Cockroach Immunotherapy in Children and Adolescents
Phase: PHASE2
Conditions: Persistent Asthma
Sponsor: National Institute of Allergy and Infectious Diseases (NIAID)

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INNER-CITY ASTHMA CONSORTIUM 
PROTOCOL ICAC-28 
COCKROACH IMMUNOTHERAPY IN CHILDREN AND ADOLESCENTS  
5.0 / 11 JANUARY 2021 
IND# 17979 
Study Sponsor(s) 
The Division of Allergy, Immunology, and Transplantation (DAIT), The 
National Institute of Allergy and Infectious Diseases (NIAID) 
NIAID Funding  
Grants 1 UM1 AI114271-01 and UM2AI117870 
IND Sponsor 
DAIT/NIAID, NIH  
Study Drug Manufacturer 
Stallergenes Greer 
 
 
PROTOCOL CO-CHAIR -  
ROBERT WOOD, MD 
Johns Hopkins University School 
of Medicine 
600 North Wolfe Street,  
CMSC 1102 
Baltimore, MD  21287 
Phone: (410) 955-5883 
Fax: (410) 955-0229 
E-mail: rwood@jhmi.edu 
 
MEDICAL MONITOR -  
PETER GERGEN, MD, MPH 
Division of Allergy, Immunology, 
and Transplantation 
National Institute of Allergy and 
Infectious Diseases 
5601 Fishers Lane, Room 6B58 
Bethesda MD 20892, USA 
Phone: (240) 627-3545 
Fax: (301) 480-2381  
E-mail: pgergen@niaid.nih.gov 
BIOSTATISTICIAN – 
CYNTHIA VISNESS, PHD 
Senior Research Scientist 
Rho, Inc. 
2635 E NC Hwy 54 
Durham, NC  27713 
Phone: (919) 408-8000 
Fax: (919) 408-0999 
E-mail:  
cindy_visness@rhoworld.com 
 
PROTOCOL CO-CHAIR –  
EDWARD ZORATTI, MD 
Henry Ford Health System 
1 Ford Place - 4B Allergy 
Detroit, MI 48202 
Phone: (313) 876-2662 
Fax: (313) 876-2094 
E-mail: ezoratt1@hfhs.org 
 
PROJECT MANAGER -  
LISA GAGALIS, RN, BSN 
Division of Allergy, Immunology, 
and Transplantation 
National Institute of Allergy and 
Infectious Diseases 
5601 Fishers Lane, Room 6B53 
Bethesda MD 20892, USA  
Phone: (240) 472-1823 
E-mail: lisa.gagalis@.nih.gov 
REGULATORY AFFAIRS OFFICER  - 
LYUDMILA LYAKH, MD, PHD 
Office of Regulatory Affairs 
Division of Allergy, Immunology,  
and Transplantation 
National Institute of Allergy and 
Infectious Diseases 
5601 Fishers Lane, Rm 7B39 
Bethesda MD 20892, USA 
Phone: (240) 627-3530 
Fax: (301) 480-1537 
E-mail: lyudmill@niaid.nih.gov 
Confidentiality Statement 
The information contained within this document is not to be disclosed in any way without the prior permission of 
the Protocol Chair, 
or the Division of Allergy, Immunology, and Transplantation, National Institute of Allergy and Infectious Diseases 
of the National Institutes of Health. 
 
 

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INVESTIGATOR SIGNATURE PAGE 
Protocol: ICAC-28 
Version/Date:  5.0 / 11 January 2021 
Title:   Cockroach Immunotherapy in Children and Adolescents 
Study Sponsor:  The National Institute of Allergy and Infectious Diseases (NIAID) 
 
INSTRUCTIONS:  The original signature page must be kept for your records. Return an electronic PDF copy 
of the signed signature page (*as described below) to the DAIT Regulatory Management Center via the 
applicable DAIT RMC email address for the protocol/network: 
DAITRegulatory_ICAC (SM) <DAITRegulatory_ICAC@ppdi.com> 
 
I confirm that I have read the above protocol in the latest version.  I understand it, and I will work 
according to the principles of Good Clinical Practice (GCP) as described in the United States Code of 
Federal Regulations (CFR) – 45 CFR part 46 and 21 CFR parts 50, 56, and 312, and in the International 
Conference on Harmonisation (ICH) document  Integrated Addendum to ICH 
E6(R1): Guideline for Good Clinical Practice E6(R2). .  Further, I will conduct the study in keeping with 
local legal and regulatory requirements. 
As the site Principal Investigator, I agree to carry out the study by the criteria written in the protocol 
and understand that no changes can be made to this protocol without the written permission of the 
IRB and NIAID. 
[*The site Principal Investigator should sign and date at the indicated location below. A written 
signature/date is acceptable (e.g., scanned and sent via email as a PDF version). An electronic signature is 
also acceptable (e.g., sent via email as a PDF version).] 
 
____________________________________ 
Site Principal Investigator (Print) 
 
____________________________________ 
Site Principal Investigator (Signature) 
________________ 
Date 

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Protocol Synopsis 
Title 
Cockroach Immunotherapy in Children and Adolescents  
Short Title 
CRITICAL 
Clinical Phase 
II 
Number of Sites 
Multiple sites in the United States 
IND Sponsor/IND Number 
DAIT NIAID, NIH /IND #17979 
Study Objectives 
The primary objective of the study is to determine if the NAC response will 
be changed with treatment with cockroach subcutaneous immunotherapy 
(SCIT). 
Secondary objectives are: 
1. To assess safety of cockroach SCIT in children and adolescents 
2. To assess the effect of cockroach SCIT on German cockroach-
specific IgE and IgG4 
Study Design 
This is a 1:1 randomized, double-blind, placebo-controlled, multicenter 
trial with 2 arms: 
 
Cockroach SCIT  
 
Placebo 
This study will enroll 80 children from 8-17 years of age who are sensitized 
to cockroach and have asthma and a positive cockroach Nasal Allergen 
Challenge (NAC) before randomization.  
Primary Endpoint(s) 
Change in mean TNSS after 12 months of treatment with cockroach SCIT.  
Secondary Endpoint(s)  
1. Rate of immunotherapy related adverse events and 
immunotherapy related serious adverse events in the course of 
treatment 
2. Change in additional NAC outcomes from baseline 
a. TNSS AUC 
b. Responsive dose 
3. Changes in German cockroach-specific IgE and IgG4 
Accrual Objective 
~80  
Study Duration 
~48 months 

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Treatment Description  
Non-standardized glycerinated German cockroach (Blattella germanica) 
allergenic extract or placebo used by subcutaneous administration in 
escalating doses up to 0.4 ml of 1:10 wt./vol. 
Inclusion Criteria 
Individuals who meet all of the following criteria are eligible for 
enrollment as study participants: 
1. Subject and/or parent guardian must be able to understand and 
provide informed consent. 
2. Are male or female children, 8-17 years of age at recruitment. 
3. Have a primary place of residence in one of the pre-selected 
recruitment census tracts as outlined in the Protocol ICAC-28 
Manual of Operations (MOP) 
a. Participants who do not live in the pre-selected census 
tracts but live within the Office of Management and 
Budget (OMB) defined Metropolitan Statistical Area and 
have publicly-funded health insurance will qualify for 
inclusion. 
4. Have a history of persistent asthma for a minimum of 1 year 
before study entry.  
a. A diagnosis of asthma will be defined as a report by the 
caretaker that the participant had a clinical diagnosis of 
asthma made by a clinician > 1 year ago, resulting in a 
prescription of preventative asthma medication. 
b. The participant must have persistent asthma defined by 
the current need for at least 88 mcg fluticasone (or the 
equivalent of another inhaled corticosteroid) to control 
asthma at the time of screening. 
5. Before randomization, the participant’s asthma must be well-
controlled as defined by: 
a. A FEV1 greater than or equal to 80% predicted, and 
b. An Asthma Control Test (ACT) or Childhood Asthma 
Control Test (CACT) score ≥ 20. 
6. Are sensitive to German cockroach as documented by a positive (≥ 
3 mm greater than negative control) skin prick test result and 
detectable German cockroach-specific IgE (≥ 0.35 kUA/L). 
 
