigator from the investigators who participate 
in this study. Selection criteria for this investigator included significant knowledge of the study 
protocol, the study medication, their expertise in the therapeutic area and the conduct of clinical 
research as well as study participation. The Signatory Coordinating Investigator will be required to 
review and sign the clinical study report and by doing so agrees that it accurately describes the 
results of the study. 


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2.3 
List of Abbreviations 
 
AE 
adverse event 
AR 
allergic rhinitis 
BMI 
body mass index 
CRF 
case report form  
CRO 
contract research organization 
CSR 
clinical study report 
CysLTs 
cysteinyl leukotreines 
DCS 
Daily combined score 
DNA 
deoxyribonucleic acid 
FDA 
Food and Drug Administration 
GCP 
Good Clinical Practice 
HIV 
human immunodeficiency virus 
ICH 
International Conference on Harmonisation 
ICS 
Inhaled corticosteroids 
IgE 
Immunoglobulin E 
IL 
interleukin 
INR 
international normalized ratio 
IRB 
institutional review board 
LFT 
liver function tests 
LTRA 
leukotriene receptor antagonists 
MedDRA 
Medical Dictionary for Regulatory Activities 
PMA 
propriatory mixture of allergens 
PAR 
perennial allergic rhinitis 
PNU 
Protein Nitrogen Units 
PTE 
pretreatment event 
RBC 
red blood cell 
RNA 
ribonucleic acid 
SAE 
serious adverse event 
SAP 
SAR 
statistical analysis plan 
seasonal allergic rhinitis 


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SOP 
standard operating procedure 
TEAE 
treatment emergent adverse event 
TNSS 
Total nasal symptom score 
ULN 
upper limit of normal 
WHO 
World Health Organization 


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3.0 
INTRODUCTION 
3.1 
Background 
Allergic rhinitis and asthma 
Allergic rhinitis (AR) is one of the most common chronic disorders, with reported prevalence 
ranging from 3% to 19% (1). It is a heterogeneous disorder that includes seasonal AR (SAR) 
symptoms (‘hay fever’) and, perennial AR (PAR). The comprehensive review of Kay and 
colleagues reports that SAR is found in approximately 10% of the general population and PAR in 
10% to 20%. (2).  
Clinical symptoms of AR include runny nose, itching, sneezing and nasal congestion. More than 
80% of persons with allergic asthma have AR and AR is a risk factor for the development of 
asthma. Hence, there is a significant comorbidity between asthma and AR which is not surprising 
since there is an uninterrupted air passage from the nose to the alveolar ducts of the lungs. The 
clearest connection between AR and asthma is based on a shared immunologic response to an 
identified foreign substance. The term often used for the response is ‘allergy’, and the foreign 
substance is an allergen. Kay (2) notes that when Clemens von Pirquet originally introduced the 
term allergy in 1906, he had applied it to the reactivity found in both protective immunity and 
hypersensitivity. However, allergy is now identified with the type 1 hypersensitivity disorder of 
the immune system associated with immunoglobulin E (IgE). 
Triggers for episodes of allergic rhinitis 
The triggers for AR are aeroallergens associated with, airborne pollens, dust mites, animal dander, 
molds that induce IgE production. The inflammatory response is similar for both AR and asthma; 
they share a similar respiratory epithelial structure of ciliated pseudostratified columnar 
epithelium with goblet cells (6). The pathophysiology of local mediator release, systemic immune 
response and eosinophil recruitment are alike. During the early-phase response, symptoms in 
patients with AR typically consist of sneezing, rhinorrhea and conjunctivitis; patients with asthma 
experience wheezing, coughing and shortness of breath, in addition to objectively demonstrable 
changes in lung function. There is a similar pattern and time course of early- and late-phase 
responses in AR and asthma. Approximately 1 hour after allergen provocation, patients with AR 
experience a peak in symptoms, while patients with asthma experience a steep decline in lung 
function, measured by forced expiratory volume in 1 second (FEV1). During the late-phase 
response, nasal congestion is sustained in patients with AR, while a prolonged fall in lung function 
is again observed in patients with asthma. Within 12 h to 24 h, both types of reactions may resolve.  
Sub-cutaneous allergen immunotherapy 


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Allergen immunotherapy by injection (desensitization or hyposensitisation) consists of an 
induction course of injections of increasing doses of the allergen extract, usually given weekly or 
bi-weekly. The maintenance phase of maximum dosage injections usually lasts between three to 5 
years (7). Injections can consist of single or mixed allergen extracts.  As reported in a recent 
Cochrane Review, speciﬁc allergen immunotherapy (SIT) for hay fever is widely considered to be 
effective where grass pollen, ragweed, and birch pollen are causal agents, and there is evidence 
that its efﬁcacy may continue for many years beyond the treatment period (8). The review 
concludes that speciﬁc allergen injection immunotherapy is a safe and efﬁcacious treatment in 
reducing symptom severity and the requirement for anti-allergic medication in AR. In view of the 
occasional occurrence of systemic side effects following injections, it is customary that injection 
immunotherapy is performed in the immediate presence of a physician and administered by 
personnel that are fully trained and who are experienced in the early recognition and treatment of 
such reactions.  
3.2 
Rationale for the Proposed Study 
The proposed study represents a novel and heretofore unpublished method of sub-cutaneous 
immunotherapy for the management of the spectrum of PAR with or without SAR. The 
immunologic concept and therapeutic management techniques to be studied in this investigation 
evolved during the past three decades in the clinical practice observations of some 20,000 patients 
as undertaken by the “inventor” of the treatment paradigm, William J. Freeman, MD, a Johns 
Hopkins University School of Medicine graduate and Diplomate of The American Board of 
Otolaryngology.  
The intrinsic difference of the Freeman technique, compared to currently used methodologies of 
sub-cutaneous immunotherapy for AR, is that a wide-spectrum propriatory mixture of 60 different 
FDA approved allergens (referenced above as PMA), refined over multiple years of clinical testing 
and observation, is used for the immunotherapy. In part due to the significantly lower dose of each 
active allergen, this form of immunotherapy has demonstrated an excellent clinical safety profile 
and not one single anaphylactoid response has been noted with the use of this propriatory mixture 
in decades of use and development. 
Current sub-cutaneous immunotherapy for the management of AR typically consist of the use of a 
limited number of relevant antigens (grass pollen, tree pollen, ragweed pollen, dust mites,etc.). 
Hence, the propriatory antigen mixture that will be used in this investigation that uses more than 
60 relevant allergens represents a new immunologic concept that has not been subjected to a 
controlled, parallel group, prospective and double-blind study. 
All the antigens used in the PMA are currently FDA approved for immunotherapy purposes. These 
consist of both standardized and non-standardized forms of allergen. For the standardized allergen 
extracts, manufacturers compare the allergen extract to a U.S. reference standard for potency, 
maintained by the FDA Center for Biologics Evaluation and Research. The precise selection of 


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antigens, the quantitative amount of the latter in the propriatory mixture and the preparation of 
three allergenic solutions of “vaccine” for immunotherapy are propriatory intellectual property. 
          


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4.0 
STUDY OBJECTIVES AND ENDPOINTS 
4.1.1 Primary Objective 
The primary efficacy endpoint for this study is the quantitative comparison of the study subject 
clinical response of active PMA immunotherapy compared to the placebo treatment. The Total 
Nasal Symptoms Score (TNSS) will be used to generate daily symptom scores. The total combined 
daily symptom and medication score (DCS) will be used as the primary validated assessment.  
4.1.2 Secondary Objective 
The secondary efficacy endpoints for this study are mini-Rhinitis Quality of Life Questionaire 
(RQLQ) and safety assessment. Serum will also be stored to evaluate changes in IgE and IgG 
subclasses.  
 
 


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5.0 
STUDY DESIGN AND METHODS 
5.1 
Study Design 
This is a phase 2 proof of concept study. It is being undertaken to characterize and quantify the 
clinical difference in signs and symptoms that may evolve when subjects with active SAR/PAR 
are administered a sub-cutaneous form of immunotherapy in a double-blind, prospective, 
controlled six weeks study wherein a PMA is compared with saline placebo.  
Randomization to active PMA versus placebo treatment is on a 1 to 1 ratio. A double-blind study 
design is used to minimize outcome bias.  Randomization measures to minimize bias at study entry 
include computerized random assigment of treatment versus placebo vials. 
Subjects who are receiving nasal steroids for their SAR/PAR at screening may continue in the 
screening process if they agree to discontinue their therapy and comence a 14 day wash-out period 
of their medication prior to receiving active/placebo immunotherapy. Potential study subjects 
who, at screening, are not on active treatment for their SAR/PAR and asthma may enter directly 
into the investigation provided they fulfil entry and exclusion criteria and screening testing 
requirements.   
The population to be studied consists of male and female adults aged 18 years to 65 years who are 
actively manifesting SAR/PAR have a score of at least 28 on the mini-RQLQ and 6 on the TNSS 
scale. 
The active treatment phase of the study will be for six weeks with a safety followup assessment at 
30 days post-treatment. No interim analysis is planned.     
The study immunotherapy that will be evaluated in this study is a new innovative propriatory 
mixture of FDA approved allergens which has been clinically developed and evaluated, during the 
past three decades, in some 20,000 patients by the inventor of the mixture (see 3.2). In clinical 
evaluation this patented antigen mixture has provided clinical symptomatic relief to patients with 
SAR/PAR in as brief a period as three administrations of immunotherapy injections and has an 
observed overall success rate of approximately 80 to 90 percent of such treated subjects. 
In this study approximately 36 study subjects will be equally randomized to active PMA or 
placebo. The duration of active PMA or placebo treatment will be 8 weeks with clinic visits 
twice-weekly during this period and a post-treatment safety follow up assessment at one month 
following the final administration of immunotherapy. All doses of immunotherapy will be 
administered in the study site clinic by the investigators or their designees.        
  
A schematic of the study design is included as Figure 5.a. A schedule of assessments is listed in 
Appendix A. 


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Figure 5.a 
Schematic of Study Design  
 
 
 
 
 
 
 
 
 
 
 
 
 
5.2 
Justification for Study Design, Dose, and Endpoints 
The question to be answered scientifically by this investigation is whether or not a new innovative, 
patented mixture of FDA approved antigens provides unequivocal superior clinical benefit in the 
symptomatic relief of individuals manifesting active SAR/PAR. Since extensive prior experience 
of managing patients with these medical conditions has demonstrated remarkable benefit from the 
immunotherapy technique within 3 to 6 weeks, the selection of study subjects and the overall study 
design can be scientifically justified.  
The dose of immunotherapy, which will be administered sub-cutaneously bi-weekly for 8 weeks, 
will be the same for all subjects and will begin with vial number #5 which will be prepared by 
serial five fold dilutions from the most concentrated vial (#1).  
The study sample size is based upon the results of prior immunotherapy investigations undertaken 
by the Investigators of this study and their colleagues in the Division of Allergy & Clinical 
Immunology, Johns Hopkins University School of Medicine. Efficacy for immunotherapy was 


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estimated to be 80% for treatmet group and 30% for placebo. Using an error rate () of 0.05 and 
80% Power we calculate a total sample size needed of 28 subjects. To account for drop off we will 
recruit up to 36 subjects. 
 
5.3 
Premature Termination or Suspension of Study or Investigational Site 
This study may be terminated at any time by the investigators or the sponsor for safety reasons or 
for just cause.  
5.3.1 Criteria for Premature Termination or Suspension of the Study 
The study will be completed as planned unless one or more of the following criteria are satisfied 
that require temporary suspension or early termination of the study. 
 New information or other evaluation regarding the safety or efficacy of the study medication 
that indicates a change in the known risk/benefit profile for the immunotherapy, such that the 
risk or benefit is no longer acceptable for subjects participating in the study. 
 Significant violation of Good Clinical Practice (GCP) that compromises the ability to achieve 
the primary study objectives or compromises subject safety. 
5.3.2 Criteria for Premature Termination or Suspension of the Investigational Site 
The study site may be terminated prematurely or suspended if the site is found in significant 
violation of GCP, protocol, or contractual agreement, is unable to ensure adequate performance of 
the study, or as otherwise permitted by the contractual agreement. 
5.3.3 Procedures for Premature Termination or Suspension of the Study or the Participation of 
the Investigational Site  
In the event that the sponsor, the institutional review board or regulatory authority elects to 
terminate or suspend the study or the participation of the investigational site, a study-specific 
procedure for early termination or suspension will be provided by the sponsor; the procedure will 
be followed by the investigational site during the course of termination or study suspension. 


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6.0 
SELECTION AND DISCONTINUATION/WITHDRAWAL OF SUBJECTS 
All entry criteria, including test results, need to be confirmed prior to the administration of first 
dose of immunotherapy.   
6.1 
Inclusion Criteria 
1. In the opinion of the investigator, the subject is capable of understanding and complying with 
protocol requirements. 
2. The subject signs and dates a written, informed consent form prior to the initiation of any study 
procedures. 
3. The subject is a male or a non-pregnant, non-lactating female between the ages of 18 and 65.  
4. The study subject is currently experiencing active symptoms and signs of moderate to severe 
PAR with or without SAR component defined as score of at least 28 on the RQLQ and 6 on the 
TNSS scale. Scores will be determined on the first and second visit (after the 14 day 
medication washout period). Both scores exceeding their threshold on either day will qualify. 
5. Skin test strongly positive (wheal at least 5mm diameter and 2mm greater than negative 
control) to at least 6 of 48 allergy skin prick tests including at least one species of dust mite.  
6.2 
Exclusion Criteria 
Any subject who meets any of the following criteria will not qualify for entry into the study:  
1. The subject has received any investigational compound within 30 days prior to screening. 
2. The subject has received multi antigen immunotherapy or SLIT in a previous clinical study or 
as a therapeutic agent within the past two years.  
3. The subject has a history or clinical manifestations of significant medical conditions 
(cardiovascular, hepatic, infectious or renal disease, etc.) which in the opinion of the 
investigator renders them unacceptable study subjects.  
4. The subject has a history of drug abuse (defined as any chronic illicit drug use) or a history of 
alcohol abuse within 5 years prior to the screening visit.    
5. The subject is required to take excluded medications listed in Section 6.3. 
6. If female, the subject is pregnant or lactating or intending to become pregnant before, during, 
or within 1 month after participating in this study; or intending to donate ova during such time 
period. 
7. Subjects found to have on physical exam significant nasal polyps, septal deviation or 
infectious sinusitis.  


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6.3 
Excluded Medications 
 Immunotherapy that is not part of the investigation 
 Beta2 agonists and angiotensin converting enzyme (ACE) inhibitors 
 Other medications that may interfere with the test, analysis, or interpretation of results. 
 Omalizumab and other anti-asthma biologics, or immune suppression treatment within 6 
months of participating in the investigation, including oral corticosteroids within the month. 
 Subjects must be instructed not to take any medications including over-the-counter products, 
without first consulting with the investigator. 
Note that prior use of  medications commonly used to treat allergic rhinitis such as nasal steroids, 
antihistamines, opthalmologic antihistamines, cromolyn, azelastine, decongestants and other OTC 
allergy medications are not excluded. However, these medication will be stopped during the 14 
day washout period. Patients are encouraged to abstain from using these medications for the 
duration of the study. If symptoms are not adequately controlled the rescue medications will be 
added in a stepwise fashion as outlined in section 12.1.3. 
 
 
 
6.4 
Criteria for Discontinuation or Withdrawal of a Subject 
The primary reason for discontinuation or withdrawal of the subject from the study or study 
medication should be recorded in the CRF using the following categories. For screen failure 
subjects, refer to Section 8.1.11. 
1. Pretreatment event (PTE) or adverse event (AE). The subject has experienced a PTE or AE that 
requires early termination because continued participation imposes an unacceptable risk to the 
subject’s health or the subject is unwilling to continue because of the PTE or AE. 
2. Significant protocol deviation. The discovery postrandomization or after the first dose of study 
immunotherapy that the subject failed to meet protocol entry criteria or did not adhere to 
protocol requirements, and continued participation poses an unacceptable risk to the subject’s 
health. 
3. Lost to follow-up. The subject did not return to the clinic and attempts to contact the subject 
were unsuccessful. Attempts to contact the subject must be documented.  
4. Voluntary withdrawal. The subject (or subject’s legally acceptable representative) wishes to 
withdraw from the study. The reason for withdrawal, if provided, should be recorded in the 


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CRF. All attempts should be made to determine the underlying reason for the withdrawal and, 
where possible, the primary underlying reason should be recorded. 
5. Study termination. The sponsor, IRB, or regulatory agency terminates the study. 
6. Pregnancy. The subject is found to be pregnant. 
Note: If the subject is found to be pregnant, the subject must be withdrawn immediately. The 
procedure is described in Section 8.1.10. 
7. The investigator has determined that continued participation would pose an unacceptable risk 
to the subject. 
Note: After the 30 minute wait period, subjects that develop local swelling at the site of the 
injection greater than 50mm diameter will have their next dose decreased by one step. Subjects 
having a Grade 1-2 systemic reaction will have their next injection decreased by two steps. 
Systemic reaction Grade 3 or more will require withdrawal from the study. Systemic reactions 
are defined by the World Allergy Organization anaphylaxis grading system (13). 


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7.0 
CLINICAL TRIAL MATERIAL MANAGEMENT 
This section contains information regarding all medication and materials provided directly by the 
sponsor, and/or sourced by other means, that are required by the study protocol, including 
important sections describing the management of clinical trial material. 
7.1 
Drugs / Substances / Devices 
Study immunotherapy solutions (noted above as PMA), composed of FDA approved allergens, 
will be supplied by the sponsor. PMA is prepared from a selection of FDA approved allergens and 
allergen mixtures listed in Appendix E     FDA Approved Allergens to be Used for Treatment. 
Allergens used for skin prick testing are listed in Appendix G     Allergens used for skin prick 
testing. 
7.1.1 Dosage Form, Preparation and Labeling 
The dosage (dilution) of PMA will be the same for all subjects and will begin with vial number #5 
which will be prepared by serial five fold dilutions from the most concentrated vial (#1).  
One PMA active treatment set will be prepared by compounding three separate concentrated vials 
(#1) each containing approximately 30 antigen mixtures (no more than about 75 total antigens 
each) and labeled mix A, B and C. No more than 0.9 ml of each manufacturer supplied stock 
material will be placed in a 100ml vial and brought to volume with diluent. Each of the #1 vials (A, 
B and C) will then be serially diluted 5 fold, several times approximately as follows: 
 
 
 
 
 
 
 
 
 
Mix A  
Mix B  
Mix C  
Exact Preparation 
 
 
(Pollens) 
(Indoor) 
(Molds)  
Vial #1 
1:1 
 
1:1 
 
1:1 
 
Described above 
Vial #2 
1:5 
 
1:5 
 
1:5 
 
20ml Vial #1 + 85ml diluent 
Vial #3 
1:25 
 
1:25 
 
1:25 
 
4ml Vial #1 + 85ml diluent 
Vial #4 
1:125  
1:125  
1:125  
4ml Vial #2 + 85ml diluent 
Vial #5 
1:625  
1:625  
1:625  
4ml Vial #3 + 85ml diluent 


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7.1.2 Vials #1-2 will have an expiration date of six months and dilutions #3-5 may be used for up 
to three months.  
 