7. Have no known contraindications to therapy with glycerinated 
German cockroach allergenic extract or placebo. 
8. Have a positive cockroach Nasal Allergen Challenge (NAC), as 
defined by reaching a Total Nasal Symptom Score (TNSS) of ≥ 6 or 
a sneezing score of 3 at dose 2 or above during the challenge 
before randomization. 
9. Have documentation of current medical insurance with 
prescription coverage at randomization. 
Exclusion Criteria 
Individuals who meet any of these criteria are not eligible for enrollment 
as study participants but may be reassessed while enrollment is ongoing. 
Participants are ineligible if they: 

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1. Are unable or unwilling to give written informed consent or 
comply with study protocol. 
2. Are pregnant or lactating. Post-menarcheal females must be 
abstinent or use a medically acceptable birth control method 
throughout the study (e.g. oral, subcutaneous, mechanical, or 
surgical contraception). 
3. Cannot perform acceptable spirometry or peak flow before 
randomization. 
4. Have an asthma severity classification of severe or unstable at the 
time of randomization, as evidenced by at least one of the 
following: 
a. Require a dose of greater than 500 mcg of fluticasone per 
day or the equivalent of another inhaled corticosteroid. 
b. Have received more than 2 courses of oral or parenteral 
corticosteroids within the 12 months or one course within 
the last 3 months prior to study entry. 
c. Have been treated with depot steroids within the 3 
months prior to study entry. 
d. Have been hospitalized for asthma within the 6 months 
prior to study entry. 
e. Have had a life-threatening asthma exacerbation that 
required intubation, mechanical ventilation, or that 
resulted in a hypoxic seizure within 2 years prior to study 
entry. 
5. Do not have access to a phone (needed for scheduling 
appointments). 
6. Have received allergen immunotherapy (SLIT or SCIT) in the last 12 
months prior to study entry or who plan to initiate or resume 
allergen immunotherapy during the study.   
7. Have received biologic therapy (e.g., anti-IgE, anti-IL-4, anti-IL-5) 
within 6 months of the NAC procedure, if applicable, or 
Randomization, if no NAC is performed.  
8. Have received an investigational drug in the 30 days prior to study 
entry or who plan to use an investigational drug during the study. 
9. Have past or current medical problems or findings from physical 
examination or laboratory testing that are not listed above, which, 
in the opinion of the investigator, may pose additional risks from 
participation in the study, may interfere with the participant’s 
ability to comply with study requirements or that may impact the 
quality or interpretation of the data obtained from the study. 
10. Have nasal polyps or other major structural abnormalities in their 
nasal cavities as assessed by anterior rhinoscopy. 
Participants who meet any of the following criteria are not eligible for 
enrollment and may not be reassessed. Participants are ineligible if they: 
1. Plan to move from the area during the study period 
2. Have a history of anaphylaxis grade 3 or higher as defined in 
section 12.3.1.1c, World Allergy Organization Subcutaneous 
Immunotherapy Systemic Reaction Grading System.  

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3. Have unstable angina, significant arrhythmia, uncontrolled 
hypertension, history of autoimmune disease, or other chronic or 
immunological diseases that in the opinion of the investigator 
might interfere with the evaluation of the investigational product 
or pose additional risk to the participant. 
4. Past or current medical problems or findings from physical 
examination or laboratory testing that are not listed above, which, 
in the opinion of the investigator, may pose additional risks from 
participation in the study, may interfere with the participant’s 
ability to comply with study requirements or that may impact the 
quality or interpretation of the data obtained from the study. 
5. Are using tricyclic antidepressants or beta-adrenergic blocker 
drugs (both oral and topical). 
Study Stopping Rules 
Study enrollment and treatment will be suspended pending expedited 
review of all pertinent data after the occurrence of: 
1) One death if at least possibly related to the investigational agent 
2) Two Grade 4 systemic reactions (see Table 12.3.1.1c) possibly related 
to the injection of the immunotherapy agent  
3) Grade 4 local reaction (see Table 12.3.1.1a) or Grade 4 systemic 
reaction (see Table 12.3.1.1c) possibly related to the Nasal Allergen 
Challenge (NAC) 
a.  The study will be halted for this occurrence pending review of 
pertinent data by DAIT MM and the DSMB. 
 
 
 
 

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Table of Contents 
COCKROACH IMMUNOTHERAPY IN CHILDREN AND ADOLESCENTS ....................................... 1 
1 
Background and Rationale .................................................................................................................. 14 
1.1 
Background and Scientific Rationale .......................................................................................... 14 
1.2 
Rationale for Selection of Investigational Product or Intervention ............................................ 15 
1.3 
Preclinical Experience ................................................................................................................. 15 
1.4 
Clinical Studies ............................................................................................................................ 15 
1.4.1 
Immunotherapy .................................................................................................................. 15 
1.4.2 
Nasal Allergen Challenge (NAC) .......................................................................................... 16 
2 
Study Hypotheses/Objectives ............................................................................................................. 17 
2.1 
Hypotheses ................................................................................................................................. 17 
2.2 
Primary Objective ....................................................................................................................... 17 
2.3 
Secondary Objectives .................................................................................................................. 17 
2.4 
Exploratory Objectives ................................................................................................................ 17 
3 
Study Design ....................................................................................................................................... 17 
3.1 
Description of Study Design ........................................................................................................ 17 
3.2 
Primary Endpoint ........................................................................................................................ 19 
3.3 
Secondary Endpoints .................................................................................................................. 19 
3.4 
Exploratory Endpoints ................................................................................................................. 19 
3.5 
Stratification, Randomization, and Blinding/Masking ................................................................ 20 
3.5.1 
Procedure for Unblinding/Unmasking ................................................................................ 20 
4 
Selection of Participants and Clinical Sites/Laboratories ................................................................... 21 
4.1 
Rationale for Study Population ................................................................................................... 21 
4.2 
Inclusion Criteria ......................................................................................................................... 21 
4.3 
Exclusion Criteria......................................................................................................................... 21 
5 
Known and Potential Risks and Benefits to Participants .................................................................... 23 
5.1 
Risks of Investigational Product or Intervention as cited in Investigator Brochure or Package 
Insert 23 
5.2 
Risks of Investigational Product Cited in Medical Literature ...................................................... 23 
5.3 
Risks of Other Protocol Specified Medications ........................................................................... 23 
5.4 
Risks of Study Procedures ........................................................................................................... 24 
5.4.1 
Skin Prick Tests .................................................................................................................... 24 
5.4.2 
Venipuncture ...................................................................................................................... 24 
5.4.3 
Spirometry and Peak Flow Measurement .......................................................................... 25 

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5.4.4 
Nasal Allergen Challenge .................................................................................................... 25 
5.4.5 
Nasal Lavage ........................................................................................................................ 25 
5.4.6 
Influenza Vaccine ................................................................................................................ 26 
5.4.7 
Questionnaires .................................................................................................................... 26 
5.5 
Potential Benefits ........................................................................................................................ 26 
6 
Investigational Agent .......................................................................................................................... 26 
6.1 
Investigational Agent .................................................................................................................. 26 
6.1.1 
Formulation, Packaging, and Labeling ................................................................................ 27 
6.2 
Placebo ........................................................................................................................................ 27 
6.2.1 
Formulation, Packaging, and Labeling ................................................................................ 27 
6.3 
Dosage, Preparation, and Administration .................................................................................. 27 
6.3.1 
Subcutaneous Immunotherapy .......................................................................................... 27 
6.4 
Drug Accountability..................................................................................................................... 27 
6.5 
Assessment of Participant Compliance with Investigational Agent ........................................... 28 
6.6 
Toxicity Prevention and Management ........................................................................................ 28 
6.7 
Premature Discontinuation of Investigational Agent ................................................................. 28 
7 
Other Medications .............................................................................................................................. 28 
7.1 
Concomitant Medications ........................................................................................................... 28 
7.1.1 
Protocol-mandated ............................................................................................................. 28 
7.1.2 
Other permitted concomitant medications ........................................................................ 34 
7.2 
Prophylactic Medications ............................................................................................................ 34 
7.3 
Prohibited Medications ............................................................................................................... 35 
7.4 
Rescue Medications .................................................................................................................... 35 
7.4.1 
Definition and Management of Acute Exacerbations ......................................................... 35 
8 
Study Procedures ................................................................................................................................ 36 
8.1 
Study Assessments ...................................................................................................................... 36 
8.1.1 
Vital Signs and Growth Parameters .................................................................................... 36 
8.1.2 
Medical History and Physical Examination ......................................................................... 36 
8.1.3 
Aeroallergen Skin Testing ................................................................................................... 36 
8.1.4 
Measurement of Pulmonary Function ................................................................................ 37 
8.1.5 
Nasal Allergen Challenge .................................................................................................... 37 
8.1.6 
Nasal Lavage ........................................................................................................................ 38 
8.1.7 
Dust Sample Collection ....................................................................................................... 38 
8.1.8 
Questionnaire Assessments ................................................................................................ 39 