7.1.3 One placebo set will also be prepared in a similar manner using sterile saline and an 
equivalent amount of glycerin/phenol. Because up to 20% of patients receiving active treatment 
may notice local swelling and itch, histamine will be added to the stock placebo vials (vial 1) at a 
concentration of 50ug/ml (0.05mg/ml). Thus vial #2 will have a final concentration of 0.01mg/ml 
histamine. This is expected to elicit a mild itch in about 20% of control subjects based on 
experience.  
 
Folic acid will also be added to the placebo vials to yield a slightly yellow color similar to 
the active treatment vials. Stock placebo (#1 vials) will contain 1mg/ml folic acid by adding 20ml 
of 5mg/ml folic acid to 80ml diluent. This will be further diluted 5 fold to yield (#2 vial) for a final 
concentration of 0.2mg/ml folic acid and so on. 
 
The labeling of study PMA and placebo solutions will be undertaken by the compounding 
pharmacy of this investigation and undertaken in conjunction with the sponsor so that a 
double-blind study technique can be employed during the investigation. Each active and placebo 
vial set will be labeled randomly either set I or II. The set, mix letter, dilution, and use by date will 
also be included as shown by the example below. Only the pharmacy and sponsor will hold the 
treatment set randomization code. Recruited subjects will alternate between sets I and II. 
 
 
Figure 7.a 
Labeling 
 
 
 
 
Set II 
Dilution #3 
Mix A 
 
Relez Therapeutics 
Use by (3.1.17) 
Set II 
Dilution #3 
Mix B 
 
Relez Therapeutics 
Use by (3.1.17) 
Set II 
Dilution #3 
Mix C 
 
Relez Therapeutics 
Use by (3.1.17) 


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7.1.3.2 Investigational immunotherapy 
The investigational immunotherapy used in this study protocol will be prepared by the Johns 
Hopkins University School of Medicine Division of Allergy and Clinical Immunology Laboratory 
(DACI) a national reference laboratory facility according to institutional policy and in accordance 
with USP 797 compounding standards. The allergens that will be used to constitute the study 
immunotherapy solutions will be directly shipped by nationally licensed corporate suppliers such 
as Greerlabs, Lenoir NC 28645-0800 and Allergy Laboratories, Oklahoma, City. All allergens 
used in the compounding of study immunotherapy solutions will be FDA approved materials.  
Sterile saline, used for the production of the study placebo solution will be supplied by the vendor 
compounding pharmacy. A comparable amount of glycerin and phenol as well as histamine will be 
added to the placebo vials to mimic any local irritant reactions that may occur in the active 
treatment vials. 
7.1.3.3 Storage 
Investigational immunotherapy solutions and placebo saline solutions will be refrigerated at 4 
degrees celcius and stored in an appropriate, limited-access, secure place until it is used for the 
investigation or returned to the sponsor or designee for destruction. Storage will comply with the 
conditions specified on the label, and remain in the original container until dispensed. A daily 
temperature log of the drug storage area must be maintained every working day. 
7.1.4 Immunotherapy Dose and Regimen  
Recruited subjects alternate to be assigned either treatment set I or II (representing either placebo 
or active PMA treatment in a binded fashion). The assigned treatment set will remain for the 
duration of the study for each subject. On the day of an injection, 0.3ml from each of the 
appropriate vial set mix (A-C)  will be combined in a sterile 5 ml bottle. Using a new sterile 
syringe, 0.15-0.60ml of the PMA solution or placebo will be removed for injection purposes 
according to the injection schedule (Appendix I).   A sterile 27G ½ inch syringe will be used for 
administration. Immunotherapy will be adminitered bi-weekly in the study clinic for a total of 
eight consecutive weeks. Appendix I lists the precise immunotherapy injection schedule. 
 
All patients are required to remain in the clinic under close observation by the study nurse for a 
period of 30 minutes following their injection. A physician is required to be present in the clinic at 
all times. In addition, one of the investigators must be present on campus and available by cell 
phone during scheduled treatment sessions. Emergency medications such as albuterol, oxygen, 
diphenhydramine, and at least two epi-pens will be readily available in the treament area. 
 


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It is important to note that the maximum concentration of each individual allergen is quite low 
compared to more traditional immunotherapy regimens. The maximum PNU/ml (Protien Nitrogen 
Units) in vial #1 will be no more than about 180 PNU/ml per allergen (eg 0.9ml of 20,000 PNU/ml 
stock material into 100ml solution). In most cases the actual concentration of each stock allegen is 
much lower than 20,0000 PNU/ml since the material may be provided as a mixture of several 
allergens. We would estimate therefore that subjects would receive no more than about 7.2 PNU of 
antigen contained in the highest injection (0.2ml Vial #2). Typically, allergens are administered 
via immunotherapy in a range of about 2000 PNU.  Thus the dosage of each allergen is less than 
0.36% of a typical dose administered in our clinics. The lower overall dosing scheme provided in 
this study would therefore be considered to be extremely safe with minimal adverse events. 
7.1.5 Overdose 
An overdose is defined as a known deliberate or accidental administration of investigational 
immunotherapy to a study subject, at a dose above that which is assigned to that individual subject 
according to the study protocol. 
All cases of overdose (with or without associated AEs) will be documented on an Overdose page 
of the CRF, in order to capture this important safety information consistently in the database. 
Cases of overdose without manifested signs or symptoms are not considered AEs. AEs associated 
with an overdose will be documented on an AE CRF according to Section 9.0, Pretreatment Events 
and Adverse Events. 
Serious adverse events (SAEs) associated with overdose should be reported according to the 
procedure outlined in Section 9.2.2, Collection and Reporting of SAEs. 
In the event of immunotherapy overdose, the subject should be treated symptomatically.  
7.2 
Investigational drug Assignment and Dispensing Procedures 
A study subject randomization schedule will be developed by the study vendor compounding 
pharmacy or designee. In addition, stratification of study subject entry into the investigation will 
be determined by the study site investigators correlated with the study subject’s clinical entry 
diagnostic criteria (see 6.1).   
Subjects will be assigned to receive their treatment according to the randomization schedule 
provided to the study site by the vendor compounding pharmacy. The immunotherapy ID Number 
will be entered onto the study subject’s CRF. All study immunotherapy will be administered to the 
study subjects while they are in the study site clinic.  
Investigational immunotherapy blind maintenance will be undertaken by the vendor compounding 
pharmacy. During regularly scheduled monitoring visits, a study monitor from the sponsor or a 
designee will perform an inventory of blinded investigational immunotherapy solutions. All 


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unassigned treatment immunotherapy solutions will be reconciled and returned to the sponsor or a 
designee before study closure. 
7.3 
Unblinding Procedure  
The investigational drug blind shall not be broken by the investigator unless information 
concerning the investigational immunotherapy is necessary for the medical treatment of the 
subject. In the event of a medical emergency, if possible, the medical monitor should be contacted 
before the investigational immunotherapy blind is broken to discuss the need for unblinding. 
For unblinding a subject, the investigational immunotherapy blind can be obtained by contacting 
the vendor compounding pharmacist. The sponsor must be notified as soon as possible if the 
investigational immunotherapy blind is broken. The date, time, and reason the blind is broken must 
be recorded in the study subject’s source documents and the same information must be recorded on 
the subject’s CRF. Investigational immunotherapy must be stopped immediately and the subject 
must be withdrawn from the study. 
7.4 
Accountability and Destruction of Sponsor-Supplied Drugs 
Immunotherapy supplies will be counted and reconciled at the site before being returned to the 
sponsor or designee. 
The investigator or designee must ensure that the sponsor-supplied immunotherapy solutions are  
used in accordance with the protocol and administered only to subjects enrolled in the study. To 
document appropriate use of sponsor-supplied immunotherapy solutions, the investigator or 
designee must maintain records of all sponsor-supplied study solutions supplied to the study site, 
site inventory, administration to each subject, and return to the sponsor or designee. 
Upon receipt of sponsor-supplied drug, the investigator or designee must verify the contents of the 
shipments against the packing list. The investigator should ensure that the quantity is correct, and 
the solutions are in good condition. If quantity and conditions are acceptable, investigator or 
designee should acknowledge the receipt of the shipment from the vendor compounding pharmacy 
by signing the packing list and confirming by fax or e-mail while maintaining aq record of the 
confirmation. The packing list should be filed in the investigator’s essential document file. 
The investigator or designee must maintain 100% accountability for all sponsor-supplied 
immunotherapy solutions during their entire participation in the study. Proper immunotherapy 
solutions accountability includes, but is not limited to: 
 Continuously monitoring expiration dates if provided by the vendor compounding pharmacy 
 Frequently verifying that actual inventory matches documented inventory. 
 Verifying that the log is completed for the solutions administered to an individual study 
subject. 


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 Verifying that all immunotherapy solution containers used are documented accurately on the 
log. 
Prior to site closure or at appropriate intervals, a representative from the sponsor or its designee 
will perform sponsor-supplied immunotherapy solutions accountability and reconciliation before 
sponsor-supplied solutions are returned to the vendor compounding pharmacy. The investigator or 
designee will retain a copy of the documentation regarding sponsor-supplied study solutions  
accountability, return, and/or destruction, and originals will be sent to the sponsor or designee. 
The investigator will be notified of any expiry date of sponsor-supplied study solutions during the 
study conduct. On expiry date notification from the vendor compounding pharmacy, the site must 
complete all instructions outlined in the notification, including segregation of expired 
sponsor-supplied study solutions for return to the vendor compounding pharmacy for destruction. 


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8.0 
STUDY PLAN 
8.1 
Study Procedures 
The following sections describe the study procedures and data to be collected. For each procedure, 
subjects are to be assessed by the same investigator or site personnel whenever possible. The 
Schedule of Study Procedures is located in Appendix A. 
8.1.1 Informed Consent Procedure 
Informed consent must be obtained prior to the subject entering into the study and before any 
protocol-directed procedures are performed. 
A unique subject identification number (subject number) will be assigned to each study subject at 
the time that the study subject signs the informed consent. This subject number will be used 
throughout the study. 
8.1.2 Demographics, Medical History, and Medication History Procedure 
Demographic information to be obtained will include date of birth, sex, ethnicity, race as described 
by the subject, and smoking status of the subject at Screening.  
Medical history to be obtained will include determining whether the subject has any significant 
conditions or diseases relevant to the diagnose of SAR/PAR (i.e., diseases under study) that 
stopped at or prior to signing of informed consent. Ongoing conditions are considered concurrent 
medical conditions (see Section 8.1.8). 
8.1.3 Physical Examination Procedure 
A baseline physical examination (defined as the assessment prior to first dose of investigational 
immunotherapy) will consist of the following body systems: (1) eyes; (2) ears, nose, throat; 
(3) cardiovascular system; (4) respiratory system; (5) gastrointestinal system; (6) dermatologic 
system; (7) extremities; (8) musculoskeletal system; (9) nervous system; (10) lymph nodes; 
(11) other. All subsequent physical examinations should assess clinically significant changes from 
the assessment prior to first immunotherapy examination. 
8.1.4 Weight, Height  
A subject should have weight and height measured while wearing indoor clothing and with shoes 
off.   
8.1.5 Vital Sign Procedure 
Vital signs will include body temperature, respiratory rate, blood pressure (resting more than 
5 minutes), pulse (bpm), and peaked flow (PFR). 


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When vital signs are scheduled at the same time as blood draws, the blood draw will take priority 
and vital signs will be obtained within 0.5 hour before or after the scheduled blood draw. 
8.1.6 Primary Efficacy Measurement  
The primary efficacy measurement is based upon validated efficacy instruments. Details of the 
efficacy assessments are described in Appendix F 
8.1.7 Documentation of Concomitant Medications 
Concomitant medication is any drug given in addition to the study immunotherapy. These may be 
prescribed by a physician or obtained by the subject over the counter. Concomitant medication is 
not provided by the study sponsor. At each study visit, subjects will be asked whether they have 
taken any medication other than the study medication (used from signing of informed consent 
through the end of the study), and all medication including vitamin supplements, over-the-counter 
medications, and oral herbal preparations, must be recorded in the CRF. 
8.1.8 Documentation of Concurrent Medical Conditions 
Concurrent medical conditions are those significant ongoing conditions or diseases that are present 
at signing of informed consent. The investigators will decide upon the significance or 
non-significance of an ongoing clinical condition or laboratory abnormality.  
8.1.9 Procedures for Clinical Laboratory Samples 
All samples will be collected in accordance with acceptable laboratory procedures. Blood will be 
drawn at the start of the study and at the completion. The maximum volume of blood at any single 
visit is less than 10.0 mL, and the approximate total volume of blood for the study is less that 20 
mL. Serum collected at the screening visit will be stored for later analysis. Blood will be redrawn 
at the final visit (week 14) so that pre and post immunoglobulin levels can be measured including 
specifc IgE, and IgG4 and possibly IgG3. 
 
The Johns Hopkins Bayview Medical Center laboratory will perform laboratory tests as indicated 
above. The investigator or designee is responsible for transcribing or attaching laboratory results 
to the CRF. The investigator will maintain a copy of the laboratory accreditation and the reference 
ranges for the laboratory used. 
8.1.10 Pregnancy 
If any subject is found to be pregnant during the study she should be withdrawn and 
immunotherapy should be immediately discontinued. If the pregnancy occurs during 
administration of active PMA study immunotherapy the pregnancy should be reported 
immediately, using a pregnancy notification form, to the contact listed in Section 1.0. 


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Should the pregnancy occur during or after administration of immunotherapy, identified as being 
PMA, the investigator must inform the subject of their right to receive treatment information. 
Subjects randomized to placebo do not need follow-up.  
8.1.11 Documentation of Screen Failure 
Investigators must account for all subjects who sign an informed consent. If screening factors 
dictate that the subject is not eligible to continue in the investigation, the investigator should 
complete the CRF. 
The primary reason for screen failure is recorded in the CRF using the following categories: 
 PTE/AE. 
 Did not meet inclusion criteria or did meet exclusion criteria. 
 Significant protocol deviation. 
 Lost to follow-up. 
 Voluntary withdrawal. 
 Study termination. 
 Other 
Subject numbers assigned to subjects who fail screening should not be reused. 
8.1.12 Documentation of Study Randomization 
Only subjects who meet all of the inclusion criteria and none of the exclusion criteria are eligible 
for randomization into the immunotherapy treatment phase. 
8.1.13 Allergen Skin Prick Testing Procedures 
All subjects will undergoallergen skin prick allergy testing (SPT) as per standard of care using the 
Multi-Test PC (Lincoln Diagnostics, Decator, IL) or comparable skin testing device.The results of 
the skin testing will dictate if subjects qualify for the study. In addition to having clinical 
symptoms of perennial allergic rhinitis, all subjects test positive to at least 6 of 48 total SPT 
including at least one dust mite species (D. farinae or D. pteronissinus). A positive skin test will be 
defined as a minimum wheal diameter of 5mm and at least 2mm greater than the saline control. A 
list of allergens used for testing is shown in Appendix H. 
8.2 
Monitoring Subject Treatment Compliance 
Study subject compliance will be monitored by the accuracy of their attendance at the study site for 
their bi-weekly immunotherapy treatments. If a subject is persistently noncompliant with the 
follow up clinic visits for immunotherapy, it may be appropriate to withdraw the subject from the 


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study. All subjects should be reinstructed about the essentiality of scheduled clinic follow-up visits 
for immunotherapy during each of their scheduled clinic visits.  
8.3 
Schedule of Observations and Procedures 
The schedule for all study-related procedures for all evaluations is shown in Appendix A. 
Assessments should be completed at the designated visit/time point(s). 
8.3.1 Screening  
Subjects will be screened prior to the 14 day medication washout period. Subjects will be screened 
in accordance with predefined inclusion and exclusion criteria as described in Section 6.0. See 
Section 8.1.11 for procedures for documenting screening failures. 
Procedures to be completed at Screening (Visit 1) include: 
 Informed consent. 
 Demographics, medical history, and medication history. 
 Physical examination. 
 Vital signs. 
 Weight, height 
 Concomitant medications.  
 Concurrent medical conditions. 
 Allergy skin prick skin testing.   
8.3.2 Study Entrance Randomization  
Study Randomization will take place on study day 1 (Visit 1). The following procedures will be 
performed and documented during Study Randomization: 
 If the subject has satisfied all of the inclusion criteria and none of the exclusion criteria for 
randomization and the investigator deems the laboratory screening and skin testing are 
acceptable for continuance in the investigation, the subject should be randomized using the 
randomization sequence provided by the sponsor.  
 Subjects will receive their first sub-cutaneous administration of immunotherapy with dose 
vial #5. 
 The procedure for documenting Screening failures is provided in Section 8.1.11. 