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8.2 
Clinical and Research Laboratory Evaluations and Specimen Collection ................................... 39 
8.2.1 
Blood Sample Collection ..................................................................................................... 39 
8.2.2 
Urine Pregnancy Testing ..................................................................................................... 39 
8.3 
Recruitment ................................................................................................................................ 39 
8.4 
Screening Procedures ................................................................................................................. 39 
8.4.1 
Screening Eligibility Visit ..................................................................................................... 39 
8.4.2 
Screening Nasal Allergen Challenge .................................................................................... 40 
8.4.3 
Asthma Control Optional Visits ........................................................................................... 41 
8.5 
Randomization ............................................................................................................................ 41 
8.6 
Follow-up .................................................................................................................................... 41 
8.6.1 
SCIT Dose Escalation ........................................................................................................... 41 
8.6.2 
Maintenance Visits .............................................................................................................. 43 
8.7 
Asthma Evaluation and Management (E&M) Visits .................................................................... 43 
8.8 
12-Month Visit ............................................................................................................................ 44 
8.9 
Early Termination Visit ................................................................................................................ 44 
8.10 
Unscheduled Visits ...................................................................................................................... 44 
8.11 
Visit Windows ............................................................................................................................. 45 
9 
Mechanistic Assays ............................................................................................................................. 45 
9.1 
Antibody Assays .......................................................................................................................... 45 
9.2 
Cellular Assays ............................................................................................................................. 45 
9.3 
Gene Expression .......................................................................................................................... 45 
10 
Biospecimen Storage ...................................................................................................................... 46 
11 
Criteria for Participant and Study Completion and Premature Study Termination ....................... 46 
11.1 
Participant Completion ............................................................................................................... 46 
11.2 
Participant Stopping Rules and Withdrawal Criteria .................................................................. 46 
11.2.1 
Discontinuation of Study Therapy ...................................................................................... 46 
11.2.2 
Discontinuation of Study Participation ............................................................................... 46 
11.3 
Participant Replacement ............................................................................................................. 47 
11.4 
Follow-up after Study Therapy Discontinuation ......................................................................... 47 
11.5 
Study Stopping Rules .................................................................................................................. 47 
12 
Safety Monitoring and Reporting ................................................................................................... 47 
12.1 
Overview ..................................................................................................................................... 47 
12.2 
Definitions ................................................................................................................................... 48 
12.2.1 
Adverse Event (AE) .............................................................................................................. 48 

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12.2.2 
Suspected Adverse Reaction (SAR) ..................................................................................... 49 
12.2.3 
Unexpected Adverse Event ................................................................................................. 49 
12.2.4 
Serious Adverse Event (SAE) ............................................................................................... 49 
12.3 
Grading and Attribution of Adverse Events ................................................................................ 50 
12.3.1 
Grading Criteria ................................................................................................................... 50 
12.3.2 
Attribution Definitions ........................................................................................................ 54 
12.4 
Collection and Recording of Adverse Events .............................................................................. 54 
12.4.1 
Collection Period ................................................................................................................. 54 
12.4.2 
Collecting Adverse Events ................................................................................................... 54 
12.4.3 
Recording Adverse Events................................................................................................... 55 
12.5 
Reporting of Serious Adverse Events and Adverse Events ......................................................... 55 
12.5.1 
Reporting of Serious Adverse Events to the IND Sponsor (DAIT/NIAID) ............................ 55 
12.5.2 
Reporting to FDA ................................................................................................................. 55 
12.5.3 
Reporting of Adverse Events to IRBs................................................................................... 56 
12.6 
Pregnancy Reporting ................................................................................................................... 56 
12.7 
Reporting of Other Safety Information ....................................................................................... 57 
12.8 
Review of Safety Information ..................................................................................................... 57 
12.8.1 
Medical Monitor Review ..................................................................................................... 57 
12.8.2 
DSMB Review ...................................................................................................................... 57 
13 
Statistical Considerations and Analytical Plan ................................................................................ 58 
13.1 
Overview ..................................................................................................................................... 58 
13.2 
Endpoints .................................................................................................................................... 58 
13.3 
Measures to Minimize Bias ......................................................................................................... 58 
13.4 
Analysis Plan ............................................................................................................................... 58 
13.4.1 
Analysis Populations ........................................................................................................... 58 
13.4.2 
Primary Analysis of Primary Endpoint................................................................................. 59 
13.4.3 
Supportive Analyses of the Primary Endpoint .................................................................... 59 
13.4.4 
Analyses of Secondary and Other Endpoints ...................................................................... 59 
13.4.5 
Analyses of Exploratory Endpoints ..................................................................................... 60 
13.4.6 
Descriptive Analyses ........................................................................................................... 61 
13.5 
Interim Analyses ......................................................................................................................... 61 
13.5.1 
Interim Analysis of Efficacy Data ......................................................................................... 61 
13.5.2 
Interim Analysis of Safety Data ........................................................................................... 61 
13.5.3 
Futility Analysis ................................................................................................................... 61 

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13.6 
Sample Size Considerations ........................................................................................................ 61 
14 
Identification and Access to Source Data ....................................................................................... 62 
14.1 
Source Data ................................................................................................................................. 62 
14.2 
Access to Source Data ................................................................................................................. 63 
15 
Protocol Deviations ......................................................................................................................... 63 
15.1 
Protocol Deviation Definitions .................................................................................................... 63 
15.1.1 
Protocol Deviation .............................................................................................................. 63 
15.1.2 
Major Protocol Deviation (Protocol Violation) ................................................................... 63 
15.1.3 
Non-Major Protocol Deviation ............................................................................................ 63 
15.2 
Reporting and Managing Protocol Deviations ............................................................................ 63 
16 
Ethical Considerations and Compliance with Good Clinical Practice .............................................. 64 
16.1 
Quality Control and Quality Assurance ....................................................................................... 64 
16.2 
Statement of Compliance ........................................................................................................... 64 
16.3 
Informed Consent Process .......................................................................................................... 64 
16.4 
Privacy and Confidentiality ......................................................................................................... 64 
17 
Publication Policy ............................................................................................................................ 65 
18 
References ...................................................................................................................................... 66 
Appendix A: Schedule of Procedures/Evaluations ...................................................................................... 68 
Appendix B: Study Restrictions Due to COVID-19....................................................................................... 69 
 
 
 
 

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Glossary of Abbreviations 
ACT 
Asthma Control Test 
AE 
Adverse Event 
ATS 
American Thoracic Society 
AUC 
Area under the curve 
BID 
Twice a day 
CASI 
Composite Asthma Severity Index 
CFR 
Code of Federal Regulations 
CR  
Cockroach 
CRF 
Case Report Form 
CTCAE 
Common Terminology Criteria for Adverse Events 
DAIT 
Division of Allergy, Immunology, and Transplantation 
DSMB 
Data Safety Monitoring Board 
eCRF 
Electronic Case Report Form 
E&M 
Evaluation and Management 
FDA 
Food and Drug Administration 
FENO 
Fractional Exhaled Nitric Oxide 
FEV1 
Forced Expiratory Volume in 1 second 
GCP 
Good Clinical Practice 
HIPPA 
Health Insurance Portability and Accountability Act 
IB 
Investigator Brochure 
ICAC 
Inner-City Asthma Consortium 
ICH 
International Conference on Harmonization 
ICS 
Inhaled Corticosteroid 
IgE 
Immunoglobulin E 
IgG 
Immunoglobulin G 
IND 
Investigational New Drug 
IRB 
Institutional Review Board 
ITT 
Intent-to-treat 
LABA 
Long-acting Beta Agonist 

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MCG 
Microgram 
MCL 
Microliter 
MM 
Medical Monitor 
MOP 
Manual of Procedures 
NAC 
Nasal Allergen Challenge 
NAEPP 
The National Asthma Education and Prevention Program 
NCI 
National Cancer Institute 
NIAID 
National Institute of Allergy and Infectious Diseases 
OMB 
Office of Management and Budget 
PCP 
Primary Care Provider 
PD 
Protocol Deviation 
PEF 
Peak Expiratory Flow 
PFT 
Pulmonary Function Tests 
PI 
[Site] Principal Investigator 
SACCC 
Statistical and Clinical Coordinating Center 
SAE 
Serious Adverse Event 
SAP 
Statistical Analysis Plan 
SAR 
Suspected Adverse Reaction 
SCIT 
Subcutaneous Immunotherapy 
SLIT 
Sublingual Immunotherapy 
SOP 
Standard Operating Procedure 
SUSAR 
Suspected Unexpected Serious Adverse Reaction 
TLC 
Total Lung Capacity 
TNSS 
Total Nasal Symptom Score 
WAO 
World Allergy Organization 
 
 
 

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1 Background and Rationale  
1.1 Background and Scientific Rationale 
Cockroach allergen has been established as one of the leading causative agents for morbidity in inner-
city children with asthma.1  Although the negative effects of cockroach exposure have been known for 
almost 20 years, eradication and avoidance, which can be impossible to achieve in the housing available 
to lower socioeconomic urban populations, is still the mainstay of treatment.2 Given these data, a major 
goal of the NIAID-funded Inner-City Asthma Consortium (ICAC) is to conduct a large multi-center efficacy 
trial of cockroach immunotherapy in inner-city asthma.  While we have pursued the possibility of using 
sublingual immunotherapy (SLIT) given its excellent safety profile, data from the completed DAIT NIAID-
sponsored Protocol ICAC-12 BioCSI and Protocol ICAC-17 BioCSI2 studies  of cockroach SLIT have 
suggested that SLIT for cockroach may not be effective due to limitations in the maximum doses that 
can be provided with currently available cockroach extracts.3,4 These studies have also generated 
concerns about the likelihood of compliance with daily SLIT therapy, an issue that may both reduce 
efficacy and potentially increase risk.  A pilot study of cockroach SCIT was conducted in 10 adults 
(Protocol ICAC-18 SCITCO) with a primary focus on safety to lay the groundwork for a possible efficacy 
study using SCIT given the distinct possibility that cockroach SLIT will not prove effective and / or 
feasible.  The SCITCO study demonstrated an excellent safety profile, as well as robust markers of 
immunologic response, and with the current study our goal is to extend that approach into a pediatric 
population.3  
There is a vast clinical and research experience with the use of SCIT for the treatment of asthma and 
allergic rhinitis, as well as stinging insect hypersensitivity.5-12 While there is a higher risk of systemic 
reactions with SCIT compared to SLIT, the overall safety profile of SCIT is very favorable, as is the overall 
SCIT risk benefit ratio given the markedly salutary effects demonstrated in most studies.  As with SLIT, 
the efficacy of SCIT depends on the use of adequate dosages, but we are confident that the available 
extracts will prove adequate in this regard.9,13  
The rationale for this study is that SCIT may be the only option for effective cockroach immunotherapy. 
In fact, the only studies that demonstrated efficacy of cockroach immunotherapy used SCIT.14,15 We 
intend in this study to test the effects of cockroach SCIT on asthma control, as well as safety and 
immunologic biomarkers, in a pediatric population.  
Unlike pollen allergy, where symptoms characteristically peak during a particular season, or allergy to 
animals (e.g., cat, dog), where symptoms are induced upon exposure, there is no specific period during 
the year at which assessment of the efficacy of SCIT on natural cockroach allergen exposure can be 
undertaken.  This only leaves the option of year-round clinical evaluations of symptoms, medication use, 
lung function and asthma exacerbations as clinical outcomes of a cockroach allergen immunotherapy 
study.  Although these are very relevant outcomes, our ability to attribute them directly to the effect of 
single allergen immunotherapy is uncertain. A negative outcome could be due either to the failure of 
SCIT to reduce allergic responses to cockroach, or because ameliorating cockroach allergy is insufficient 
to change the clinical outcome in polysensitized individuals with asthma.  In this context, provocation 
testing with cockroach allergen could be used to objectively document the response to SCIT.  Nasal 
Allergen Challenge (NAC) is an established type of provocation testing commonly used in the research 
setting to assess early stage efficacy of nasal allergy treatments, including allergen immunotherapy, and 
to study the pathophysiology of allergic reactions in an accessible part of the respiratory tract.16,17  The 

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outcomes of Nasal Allergen Challenge (NAC) are not lower airway outcomes, but the purpose of using 
this form of assessment in the context of this trial is to establish that treatment is effective against 
mucosal reactions to the allergen in question and not to substitute for asthma outcomes.  As the 
majority of children with allergic asthma also have allergic rhinitis and improvement in upper respiratory 
control is beneficial in asthma, the nasal challenge may have a direct clinical relevance in a study of 
allergen immunotherapy for asthma.  An alternative approach would have been to establish a bronchial 
cockroach allergen provocation18, but this procedure raises more safety concerns and is more 
complicated and time consuming than Nasal Allergen Challenge (NAC).       
Very few studies examining nasal challenge with cockroach allergen have been reported, and no study 
provides adequate information on safety and dosing in adults or children.19-21 For further details, please 
refer to DAIT NIAID’s Investigator Brochure (IB) for German Cockroach Allergenic Extract for Nasal 
Allergen Challenge (NAC).   
1.2 Rationale for Selection of Investigational Product or Intervention 
The investigational agent for Protocol ICAC-28 is 1:10 w/v non-standardized glycerinated German 
cockroach (Blattella germanica) allergenic extract obtained from Stallergenes Greer (Lenoir, NC) 
administered by the subcutaneous route. Placebo for immunotherapy is (glycerin 50% v/v, Sodium 
Bicarbonate 0.091%, Sodium Chloride 0.166%, water for injection q.s.) administered by the 
subcutaneous route obtained from Allergy Laboratories, Inc. (Oklahoma City, OK).   
The selection of this particular extract was based on the potency of German cockroach extracts available 
for skin testing and allergen immunotherapy on the market. The maintenance dose for ICAC-28 will be 
approximately 6 micrograms (mcg).  No data exists as to the clinically effective dose allergen for SCIT. 
Therfore the maintenance dose was selected based on information from other allergens where 
maintenance doses range from 5 to 15 micrograms have proven effective,9,13 and in the SCITCO trial 
(Protocol ICAC-18) a maintenance containing 6 mcg of Bla g 2 induced consistent immunologic 
responses.3      
1.3 Preclinical Experience 
Not applicable. 
1.4 Clinical Studies 
1.4.1 
Immunotherapy 
While only two published studies have assessed the potential efficacy of cockroach SCIT,14,15 there is a 
vast body of literature and clinical experience with the use of SCIT for other allergens.  A recent practice 
parameter detailed the use of SCIT for inhalant allergens as well as stinging insects.5  In addition, meta-
analyses have confirmed the effectiveness of SCIT for the treatment of asthma, allergic rhinitis, and 
stinging insect hypersensitivity.7,8,11,12 A 2003 Cochrane review of 75 trials including 3188 patients with 
asthma found that overall SCIT led to a significant reduction in asthma symptoms, medication use, and 
bronchial hyperreactivity.8  For example, in that review, it was determined that it would have been 
necessary to treat 4 patients with immunotherapy to avoid 1 deterioration in asthma symptoms and 5 
patients to avoid 1 requiring increased asthma medication. 
With regard to the published studies on allergy to cockroach, Kang et al. studied 28 adults with asthma 
and positive cockroach allergen skin tests; all had positive skin tests to other inhalant allergens as well.14 

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Subjects were randomized to immunotherapy with cockroach allergen extract (active group, n = 15) or 
immunotherapy with allergens other than cockroach (control, n = 13), and treated for 5 years. Upon 
study completion, 5 of the control subjects had switched to cockroach immunotherapy and 6 subjects (4 
active, 2 control) were dropped from the study. In the active group, average symptom scores decreased 
from 7.2 at baseline to 1.2, while the control group showed no change. IgG antibodies against cockroach 
increased in the treated group. Adverse reactions were not mentioned.  We do not know how the 
extract used in this trial compares in terms of antigen content and stability with the one that will be 
used in Protocol ICAC-28. 
The second study on cockroach SCIT actually focused on American cockroach, an allergen far less 
important in inner cities, and the U.S. in general, than German cockroach.15  In this double-blind, 
placebo-controlled trial, 50 patients with asthma, rhinitis or both were treated with cockroach SCIT or 
placebo for one year.  They found that active SCIT led to significant improvement in clinical parameters 
compared with baseline values and the placebo group.  They also demonstrated modest reductions in 
cockroach-specific IgE levels and significant increases in specific IgG4 levels.   
1.4.2 
Nasal Allergen Challenge (NAC) 
There have been three reports of Nasal Allergen Challenge (NAC) with cockroach extract in the 
literature.19-21  
In the Hosen study, 174 patients of unreported ages underwent nasal provocation testing to insects 
common to Texas.  An unclear number of these patients underwent nasal provocation testing 
specifically to cockroach.  The extract used as the diagnostic agent was a powdered concentration of 
cockroach, which was directly inhaled by the patients in the setting of Nasal Allergen Challenge (NAC) 
with multiple allergen extracts in powdered form.  Participants would be treated with phenylephrine 
hydrochloride and, if needed, a bronchodilator in between allergen challenges.  Sixty-nine patients were 
reported to have had a systemic reaction to 1 of the allergen extracts.  For cockroach in particular, 16 
total reactions were reported, of which 11 were nasal, 2 were listed as bronchial asthma, and 3 were 
listed as post-nasal and upper bronchial.21  
In the Okuda study, 560 patients from the ages of 4 to 80 years old (mean 31.3 years; 112 participants 
were 19 years old or younger) with allergic rhinitis were recruited to undergo an evaluation for insect 
allergy.  Sixty-five participants of unknown ages were selected by unspecified means from the pool of 
560 patients to undergo Nasal Allergen Challenge (NAC) with a mixture of German cockroach, 
Chironomus yoshimatsui, and silkworm moth.  The publication did not mention whether there were any 
adverse reactions from the Nasal Allergen Challenge (NAC).19  
The most recent and informative study evaluated the concept of localized allergy in patients with 
nonallergic rhinitis.  In that study, 16 adult volunteers underwent sequential nasal allergen testing with a 
variety of aeroallergens, including a cockroach extract mix.  The cockroach mix nasal allergen testing was 
done with an arbitrarily chosen single dose of 100 µL of 1:5000 (w/v), and no testing was conducted 
prior to the challenge to establish a dose.  No adverse events were reported in this published report.20  
For further details, please refer to the Investigator Brochure for German Cockroach Allergenic Extract for 
Nasal Allergen Challenge (NAC). 
 