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8.3.3 Treatment Phase 
Study visits 1 through 12 will be conducted (Figure 6a) in the study clinic and at each of these 
visits the study subject will have a safety and efficacy assessment and if deemed appropriate by the 
investigator will receive their next sub-cutaneous administration of study immunotherapy. A 60 
minute post treatment in-clinic safety assessment will be conducted.   
8.3.4 Final Visit or Early Termination 
The Final Visit will be performed on visit 18 or at an Early Termination Visit. The following 
procedures will be performed and documented: 
 Physical examination. 
 Vital signs. 
 Concomitant medications.  
 Concurrent medical conditions. 
 Efficacy assessment. 
 Safety assessment. 
 Blood draw. 
For all subjects receiving study medication, the investigator must complete the End of Study CRF 
page. 
8.3.5 Follow-up  
Follow-up will begin the first day after the last injection and will continue until for 30 days at 
which time a final in-clinic visit (visit 18) will be conducted for a safety assessment and blood 
draw.  
8.3.6 Post Study Care 
The study immunotherapy will not be available upon completion of the subject’s participation in 
the study. The subject should be returned to the care of a physician and standard therapies as 
required. 
Subject to applicable laws and feasibility, access to the study immunotherapy may be available to 
individual subjects for whom the investigators deem the treatment to be essential and wherein the 
subject is at risk of significant morbidity or mortality. The investigator should contact the medical 
monitor to determine if access is possible. 


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9.0 
PRETREATMENT EVENTS AND ADVERSE EVENTS 
9.1 
Definitions 
9.1.1 PTEs 
A PTE is defined as any untoward medical occurrence in a clinical investigation subject who has 
signed informed consent to participate in a study but prior to administration of any study 
medication; it does not necessarily have to have a causal relationship with study participation. 
9.1.2 AEs 
An AE is defined as any untoward medical occurrence in a clinical investigation subject 
administered a drug; it does not necessarily have to have a causal relationship with this treatment. 
An AE can therefore be any unfavorable and unintended sign (eg, a clinically significant abnormal 
laboratory finding), symptom, or disease temporally associated with the use of a drug whether or 
not it is considered related to the drug. 
9.1.3 Additional Points to Consider for PTEs and AEs 
An untoward finding generally may: 
 Indicate a new diagnosis or unexpected worsening of a pre-existing condition. (Intermittent 
events for pre existing conditions underlying disease should not be considered PTEs or AEs.) 
 Necessitate therapeutic intervention. 
 Require an invasive diagnostic procedure. 
 Require discontinuation or a change in dose of study medication or a concomitant medication. 
 Be considered unfavorable by the investigator for any reason. 
 PTEs/AEs caused by a study procedure (eg, a bruise after blood draw) should be recorded as a 
PTE/AE. 
Diagnoses vs signs and symptoms: 
 Each event should be recorded to represent a single diagnosis. Accompanying signs or 
symptoms should NOT be recorded as additional AEs. If a diagnosis is unknown, sign(s) or 
symptom(s) should be recorded appropriately as a PTE(s) or as an AE(s). 
Pre-existing conditions: 
 Pre-existing conditions (present at the time of signing of informed consent) are considered 
concurrent medical conditions and should NOT be recorded as PTEs or AEs. Baseline 
evaluations (eg, laboratory tests, ECG, X-rays etc.) should NOT be recorded as PTEs unless 


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related to study procedures. However, if the subject experiences a worsening or complication 
of such a concurrent condition, the worsening or complication should be recorded 
appropriately as a PTE (worsening or complication occurs before start of study medication) or 
an AE (worsening or complication occurs after start of study medication). Investigators should 
ensure that the event term recorded captures the change in the condition (eg, “worsening 
of…”). 
 If a subject has a pre-existing episodic condition (eg, gout, epilepsy) any occurrence of an 
episode should only be captured as a PTE/AE if the episodes become more frequent, serious or 
severe in nature, that is, investigators should ensure that the AE term recorded captures the 
change in the condition from Baseline (eg “worsening of…”). 
Worsening of PTEs or AEs: 
 If the subject experiences a worsening or complication of a PTE after starting administration of 
the study medication, the worsening or complication should be recorded appropriately as an 
AE. Investigators should ensure that the AE term recorded captures the change in the condition 
(eg, “worsening of…”). 
 If the subject experiences a worsening or complication of an AE after any change in study 
medication, the worsening or complication should be recorded as a new AE. Investigators 
should ensure that the AE term recorded captures the change in the condition (eg, “worsening 
of…”). 
Changes in severity of AEs /Serious PTEs: 
 If the subject experiences changes in severity of an AE/serious PTE, the event should be 
captured once with the maximum severity recorded. 
Preplanned surgeries or procedures: 
 Preplanned procedures (surgeries or therapies) that were scheduled prior to signing of 
informed consent are not considered PTEs or AEs. However, if a preplanned procedure is 
performed early (eg, as an emergency) due to a worsening of the pre-existing condition, the 
worsening of the condition should be captured appropriately as a PTE or an AE. Complications 
resulting from any planned surgery should be reported as AEs. 
Elective surgeries or procedures: 
 Elective procedures performed where there is no change in the subject’s medical condition 
should not be recorded as PTEs or AEs, but should be documented in the subject’s source 
documents. Complications resulting from an elective surgery should be reported as AEs. 


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Insufficient clinical response (lack of efficacy): 
 Insufficient clinical response, efficacy, or pharmacologic action, should NOT be recorded as 
an AE. The investigator must make the distinction between exacerbation of pre-existing illness 
and lack of therapeutic efficacy. 
Overdose: 
 Cases of overdose with the immunotherapy without manifested side effects are NOT 
considered PTEs or AEs, but instead will be documented on an Overdose page of the CRF. 
Any manifested side effects will be considered PTEs or AEs and will be recorded on the AE 
page of the CRF. 
9.1.4 SAEs 
An SAE is defined as any untoward medical occurrence that at any dose: 
1. Results in DEATH. 
2. Is LIFE THREATENING. 
 The term “life threatening” refers to an event in which the subject was at risk of death at the 
time of the event; it does not refer to an event that hypothetically might have caused death 
if it were more severe. 
3. Requires inpatient HOSPITALIZATION or prolongation of existing hospitalization. 
4. Results in persistent or significant DISABILITY/INCAPACITY. 
5. Leads to a CONGENITAL ANOMALY/BIRTH DEFECT. 
6. Is an IMPORTANT MEDICAL EVENT that satisfies any of the following: 
 May require intervention to prevent items 1 through 5 above. 
 May expose the subject to danger, even though the event is not immediately life 
threatening or fatal or does not result in hospitalization. 
 Includes any event or synonym described in the Takeda Medically Significant AE List 
(Table 9.a). 
Table 9.a 
Sponsor’s Medically Significant AE List  
Term 
Acute respiratory failure/acute respiratory 
distress syndrome 
Hepatic necrosis 
Torsade de pointes / ventricular fibrillation / 
ventricular tachycardia 
Acute liver failure 
Anaphylactic shock 


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Malignant hypertension 
Acute renal failure 
Convulsive seizure 
Pulmonary hypertension 
Agranulocytosis 
Pulmonary fibrosis  
Aplastic anemia 
Confirmed or suspected endotoxin shock 
Toxic epidermal necrolysis/Stevens-Johnson 
syndrome 
Confirmed or suspected transmission of 
infectious agent by a medicinal product 
 
Neuroleptic malignant syndrome / malignant 
hyperthermia 
 
Spontaneous abortion / stillbirth and fetal death 
 
PTEs that fulfill 1 or more of the serious criteria above are also to be considered SAEs and should 
be reported and followed up in the same manner (see Sections 9.2.2 and 9.3). 
It is important to note that out of more than 20,000 patients personally treated with the proprietary 
PMA allergen immunotherapy by Dr. William Freeman over the past 40 years, there HAS NEVER 
BEEN AN INCIDENT OF ANAPHYLAXIS OR SERIOUS SYSTEMIC REACTION attributed 
to the treatment. Epinephrine has never been required because of the treatment. Typical but 
uncommon side effects have included mild-moderate local swelling. These mild reactions occur at 
a rate of less than 20 percent. 
9.1.5 Severity of PTEs and AEs 
The different categories of intensity (severity) are characterized as follows: 
Mild: 
The event is transient and easily tolerated by the subject.  
Moderate: 
The event causes the subject discomfort and interrupts the subject’s usual 
activities. 
Severe: 
The event causes considerable interference with the subject’s usual activities. 
9.1.6 Causality of AEs 
The relationship of each AE to study immunotherapy will be assessed using the following 
categories: 
Related: 
An AE that follows a reasonable temporal sequence from administration of the 
immunotherapy (including the course after withdrawal of the study 
immunotherapy), or for which possible involvement of the immunotherapy 
cannot be ruled out, although factors other than the immunotherapy, such as 
underlying diseases, complications, concomitant drugs and concurrent 
treatments, may also be responsible. 


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Not Related: 
An AE that does not follow a reasonable temporal sequence from administration 
of the immunotherapy and/or that can reasonably be explained by other factors, 
such as underlying diseases, complications, concomitant drugs and concurrent 
treatments. 
9.1.7 Relationship to Study Procedures 
Relationship (causality) to study procedures should be determined for all PTEs and AEs. 
The relationship should be assessed as Related if the investigator considers that there is reasonable 
possibility that an event is due to a study procedure. Otherwise, the relationship should be assessed 
as Not Related.  
9.1.8 Start Date 
The start date of the AE/PTE is the date that the first signs/symptoms were noted by the subject 
and/or physician. 
9.1.9 
Stop Date  
The stop date of the AE/PTE is the date at which the subject recovered, the event resolved but with 
sequelae or the subject died. 
9.1.10 
Frequency  
Episodic AEs/PTE (eg, vomiting) or those which occur repeatedly over a period of consecutive 
days are intermittent. All other events are continuous. 
9.1.11 
Action Concerning Study Medication  
 Stop immunotherapy – the study immunotherapy is stopped due to the particular AE. 
 Immunotherapy not changed – the particular AE did not require stopping the study 
immunotherapy. 
 Unknown – only to be used if it has not been possible to determine what action has been taken. 
 Not Applicable – the immunotherapy was stopped for a reason other than the particular AE eg, 
the study has been terminated, the subject died, dosing with the study immunotherapy was 
already stopped before the onset of the AE. 
9.1.12 
Outcome 
 Recovered/Resolved – Subject returned to first assessment status with respect to the AE/PTE. 
 Recovering/Resolving – the intensity is lowered by one or more stages: the diagnosis or 
signs/symptoms has almost disappeared; the abnormal laboratory value improved, but has not 


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returned to the normal range or to baseline; the subject died from a cause other than the 
particular AE/PTE with the condition remaining “recovering/resolving”. 
 Not recovered/not resolved – there is no change in the diagnosis, signs or symptoms; the 
intensity of the diagnosis, signs/ symptoms or laboratory value on the last day of the observed 
study period has got worse than when it started; is an irreversible congenital anomaly; the 
subject died from another cause with the particular AE/PTE state remaining “Not 
recovered/not resolved”. 
 Resolved with sequelae – the subject recovered from an acute AE/PTE but was left with 
permanent/significant impairment (eg, recovered from a cardiovascular accident but with 
some persisting paresis. 
 Fatal – the AEs/PTEs which are considered as the cause of death.  
 Unknown – the course of the AE/PTE cannot be followed up due to hospital change or 
residence change at the end of the subject’s participation in the study. 
9.2 
Procedures 
9.2.1 Collection and Reporting of AEs 
9.2.1.1 PTE and AE Collection Period 
Collection of PTEs will commence from the time the subject signs the informed consent to 
participate in the study and continue until the subject is first administered study immunotherapy  
(visit 2) or until screen failure. For subjects who discontinue prior to study immunotherapy 
administration, PTEs are collected until the subject discontinues study participation. 
Collection of AEs will commence from the time that the subject is first administered study 
immunotherapy (visit 2). Routine collection of AEs will continue until visit 14 .  
9.2.1.2 PTE and AE Reporting 
At each study visit, the investigator will assess whether any subjective AEs have occurred. A 
neutral question, such as “How have you been feeling since your last visit?” may be asked. 
Subjects may report AEs occurring at any other time during the study. Subjects experiencing a 
serious PTE must be monitored until the symptoms subside and any clinically relevant changes in 
laboratory values have returned to baseline or there is a satisfactory explanation for the change. 
Non-serious PTEs, related or unrelated to the study, need not to be followed-up for the purposes of 
the protocol. 
All subjects experiencing AEs, whether considered associated with the use of the study 
immunotherapy or not, must be monitored until the symptoms subside and any clinically relevant 
changes in laboratory values have returned to baseline or until there is a satisfactory explanation 


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for the changes observed. All PTEs and AEs will be documented in the PTE/AE page of the CRF, 
whether or not the investigator concludes that the event is related to the immunotherapy. The 
following information will be documented for each event: 
1. Event term. 
2. Start and stop date. 
3. Severity. 
4. Investigator’s opinion of the causal relationship between the event and administration of study 
immunotherapy (related or not related) (not completed for PTEs). 
5. Investigator’s opinion of the causal relationship to the study immunotherapy, including the 
details of the suspected immunotherapy administration. 
6. Action concerning study immunotherapy (not applicable for PTEs). 
7. Outcome of event. 
8. Seriousness. 
9.2.2 Collection and Reporting of SAEs 
When an SAE occurs through the AE collection period it should be reported according to the 
following procedure: 
A sponsor SAE form must be completed, in English, and signed by the investigator immediately or 
within 24 hours of first onset or notification of the event. The information should be completed as 
fully as possible but contain, at a minimum: 
An SAE should be reported to the sponsor (described in the separate contact information list) 
within 1 business day of first onset or subject’s notification of the event. The principal investigator 
should submit the completed SAE form within 10 calendar days. The information should be 
completed as fully as possible but contain, at a minimum: 
 A short description of the event and the reason why the event is categorized as serious. 
 Subject identification number. 
 Investigator’s name. 
 Name of the study immunotherapy. 
 Causality assessment. 
The SAE form should be transmitted within 24 hours to the attention of the contact listed in 
Section 1.0.  


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Any SAE spontaneously reported to the investigator following the AE collection period should be 
reported to the sponsor if considered related to study participation. 
Reporting of Serious PTEs will follow the procedure described for SAEs. 
9.3 
Follow-up of SAEs 
If information not available at the time of the first report becomes available at a later date, the 
investigator should complete a follow-up SAE form or provide other written documentation and 
fax it immediately within 24 hours of receipt. Copies of any relevant data from the hospital notes 
(eg, ECGs, laboratory tests, discharge summary, postmortem results) should be sent to the 
addressee, if requested. 
All SAEs should be followed up until resolution or permanent outcome of the event. The timelines 
and procedure for follow-up reports are the same as those for the initial report. 
9.3.1 Safety Reporting to the Johns Hopkins IRB and Regulatory Authorities 
The study site investigators, in conjunction with the sponsor, will be responsible for reporting all 
suspected unexpected serious adverse reactions (SUSARs) and any other applicable SAEs to the 
Hopkins IRB. Relative to the first awareness of the event by/or further provision to the sponsor or 
sponsor’s designee, SUSARs will be submitted to the regulatory authorities as expedited report 
within 3 business days for fatal and life-threatening events and 10 business days for other serious 
events, unless otherwise required by Hopkins IRB regulations. 


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10.0 
STUDY-SPECIFIC COMMITTEES 
No study specific committees are being used for this study.  


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11.0 
DATA HANDLING AND RECORDKEEPING 
The full details of procedures for data handling will be documented in the Data Management Plan. 
AEs, PTEs, medical history, and concurrent conditions will be coded using the Medical Dictionary 
for Regulatory Activities (MedDRA). 
11.1 
CRFs (Paper) 
Completed CRFs are required for each subject who signs an informed consent. 
The sponsor will supply the investigative site with paper CRFs. These forms are used to transmit 
the information collected in the performance of this study to the sponsor and regulatory authorities. 
All paper CRFs must be filled out legibly in black or blue ballpoint ink. 
After completion of the entry process, queries may be issued by the sponsor or contracted CRO 
and will be answered by the site.  
Corrections to the CRF are to be made by making a single-line strikeout of the incorrect 
information and writing in the revisions. All corrections must be initialed and dated.  
The principal investigator must review the CRFs for completeness and accuracy and must sign and 
date the appropriate CRFs as indicated. Furthermore, the investigator must retain full 
responsibility for the accuracy and authenticity of all data entered on the CRFs. 
After submission of the CRFs to the sponsor, any change of, modification of or addition to the data 
on CRFs should be made by the investigator with use of change and modification records of CRFs 
(Data Clarification Form) provided by the sponsor. The principal investigator must review the 
Data Clarification Form for completeness and accuracy, and must sign and date the form.  
After the lock of the clinical study database, any change of, modification of or addition to the data 
on the CRFs should be made by the investigator with use of a Data Clarification Form provided by 
the sponsor. The principal investigator must review the data change for completeness and 
accuracy, and must sign and date. 
CRFs will be reviewed for completeness and acceptability at the study site during periodic visits 
by the study monitor. The sponsor or its designee will be permitted to review the subject’s medical 
and hospital records pertinent to the study to ensure accuracy of the CRFs. The completed CRFs 
are the sole property of the sponsor and should not be made available in any form to third parties, 
except for authorized representatives of appropriate governmental health or regulatory authorities, 
without written permission of the sponsor. 
11.2 
Record Retention 
The investigator agrees to keep the records stipulated in Section 11.1 (clarify correct number) and 
those documents that include (but are not limited to) the study-specific documents, the 
identification log of all participating subjects, medical records, source worksheets, all original 


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signed and dated informed consent forms, copies of all paper CRFs and query responses and 
detailed records of the study immunotherapy solutions to enable evaluations or audits from 
regulatory authorities, the sponsor or its designees. The ICH E6 Section 4.9.5 states that the study 
records should be retained until an amount of time specified by applicable regulatory requirements 
or for a time specified in the Clinical Study Site Agreement. The investigator should contact and 
receive written approval from the sponsor before disposing of any such documents. 