 

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2 Study Hypotheses/Objectives 
2.1 Hypotheses 
The primary hypothesis to be tested by this study is that subcutaneous treatment with German 
cockroach (Blattella germanica) extract will induce changes in nasal allergen challenge outcomes.  A 
major secondary hypothesis is that subcutaneous treatment with German cockroach (Blattella 
germanica) extract will induce significant changes in immunologic biomarkers indicative of 
desensitization in children with persistent, well-controlled asthma. 
2.2 Primary Objective 
The primary objective of this study is to determine if the response to nasal allergen challenge (NAC) will 
be changed with treatment with cockroach SCIT.   
2.3 Secondary Objectives 
1. To assess safety of cockroach SCIT in adolescents and children 
2. To assess the effect of cockroach SCIT on German cockroach-specific IgE and IgG4 
2.4 Exploratory Objectives 
1. To assess the effect of cockroach SCIT on asthma severity as measured by the CASI score 
2. To assess improvements in components of the CASI asthma severity score 
3. To assess the effect of cockroach SCIT on rhinitis symptoms and medication requirements 
4. To assess the effect of cockroach SCIT on component allergens, including, but not limited to, Bla 
g 1, Bla g 2, Bla g 4, Bla g 5, and Per A 1 
5. To assess the effect of cockroach SCIT on cockroach-specific blocking antibodies 
6. To assess the effect of cockroach SCIT on skin test reactivity 
7. To assess the effect of cockroach SCIT on other key mechanistic parameters 
8. To assess the role of environmental cockroach exposure on the relationship between treatment 
with cockroach SCIT and asthma and rhinitis outcomes  
9. To assess the relationship of change in NAC to change in CASI 
3 Study Design 
3.1 Description of Study Design  
This study is a randomized, double-blind, placebo-controlled, multicenter trial of non-standardized 
glycerinated German cockroach (Blattella germanica) allergenic extract or placebo treatment 
administered by subcutaneous injection. 
Participants will be randomized to 1 of 2 treatment groups in a ratio of 1:1: 
1. German cockroach allergenic extract administered by subcutaneous injection. 
2. Placebo administered by subcutaneous injection.  
Protocol ICAC-28 will enroll eighty 8 to 17-year-old cockroach sensitive children with asthma with a 
positive cockroach Nasal Allergen Challenge (NAC) before randomization.  
 

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The intended maintenance dose of German cockroach allergenic extract is ≈6 mcg of Bla g 2. The study 
will be based on a treatment schedule with German cockroach allergenic extract or placebo for 12 
months. 
There will be a Screening phase to determine eligibility, including a positive IgE and skin test to German 
cockroach. If asthma control parameters are not met, participants will begin a run-in period, during 
which participants’ asthma medications will be adjusted for up to 4 months to achieve symptom control 
before completing an initial NAC procedure. Eligible participants with a positive NAC will then be 
randomized to one of the two treatment arms and receive their first injection.  Up to 2 doses of SCIT will 
be given weekly during dose escalation, separated by a minimum of 2 days. Dose escalation can be 
delayed at any point for systemic or local reactions, although to continue to maintenance each 
participant will need to reach the minimum maintenance dose in a maximum of 40 weeks (see Appendix 
B: Study Restrictions Due to COVID-19).  Once the maintenance dose is achieved, participants will 
receive two additional maintenance level-doses (for a total of three maintenance level-doses) spaced 
approximately 2 weeks apart, followed by maintenance injections every 4 weeks for the remainder of 
the treatment period.   
At Randomization and every 2 months during treatment, an asthma Evaluation and Management (E&M) 
process will occur where participants’ asthma medication regimen will be adjusted based on symptoms, 
albuterol/levalbuterol use, FEV1, recent exacerbations, and their current level of therapy.  
All participants must have a positive cockroach NAC, as defined by reaching a Total Nasal Symptom 
Score (TNSS) of ≥ 6 or a sneezing score of 3 at Dose 2 or higher during the challenge before 
randomization and will undergo follow-up NAC procedures at 12 months.  
Blood will be collected at Screening, prior to Randomization, and after 12 months of treatment for 
assessment of biomarkers of allergen immunotherapy, such as cockroach-specific IgE, IgG4, and 
component allergens, including Bla g 1, Bla g 2, Bla g 4, Bla g 5, and Per A 1, and inhibition of cockroach 
antigen binding to B-cells. Skin testing (German cockroach) will be performed during the Screening 
phase and at 12 months.  CASI will be collected every 2 months (See Visit Activities Summary, Appendix 
A).  
Adverse events (AEs) will be assessed at each study visit. Pulmonary function and rhinitis and asthma 
symptom questionnaires will also be administered at Screening and every two months thereafter.  

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Figure 1. Protocol ICAC-28 CRITICAL Study Design Schematic  
3.2 Primary Endpoint 
The primary study endpoint is the change in mean TNSS after 12 months of treatment with cockroach 
SCIT. 
3.3 Secondary Endpoints 
1. Rate of immunotherapy related adverse events and immunotherapy related serious adverse 
events in the course of treatment 
2. Change in additional NAC outcomes from baseline 
a. TNSS AUC 
b. Responsive dose 
3. Changes in German cockroach-specific IgE and IgG4 
3.4 Exploratory Endpoints 
1. CASI score over the 2 assessments occurring between 10 and 12 months of treatment  
2. Additional asthma severity outcome measures 
a. Number of days with asthma symptoms (wheezing or tightness in the chest or cough) 
b. Number of nights with asthma symptoms (waking up because of wheezing or tightness 
in the chest or cough) 
c. Number of days with albuterol use 
d. Number of nights with albuterol use 
e. Asthma treatment step (medication requirements) 
f. Asthma exacerbations 
g. FEV1 

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3. Rhinitis severity outcome measures 
a. Modified Rhinitis Symptom Utility Index 
b. Rhinitis treatment step (medication requirements) 
4. Changes in component allergens, including Bla g 1, Bla g 2, Bla g 4, Bla g 5, and Per A 1 
5. Change in cockroach-specific blocking antibodies 
6. Change in cockroach skin test reactivity 
7. Changes in cockroach-specific T cell response  
8. Changes in PBMC gene expression response to CR stimulation  
9. Changes in nasal lavage gene expression 
3.5 Stratification, Randomization, and Blinding/Masking 
The randomization schedule will be generated by the DAIT NIAID Statistical and Clinical Coordinating 
Center (SACCC) and implemented in a validated system that will be used by site personnel to automate 
the random assignment of treatment groups to study participants.  The randomization scheme will be 
reviewed and approved by a statistician at the DAIT SACCC and will not be modified thereafter except to 
accommodate any changes required by amendments to the protocol . Participants will be randomized 
using a 1:1 ratio of active (German cockroach extract) and control (placebo) participants. Randomization 
will be stratified by site. 
Randomization data will be kept strictly confidential, accessible only to authorized persons, until the 
time of unblinding. When the study has been completed, the data files verified, and the protocol 
deviations determined, the investigational agent codes will be broken and made available for data 
analysis. 
The clinical site’s research pharmacy will dispense to the clinical research site unblinded nurse the study 
drug based on the unique vial IDs communicated by the randomization system at randomization and any 
subsequent dosing visits. The SCIT injections will be administered by trained clinical research staff. Prior 
to injection, an unblinded staff member will confirm the expiration date, the dose, and 
randomization/investigational product assignment kit number.  
3.5.1 
Procedure for Unblinding/Unmasking 
Unblinding must be approved by the DAIT/NIAID Medical Monitor (MM) unless an immediate life-
threatening condition has developed and the Medical Monitor is not accessible.  Automatic notifications 
of any unblinding event will be sent to study personnel as specified in the Protocol ICAC-28 MOP. 
Unblinding events will also be reported to the NIAID Allergy and Asthma Data and Safety Monitoring 
Board (DSMB). 
A full account of the event will be recorded, including the date and time of the unblinding, the reason 
for the decision to unblind, and the name of the individual who made the decision and the names of the 
DAIT NIAID Medical Monitor and others who were notified. The reasons for unblinding of a participant’s 
treatment will be included in the final clinical study report. 
Unblinding the study due to an approved interim analysis, final analysis, or study termination will 
require written approval from the DAIT NIAID Medical Monitor. 