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12.0 
STATISTICAL METHODS 
12.1 
Statistical and Analytical Plans 
A statistical analysis plan (SAP) will be prepared and finalized prior to unblinding of subject’s 
treatment assignment. This document will provide further details regarding the definition of 
analysis variables and analysis methodology to address all study objectives. 
A blind data review will be conducted prior to unblinding of subject’s treatment assignment. This 
review will assess the accuracy and completeness of the study database, subject evaluability, and 
appropriateness of the planned statistical methods. 
12.1.1 Analysis Sets 
All efficacy and safety analyses will be analyzed using the full analysis set (FAS). The FAS will 
consist of all subjects who were randomized and received at least one dose of double-blind study 
immunotherapy. Efficacy analyses will be analyzed according to the treatment received and safety 
analyses will be analyzed according to the actual treatment received. 
Unless otherwise specified, all statistical tests and confidence intervals will be two-sided and 
conducted at the 0.05 significance level. 
12.1.2 Analysis of Demographics and Other Baseline Characteristics 
Demographic and baseline characteristics (eg, age, race, gender, height, weight, etc) will be 
summarized using descriptive statistics for all subjects and by Sequence group if necessary. For 
categorical variables (eg, race, gender, etc) the number and percent of subjects in specified 
categories will be presented. Unless otherwise specified, descriptive statistics on continuous 
variables (eg, age, height, weight) will consist of the number of subjects (N), mean, standard 
deviation (SD), median, minimum and maximum. 
12.1.3 Efficacy Analysis 
The intent-to-treat approach will be used. Baseline characteristics will be described using mean 
and standard deviation for continuous variables and medians and ranges for discrete variables. The 
primary efficacy variable of comparing PMA versus placebo will be undertaken by quantifying the 
instrument-asessment scores of each study subject in each of the two therapeutic arms of the 
investigation. The p-value, least square (LS) treatment means, difference between the LS 
treatment means, and 95% confidence intervals for the treatment differences will be presented. 
The success of blinding will be assessed by asking the patient and staff which treatment set they 
thought they were getting, i.e. active treatment or placebo. The results will be recorded at each 
study visit.  
Total Nasal Symptoms Score (TNSS) and the Mini-RQLQ attached in Appendix F will be used to 
evaluate clinical efficacy. TNSS along with rescue medication use is recorded at home on a daily 


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card as shown in Appendix K. Daily scores will only be recorded on weeks 2, 10, and 14. The 
mini-RQLQ will be recorded in person at screening, during each study visit, and at followup. The 
correct use of the TNSS survey is to score 0-12 based on symptoms reported that day while the 
mini-RQLQ is scored 0-84 based on symptoms reported over the past week. Higher scores indicate 
worse symptoms.  
 
The primary outcome measure is the average daily combined score (DCS) which is calculated by 
adding the average TNSS + average medication score as well as the mini-RQLQ at weeks 2,10 and 
14.  
 
Secondary outcomes will include the adverse events rate and TNSS between both groups using a 
one-tailed Fischer’s exact test and/or unpaired t test. 
 
Other outcomes include baseline characteristics, use of epinephrine, and drop out between both 
treatment groups I and II using a one-tailed Fischer’s exact test and/or unpaired t test. Trend tests 
for comparison of both groups will be performed such as the Jonckheere-Terptsra trend test. A sum of 
Mann-Whitney-Wilcoxon tests may also be sensitive and reveal a mild trend. Other trend tests may 
also be used. 
A Kaplan-Meier or similar product limit estimator function will also be used to calculate the effect 
of treatment over time. 
 
Medications commonly used to treat allergic rhinitis such as nasal steroids, antihistamines, 
opthalmologic antihistamines, cromolyn, azelastine, decongestants and other OTC allergy 
medications will be stopped during the 14 day washout period. Patients must abstain from using 
these medications for the duration of the study, however rescue medications will be offered in a 
predetermined manner as follows. At each study visit the patient will be asked subjectively if 
symptoms are adequately controlled. If symptoms are uncontrolled then medications will be added 
in the following stepwise fashion according to Appendix I. Rescue medications will not be 
increased after week ten.  
Medication use is recorded daily at home during weeks 2, 10, and 14 and at each bi-weekly  study 
visit so that adjustments can be made. Each allergy rescue medication will be assigned a numerical 
score as per Appendix I. We expect that most subjects will have daily medication scores between 
0-6. 
 


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12.1.4 Safety Analysis 
Overall safety and tolerability will be assessed by evaluating the incidence of TEAE, laboratory 
tests, vital signs, and other safety variables. Treatment-emergent adverse events will be defined as 
any AEs, regardless of relationship to study immunotherapy, that occur on or after the first double 
blind immunotherapy administration date and up to 30 days after the last dose date of the 
double-blind immunotherapy and will be assigned to the treatment at the time of the event. 
Treatment-emergent adverse events will be summarized using the full analysis set. Adverse events 
will be summarized using the MedDRA coding dictionary. In general, AEs will be tabulated at 
each of the following levels: overall summary (subject with at least 1 AE), the MedDRA system 
organ class (SOC) and the MedDRA preferred term (PT). Tabulations at each level of a term will 
present count (n) and percentage of subjects reporting any event for that term. Subjects reporting 
more than one occurrence for the term (level) being summarized will be counted only once and 
assigned to the drug assignment at time of the event. 
Laboratory test variables will be summarized by active PMA or placebo assignment and study visit 
using descriptive statistics. Laboratory data collected from baseline and up to 7 days after a 
subject’s last dose of study immunotherapy will be included in the analysis. Markedly abnormal 
laboratory values will be determined and listed by study group. The number and percentage of 
subjects with marked abnormality in each of the laboratory parameters will be presented. 
Descriptive statistics will be used to summarize vital signs by treatment group and study visit. 
Vital sign data collected from baseline and up to a subject’s last dose of study immunotherapy will 
be included in the analysis. 
12.2 
Interim Analysis and Criteria for Early Termination 
No interim analyses are planned. 
12.3 
Determination of Sample Size 
The study sample size is based upon the results of prior immunotherapy investigations undertaken 
by the Investigators of this study and their colleagues in the Division of Allergy & Clinical 
Immunology, Johns Hopkins University School of Medicine. Efficacy for immunotherapy was 
estimated to be 80% for treatmet group and 30% for placebo. Using an error rate () of 0.05 and 
80% Power we calculate a total sample size needed of 28 subjects. To account for drop off we will 
recruit up to 36 subjects. 


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13.0 
QUALITY CONTROL AND QUALITY ASSURANCE 
13.1 
Study-Site Monitoring Visits  
Monitoring visits to the study site will be made periodically during the study to ensure that all 
aspects of the protocol are followed. Source documents will be reviewed for verification of data 
recorded on the CRFs. Source documents are defined as original documents, data, and records. 
The investigator and institution guarantee access to source documents by the sponsor. 
All aspects of the study and its documentation will be subject to review by the sponsor or designee 
(as long as blinding is not jeopardized), including but not limited to the Investigator’s Binder, 
study medication, subject medical records, informed consent documentation, and review of CRFs 
and associated source documents. It is important that the investigator and other study personnel are 
available during the monitoring visits and that sufficient time is devoted to the process. 
13.2 
Protocol Deviations 
The investigator should not deviate from the protocol, except where necessary to eliminate an 
immediate hazard to study subjects. Should other unexpected circumstances arise that will require 
deviation from protocol-specified procedures, the investigator should consult with the sponsor or 
designee (and IRB, as required) to determine the appropriate course of action. There will be no 
exemptions for a prospectively approved deviation from the inclusion or exclusion criteria. 
The site should document all protocol deviations in the subject’s source documents. In the event of 
a significant deviation, the site should notify the sponsor or its designee (and IRB, as required). 
Significant deviations include, but are not limited to, those that involve fraud or misconduct, 
increase the health risk to the subject, or confound interpretation of primary study assessment. A 
Protocol Deviation Form should be completed by the site and signed by the sponsor or designee for 
any significant deviation from the protocol.  
Quality Assurance Audits and Regulatory Agency Inspections 
The study site also may be subject to quality assurance audits by the sponsor or designees. In this 
circumstance, the sponsor-designated auditor will contact the site in advance to arrange an 
auditing visit. The auditor may ask to visit the facilities where laboratory samples are collected, 
where the immunotherapy medication is stored and prepared, and any other facility used during the 
study. In addition, there is the possibility that this study may be inspected by regulatory agencies, 
including the FDA. If the study site is contacted for an inspection by a regulatory body, the sponsor 
should be notified immediately. The investigator and institution guarantee access for quality 
assurance auditors to all study documents as described in Section 13.1. 


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14.0 
ETHICAL ASPECTS OF THE STUDY 
This study will be conducted with the highest respect for the individual study participants. In the 
study protocol, the ethical principles that have been described that have their origin in the 
Declaration of Helsinki, and the ICH Harmonised Tripartite Guideline for GCP. The investigators 
will conduct the study according to applicable Hopkins IRB requirements and align their conduct 
in accordance with the “Responsibilities of the Investigator” that are listed in Appendix B. The 
principles of Helsinki are addressed through the protocol and through appendices containing 
requirements for informed consent and investigator responsibilities. 
14.1 
IRB Approval 
The Johns Hopkins Hospital IRB must be constituted according to the applicable requirements. 
The sponsor or designee will require documentation noting the Federal Wide Assurance Number 
or comparable number assigned by the Department of Health and Human Services. 
The sponsor or designee in conjunction with the study site investigators will supply relevant 
documents for submission to the Hopkins IRB for the protocol’s review and approval. This 
protocol, a copy of the informed consent form, and, if applicable, subject recruitment materials 
and/or advertisements and other documents required by all applicable laws and regulations, must 
be submitted to the IRB for approval. The IRB’s written approval of the protocol and subject 
informed consent must be obtained and submitted to the sponsor or designee before 
commencement of the study (ie, before shipment of the sponsor-supplied immunotherapy). The 
IRB approval must refer to the study by exact protocol title, number, and version date; identify 
versions of other documents (eg, informed consent form) reviewed; and state the approval date. 
The sponsor will supply immunotherapy solutions once the sponsor has confirmed the adequacy of 
site regulatory documentation and the sponsor has received permission from the competent 
authorities  (Hopkins contracting office and Hopkins IRB) to begin the trial. Until the site receives 
the study immunotherapy no protocol activities, including screening may occur. 
The study site must adhere to all requirements stipulated by the IRB. This may include notification 
to the IRB regarding protocol amendments, updates to the informed consent form, recruitment 
materials intended for viewing by subjects, safety reporting requirements, reports and updates 
regarding the ongoing review of the study at intervals specified by the IRB, and submission of the 
investigator’s final status report to the IRB. All IRB approvals and relevant documentation for 
these items must be provided to the sponsor or its designee. 
Subject incentives should not exert undue influence for participation. Payments to subjects must 
be approved by the IRB and sponsor. 
14.2 
Risks 
Allergy Skin test  The risk of performing allergy skin testing is minimal. Serious reactions are rare. 
This study uses histamine and allergen for testing, which very rarely can cause serious reactions. 


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Most individuals experience mild to moderate itching at the site of testing that spontaneously 
resolves. You may feel some mild discomfort from the skin prick device itself. 
 
Immunotherapy The most common side effect from allergen immunotherapy is slight swelling 
and discomfort at the site of the injection. This usually resolves in 1-2 days with the use of a cool 
pack. There is a very small chance of having a serious allergic reaction. If symptoms of a serious 
allergic reaction occur we would administer epinephrine and possibly other allergy medications 
such as antihistamines. 
 
Some participants will receive placebo instead of active immunotherapy. These individuals may 
not see an improvement in their symptoms. All patients will be required to discontinue nasal 
steroids for two weeks prior to starting treatment. There is a risk that nasal symptoms could worsen 
when you stop the medication. 
 
Blood Draw The most common side effect of blood draw is discomfort from the needle. This can 
sometimes lead to bruising of the skin. There is a very small chance of getting an infection from 
puncturing the skin. 
 
Other risks There always exists the potential for loss of confidentiality; however, there are 
procedures in place to minimize this. Study information will not be associated with your private 
demographic information directly but linked via a numerical code only to be accessed by the study 
designers. However, there still remains the possibility that information about you may become 
known to people outside of this study. 
 
You may get tired or bored when we are asking you questions or you are completing 
questionnaires. You do not have to answer any question you do not want to answer. There may be 
side effects and discomforts that are not yet known.   
 
14.3 
Benefits 
There is no direct benefit to subjects for being in this study. Taking part in this study, may help 
others in the future. 
Subjects will be paid up to $325 for time and effort ($18 per visit). A parking pass will also be 
provided for subjects who need this. Total payment will be prorated based on the number of study 
visits completed and paid in two lump sums made once the study regimen begins and the rest will 


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be paid at the end of the study. Payment will be made by mailing a check within 1-2 weeks. Checks 
will be mailed to the address provides at the time of the consent. 
 
 
14.4 
Subject Information, Informed Consent, and Subject Authorization 
Written consent documents will embody the elements of informed consent as described in the 
Declaration of Helsinki and the ICH Guidelines for GCP and will be in accordance with all 
applicable laws and regulations. The informed consent form describes the planned and permitted 
uses, transfers, and disclosures of the subject’s personal and personal health information for 
purposes of conducting the study. The informed consent form further explains the nature of the 
study, its objectives, and potential risks and benefits, as well as the date informed consent is given. 
The informed consent form will detail the requirements of the participant and the fact that he or she 
is free to withdraw at any time without giving a reason and without prejudice to his or her further 
medical care. 
The investigators in conjunction with the sponsor is responsible for the preparation, content, and 
IRB approval of the informed consent form. The informed consent form must be approved by both 
the IRB and the sponsor prior to use. 
The informed consent form must be written in a language fully comprehensible to the prospective 
subject. It is the responsibility of the investigator to explain the detailed elements of the informed 
consent form to the study subject. Information should be given in both oral and written form 
whenever possible and in the manner deemed appropriate by the Hopkins IRB. In the event the 
subject is not capable of rendering adequate written informed consent, then the subject’s legally 
acceptable representative may provide such consent for the subject in accordance with the IRB 
regulations. 
The subject, or the subject’s legally acceptable representative, must be given ample opportunity to: 
(1) inquire about details of the study and (2) decide whether or not to participate in the study. If the 
subject, or the subject’s legally acceptable representative, determines he or she will participate in 
the study, then the informed consent form must be signed and dated by the subject, or the subject’s 
legally acceptable representative, at the time of consent and prior to the subject entering into the 
study. The subject or the subject’s legally acceptable representative should be instructed to sign 
using their legal names, not nicknames, using blue or black ballpoint ink. The investigator must 
also sign and date the informed consent form at the time of consent and prior to subject entering 
into the study; however, the sponsor may allow a designee of the investigator to sign to the extent 
permitted by the Hopkins IRB. 


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Once signed, the original informed consent form will be stored in the investigator’s site file. The 
investigator must document the date the subject signs the informed consent in the subject’s 
medical record. A copies of the signed informed consent form shall be given to the subject. 
All revised informed consent forms must be reviewed and signed by relevant subjects or the 
relevant subject’s legally acceptable representative in the same manner as the original informed 
consent. The date the revised consent was obtained should be recorded in the subject’s medical 
record, and the subject should receive a copy of the revised informed consent form. 
14.5 
Subject Confidentiality 
The sponsor and designees affirm and uphold the principle of the subject’s right to protection 
against invasion of privacy. Throughout this study, a subject’s source data will only be linked to 
the sponsor’s clinical study database or documentation via a unique identification number. As 
permitted by all applicable laws and regulations, limited subject attributes, such as sex, age, or date 
of birth, and subject initials may be used to verify the subject and accuracy of the subject’s unique 
identification number. 
To comply with ICH Guidelines for GCP and to verify compliance with this protocol, the sponsor 
requires the investigator to permit its monitor or designee’s monitor, representatives from any 
regulatory authority (eg, FDA) the sponsor’s designated auditors, and the Hopkins IRB to review 
the subject’s original medical records (source data or documents), including, but not limited to, 
laboratory test result reports, ECG reports, admission and discharge summaries for hospital 
admissions occurring during a subject’s study participation, and autopsy reports. Access to a 
subject’s original medical records requires the specific authorization of the subject as part of the 
informed consent process. 
Copies of any subject source documents that are provided to the sponsor must have certain 
personally identifiable information removed (ie, subject name, address, and other identifier fields 
not collected on the subject’s CRF). 
14.6 
Publication, Disclosure, and Clinical Trial Registration Policy 
14.6.1 Publication and Disclosure 
The investigator is obliged to provide the sponsor with complete test results and all data derived by 
the investigator from the study. During and after the study, only the sponsor may make study 
information available to other investigators or to regulatory agencies, except as required by law or 
regulation. Except as otherwise allowable in the clinical study site agreement, any public 
disclosure (including publicly accessible websites) related to the protocol or study results, other 
than study recruitment materials and/or advertisements, is the sole responsibility of the sponsor. 
The sponsor may publish any data and information from the study (including data and information 
generated by the investigator) without the consent of the investigator. Manuscript authorship for 


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any peer-reviewed publication will appropriately reflect contributions to the production and 
review of the document. All publications and presentations must be prepared in accordance with 
this section and the Clinical Study Site Agreement. In the event of any discrepancy between the 
protocol and the Clinical Study Site Agreement, the Clinical Study Site Agreement will prevail. 
14.6.2 Clinical Trial Registration 
In order to ensure that information on clinical trials reaches the public in a timely manner and to 
comply with applicable laws, regulations and guidance, the sponsor will register this study on 
ClinicalTrials.gov.   
14.6.3 Clinical Trial Results Disclosure 
The sponsor will post the results of this investigation on ClinicalTrials.gov.  
14.7 
Insurance and Compensation for Injury 
Refer to the Clinical Study Site Contract and Written Consent Form regarding the policy on 
subject compensation and treatment for injury.  
 
REFERENCES 
1. Mucci T, Govindaraj S, Tversky J. Allergic Rhinitis. Mount Sinai J of Med. 2011. 78:634-644. 
2. Kim H, Bouchard J and Renzix PM, The link between allergic rhinitis and asthma: A role for 
antileukotrienes? Can Respir J. 2008 Mar; 15(2): 91–98. 
3. Kay AB. Allergy and allergic diseases. First of two parts. N Engl J Med. 2001;344:30–7. 
4. Meltzer EO. Role for cysteinyl leukotriene receptor antagonist therapy in asthma and their 
potential role in allergic rhinitis based on the concept of “one linked airway disease”. Ann 
Allergy Asthma Immunol. 2000;84:176–85. 
5. Inman MD, Ellis R, Wattie J, Denburg JA, O’Byrne PM. Allergen-induced increase in airway 
responsiveness, airway eosinophilia, and bone-marrow eosinophil progenitors in mice. Am J 
Respir Cell Mol Biol. 1999;21:473–9. 
6. Kaiko GE, Horvat JC, Beagley KW, Hansbro PM. Immunological decision-making: How does 
the immune system decide to mount a helper T-cell response? Immunology. 2008;123:326–38. 
7. Simons FE. Allergic rhinobronchitis: The asthma-allergic rhinitis link. J Allergy Clin 
Immunol. 1999;104:534–40. 
8. Frew AJ, Powell RJ, Corrigan CJ, Durham SR, on behalf of the UK Immunotherapy Study 
Group. Efﬁcacy and safety of speciﬁc immunotherapy with SQ allergen extract in 


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treatment-resistant seasonal allergic rhinoconjunctivitis. Journal of Allergy and Clinical 
Immunology. 2006;117:319–25. 
9. Calderon MA, Alves B, Jacobson M, Hurwitz B, Sheikh A and Durham S. Allergen injection 
immunotherapy for seasonal allergic rhinitis. Evid.-Based Child Health. 5: 1279–1379 (2010) 
10. Norman P, Creticos P, Marsh D. Frequency of booster injections of allergoids. Journal of 
Allergy and Clinical Immunology. 1990;85(1 (Pt 1)):88–94. 
11. Calderon M, Bernstein D, Blaiss M, Anderson J, Nolte H. A comparitive analysis of symptoms 
and and medication scoring methods used in clinical trials of sublingual immunotherapy for 
seasonal allergic rhinitis. Clin & Exp Allergy. 2014; 44:1228-1239. 
12. Norman P, Lichtenstein L, Sabotka A, Marsh D. Controlled evaluation of allergoid in the 
immunotherapy of ragweed hay fever. Journal of Allergy and Clinical Immunology. 1982; 
70:248-260. 
13. Simons E, Ardusso L, et al. World Allergy Organization anaphylaxis guidelines: summary. 
Journal of Allergy and Clinical Immunology. 2011;127(3):587-93. 


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Appendix A Schedule of Study Procedures 
 
 
Study Week: 
Screen 
(Week 1) 
Washout 
(Week 1-2) 
Treatment 
(Week 3-11) 
Follow-up safety assessment 
(Week 14) 
Visit Number: 
1 
N/A 
2-17 
18 
Discussion and Recruitment 
X 
 
 
 
Informed consent 
X 
 
 
 
Inclusion/exclusion criteria 
X 
 
 
 
Demographics and medical history 
X 
 
 
 
Medication history 
X 
 
 
 
Physical examination 
X 
 
 
 
Vital signs 
X 
 
X 
 
Weight and height 
X 
 
 
 
Concomitant medications 
X 
X 
X 
X 
Concurrent medical conditions 
X 
 
 
X 
Skin Testing 
X 
 
 
 
Blood Draw 
X 
 
 
X 
Post-immunotherapy safety f/u 
 
 
 
X 
Administer immunotherapy/safety f/u 
 
 
X 
 
Clinical Survey (RQLQ) and TNSS 
X 
 
X 
X 
Site return compliance 
X 
 
X 
 
 X 
PTE assessment 
X 
X 
 
 
AE assessment 
 
X 
X 
X 
 
 


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Appendix B Responsibilities of the Investigator 
Clinical research studies sponsored by the sponsor are subject to ICH GCP and all the applicable 
local laws and regulations. 
The investigator agrees to assume the following responsibilities by signing the FDA form 1572 if 
needed. 
1. Conduct the study in accordance with the protocol. 
2. Personally conduct or supervise the staff who will assist in the protocol. 
3. Ensure that study related procedures, including study specific (non routine/non standard panel) 
screening assessments are NOT performed on potential subjects, prior to the receipt of written 
approval from relevant governing bodies/authorities. 
4. Ensure that all colleagues and employees assisting in the conduct of the study are informed of 
these obligations. 
5. Secure prior approval of the study and any changes by an appropriate IRB/IEC that conform to 
CFR Part 56 if needed. ICH, and local regulatory requirements. 
6. Ensure that the IRB will be responsible for initial review, continuing review, and approval of 
the protocol. Promptly report to the IRB all changes in research activity and all anticipated 
risks to subjects. Make at least yearly reports on the progress of the study to the IRB, and issue 
a final report within 3 months of study completion. 
7. Ensure that requirements for informed consent, as outlined in CFR Part 56 if needed. ICH and 
local regulations, are met. 
8. Obtain valid informed consent from each subject who participates in the study, and document 
the date of consent in the subject’s medical chart. Valid informed consent is the most current 
version approved by the IRB. Each informed consent form should contain a subject 
authorization section that describes the uses and disclosures of a subject’s personal 
information (including personal health information) that will take place in connection with the 
study.  
9. Prepare and maintain adequate case histories of all persons entered into the study, including 
CRFs, hospital records, laboratory results, etc, and maintain these data for a minimum of 
2 years following notification by the sponsor that all investigations have been discontinued or 
that the regulatory authority has approved the marketing application. The investigator should 
contact and receive written approval from the sponsor before disposing of any such 
documents. 
10. Allow possible inspection and copying by the regulatory authority of GCP-specified essential 
documents. 


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11. Maintain current records of the receipt, administration, and disposition of sponsor-supplied 
immunotherapy, and return all unused sponsor-supplied study solutions to the sponsor.  
12. Report adverse reactions to the sponsor promptly. In the event of an SAE, notify the sponsor 
within 24 hours. 


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Appendix C Elements of the Subject Informed Consent  
 
In seeking informed consent, the following information shall be provided to each subject: 
1. A statement that the study involves research. 
2. An explanation of the purposes of the research. 
3. The expected duration of the subject’s participation. 
4. A description of the procedures to be followed, including invasive procedures. 
5. The identification of any procedures that are experimental. 
6. The estimated number of subjects involved in the study. 
7. A description of the subject’s responsibilities. 
8. A description of the conduct of the study. 
9. A statement describing the immunotherapy treatment and the probability for random 
assignment to each treatment. 
10. A description of the possible side effects of the treatment that the subject may receive. 
11. A description of any reasonably foreseeable risks or discomforts to the subject and, when 
applicable, to an embryo, fetus, or nursing infant. 
12. A description of any benefits to the subject or to others that reasonably may be expected from 
the research.  
13. Disclosures of appropriate alternative procedures or courses of treatment, if any, that might be 
advantageous to the subject and their important potential risks and benefits. 
14. A statement describing the extent to which confidentiality of records identifying the subject 
will be maintained, and a note of the possibility that regulatory agencies, auditor(s), IRB, and 
the monitor may inspect the records. By signing a written informed consent form, the subject 
or the subject’s legally acceptable representative is authorizing such access. 
15. For research involving more than minimal risk, an explanation as to whether any compensation 
and an explanation as to whether any medical treatments are available if injury occurs and, if 
so, what they consist of or where further information may be obtained. 
16. The anticipated prorated payment(s), if any, to the subject for participating in the study. 
17. The anticipated expenses, if any, to the subject for participating in the study. 
18. An explanation of how to contact the investigators or designees for answers to pertinent 
questions about the research, subject’s rights, and IRB and whom to contact in the event of a 
research-related injury to the subject. 


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19. A statement that participation is voluntary, that refusal to participate will involve no penalty or 
loss of benefits to which the subject otherwise is entitled, and that the subject may discontinue 
participation at any time without penalty or loss of benefits to which the subject is otherwise 
entitled. 
20. The consequences of a subject’s decision to withdraw from the research and procedures for 
orderly termination of participation by the subject. 
21. A statement that the subject or the subject’s legally acceptable representative will be informed 
in a timely manner if information becomes available that may be relevant to the subject’s 
willingness to continue participation in the study. 
22. The foreseeable circumstances or reasons under which the subject’s participation in the study 
may be terminated. 
23. A written subject authorization (either contained within the informed consent form or provided 
as a separate document) describing to the subject the contemplated and permissible uses and 
disclosures of the subject’s personal information (including personal health information) for 
purposes of conducting the study. The subject authorization must contain the following 
statements regarding the uses and disclosures of the subject’s personal information: 
a) that personal information (including personal health information) may be processed by or 
transferred to other parties for clinical research and safety reporting purposes, including, 
without limitation, to the following: (1) the sponsor, (2) business partners assisting the 
sponsor (3) regulatory agencies and other health authorities; and (4) the Hopkins IRB; 
b) the sponsor will make every effort to keep your personal information confidential, and 
your name will not be disclosed outside the clinic unless required by law; 
c) that personal information (including personal health information) may be added to the 
sponsor’s research database for purposes of developing a better understanding of the safety 
and effectiveness of the study immunotherapy, studying other therapies for patients, 
developing a better understanding of disease, and improving the efficiency of future 
clinical studies; 
d) that subjects agree not to restrict the use and disclosure of their personal information 
(including personal health information) upon withdrawal from the study to the extent that 
the restricted use or disclosure of such information may impact the scientific integrity of 
the research; and 
e) that the subject’s identity will remain confidential in the event that study results are 
published. 
24. Female subjects of childbearing potential (eg, nonsterilized, premenopausal female subjects) 
who are sexually active must use adequate contraception (as defined in the informed consent) 
from Screening throughout the duration of the study. Regular pregnancy tests will be 


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CONFIDENTIAL PROPERTY OF RELEZ THERAPEUTICS, LLC 
 
performed throughout the study for all female subjects of childbearing potential. If a subject is 
found to be pregnant during study, study immunotherapy will be discontinued and the 
investigator will offer the subject the choice to receive unblinded treatment information. 
25. Male subjects must use adequate contraception (as defined in the informed consent) from 
Screening throughout the duration of the study. If the partner or wife of the subject is found to 
be pregnant during the study, the investigator will offer the subject the choice to receive 
unblinded treatment information. 
26. A statement that clinical trial information from this trial will be publicly disclosed in a publicly 
accessible website, such as ClinicalTrials.gov. 
 
 
 
 


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Appendix D     Allergen skin prick testing and interpretation methodology  
 
Allergen is indirectly transferred to the skin by first dipping a disposable skin test device into a 
well containing allergen extract material. Six Multi-Test PC devices will be required for each 
subject (48 individual tests).  
  
 Skin prick testing proceeds as follows:  
1. 
Gather the materials required for skin testing  
2. 
Discuss with the patient what will be done and what to expect  
3. 
Ensure that antihistamines have been avoided for at least 7 days 
4. 
Put on gloves  
5. 
Clean the work space with alcohol and prep the patients skin  
6. 
Mark the skin on the forearm (or back) with a skin safe marker  
7. 
Place negative then positive histamine control tests first  
8. 
Then place the remaining allergens on the skin sequentially  
9. 
Set a 15-minute timer  
  
Allergens are usually placed at least 2cm apart from each other. The wrist and antecubital fossa 
should be avoided. To ensure reproducibility it is essential that the technician take care to use the 
exact same methods every time a chosen device is used. If for example, the histamine control were 
to be placed with hard pressure but the allergens are placed with light pressure this could lead to a 
false negative result. In some cases where the identification of allergens suspected of causing 
anaphylaxis, misreading a test as negative could have serious implications.  
  
Measurement of Wheal 
Patients are asked to avoid scratching while skin tests are developing. Gentle blowing may 
alleviate some of the discomfort. Once the 15-minute timer rings measurements may begin using a 
clean ruler or disposable caliper with 1mm increments.  Digital image of the skin tests will also be 
recorded using the Flare Diagnostics (Baltimore, MD) automated skin test reading device. A 
positve result is defined as an average wheal diameter greater than or equal 5mm and at least 2mm 
greater than negative control. Readings must be performed in a rotation consistent with the pattern 
of placement. Careful measurements may take several minutes and therefore allergens placed last 
should subsequently be read last so that all allergens have had the same amount of time to develop. 
 


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CONFIDENTIAL PROPERTY OF RELEZ THERAPEUTICS, LLC 
 
Appendix E     FDA Approved Allergens to be Used for Treatment  
 
 
 
 
(Note: Only a proprietary selection of allergens will be used for treatment.) 
Type 
Allergen 
Stock Concentration 
Manufacturer 
Cat Std 
Standardized Cat Hair 
10,000 BAU/ml 
Greer Labs 
Mite Std 
Dermatophagoides farinae 
10,000 BAU/ml 
Greer Labs 
Mite Std 
Dermatophagoides pteronyssinus 
10,000 BAU/ml 
Greer Labs 
Mite Std 
Mite Mix, Standardized 
10,000 BAU/ml 
Greer Labs 
Grass Std 
Bermuda Cynodon dactylon 
100,000 BAU/ml 
Greer Labs 
Grass Std 
Kentucky Blue/JunePoa pratensis 
100,000 BAU/ml 
Greer Labs 
Grass Std 
Meadow FescueLolium pratensis 
100,000 BAU/ml 
Greer Labs 
Grass Std 
Orchard Dactylis glomerata 
100,000 BAU/ml 
Greer Labs 
Grass Std 
Red Top Agrostis gigantean 
100,000 BAU/ml 
Greer Labs 
Grass Std 
Ryegrass, Perennial Lolium perenne 
100,000 BAU/ml 
Greer Labs 
Grass Std 
Sweet Vernal Anthoxanthum odoratum 
100,000 BAU/ml 
Greer Labs 
Grass Std 
Timothy Phleum pratense 
100,000 BAU/ml 
Greer Labs 
Grass Std 
Timothy/Orchard Grass Mix 
100,000 BAU/ml 
Greer Labs 
Grass Std 
7 Grass Mix 
100,000 BAU/ml 
Greer Labs 
Grass Std 
9 Southern Grass Mix (Concentrate) 
100,000 BAU/ml 
Greer Labs 
Weed Std 
Ragweed, Short Ambrosia artemisiifolia 
100,000 BAU/ml 
Greer Labs 
Weed Std 
National Weed Mix  
100,000 BAU/ml 
Greer Labs 
Weed Std 
Ragweed Mix 
100,000 BAU/ml 
Greer Labs 
Tree 
Acacia Acacia spp 
40,000 PNU/ml 
Greer Labs 
Tree 
Alder, Red 
40,000 PNU/ml 
Greer Labs 
Tree 
Alnus rubra 
40,000 PNU/ml 
Greer Labs 
Tree 
Alder, Hazel 
40,000 PNU/ml 
Greer Labs 
Tree 
Alder, White 
40,000 PNU/ml 
Greer Labs 
Tree 
Ash, Arizona 
40,000 PNU/ml 
Greer Labs 
Tree 
Ash, Oregon 
40,000 PNU/ml 
Greer Labs 
Tree 
Ash, Red/Green 
40,000 PNU/ml 
Greer Labs 
Tree 
Ash, White 
40,000 PNU/ml 
Greer Labs 
Tree 
Aspen 
40,000 PNU/ml 
Greer Labs 
Tree 
Bayberry/Wax Myrtle 
40,000 PNU/ml 
Greer Labs 
Tree 
Beech, American 
40,000 PNU/ml 
Greer Labs 
Tree 
Beefwood/Australian Pine 
40,000 PNU/ml 
Greer Labs 
Tree 
Birch, Black/Sweet 
40,000 PNU/ml 
Greer Labs 
Tree 
Birch, River 
40,000 PNU/ml 
Greer Labs 
Tree 
Birch, Spring 
40,000 PNU/ml 
Greer Labs 


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Tree 
Birch, White 
40,000 PNU/ml 
Greer Labs 
Tree 
Box Elder 
40,000 PNU/ml 
Greer Labs 
Tree 
Cedar, Mountain 
40,000 PNU/ml 
Greer Labs 
Tree 
Cedar, Red 
40,000 PNU/ml 
Greer Labs 
Tree 
Cedar, Salt/Tamarisk 
40,000 PNU/ml 
Greer Labs 
Tree 
Cottonwood, Black 
40,000 PNU/ml 
Greer Labs 
Tree 
Cottonwood, Eastern 
40,000 PNU/ml 
Greer Labs 
Tree 
Cottonwood, Fremont 
40,000 PNU/ml 
Greer Labs 
Tree 
Cottonwood, Western 
40,000 PNU/ml 
Greer Labs 
Tree 
Cypress, Arizona 
40,000 PNU/ml 
Greer Labs 
Tree 
Cypress, Bald 
40,000 PNU/ml 
Greer Labs 
Tree 
Elm, American 
40,000 PNU/ml 
Greer Labs 
Tree 
Elm, Cedar/Fall Blooming 
40,000 PNU/ml 
Greer Labs 
Tree 
Elm, Siberian 
40,000 PNU/ml 
Greer Labs 
Tree 
Eucalyptus 
40,000 PNU/ml 
Greer Labs 
Tree 
Hackberry 
40,000 PNU/ml 
Greer Labs 
Tree 
Hazelnut, American 
40,000 PNU/ml 
Greer Labs 
Tree 
Hickory, Shagbark 
40,000 PNU/ml 
Greer Labs 
Tree 
Hickory, Shellbark 
40,000 PNU/ml 
Greer Labs 
Tree 
Hickory, White 
40,000 PNU/ml 
Greer Labs 
Tree 
Juniper, Oneseed 
40,000 PNU/ml 
Greer Labs 
Tree 
Juniper, Pinchot 
40,000 PNU/ml 
Greer Labs 
Tree 
Juniper, Rocky Mountain 
40,000 PNU/ml 
Greer Labs 
Tree 
Juniper, Utah 
40,000 PNU/ml 
Greer Labs 
Tree 
Juniper, Western 
40,000 PNU/ml 
Greer Labs 
Tree 
Locust Blossom, Black 
40,000 PNU/ml 
Greer Labs 
Tree 
Mango Blossom 
40,000 PNU/ml 
Greer Labs 
Tree 
Maple, Red 
40,000 PNU/ml 
Greer Labs 
Tree 
Maple, Soft/Silver 
40,000 PNU/ml 
Greer Labs 
Tree 
Maple, Sugar/Hard 
40,000 PNU/ml 
Greer Labs 
Tree 
Melaleuca 
40,000 PNU/ml 
Greer Labs 
Tree 
Mesquite 
40,000 PNU/ml 
Greer Labs 
Tree 
Mulberry, Paper 
40,000 PNU/ml 
Greer Labs 
Tree 
Mulberry, Red 
40,000 PNU/ml 
Greer Labs 
Tree 
Mulberry, White 
40,000 PNU/ml 
Greer Labs 
Tree 
Oak, Arizona/Gambel 
40,000 PNU/ml 
Greer Labs 
Tree 
Oak, Black 
40,000 PNU/ml 
Greer Labs 
Tree 
Oak, Bur 
40,000 PNU/ml 
Greer Labs 
Tree 
Oak, California Black 
40,000 PNU/ml 
Greer Labs 