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4 Selection of Participants and Clinical Sites/Laboratories 
4.1 Rationale for Study Population 
Because the combination of cockroach allergy and cockroach exposure is one of the most important 
factors contributing to the increased asthma morbidity seen in inner-city children with asthma, a major 
goal of the NIAID-funded ICAC is to conduct a large multi-center efficacy trial of cockroach 
immunotherapy in this population. DAIT NIAID-sponsored studies of SLIT – Protocols ICAC-10, ICAC-12, 
and ICAC-17 (IND # 13163) in both adults and children had limited success and pointed to challenges 
with adherence to the daily dosing regimen. Daily adherence may be particularly difficult for children 
and adolescents. DAIT NIAID-sponsored Protocol ICAC-18 SCITCO (IND exempt, BB-IND # 14330) study in 
adults, on the other hand, demonstrated an excellent safety profile, as well as robust biomarkers of 
immunologic response, and with the current study our goal is to extend that approach into a pediatric 
population using CASI as the primary measure of efficacy. 
4.2 Inclusion Criteria 
Individuals who meet all of the following criteria are eligible for enrollment as study participants:  
1. Subject and/or parent guardian must be able to understand and provide informed consent. 
2. Are male or female children, 8 through 17 years of age at recruitment. 
3. Have a primary place of residence in one of the pre-selected recruitment census tracts as outlined in 
the Protocol ICAC-28 Manual of Operations (MOP). 
a. Participants who do not live in the pre-selected census tracts but live within the Office of 
Management and Budget (OMB) defined Metropolitan Statistical Area and have publicly-
funded health insurance will qualify for inclusion. 
4. Have a history of persistent asthma, for a minimum of 1 year before study entry. 
a. A diagnosis of asthma will be defined as a report by the caretaker that the participant had a 
clinical diagnosis of asthma made by a clinician > 1 year ago, resulting in a prescription of 
preventative asthma medication. 
b. The participant must have persistent asthma defined by the current need for at least 88 mcg 
fluticasone (or the equivalent of another inhaled corticosteroid) to control asthma at the 
time of screening.  
5. Before randomization, the participant’s asthma must be well-controlled as defined by: 
a. A FEV1 greater than or equal to 80% predicted 
b. An Asthma Control Test (ACT) or Childhood Asthma Control Test (CACT) score ≥ 20. 
6. Are sensitive to German cockroach as documented by a positive (≥ 3 mm greater than negative 
control) skin prick test result and detectable German cockroach-specific IgE (≥ 0.35 kUA/L). 
7. Have no known contraindications to therapy with glycerinated German cockroach allergenic extract 
or placebo. 
8. Have a positive cockroach Nasal Allergen Challenge (NAC), as defined by reaching a Total Nasal 
Symptom Score (TNSS) of ≥ 6 or a sneezing score of 3 at dose 2 or above during the challenge before 
randomization. 
9. Have documentation of current medical insurance with prescription coverage at randomization. 
4.3 Exclusion Criteria 
Individuals who meet any of these criteria are not eligible for enrollment as study participants but may 
be reassessed while enrollment is ongoing. Participants are ineligible if they: 

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1. Are unable or unwilling to give written informed consent or comply with study protocol. 
2. Are pregnant or lactating. Post-menarcheal females must be abstinent or use a medically 
acceptable birth control method throughout the study (e.g. oral, subcutaneous, mechanical, or 
surgical contraception). 
3. Cannot perform spirometry or peak flow before randomization. 
4. Have an asthma severity classification at the time of randomization of severe persistent, using 
the NAEPP classification, as evidenced by at least one of the following: 
a. Require a dose of greater than 500 mcg of fluticasone per day or the equivalent of another 
inhaled corticosteroid. 
b. Have received more than 2 courses of oral or parenteral corticosteroids within the 12 
months or one course within the last 3 months prior to study entry. 
c. Have been treated with depot steroids within the 3 months prior to study entry. 
d. Have been hospitalized for asthma within the 6 months prior to study entry. 
e. Have had a life-threatening asthma exacerbation that required intubation, mechanical 
ventilation, or that resulted in a hypoxic seizure within 2 years prior to study entry. 
5. Do not have access to a phone (needed for scheduling appointments). 
6. Have received allergen immunotherapy (SLIT or SCIT) in the last 12 months or who plan to 
initiate or resume allergen immunotherapy during the study. 
7. Have received biologic therapy (e.g., anti-IgE, anti-IL-4, anti-IL-5) within 6 months of the NAC 
procedure, if applicable, or Randomization, if no NAC is performed. 
8. Have received an investigational drug in the 30 days prior to recruitment or who plan to use an 
investigational drug during the study. 
9. Have past or current medical problems or findings from physical examination or laboratory 
testing that are not listed above, which, in the opinion of the investigator, may pose additional 
risks from participation in the study, may interfere with the participant’s ability to comply with 
study requirements or that may impact the quality or interpretation of the data obtained from 
the study. 
10. Have nasal polyps or other major structural abnormalities in their nasal cavities as assessed by 
anterior rhinoscopy. 
Participants who meet any of the following criteria are not eligible for enrollment and may not be 
reassessed. Participants are ineligible if they: 
1. Plan to move from the area during the study period. 
2. Have a history of anaphylaxis grade 3 or higher as defined in section 12.3.1.1c, World Allergy 
Organization Subcutaneous Immunotherapy Systemic Reaction Grading System.  
3. Have unstable angina, significant arrhythmia, uncontrolled hypertension, history of autoimmune 
disease, or other chronic or immunological diseases that in the opinion of the investigator might 
interfere with the evaluation of the investigational product or pose additional risk to the 
participant. 
4. Past or current medical problems or findings from physical examination or laboratory testing 
that are not listed above, which, in the opinion of the investigator, may pose additional risks 
from participation in the study, may interfere with the participant’s ability to comply with study 
requirements or that may impact the quality or interpretation of the data obtained from the 
study. 

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5. Are using tricyclic antidepressants or beta-adrenergic blocker drugs (both oral and topical). 
5 Known and Potential Risks and Benefits to Participants 
5.1 Risks of Investigational Product or Intervention as cited in Investigator Brochure or Package Insert 
Per “Allergenic Extract: Instructions for Use and Dosing Schedule”  (Allermed Laboratories, Inc., San 
Diego, CA), “Allergenic Extracts Pollens, Mold, Intradermal, Insects, Dust, Food and Miscellaneous  
Inhalants: Suggested Dose Schedule and Instructions” (Greer, Lenoir, NC) and the current version of 
DAIT NIAID’s Investigator Brochure German Cockroach Allergenic for Nasal Allergen Challenge (NAC) , 
risks of exposing participants to allergens via immunotherapy include, but are not limited to: itching of 
the mouth, ears, and throat, itching or swelling of the eyes, nasal congestion, sneezing, rhinorrhea, oral 
or throat angioedema, cough, chest tightness, wheezing, gastrointestinal symptoms (vomiting, diarrhea, 
abdominal pain), skin symptoms (rash, hives, swelling, itching), and anaphylaxis. We expect that the 
main sign and/or symptom experienced by participants will be localized swelling at the injection site 
occurring within 30 minutes after administration of the immunotherapy injection. Large local reactions 
associated with allergen immunotherapy are common, with a frequency ranging from 26% to 86% of 
injections.22 
Additionally, clinical research staff may apply a topical anesthetic to the skin before giving the injection 
to reduce the discomfort of the stick. Side effects from topical anesthetics include erythema, burning, 
paleness at the skin site, edema, and alterations in temperature. Reactions are mild and transient. There 
is a potential for cutaneous allergic reactions to topical anesthetics.  
The risks to a fetus are unknown and SCIT is generally not initiated during pregnancy. Pregnant females 
will be excluded from the Protocol ICAC-28. All females who have reached menarche will be required to 
have a urine pregnancy test before completing study activities at Screening, Randomization, 12-month 
visit, visits where the NAC is performed, monthly during the escalation phase, and at each Evaluation 
and Management Visit (E&M) during maintenance. Urine pregnancy testing will ensure no pregnant 
female will be entered into the study, and any female becoming pregnant during the study will be 
discontinued. Safety follow-up of pregnant participants is described in section 12.6. 
5.2 Risks of Investigational Product Cited in Medical Literature 
In published studies of SCIT,  systemic anaphylactic reactions with other inhalant allergens have been 
reported to occur in from 1% of patients to as many as 36% of patients receiving SCIT using a rush 
schedule.23,24 Protocol ICAC-28 does not involve a rush immunotherapy schedule. Fatalities are very rare 
but have been reported, as have specific risk factors for fatal reactions, which include unstable asthma, 
beta-blocker therapy, rush immunotherapy, and use of high doses of potent standardized extracts.23 In 
our SCITCO study (Protocol ICAC-18), in 10 adults undergoing six months of SCIT, there were 2 serious 
adverse neither of which were considered related to the therapy.3  
5.3 Risks of Other Protocol Specified Medications 
The risks from inhaled corticosteroids (ICS) are minimal but may include upper respiratory tract 
infection, throat irritation, sinusitis/sinus infection, upper respiratory inflammation, rhinitis, oral 
candidiasis, nausea and vomiting, gastrointestinal discomfort, viral gastrointestinal infection, non-
specific fever, viral infection, viral respiratory infection, cough, bronchitis, headache, muscle injury, 

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musculoskeletal pain, and injury. ICS have also been associated with modest growth effects. Height will 
be monitored throughout the study, by calibrated stadiometers.   
Oral corticosteroids can cause hoarseness, sore throat, and yeast infection of the mouth or throat if 
taken in high doses for lengthy periods of time.  In addition, they can cause effects on the body such as 
weight gain, growth delay, bruising of the skin, cataracts, and diabetes. These effects are more likely if 
the medicine is taken at very high doses for extended periods of time.  These side effects are not 
anticipated in this study because of the length of time (4 days on any occasion) that oral corticosteroids 
will be taken. 
The risks of long acting beta agonists (LABAs) include diarrhea, nausea, asthma exacerbation, bronchitis, 
respiratory infection, anxiety, fever, dizziness, insomnia, chest pain.  There is also a small, but 
statistically significant risk of asthma-related death. This study will follow black box guidelines by using 
LABAs as an adjuvant therapy in patients not adequately controlled on inhaled steroids. 
The risks from inhaled albuterol include increased heart rate and blood pressure, nausea, headache, and 
a jittery or nervous feeling. These symptoms usually resolve within one hour. 
5.4 Risks of Study Procedures  
5.4.1 
Skin Prick Tests 
Participants may experience mild to moderate pruritus or local discomfort at the sites of skin pricks with 
allergen and the positive control (histamine dihydrochloride 10 mg/mL). Usually, the allergen-induced 
wheal and flare responses resolve within 1–2 hours, but rarely a participant may have local swelling that 
takes 2-3 days to clear entirely. Rarely skin testing will cause the participant being tested to have 
systemic allergic symptoms. These symptoms may include sneezing, ocular pruritus and tearing, 
rhinorrhea and/or generalized pruritus or urticaria. Treatment with topical corticosteroids and oral 
antihistamines is available and is effective. A study clinician is always present and drugs and equipment 
for treatment of anaphylactic reactions are available. Stopping antihistamines before skin testing may 
make allergy (but not asthma) symptoms worse. Participants will be told they can take their medications 
if they need them, but the test will need to be rescheduled. 
There is also a very rare chance that the participant may experience a systemic allergic reaction or 
fainting.  A study clinician will be available to provide immediate treatment, if needed.  Further, we 
believe that performance of such allergen evaluation is consistent with national asthma guidelines, and 
provides direct benefits to participants. The results of the skin tests are provided to participants. 
5.4.2 
Venipuncture 
The risks associated with a blood draw include possible pain from the stick, as well as bleeding, bruising, 
and infection of the skin. Lightheadedness and fainting rarely occur. To minimize these risks, a clinical 
research staff member who is trained to draw blood from children will collect the samples. Additionally, 
clinical research staff may apply a topical anesthetic to the skin before the blood draw to reduce the 
discomfort of the stick. Side effects from topical anesthetics include erythema, burning, paleness at the 
skin site, edema, and alterations in temperature. Reactions are mild and transient. There is a potential 
for cutaneous allergic reactions to topical anesthetics. Topical anesthetics are routinely used for usual 
care venipunctures to minimize discomfort. The amount of blood to be collected is within the NIH 
pediatric guidelines. 

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5.4.3 
Spirometry and Peak Flow Measurement 
Spirometry and peak flow measurements will be performed by trained and certified clinical research 
staff according to American Thoracic Society (ATS) standards as performed routinely in usual care as part 
of subspecialist management of asthma. 
Spirometry and peak expiratory flow measurement can cause coughing or lightheadedness, which will 
go away shortly after the test is finished.  
5.4.4 
Nasal Allergen Challenge 
Nasal Allergen Challenge (NAC) involves the direct application by trained clinical research staff of one or 
more defined doses of allergen onto the participant’s nasal mucosa using a nasal drug delivery system 
(LMA® MAD Nasal delivery system LMA/Teleflex, San Diego, CA). Nasal Allergen Challenge is expected to 
cause allergic symptoms such as nasal congestion, sneezing, nasal discharge, and itchy, watery eyes 
which may last up to several hours after the last dose is administered. If nasal and/or ocular symptoms 
persist after the period of observation in the clinical unit, participants will be offered treatment with oral 
antihistamines. There is a very small risk of provoking asthma symptoms. If PEF is reduced by more than 
20% from baseline or if asthma symptoms develop at any step during the NAC, the procedure will be 
suspended, the participant will be treated, and FEV1 will be measured. To minimize this risk, individuals 
with a pre-bronchodilator FEV1 of less than 80% of predicted are not allowed to perform this procedure.  
In addition, a targeted pulmonary exam will be conducted at each NAC visit. The allergen will be 
delivered to the nose while subjects are breath holding at Total Lung Capacity (TLC) and will be asked to 
exhale through their nose thereafter thus minimizing the potential for allergen to reach the lower 
airways.  As for any intervention with allergen to which the patient is sensitive, there is the slight risk of 
developing an anaphylactic reaction. Trained personnel, including a study clinician, as well as 
medications and equipment, will be immediately available to treat any reaction. 
A recent DAIT NIAID-sponsored clinical study evaluated the safety of cockroach nasal allergen challenge 
in adults and children with asthma. Protocol ICAC-27 CoNAC conducted under DAIT NIAID-sponsored 
IND #16512 performed cockroach nasal allergen challenges on twenty-five children, and no reportable 
adverse events were linked to the study drug. Nasal allergen challenge has been performed with other 
allergens (perennial and seasonal) in children with asthma and found to be low risk.  Mild cough or 
wheezing developed shortly after the nasal challenge in 2 out of 25 children,25 while in another study a 
slight drop (10%) in FEV1 was noted in 1 out of 50 children immediately following nasal allergen 
challenge.26  Twenty-four hours after the NAC, 1 out of 50 children had an asthma exacerbation with a 
febrile viral infection.26 Pedroletti et al. demonstrated that a single nasal allergen challenge with cat 
allergen was not associated with increased bronchial inflammation, as assessed by FENO, among cat 
allergic children with asthma.27 For further details, please refer to the Investigator Brochure for German 
Cockroach Allergenic Extract for Nasal Allergen Challenge. 
 
5.4.5 
Nasal Lavage 
Nasal lavage may be associated with some transient discomfort due to the <10 second breath hold and 
the feeling of fluid in the nares. A very rare potential complication of nasal lavage is acute bacterial 
sinusitis (sinus infection). The nasal lavage procedure is considered minimal risk, and is often referred to 
as a nasal wash or nasal irrigation. A variety of over-the-counter products (such as the neti-pot filled 
with a saline solution) have been widely available for home use to safely flush out nasal passages and 
alleviate both nasal congestion and even sinusitis symptoms.  

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The study clinician may use their discretion as to whether to administer a nasal decongestant prior to 
the nasal lavage. The nasal decongestant may be associated with temporary discomfort such as burning, 
stinging, sneezing, or an increase in nasal discharge. 
5.4.6 
Influenza Vaccine  
As part of standard of care, the study clinician will recommend the participant obtain the current 
influenza vaccine. Minor side effects are soreness, redness or swelling at the injection site, low grade 
fever and aches. If these problems occur, they begin soon after vaccination and are mild and short-lived. 
Almost all people who receive influenza vaccine have no serious problems from it. On rare occasions, flu 
vaccination can cause serious problems, such as severe allergic reactions. 
5.4.7 
Questionnaires  
There is a possibility that participants may find the questions too personal.  Participants may refuse to 
answer any questions that make them feel uncomfortable. 
5.5 Potential Benefits 
The results of the skin testing will be provided to participants. Participants will receive relevant asthma 
education consistent with Guidelines for the Diagnosis and Management of Asthma (EPR 3) for patients 
with asthma, including handouts listing ways to avoid common allergy and asthma triggers. The national 
asthma guidelines have emphasized that exposure of patients who have asthma to allergens to which 
they are sensitive has been shown to increase asthma symptoms and precipitate asthma exacerbations. 
Guidelines for the Diagnosis and Management of Asthma (EPR 3) state that the clinician should evaluate 
the potential role of allergens, particularly indoor inhalant allergens via medical history and skin testing, 
and then assess the significance of positive tests in the context of the patient’s medical history. Patients 
who have asthma at any level of severity should: (1) reduce, if possible, exposure to allergens to which 
the patient is sensitized and exposed; (2) know that effective allergen avoidance requires a 
comprehensive approach; and (3) be provided with relevant educational materials for control of 
environmental factors.  
While the participant’s asthma may or may not improve while in this study, participants may directly 
benefit from study participation by receiving study-based asthma assessments and care from an asthma 
specialist. The participants will receive close monitoring and direct management of asthma 
exacerbations on a 24/7 basis throughout the study. Participants with uncontrolled asthma at Screening 
will benefit by having additional visits to bring their asthma under control before Randomization. 
Participant families will receive contact numbers for the study site and a tailored asthma action plan and 
education. A supply of prednisone will be provided in concert with this management.  
In the longer term, this study may promote the further development of cockroach SCIT for asthma and 
allergic rhinitis, which could be a major advance in the care of individuals with these conditions who are 
allergic to cockroach antigens.   
6 Investigational Agent  
6.1 Investigational Agent 
Non-standardized glycerinated German cockroach (Blattella germanica) allergenic extract (50% glycerin) 
will be used as the investigational agent in Protocol ICAC-28. Commercially-labeled licensed product was 