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CONFIDENTIAL PROPERTY OF RELEZ THERAPEUTICS, LLC 
 
Tree 
Oak, California Live 
40,000 PNU/ml 
Greer Labs 
Tree 
Oak, California White 
40,000 PNU/ml 
Greer Labs 
Tree 
Oak, Post 
40,000 PNU/ml 
Greer Labs 
Tree 
Oak, Red 
40,000 PNU/ml 
Greer Labs 
Tree 
Oak, Virginia Live 
40,000 PNU/ml 
Greer Labs 
Tree 
Oak, Water 
40,000 PNU/ml 
Greer Labs 
Tree 
Oak, Western White 
40,000 PNU/ml 
Greer Labs 
Tree 
Oak, White 
40,000 PNU/ml 
Greer Labs 
Tree 
Olive 
40,000 PNU/ml 
Greer Labs 
Tree 
Olive, Russian 
40,000 PNU/ml 
Greer Labs 
Tree 
Orange Pollen 
40,000 PNU/ml 
Greer Labs 
Tree 
Palm, Queen 
40,000 PNU/ml 
Greer Labs 
Tree 
Pecan 
40,000 PNU/ml 
Greer Labs 
Tree 
Pepper Tree 
40,000 PNU/ml 
Greer Labs 
Tree 
Pine, Loblolly 
40,000 PNU/ml 
Greer Labs 
Tree 
Pine, Longleaf 
40,000 PNU/ml 
Greer Labs 
Tree 
Pine, Ponderosa 
40,000 PNU/ml 
Greer Labs 
Tree 
Pine, Virginia Scrub 
40,000 PNU/ml 
Greer Labs 
Tree 
Pine, White/Eastern 
40,000 PNU/ml 
Greer Labs 
Tree 
Pine, White/Western 
40,000 PNU/ml 
Greer Labs 
Tree 
Pine, Yellow 
40,000 PNU/ml 
Greer Labs 
Tree 
Poplar, Lombardy 
40,000 PNU/ml 
Greer Labs 
Tree 
Poplar, White 
40,000 PNU/ml 
Greer Labs 
Tree 
Privet, Common 
40,000 PNU/ml 
Greer Labs 
Tree 
Sweet Gum 
40,000 PNU/ml 
Greer Labs 
Tree 
Sycamore, American/Eastern 
40,000 PNU/ml 
Greer Labs 
Tree 
Sycamore, Western 
40,000 PNU/ml 
Greer Labs 
Tree 
Walnut, Black 
40,000 PNU/ml 
Greer Labs 
Tree 
Willow, Arroyo 
40,000 PNU/ml 
Greer Labs 
Tree 
Willow, Black 
40,000 PNU/ml 
Greer Labs 
Weed 
Allscale 
20,000 PNU/ml 
Greer Labs 
Weed 
Baccharis 
20,000 PNU/ml 
Greer Labs 
Weed 
Burrobrush 
20,000 PNU/ml 
Greer Labs 
Weed 
Careless Weed,Amaranth/Green 
20,000 PNU/ml 
Greer Labs 
Weed 
Cocklebur 
20,000 PNU/ml 
Greer Labs 
Weed 
Dock, Yellow/Curly 
20,000 PNU/ml 
Greer Labs 
Weed 
Dog Fennel 
20,000 PNU/ml 
Greer Labs 
Weed 
Firebush/Kochia 
20,000 PNU/ml 
Greer Labs 
Weed 
Goldenrod 
20,000 PNU/ml 
Greer Labs 


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CONFIDENTIAL PROPERTY OF RELEZ THERAPEUTICS, LLC 
 
Weed 
Hemp, Water 
20,000 PNU/ml 
Greer Labs 
Weed 
Iodine Bush 
20,000 PNU/ml 
Greer Labs 
Weed 
Lamb's Quarter 
20,000 PNU/ml 
Greer Labs 
Weed 
Lenscale/Quailbrush 
20,000 PNU/ml 
Greer Labs 
Weed 
Marsh Elder, Burweed/Giant Poverty 
20,000 PNU/ml 
Greer Labs 
Weed 
Marsh Elder, True/Rough 
20,000 PNU/ml 
Greer Labs 
Weed 
Mugwort, Common 
20,000 PNU/ml 
Greer Labs 
Weed 
Mugwort, Darkleaved/ Sagebrush, Prairie 
20,000 PNU/ml 
Greer Labs 
Weed 
Nettle 
20,000 PNU/ml 
Greer Labs 
Weed 
Palmer's Amaranth 
20,000 PNU/ml 
Greer Labs 
Weed 
Pigweed, Rough/Redroot 
20,000 PNU/ml 
Greer Labs 
Weed 
Pigweed, Spiny 
20,000 PNU/ml 
Greer Labs 
Weed 
Plantain, English 
20,000 PNU/ml 
Greer Labs 
Weed 
Rabbit Bush 
20,000 PNU/ml 
Greer Labs 
Weed 
Ragweed, Desert 
20,000 PNU/ml 
Greer Labs 
Weed 
Ragweed, False 
20,000 PNU/ml 
Greer Labs 
Weed 
Ragweed, Giant 
20,000 PNU/ml 
Greer Labs 
Weed 
Ragweed, Short 
20,000 PNU/ml 
Greer Labs 
Weed 
Ragweed, Slender 
20,000 PNU/ml 
Greer Labs 
Weed 
Ragweed, Southern 
20,000 PNU/ml 
Greer Labs 
Weed 
Ragweed, Western 
20,000 PNU/ml 
Greer Labs 
Weed 
Russian Thistle 
20,000 PNU/ml 
Greer Labs 
Weed 
Sagebrush, Coast 
20,000 PNU/ml 
Greer Labs 
Weed 
Sagebrush, Common 
20,000 PNU/ml 
Greer Labs 
Weed 
Sagebrush, Pasture 
20,000 PNU/ml 
Greer Labs 
Weed 
Saltbush, Annual 
20,000 PNU/ml 
Greer Labs 
Weed 
Sorrel, Sheep/Red 
20,000 PNU/ml 
Greer Labs 
Weed 
Wingscale 
20,000 PNU/ml 
Greer Labs 
Grass 
Bahia Grass 
20,000 PNU/ml 
Greer Labs 
Grass 
Bermuda Grass 
10,000 PNU/ml 
Greer Labs 
Grass 
Brome Grass, Smooth 
40,000 PNU/ml 
Greer Labs 
Grass 
Canarygrass, Reed 
40,000 PNU/ml 
Greer Labs 
Grass 
Corn, Cultivated 
40,000 PNU/ml 
Greer Labs 
Grass 
Couch/Quack Grass 
40,000 PNU/ml 
Greer Labs 
Grass 
Johnson Grass 
40,000 PNU/ml 
Greer Labs 
Grass 
Kentucky Blue/June 
40,000 PNU/ml 
Greer Labs 
Grass 
Meadow Fescue 
40,000 PNU/ml 
Greer Labs 
Grass 
Oats, Common/Cultivated 
40,000 PNU/ml 
Greer Labs 
Grass 
Orchard 
40,000 PNU/ml 
Greer Labs 


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CONFIDENTIAL PROPERTY OF RELEZ THERAPEUTICS, LLC 
 
Grass 
Redtop 
40,000 PNU/ml 
Greer Labs 
Grass 
Rye, Cultivated 
40,000 PNU/ml 
Greer Labs 
Grass 
Ryegrass, Giant Wild 
40,000 PNU/ml 
Greer Labs 
Grass 
Ryegrass, Italian 
40,000 PNU/ml 
Greer Labs 
Grass 
Ryegrass, Perennial 
40,000 PNU/ml 
Greer Labs 
Grass 
Sweet Vernal 
40,000 PNU/ml 
Greer Labs 
Grass 
Timothy 
40,000 PNU/ml 
Greer Labs 
Grass 
Velvetgrass 
40,000 PNU/ml 
Greer Labs 
Grass 
Wheat, Cultivated 
40,000 PNU/ml 
Greer Labs 
Grass 
Wheatgrass, Western 
40,000 PNU/ml 
Greer Labs 
Mold 
Acremonium strictum 
40,000 PNU/ml 
Greer Labs 
Mold 
Alternaria alternat 
40,000 PNU/ml 
Greer Labs 
Mold 
Aspergillus amstelodami 
40,000 PNU/ml 
Greer Labs 
Mold 
Aspergillus flavus 
40,000 PNU/ml 
Greer Labs 
Mold 
Aspergillus fumigatus 
40,000 PNU/ml 
Greer Labs 
Mold 
Aspergillus nidulans 
40,000 PNU/ml 
Greer Labs 
Mold 
Aspergillus nige 
40,000 PNU/ml 
Greer Labs 
Mold 
Aureobasidium pullulan 
40,000 PNU/ml 
Greer Labs 
Mold 
Bipolaris sorokinian 
40,000 PNU/ml 
Greer Labs 
Mold 
Botrytis cinere 
40,000 PNU/ml 
Greer Labs 
Mold 
Candida albican 
40,000 PNU/ml 
Greer Labs 
Mold 
Chaetomium globosu 
40,000 PNU/ml 
Greer Labs 
Mold 
Cladosporium herbarum 
40,000 PNU/ml 
Greer Labs 
Mold 
Cladosporium sphaerospermum 
40,000 PNU/ml 
Greer Labs 
Mold 
Drechslera spicifera 
40,000 PNU/ml 
Greer Labs 
Mold 
Epicoccum nigrum 
40,000 PNU/ml 
Greer Labs 
Mold 
Epidermophyton floccosum 
40,000 PNU/ml 
Greer Labs 
Mold 
Fusarium moniliform 
40,000 PNU/ml 
Greer Labs 
Mold 
Fusarium solani 
40,000 PNU/ml 
Greer Labs 
Mold 
Geotrichum candidum 
40,000 PNU/ml 
Greer Labs 
Mold 
Gliocladium viride 
40,000 PNU/ml 
Greer Labs 
Mold 
Helminthosporium solani 
40,000 PNU/ml 
Greer Labs 
Mold 
Microsporum canis 
40,000 PNU/ml 
Greer Labs 
Mold 
Mucor circinelloides f. circinelloides 
40,000 PNU/ml 
Greer Labs 
Mold 
Mucor circinelloides f. lusitanicus 
40,000 PNU/ml 
Greer Labs 
Mold 
Mucor plumbeus 
40,000 PNU/ml 
Greer Labs 
Mold 
Mycogone perniciosa 
40,000 PNU/ml 
Greer Labs 
Mold 
Neurospora intermedia 
40,000 PNU/ml 
Greer Labs 
Mold 
Nigrospora oryzae 
40,000 PNU/ml 
Greer Labs 


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Protocol: Novel biologic therapy for allergic rhinitis 
 
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CONFIDENTIAL PROPERTY OF RELEZ THERAPEUTICS, LLC 
 
Mold 
Paecilomyces variotii 
40,000 PNU/ml 
Greer Labs 
Mold 
Penicillium digitatum 
40,000 PNU/ml 
Greer Labs 
Mold 
Penicillium chrysogenum 
40,000 PNU/ml 
Greer Labs 
Mold 
Phoma betae 
40,000 PNU/ml 
Greer Labs 
Mold 
Rhizopus oryzae 
40,000 PNU/ml 
Greer Labs 
Mold 
Rhizopus stolonife 
40,000 PNU/ml 
Greer Labs 
Mold 
Rhodotorula mucilaginosa 
40,000 PNU/ml 
Greer Labs 
Mold 
Saccharomyces cerevisiae 
40,000 PNU/ml 
Greer Labs 
Mold 
Stemphylium solani 
40,000 PNU/ml 
Greer Labs 
Mold 
Trichoderma harzianum 
40,000 PNU/ml 
Greer Labs 
Mold 
Trichophyton mentagrophytes 
40,000 PNU/ml 
Greer Labs 
Mold 
Trichophyton rubrum 
40,000 PNU/ml 
Greer Labs 
Mold 
Trichothecium roseum 
40,000 PNU/ml 
Greer Labs 
Animal 
Cattle Epithelia 
20,000 PNU/ml 
Greer Labs 
Animal 
Dog Epithelia 
20,000 PNU/ml 
Greer Labs 
Animal 
Gerbil Epithelia 
20,000 PNU/ml 
Greer Labs 
Animal 
Goat Epithelia 
20,000 PNU/ml 
Greer Labs 
Animal 
Guinea Pig Epithelia 
20,000 PNU/ml 
Greer Labs 
Animal 
Hamster Epithelia 
20,000 PNU/ml 
Greer Labs 
Animal 
Hog Epithelia 
20,000 PNU/ml 
Greer Labs 
Animal 
Horse Epithelia 
20,000 PNU/ml 
Greer Labs 
Animal 
Mouse Epithelia 
20,000 PNU/ml 
Greer Labs 
Animal 
Rabbit Epithelia 
20,000 PNU/ml 
Greer Labs 
Animal 
Rat Epithelia 
20,000 PNU/ml 
Greer Labs 
Animal 
2 Cockroach Mix  
40,000 PNU/ml 
Greer Labs 
Tree 
ACACIA Acacia spp. 
40,000 PNU/ml 
Allergy Laboratories 
Tree 
ALDER, RED Alnus rubra  
40,000 PNU/ml 
Allergy Laboratories 
Tree 
ALDER, SMOOTH Alnus rugosa  
40,000 PNU/ml 
Allergy Laboratories 
Tree 
ASH, ARIZONA Fraxinus velutina 
40,000 PNU/ml 
Allergy Laboratories 
Tree 
ASH, GREEN (RED) Fraxinus pennsylvanica 
40,000 PNU/ml 
Allergy Laboratories 
Tree 
ASH, WHITE Fraxinus Americana 
40,000 PNU/ml 
Allergy Laboratories 
Tree 
ASH MIX (Green & White)  
40,000 PNU/ml 
Allergy Laboratories 
Tree 
ASPEN, QUAKING Populus tremuloides 
40,000 PNU/ml 
Allergy Laboratories 
Tree 
BAYBERRY Myrica cerifera  
40,000 PNU/ml 
Allergy Laboratories 
Tree 
BEECH, AMERICAN Fagus grandifolia  
40,000 PNU/ml 
Allergy Laboratories 
Tree 
BIRCH, RIVER Betula nigra 
40,000 PNU/ml 
Allergy Laboratories 
Tree 
BIRCH MIX (River, Paper, Sweet & White)  
40,000 PNU/ml 
Allergy Laboratories 
Tree 
BIRCH, WHITE (GRAY) Betula populifolia 
40,000 PNU/ml 
Allergy Laboratories 
Tree 
BOX ELDER Acer negundo 
40,000 PNU/ml 
Allergy Laboratories 


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Protocol: Novel biologic therapy for allergic rhinitis 
 
Version 6.9.1 
 
CONFIDENTIAL PROPERTY OF RELEZ THERAPEUTICS, LLC 
 
Tree 
CEDAR, MOUNTAIN Juniperus sabinoides 
40,000 PNU/ml 
Allergy Laboratories 
Tree 
CEDAR, PINCHOT Juniperus pinchotii  
40,000 PNU/ml 
Allergy Laboratories 
Tree 
CEDAR, RED Juniperus virginiana  
40,000 PNU/ml 
Allergy Laboratories 
Tree 
COTTONWOOD, EASTERN Populus deltoids 
40,000 PNU/ml 
Allergy Laboratories 
Tree 
COTTONWOOD, WESTERN Populus sargentii 
40,000 PNU/ml 
Allergy Laboratories 
Tree 
COTTONWOOD MIX, EASTERN/WESTERN 
40,000 PNU/ml 
Allergy Laboratories 
Tree 
CYPRESS, ARIZONA Cupressus  arizonica 
40,000 PNU/ml 
Allergy Laboratories 
Tree 
CYPRESS, BALD Taxodium distichum  
40,000 PNU/ml 
Allergy Laboratories 
Tree 
ELM, AMERICAN Ulmus americana 
40,000 PNU/ml 
Allergy Laboratories 
Tree 
ELM, CEDAR (FALL BLOOMING) Ulmus crassifolia  
40,000 PNU/ml 
Allergy Laboratories 
Tree 
ELM, CHINESE (SIBERIAN) Ulmus pumila  
40,000 PNU/ml 
Allergy Laboratories 
Tree 
ELM MIX (American, Chinese & Slippery)  
40,000 PNU/ml 
Allergy Laboratories 
Tree 
EUCALYPTUS (BLUE GUM) Eucalyptus globulus 
40,000 PNU/ml 
Allergy Laboratories 
Tree 
FIR, DOUGLAS Pseudotsuga taxifolia  
40,000 PNU/ml 
Allergy Laboratories 
Tree 
SWEETGUM Liquidambar styraci ua  
40,000 PNU/ml 
Allergy Laboratories 
Tree 
HACKBERRY Celtis occidentalis 
40,000 PNU/ml 
Allergy Laboratories 
Tree 
HICKORY, SHAGBARK Carya ovata  
40,000 PNU/ml 
Allergy Laboratories 
Tree 
HICKORY, WHITE Carya tomentosa 
40,000 PNU/ml 
Allergy Laboratories 
Tree 
HICKORY MIX (Pignut, Shagbark, Shellbar, White) 
40,000 PNU/ml 
Allergy Laboratories 
Tree 
JUNIPER, ONE SEED Juniperus monosperma 
40,000 PNU/ml 
Allergy Laboratories 
Tree 
JUNIPER, ROCKY MOUNTAIN 
40,000 PNU/ml 
Allergy Laboratories 
Tree 
LOCUST, BLACK Robinia pseudoacacia  
40,000 PNU/ml 
Allergy Laboratories 
Tree 
MAPLE, SUGAR (HARD) Acer saccharum  
40,000 PNU/ml 
Allergy Laboratories 
Tree 
MAPLE MIX (Red, Silver & Sugar) 
40,000 PNU/ml 
Allergy Laboratories 
Tree 
MESQUITE Prosopis spp. 
40,000 PNU/ml 
Allergy Laboratories 
Tree 
MULBERRY, PAPER Broussonetia papyrifera  
40,000 PNU/ml 
Allergy Laboratories 
Tree 
MULBERRY, RED Morus rubra 
40,000 PNU/ml 
Allergy Laboratories 
Tree 
MULBERRY, WHITE Morus alba  
40,000 PNU/ml 
Allergy Laboratories 
Tree 
OAK, BLACK Quercus velutina  
40,000 PNU/ml 
Allergy Laboratories 
Tree 
OAK, BLACKJACK Quercus marilandica  
40,000 PNU/ml 
Allergy Laboratories 
Tree 
OAK, BUR Quercus macrocarpa  
40,000 PNU/ml 
Allergy Laboratories 
Tree 
OAK, LIVE Quercus virginiana 
40,000 PNU/ml 
Allergy Laboratories 
Tree 
2-OAK MIX (Red & White) 
40,000 PNU/ml 
Allergy Laboratories 
Tree 
3-OAK MIX (Black, Blackjack & Post) 
40,000 PNU/ml 
Allergy Laboratories 
Tree 
5-OAK MIX (Blackjack, Bur, Post, Red & White)  
40,000 PNU/ml 
Allergy Laboratories 
Tree 
OAK, POST Quercus stellata  
40,000 PNU/ml 
Allergy Laboratories 
Tree 
OAK, WHITE Quercus alba  
40,000 PNU/ml 
Allergy Laboratories 
Tree 
OLIVE, EUROPEAN Olea europaea  
40,000 PNU/ml 
Allergy Laboratories 
Tree 
OSAGE ORANGE Maclura pomifera  
40,000 PNU/ml 
Allergy Laboratories 


Propriatory antigen preparation 
 
Study Number: PMA 001  
Page 74 of 84 
Protocol: Novel biologic therapy for allergic rhinitis 
 
Version 6.9.1 
 
CONFIDENTIAL PROPERTY OF RELEZ THERAPEUTICS, LLC 
 
Tree 
PALM, DATE Phoenix dactylifera  
40,000 PNU/ml 
Allergy Laboratories 
Tree 
PALM QUEEN, Arecastrum spp.  
40,000 PNU/ml 
Allergy Laboratories 
Tree 
PECAN POLLEN Carya illinoinensis  
40,000 PNU/ml 
Allergy Laboratories 
Tree 
PINE, WHITE Pinus strobus 
40,000 PNU/ml 
Allergy Laboratories 
Tree 
4 PINE MIX (Austrian, Loblolly, Scotch & White)  
40,000 PNU/ml 
Allergy Laboratories 
Tree 
POPLAR, LOMBARDY Populus nigra  
40,000 PNU/ml 
Allergy Laboratories 
Tree 
POPLAR, WHITE Populus alba  
40,000 PNU/ml 
Allergy Laboratories 
Tree 
PRIVET Ligustrum spp.  
40,000 PNU/ml 
Allergy Laboratories 
Tree 
SPRUCE, BLUE Picea pungens  
40,000 PNU/ml 
Allergy Laboratories 
Tree 
SUMAC, UPLAND Rhus glabra  
40,000 PNU/ml 
Allergy Laboratories 
Tree 
SYCAMORE Platanus occidentalis  
40,000 PNU/ml 
Allergy Laboratories 
Tree 
TREE OF HEAVEN Ailanthus altissima  
40,000 PNU/ml 
Allergy Laboratories 
Tree 
WALNUT, BLACK (POLLEN) Juglans nigra 
40,000 PNU/ml 
Allergy Laboratories 
Tree 
WILLOW, BLACK Salix nigra 
40,000 PNU/ml 
Allergy Laboratories 
Grass 
ALFALFA Medicago sativa  
40,000 PNU/ml 
Allergy Laboratories 
Grass 
BAHIA GRASS Paspalum notatum  
40,000 PNU/ml 
Allergy Laboratories 
Grass 
BARLEY, CULTIVATED Hordeum vulgare  
40,000 PNU/ml 
Allergy Laboratories 
Grass 
SUGAR BEET POLLEN Beta vulgaris  
40,000 PNU/ml 
Allergy Laboratories 
Grass 
BENT GRASS, CREEPING Agrostis stolonifera  
40,000 PNU/ml 
Allergy Laboratories 
Grass Std 
BERMUDA GRASS  
10,000 PNU/ml 
Allergy Laboratories 
Grass 
BLUEGRASS, ANNUAL Poa annua 
40,000 PNU/ml 
Allergy Laboratories 
Grass 
BROME, HUNGARIAN (SMOOTH) Bromus inermis  
40,000 PNU/ml 
Allergy Laboratories 
Grass 
CANARY GRASS Phalaris minor  
40,000 PNU/ml 
Allergy Laboratories 
Grass 
CORN, CULTIVATED Zea mays  
40,000 PNU/ml 
Allergy Laboratories 
Grass 
JOHNSON GRASS Sorghum halepense  
40,000 PNU/ml 
Allergy Laboratories 
Grass 
KENTUCKY (JUNEGRASS) BLUEGRASS  
100,000 PNU/ml 
Allergy Laboratories 
Grass Std 
MEADOW FESCUE GRASS  
100,000 PNU/ml 
Allergy Laboratories 
Grass 
OAT GRASS, TALL Arrhenatherum elatius  
40,000 PNU/ml 
Allergy Laboratories 
Grass 
OATS, CULTIVATED Avena sativa  
40,000 PNU/ml 
Allergy Laboratories 
Grass Std 
ORCHARD GRASS 
100,000 PNU/ml 
Allergy Laboratories 
Grass Std 
PERENNIAL RYEGRASS 
100,000 PNU/ml 
Allergy Laboratories 
Grass 
REDTOP GRASS, STANDARDIZED Agrostis alba 
100,000 BAU/ml 
Allergy Laboratories 
Grass 
RYEGRASS, ITALIAN Lolium multi orum  
40,000 PNU/ml 
Allergy Laboratories 
Grass 
SORGHUM, GRAIN Sorghum vulgare  
40,000 PNU/ml 
Allergy Laboratories 
Grass 
SUDAN GRASS Sorghum vulagare var. sudanense  
40,000 PNU/ml 
Allergy Laboratories 
Grass 
SWEET VERNAL GRASS  
100,000 PNU/ml 
Allergy Laboratories 
Grass 
TIMOTHY GRASS  
100,000 PNU/ml 
Allergy Laboratories 
Grass 
WHEAT, CULTIVATED Triticum aestivum 
40,000 PNU/ml 
Allergy Laboratories 
Weed 
BROOMWEED Gutierrezia dracunculoides 
20,000 PNU/ml 
Allergy Laboratories 


Propriatory antigen preparation 
 
Study Number: PMA 001  
Page 75 of 84 
Protocol: Novel biologic therapy for allergic rhinitis 
 
Version 6.9.1 
 
CONFIDENTIAL PROPERTY OF RELEZ THERAPEUTICS, LLC 
 
Weed 
CARELESS WEED Amaranthus palmeri  
20,000 PNU/ml 
Allergy Laboratories 
Weed 
COCKLEBUR Xanthium commune  
20,000 PNU/ml 
Allergy Laboratories 
Weed 
DOCK, SOUR (SHEEP SORREL) Rumex acetosella  
20,000 PNU/ml 
Allergy Laboratories 
Weed 
DOCK, YELLOW (CURLY) Rumex crispus  
20,000 PNU/ml 
Allergy Laboratories 
Weed 
DOCK MIX, SOUR (SHEEP SORREL)/YELLOW 
20,000 PNU/ml 
Allergy Laboratories 
Weed 
FIREBUSH (KOCHIA) Kochia scoparia 
20,000 PNU/ml 
Allergy Laboratories 
Weed 
GOLDENROD Solidago spp. 
20,000 PNU/ml 
Allergy Laboratories 
Weed 
GREASEWOOD Sarcobatus vermiculatus 
20,000 PNU/ml 
Allergy Laboratories 
Weed 
GROUNDSEL TREE Baccharis halimifolia 
20,000 PNU/ml 
Allergy Laboratories 
Weed 
LAMB’S QUARTERS Chenopodium album 
20,000 PNU/ml 
Allergy Laboratories 
Weed 
MARSHELDER, BURWEED Iva xanthifolia 
20,000 PNU/ml 
Allergy Laboratories 
Weed 
MARSHELDER, NARROWLEAF Iva angustifolia 
20,000 PNU/ml 
Allergy Laboratories 
Weed 
MARSHELDER, ROUGH Iva ciliata 
20,000 PNU/ml 
Allergy Laboratories 
Weed 
MUGWORT, COMMON Artemisia vulgaris  
20,000 PNU/ml 
Allergy Laboratories 
Weed 
NETTLE Urtica dioica  
20,000 PNU/ml 
Allergy Laboratories 
Weed 
PIGWEED MIX (Rough/Spiny)  
20,000 PNU/ml 
Allergy Laboratories 
Weed 
PIGWEED, ROUGH (REDROOT)  
20,000 PNU/ml 
Allergy Laboratories 
Weed 
PIGWEED, SPINY Amaranthus spinosus  
20,000 PNU/ml 
Allergy Laboratories 
Weed 
PLANTAIN, ENGLISH Plantago lanceolata  
20,000 PNU/ml 
Allergy Laboratories 
Weed 
RAGWEED, FALSE (BUR) Ambrosia acanthicarpa  
20,000 PNU/ml 
Allergy Laboratories 
Weed 
RAGWEED, GIANT Ambrosia trida  
20,000 PNU/ml 
Allergy Laboratories 
Weed Std 
SHORT RAGWEED 
100,000 PNU/ml 
Allergy Laboratories 
Weed 
RAGWEED, WESTERN Ambrosia psilostachya  
20,000 PNU/ml 
Allergy Laboratories 
Weed 
3-RAGWEED MIX (Giant/Short/ Western)  
20,000 PNU/ml 
Allergy Laboratories 
Weed Std 
RAGWEED MIX, GIANT/SHORT  
100,000 PNU/ml 
Allergy Laboratories 
Weed 
RUSSIAN THISTLE Salsola kali 
20,000 PNU/ml 
Allergy Laboratories 
Weed 
SAGEBRUSH, COMMON (BIG) Artemisia tridentata  
20,000 PNU/ml 
Allergy Laboratories 
Weed 
SAGE, PRAIRIE (DARK-LEAVED)  
20,000 PNU/ml 
Allergy Laboratories 
Weed 
SALTBUSH, ANNUAL Atriplex wrightii  
20,000 PNU/ml 
Allergy Laboratories 
Weed 
SHADSCALE Atriplex confertifolia  
20,000 PNU/ml 
Allergy Laboratories 
Weed 
WATER-HEMP Acnida tamariscina  
20,000 PNU/ml 
Allergy Laboratories 
Weed 
WINGSCALE Atriplex canescens  
20,000 PNU/ml 
Allergy Laboratories 
Weed 
WORMWOOD, ANNUAL Artemisia annua  
20,000 PNU/ml 
Allergy Laboratories 
Weed 
WORMWOOD, COMMON Artemisia absinthium  
20,000 PNU/ml 
Allergy Laboratories 
Mold 
ALTERNARIA TENUIS (ALTERNATA)  
40,000 PNU/ml 
Allergy Laboratories 
Mold 
ASPERGILLUS FUMIGATUS 
40,000 PNU/ml 
Allergy Laboratories 
Mold 
ASPERGILLUS NIGER 
40,000 PNU/ml 
Allergy Laboratories 
Mold 
BOTRYTIS CINEREA 
40,000 PNU/ml 
Allergy Laboratories 
Mold 
CANDIDA (MONILA) ALBICANS  
40,000 PNU/ml 
Allergy Laboratories 


Propriatory antigen preparation 
 
Study Number: PMA 001  
Page 76 of 84 
Protocol: Novel biologic therapy for allergic rhinitis 
 
Version 6.9.1 
 
CONFIDENTIAL PROPERTY OF RELEZ THERAPEUTICS, LLC 
 
Mold 
CEPHALOSPORIUM ACREMONIUM 
40,000 PNU/ml 
Allergy Laboratories 
Mold 
CHAETOMIUM GLOBOSUM  
40,000 PNU/ml 
Allergy Laboratories 
Mold 
CLADOSPORIUM FULVUM  
40,000 PNU/ml 
Allergy Laboratories 
Mold 
CURVULARIA SPICIFERA  
40,000 PNU/ml 
Allergy Laboratories 
Mold 
EPICOCCUM NIGRUM  
40,000 PNU/ml 
Allergy Laboratories 
Mold 
EPIDERMOPHYTON FLOCCOSUM  
40,000 PNU/ml 
Allergy Laboratories 
Mold 
FUSARIUM VASINFECTUM (OXYSPORUM)  
40,000 PNU/ml 
Allergy Laboratories 
Mold 
FUSARIUM SOLANI 
40,000 PNU/ml 
Allergy Laboratories 
Mold 
GEOTRICHUM CANDIDUM 
40,000 PNU/ml 
Allergy Laboratories 
Mold 
HELMINTHOSPORIUM SATIVUM  
40,000 PNU/ml 
Allergy Laboratories 
Mold 
HORMODENDRUM (CLADOSPORIUM)  
40,000 PNU/ml 
Allergy Laboratories 
Mold 
MUCOR PLUMBEUS  
40,000 PNU/ml 
Allergy Laboratories 
Mold 
MUCOR RACEMOSUS  
40,000 PNU/ml 
Allergy Laboratories 
Mold 
NEUROSPORA SITOPHILA  
40,000 PNU/ml 
Allergy Laboratories 
Mold 
NIGROSPORA SPHAERICA  
40,000 PNU/ml 
Allergy Laboratories 
Mold 
PENICILLIUM NOTATUM (CHRYSOGENUM)  
40,000 PNU/ml 
Allergy Laboratories 
Mold 
PHOMA DESTRUCTIVA  
40,000 PNU/ml 
Allergy Laboratories 
Mold 
PULLULARIA PULLULANS  
40,000 PNU/ml 
Allergy Laboratories 
Mold 
RHIZOPUS NIGRICANS  
40,000 PNU/ml 
Allergy Laboratories 
Mold 
RHODOTORULA MUCILAGINOSA  
40,000 PNU/ml 
Allergy Laboratories 
Mold 
RINKEL MOLD MIX A  
40,000 PNU/ml 
Allergy Laboratories 
Mold 
RINKEL MOLD MIX B  
40,000 PNU/ml 
Allergy Laboratories 
Mold 
RINKEL MOLD MIX C  
40,000 PNU/ml 
Allergy Laboratories 
Mold 
STEMPHYLLIUM SARCINAEFORME  
40,000 PNU/ml 
Allergy Laboratories 
Mold 
TRICHODERMA LIGNORUM  
40,000 PNU/ml 
Allergy Laboratories 
Mold 
TRICHOPYHTON MENTAGROPHYTES  
40,000 PNU/ml 
Allergy Laboratories 
Mold 
TRICHOPYHTON RUBRUM  
40,000 PNU/ml 
Allergy Laboratories 
Mold 
TRICHOPYHTON TONSURANS  
40,000 PNU/ml 
Allergy Laboratories 
Smut 
VERTICILLIUM ALBO-ATRUM  
40,000 PNU/ml 
Allergy Laboratories 
Smut 
BERMUDA GRASS SMUT  
20,000 PNU/ml 
Allergy Laboratories 
Smut 
CORN SMUT  
20,000 PNU/ml 
Allergy Laboratories 
Smut 
JOHNSON GRASS SMUT  
20,000 PNU/ml 
Allergy Laboratories 
Smut 
WHEAT RUST  
20,000 PNU/ml 
Allergy Laboratories 
Flower 
DANDELION Taraxacum of cinale  
40,000 PNU/ml 
Allergy Laboratories 
Flower 
SUNFLOWER Helianthus annuus  
40,000 PNU/ml 
Allergy Laboratories 
Environmental 
COTTON LINTERS Gossypium hirsutum  
40,000 PNU/ml 
Allergy Laboratories 
Environmental 
COTTON SEED  
40,000 PNU/ml 
Allergy Laboratories 
Environmental 
FLAX SEED  
40,000 PNU/ml 
Allergy Laboratories 
Environmental 
KAPOK Ceiba pentandra  
40,000 PNU/ml 
Allergy Laboratories 


Propriatory antigen preparation 
 
Study Number: PMA 001  
Page 77 of 84 
Protocol: Novel biologic therapy for allergic rhinitis 
 
Version 6.9.1 
 
CONFIDENTIAL PROPERTY OF RELEZ THERAPEUTICS, LLC 
 
Environmental 
ORRIS ROOT Iris orentina 
40,000 PNU/ml 
Allergy Laboratories 
Environmental 
PYRETHRUM Chrysanthemum 
40,000 PNU/ml 
Allergy Laboratories 
Environmental 
SILK  
40,000 PNU/ml 
Allergy Laboratories 
Cat Hair Std 
Felis domesticus 
40,000 PNU/ml 
Allergy Laboratories 
Animal 
CATTLE HAIR & EPITHELIA Bos taurus  
20,000 PNU/ml 
Allergy Laboratories 
Animal 
DOG HAIR & EPITHELIA Canis familiaris 
20,000 PNU/ml 
Allergy Laboratories 
Animal 
GUINEA PIG HAIR & EPITHELIA Cavia porcellus 
20,000 PNU/ml 
Allergy Laboratories 
Animal 
HAMSTER HAIR & EPITHELIA Cricetus cricetus 
20,000 PNU/ml 
Allergy Laboratories 
Animal 
COCKROACH, AMERICAN  
20,000 PNU/ml 
Allergy Laboratories 
Animal 
HOG HAIR & EPITHELIA Sus scrofa 
20,000 PNU/ml 
Allergy Laboratories 
Animal 
HORSE HAIR & DANDER Equus caballus 
20,000 PNU/ml 
Allergy Laboratories 
Animal 
MOUSE HAIR & EPITHELIA Mus musculus 
20,000 PNU/ml 
Allergy Laboratories 
Animal 
RABBIT HAIR & EPITHELIA Oryctolagus cuniculus 
20,000 PNU/ml 
Allergy Laboratories 
Feathers 
CHICKEN FEATHERS Gallus gallus 
20,000 PNU/ml 
Allergy Laboratories 
Feathers 
DUCK FEATHERS Anas platyrhynchos  
20,000 PNU/ml 
Allergy Laboratories 
Feathers 
GOOSE FEATHERS Anser anser 
20,000 PNU/ml 
Allergy Laboratories 
Feathers 
FEATHER MIX (Chicken, Duck, & Goose)  
20,000 PNU/ml 
Allergy Laboratories 
Mite Std 
Dermatophagoides farinae 
10,000 AU/ml 
Allergy Laboratories 
Mite Std 
Dermatophagoides pteronyssinus 
10,000 AU/ml 
Allergy Laboratories 
 
 
 


Propriatory antigen preparation 
 
Study Number: PMA 001  
Page 78 of 84 
Protocol: Novel biologic therapy for allergic rhinitis 
 
Version 6.9.1 
 
CONFIDENTIAL PROPERTY OF RELEZ THERAPEUTICS, LLC 
 
Appendix F     Immunotherapy efficacy assessment instruments 
 
Mini-RQLQ 
 
 
Total Nasal Symptoms Score (TNSS) 
The Total Nasal Symptom Score (TNSS; possible score of 0-12) is the sum of 4 individual 
participant-assessed symptom scores for rhinorrhea, nasal congestion, nasal itching, and sneezing, 
each evaluated using a scale of 0=None, 1=Mild, 2=Moderate, or 3=Severe. 
 


Propriatory antigen preparation 
 
Study Number: PMA 001  
Page 79 of 84 
Protocol: Novel biologic therapy for allergic rhinitis 
 
Version 6.9.1 
 
CONFIDENTIAL PROPERTY OF RELEZ THERAPEUTICS, LLC 
 
Appendix G     Allergens used for skin prick testing  
 
Type  
Allergen 
Stock Concentration 
Manufacturer 
Tree 
Oak 
20,000 PNU/ml 
Greer 
Tree 
Birch 
20,000 BAU/ml 
Greer 
Tree 
Beech 
20,000 BAU/ml 
Greer 
Tree 
Elm 
20,000 BAU/ml 
Greer 
Tree 
Ash 
20,000 BAU/ml 
Greer 
Tree 
Sycamore 
20,000 BAU/ml 
Greer 
Tree 
Poplar 
20,000 BAU/ml 
Greer 
Tree 
Hickory 
20,000 BAU/ml 
Greer 
Tree 
Walnut 
20,000 BAU/ml 
Greer 
Tree 
Mulberry 
20,000 BAU/ml 
Greer 
Tree 
Pine 
20,000 BAU/ml 
Greer 
Tree 
Willow 
20,000 BAU/ml 
Greer 
Grass 
Timothy 
100,000 BAU/ml 
Greer 
Grass 
Orchard 
100,000 BAU/ml 
Greer 
Grass 
Johnson 
100,000 BAU/ml 
Greer 
Grass 
June 
100,000 BAU/ml 
Greer 
Grass 
Rye 
100,000 BAU/ml 
Greer 
Grass 
Fescue 
100,000 BAU/ml 
Greer 
Grass 
Bermuda 
10,000 BAU/ml 
Greer 
Weed 
Ragweed 
100,000 AU/ml 
Greer 
Weed 
Plantain 
40,000 PNU/ml 
Greer 
Weed 
Pigweed 
40,000 PNU/ml 
Greer 
Weed 
Lambsquarter 
40,000 PNU/ml 
Greer 
Weed 
Sage/Mugwart 
40,000 PNU/ml 
Greer 
Weed 
Sheep Sorrel 
40,000 PNU/ml 
Greer 
Weed 
Cocklebur 
40,000 PNU/ml 
Greer 
Mold 
Aspergillus 
40,000 PNU/ml 
Greer 
Mold 
Penicillium 
40,000 PNU/ml 
Greer 
Mold 
Mucor 
40,000 PNU/ml 
Greer 
Mold 
Fusarium 
40,000 PNU/ml 
Greer 
Mold 
Alternaria 
40,000 PNU/ml 
Greer 
Mold 
Helminthosporium 
40,000 PNU/ml 
Greer 
Mold 
Botrytis 
40,000 PNU/ml 
Greer 
Mold 
Cladosporium 
40,000 PNU/ml 
Greer 
Mold 
Curvularia 
40,000 PNU/ml 
Greer 
Animal 
Cat Hair 
10,000 BAU/ml 
Greer 


Propriatory antigen preparation 
 
Study Number: PMA 001  
Page 80 of 84 
Protocol: Novel biologic therapy for allergic rhinitis 
 
Version 6.9.1 
 
CONFIDENTIAL PROPERTY OF RELEZ THERAPEUTICS, LLC 
 
Animal 
AP Cat 
10,000 BAU/ml 
Hollister 
Animal 
Dog epithelia 
20,000 PNU/ml 
Greer 
Animal 
AP Dog 
10,000 PNU/ml 
Hollister 
Animal 
Mouse 
20,000 PNU/ml 
Greer 
Animal 
Cockroach Mix 
20,000 PNU/ml 
Greer 
Animal 
Rat 
20,000 PNU/ml 
Greer 
Animal 
Horse 
20,000 PNU/ml 
Greer 
Animal 
Rabbit 
20,000 PNU/ml 
Greer 
Dust Mite  
D. farinae 
10,000 BAU/ml 
Greer 
Dust Mite 
D. pteronyssinus 
10,000 BAU/ml 
Greer 
Control 
Saline  
 
Hollister 
Control 
Histamine  
1mg/ml 
Hollister 
 


Propriatory antigen preparation 
 
Study Number: PMA 001  
Page 81 of 84 
Protocol: Novel biologic therapy for allergic rhinitis 
 
Version 6.9.1 
 
CONFIDENTIAL PROPERTY OF RELEZ THERAPEUTICS, LLC 
 
Appendix H     Immunotherapy Injection Schedule  
 
Visit Day 
Vial Number 
Dilution 
A, B, C (ml) 
Injection Volume (ml) 
2 
#5 
1:625 
0.05 
0.15 
3 
#5 
1:625 
0.10 
0.30 
4 
#5 
1:625 
0.15 
0.45 
5 
#5 
1:625 
0.20 
0.60 
6 
#4 
1:125 
0.05 
0.15 
7 
#4 
1:125 
0.10 
0.30 
8 
#4 
1:125 
0.15 
0.45 
9 
#4 
1:125 
0.20 
0.60 
10 
#3 
1:25 
0.05 
0.15 
11 
#3 
1:25 
0.10 
0.30 
12 
#3 
1:25 
0.15 
0.45 
13 
#3 
1:25 
0.20 
0.60 
14 
#2 
1:5 
0.05 
0.15 
15 
#2 
1:5 
0.10 
0.30 
16 
#2 
1:5 
0.15 
0.45 
17 
#2 
1:5 
0.20 
0.60 
 


Propriatory antigen preparation 
 
Study Number: PMA 001  
Page 82 of 84 
Protocol: Novel biologic therapy for allergic rhinitis 
 
Version 6.9.1 
 
CONFIDENTIAL PROPERTY OF RELEZ THERAPEUTICS, LLC 
 
Appendix I 
Allergy Rescue Medication Action Plan  
 
Ask patient if symptoms are adequately controlled at each bi-weekly visit. The response dictates 
whether a medication is added or subtracted. Resuce medications will not be increased after week 
10. 
 
Symptoms Controlled? 
Medication Action 
no 
Add medication 
yes 
Subtract medication 
 
 
 
Step 
Rescue Medication   
 
 
 
 
 
 
Score 
A 
None  
 
 
 
 
 
 
 
 
0 points 
B 
Loratadine 10mg PO Daily 
 
 
 
 
 
 
1 point 
C 
Loratadine 10mg PO BID 
 
 
 
 
 
 
2 points 
D 
Loratadine BID plus Triamcinolone Daily 
 
 
 
 
4 points 
E 
Loratadine BID plus Triamcinolone BID 
 
 
 
 
6 points 
F 
Loratadine BID plus Triamcinolone BID plus Prednisone 5mg Daily 
9 points 
G 
Loratadine BID plus Triamcinolone BID plus Prednisone 5mg BID 
12 points 
 
 
 
 
Note: To calculate the daily medication score add the total points for all medications noted above. 
Any other allergy rescue medications inadvertently added will also be counted in a similar manner 
as follows; other oral antihistamines (1 points each tablet), ophthalmic allergy medications (1 
points each use), other nasal steroids, cromolyn, azelastine (2 points daily, 4 points BID). 
Symptoms and medication use are recorded daily at home.  
 


Propriatory antigen preparation 
 
Study Number: PMA 001  
Page 83 of 84 
Protocol: Novel biologic therapy for allergic rhinitis 
 
Version 6.9.1 
 
CONFIDENTIAL PROPERTY OF RELEZ THERAPEUTICS, LLC 
 
Appendix J 
Clinical Visit Summary  
 
Subject ID 
 
 
 
 
Date  
 
 
Visit # 
Initials 
 
Allergy medications currently taking  _______________________________________________ 
____________________________________________________________________________ 
 
Daily symptom cards collected   Y/N 
Today’s RQLQ  __________ 
 
 
Baseline RQLQ   __________ 
 
 
Symptoms controlled  Y/N  
 
 
Medication added  
_____________ 
Medication removed _____________ 
 
Initial Vitals 
P      BP        RR        Temp 
   Sats     PFR  
Time  
Initials 
 
Physical Exam 
______________________________________  
Time  
Initials 
_____________________________________________________ 
_____________________________________________________ 
 
Vial ID __________ Vial # __________ Dose (ml) _________  
Time  
Initials 
 
Exit Vitals 
P  
BP 
 
Sats 
 
PFR 
 
Time  
Initials 
 
Reactions or Other Notes ________________________________________________________ 
_____________________________________________________________________________ 
 


Propriatory antigen preparation 
 
Study Number: PMA 001  
Page 84 of 84 
Protocol: Novel biologic therapy for allergic rhinitis 
 
Version 6.9.1 
 
CONFIDENTIAL PROPERTY OF RELEZ THERAPEUTICS, LLC 
 
Appendix K 
Symptom and Medication Card 
 
Daily Symptoms and Medication Use 
 
 
Initials  
 
 
ID  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Try to fill out this card every day at the same time before you go to bed. 
If found please return to Dr Jody Tversky 5501 Hopkins Bayview Circle, Batimore, MD 21224 
Date 
 
 
 
Symptoms 
None 
Mild 
Mod 
Severe 
Runny nose 
0 
1 
2 
3 
Nasal stuffiness 
0 
1 
2 
3 
Nasal itching 
0 
1 
2 
3 
Sneezing  
0 
1 
2 
3 
 
Medications Taken 
None 
Once 
Twice 
Loratadine tablet 
 
 
 
 
Triamcinolone spray 
 
 
 
Prednisone tablet 
 
 
 
 
Other medications __________________________ 
Date 
 
 
 
Symptoms 
None 
Mild 
Mod 
Severe 
Runny nose 
0 
1 
2 
3 
Nasal stuffiness 
0 
1 
2 
3 
Nasal itching 
0 
1 
2 
3 
Sneezing  
0 
1 
2 
3 
 
Medications Taken 
None 
Once 
Twice 
Loratadine tablet 
 
 
 
 
Triamcinolone spray 
 
 
 
Prednisone tablet 
 
 
 
 
Other medications __________________________ 
Date 
 
 
 
Symptoms 
None 
Mild 
Mod 
Severe 
Runny nose 
0 
1 
2 
3 
Nasal stuffiness 
0 
1 
2 
3 
Nasal itching 
0 
1 
2 
3 
Sneezing  
0 
1 
2 
3 
 
Medications Taken 
None 
Once 
Twice 
Loratadine tablet 
 
 
 
 
Triamcinolone spray 
 
 
 
Prednisone tablet 
 
 
 
 
Other medications __________________________ 
Date 
 
 
 
Symptoms 
None 
Mild 
Mod 
Severe 
Runny nose 
0 
1 
2 
3 
Nasal stuffiness 
0 
1 
2 
3 
Nasal itching 
0 
1 
2 
3 
Sneezing  
0 
1 
2 
3 
 
Medications Taken 
None 
Once 
Twice 
Loratadine tablet 
 
 
 
 
Triamcinolone spray 
 
 
 
Prednisone tablet 
 
 
 
 
Other medications __________________________ 


SAP for Novel biologic therapy for allergic rhinitis                                                     Version 1 
 
3 
 
 
The purpose of this document is to provide a description of the statistical methods and 
procedures to be implemented for the analysis of data derived from the study entitled: “A 
double-blind, prospective, parallel group evaluation of a novel biologic therapy for perennial 
allergic rhinitis” sponsored by Relez Therapeutics, LLC, and conducted at the Johns Hopkins 
Bayview Medical Center, Baltimore, Maryland. The protocol version used for the plan is Version 
6.9 dated February 10, 2017. At the time of development of this statistical analysis plan (SAP) 
the study Principal Investigator is Jody R. Tversky, MD, Johns Hopkins University School of 
Medicine, Baltimore, MD 
Any revisions to the SAP (both alternative and additional methods) will be made prior to 
database lock and reasons for such revisions will be described in the final Clinical Study Report 
(CSR). 
 
STUDY OVERVIEW 
 
Endpoints  
Primary Endpoints  
The primary endpoint is to quantify and compare the clinical difference in signs and symptoms 
and medication usage as well as the global RQLQ index that may be apparent when subjects with 
active perennial allergic rhinitis (PAR) with or without seasonal symptoms (SAR) are treated in a 
double-blind, prospective, controlled eight weeks study with a proprietary mixture of FDA 
approved allergens (PMA) versus placebo.   
 
Secondary Endpoint 
The secondary endpoints include a symptom score trend analysis, drop out rates, and adverse events 
profile (AE). Serum will also be stored for measurement of immunoglobulins at a later time.  
 


SAP for Novel biologic therapy for allergic rhinitis                                                     Version 1 
 
4 
 
STUDY DESIGN AND METHODS 
Study Design 
This is a phase 2 proof of concept study. It is being undertaken to characterize and quantify the 
clinical difference in signs and symptoms that may evolve when subjects with active seasonal or 
perennial allergic rhinitis (SAR/PAR) are administered a sub-cutaneous form of immunotherapy 
in a double-blind, prospective, controlled six weeks study wherein a proprietary mixture of FDA 
approved allergens (PMA) is compared with saline placebo.  
Randomization to active PMA versus placebo treatment is on a 1 to 1 ratio. A double-blind study 
design is used to minimize outcome bias.  Randomization measures to minimize bias at study 
entry include computerized random assignment of treatment versus placebo vials. 
Subjects who are receiving nasal steroids for their SAR/PAR at screening may continue in the 
screening process if they agree to discontinue their therapy and commence a 14-day wash-out 
period of their medication prior to receiving active/placebo immunotherapy. Potential study 
subjects who, at screening, are not on active treatment for their SAR/PAR and asthma may enter 
directly into the investigation provided they fulfil entry and exclusion criteria and screening 
testing requirements.   
The population to be studied consists of male and female adults aged 18 years to 65 years who 
are actively manifesting SAR/PAR have a score of at least 28 on the mini-RQLQ and 6 on the 
TNSS scale. 
The active treatment phase of the study will be for six weeks with a safety follow-up assessment 
at 30 days post-treatment. No interim analysis is planned.     
The study immunotherapy that will be evaluated in this study is a new innovative proprietary 
mixture of FDA approved allergens which has been clinically developed and evaluated, during 
the past three decades, in some 20,000 patients by the inventor of the mixture (see 3.2). In 
clinical evaluation this patented antigen mixture has provided clinical symptomatic relief to 
patients with SAR/PAR in as brief a period as three administrations of immunotherapy injections 
and has an observed overall success rate of approximately 80 to 90 percent of such treated 
subjects. 
In this study approximately 36 study subjects will be equally randomized to active PMA or 
placebo. The duration of active PMA or placebo treatment will be 8 weeks with clinic visits 
twice-weekly during this period and a post-treatment safety follow up assessment at one month 
following the final administration of immunotherapy. All doses of immunotherapy will be 
administered in the study site clinic by the investigators or their designees.        
  
A schematic of the study design is included in the Figure below. A schedule of assessments is 
listed in Error! Reference source not found. of the protocol. 


SAP for Novel biologic therapy for allergic rhinitis                                                     Version 1 
 
5 
 
Figure 
Schematic of Study Design  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
The SAP will follow the study protocol sections 12.1 to 12.3. Statistical methodology was 
developed in conjunction with the faculty of the Johns Hopkins Bloomberg School of Public 
Health Department of Biostatistics. Specific calculations include the following wherein “p" values 
as well as 95% confidence intervals will be calculated. 
 
Primary Outcomes 
 
1. Daily Combined Score (DCS) – Comparison of the delta visit 2 to visit 17 (change in score) 
between both treatment groups I and II using an unpaired t test. 
 
2. Daily Combined Score (DCS) – Comparison of the delta visit 2 to visit 18 (change in score) 
between both treatment groups I and II using an unpaired t test. 
 
3. mini-rhinoconjunctivitis quality of life questionnaire (RQLQ) - Comparison of the delta visit 2 to 
visit 17 (change in score) between both treatment groups I and II using an unpaired t test. 
 
4. mini-RQLQ - Comparison of the delta visit 2 to visit 18 (change in score) between both 
treatment groups I and II using an unpaired t test. 
 


SAP for Novel biologic therapy for allergic rhinitis                                                     Version 1 
 
6 
 
 
 
Secondary Outcomes 
 
1. Total nasal symptoms score (TNSS)- Comparison of the delta visit 2 to visit 17 (change in 
score) between both treatment groups I and II using an unpaired t test. 
 
2. TNSS - Comparison of the delta visit 2 to visit 18 (change in score) between both treatment 
groups I and II using an unpaired t test. 
 
3. Adverse Events - Adverse events (AEs) were to be spontaneously reported or elicited during 
open-ended questioning, examination, or evaluation of a patient. Comparison of the rates of 
adverse events between both treatment groups I and II will be evaluated using a one-tailed 
Fischer’s exact test. 
 
Other Comparisons and Outcomes 
 
1. Baseline characteristics - Comparison of the rates of specific characteristics between both 
treatment groups I and II using a one-tailed Fischer’s exact test and/or unpaired t test. 
 
2. Use of epinephrine - Comparison of the rates of epinephrine rescue medication use between 
both treatment groups I and II using a one-tailed Fischer’s exact test. 
 
3. Mini-RQLQ - Kaplan-Meier or similar repeated measures test will also be used to calculate 
the effect of treatment over time between both groups I and II. 
 
4. Drop out - Comparison of the drop out rates between both groups I and II using a one-tailed 
Fischer’s exact test. 
 
5. Trend tests - For these study data, representing a continuous response, an appropriate 
test, such as the Jonckheere-Terptsra trend test, based on a sum of Mann-Whitney-
Wilcoxon tests may be sensitive and reveal a mild trend where pair-wise comparisons may 
not be able to find significant differences and not be as helpful. Other trend tests may also 
be used.