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purchased by the IND Sponsor from the manufacturer - Stallergenes Greer (Lenoir, NC) and distributed 
to the clinical research sites by DAIT NIAID drug distributor (Eminent Services Corporation, Frederick, 
MD).   
6.1.1 
Formulation, Packaging, and Labeling 
The active ingredient of the investigational product is a non-standardized allergen derived from the 
extraction and purification of proteins from German cockroach (Blattella germanica).  The allergenic 
extract contains the aqueous extractable from allergenic source material in extracting solution 
containing 0.25% sodium chloride, 0.125% sodium bicarbonate, and 50% glycerol.  Phenol (0.4%) is 
added after extraction as a preservative.   
Non-standardized glycerinated German cockroach allergenic extract is approved in the United States for 
diagnostic skin testing and immunotherapy by subcutaneous injection (U.S. License 467).  It has been 
used in humans for at least 35 years. The recommended storage conditions for the investigational agent 
are 2°C to 8°C. For this protocol, German cockroach extract will be stored at minus 20°C. Storage at 
minus 20°C is to decrease the rate of degradation of allergen (Bla g5) in the extract.    
6.2 Placebo 
The placebo product for SCIT in Protocol ICAC-28 is a commercially-labeled licensed product, sterile 
diluent for allergenic extract [glycerin (50%), sodium bicarbonate (0.091%), sodium chloride (0.166%) 
with water for injection (q.s.)]. The commercially-labeled licensed product was purchased by the IND 
Sponsor from the manufacturer – Allergy Laboratories (Oklahoma, OK) and distributed to the clinical 
research sites by DAIT NIAID drug distributor (Eminent Services Corporation, Frederick, MD). 
6.2.1 
Formulation, Packaging, and Labeling 
The placebo for immunotherapy will consist of the same inactive ingredients as the non-standardized 
glycerinated German cockroach allergen extract. It is not colored and is in 8mL multi-dose vials.  
6.3 Dosage, Preparation, and Administration 
6.3.1 
Subcutaneous Immunotherapy 
Cockroach allergenic extract or placebo is prepared by the clinical site research pharmacist. Complete 
details of the dilutions can be found in the Pharmacy Manual: Investigational Product Preparation and 
Dispensing for Subcutaneous Immunotherapy (SCIT) for Protocol ICAC-28.   
Participants will receive escalating doses of glycerinated German cockroach allergenic extract or placebo 
administered subcutaneously according to the dose escalation schedule (Section 8.7.1). 
6.4 Drug Accountability 
Under Title 21 of the Code of Federal Regulations (21CFR §312.62) the investigator will maintain 
adequate records of the disposition of the investigational agent, including the date and quantity of the 
drug received, to whom the drug was dispensed (participant-by-participant accounting), and a detailed 
accounting of any drug accidentally or deliberately destroyed. 
Records for receipt, storage, use, and disposition will be maintained by the study site.  The drug-
dispensing log will be kept current for each participant.  These logs will contain the identification of each 
participant and the date and quantity of drug dispensed. 

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All remaining unused investigational product will be returned to the IND sponsor (DAIT, NIAID) or 
sponsor’s representative after study termination, or destroyed with the permission of the sponsor in 
accordance with applicable law and study site procedures.   
All records regarding disposition of the investigational product will be available for inspection by the 
clinical trial monitor. 
6.5 Assessment of Participant Compliance with Investigational Agent 
As participants receive their injections in the clinic, compliance will be monitored by assessing the 
number of expected and completed injection visits. 
6.6 Toxicity Prevention and Management 
In the case of a reaction to the subcutaneous investigational agent, dosing will be altered according to 
Section 8.6.1 Dose Escalation and 8.6.2. Maintenance Visits. 
6.7 Premature Discontinuation of Investigational Agent 
Participants who are unable to reach the minimum maintenance dose by 40 weeks following the start of 
dose escalation will be unable to proceed to the maintenance period and will have their study therapy 
discontinued (see Section 11.2.1 Discontinuation of Study Therapy; see Appendix B Study Restrictions 
Due to COVID-19). 
Study therapy may be prematurely discontinued for any participant for any of the reasons identified in 
Section 11.2.1 Discontinuation of Study Therapy. Study therapy may also be prematurely discontinued 
for any participant if the study clinician believes that the study treatment is no longer in the best 
interest of the participant. Participants whose therapy is prematurely discontinued will be followed 
when possible for the duration of the study and seen for all remaining visits except Injection Visits.  
7 Other Medications 
7.1 Concomitant Medications 
7.1.1 
Protocol-mandated 
All participants will receive asthma step care according to the Guidelines for the Diagnosis and 
Management of Asthma.28 Treatment will be supervised by a study clinician. The study clinician will 
prescribe initial appropriate concomitant asthma therapies (see Section 7.1.1.1) and will provide a 
written Asthma Action Plan for the participant at Screening, Randomization, and every two months 
thereafter (see Section 7.1.1.4). The regimen will then be adjusted as necessary at those visits 
throughout the duration of the trial based on the principles of the EPR-3 guidelines (see Table 7.1.1.2a, 
below).  
The study clinician will prescribe the appropriate step controller therapy according to the participant’s 
insurance/health maintenance organization guidelines. The preferred controller steps and alternate 
equivalent medications may be modified or updated based on changes in standard clinical practice, 
discontinuation of current medications, or the introduction of new medications. For the standardized 
treatment of asthma exacerbations, the clinical research staff will provide oral prednisone and written 
instructions for use.  

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All participants are required to have medical insurance that will cover, at least in part, the costs of their 
asthma medications. It is likely, however, that some participants may lose this coverage during the time 
that they are in the study. To maintain participant safety and avoid a loss of these participants to the 
study, Protocol ICAC-28 CRITICAL will fund the cost of these participants’ asthma medications during the 
remainder of the study or until the participant regains insurance coverage during the study. Medications 
will be prescribed in the same manner using the same algorithms as all insured participants. Each 
research site will develop plans to use local pharmacies in a cost efficient and timely manner. This design 
is in place to mimic the support typical insured participants receive, i.e. they receive a prescription and 
have to fill it at a pharmacy. To limit the time that Protocol ICAC-28 CRITICAL is required to fund the cost 
of asthma medications for a participant who has lost coverage, each research site will develop a plan for 
evaluation of insurance options and referral to appropriate support systems to obtain coverage for 
medication costs. In addition to addressing potential insurance from employers and governmental 
sources, this may include free clinics and support programs available through pharmaceutical firms. 
The study clinician is allowed to prescribe treatment for rhinitis symptoms as clinically indicated.  No 
specific rhinitis medications are recommended or required to be used. The choice is study clinician 
discretion. 
7.1.1.1 
Initial Regimen 
At the Screening Visit, the study clinician will determine the appropriate asthma control regimen that 
will be prescribed for the participant. Along with the participant’s medical history and physical 
examination results, the medication regimen is determined by the participant’s symptoms, number of 
systemic corticosteroid bursts in the past 6 months, percent-predicted forced expiratory volume in 1 
second (FEV1), and current level of asthma controller therapy.  
First, the study clinician will determine the highest “control level” of the participant’s morbidity across 
the 4 categories in Table 7.1.1.1a. For example, if the participant has 8 days with symptoms (control 
level 2), 1 night with symptoms (control level 1), is at 75% predicted FEV1 (control level 3), and has 0 
systemic steroid bursts, (control level 1), then the participant is at control level 3 because that is the 
highest of these 4 categories. 
 
Table 7.1.1.1a Asthma Symptoms for Determining Run-in Asthma Medication Regimen 
Control Level 
Maximum of 1) # days 
with asthma 
symptoms/ two weeks 
and 2) # days with 
rescue albuterol or 
levalbuterol use/ two 
weeks* 
Maximum of 1) # 
nights of sleep 
disruption due to 
asthma/ 2 weeks and 
2) # nights use of 
albuterol or 
levalbuterol for 
awakening / 2 weeks* 
FEV1 
(% pred)** 
Courses of 
systemic steroids 
in the last 6 
months*** 
1 
0-3 days 
0-1 night 
≥ 85 
0 
2 
4-9 days 
2 nights 
80 - < 85 
1 
3  
10-13 days 
3-4 nights 
70 - < 80 
2 

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4 
14 days 
5-14 nights 
< 70 
>2 
FEV1 = forced expiratory volume in 1 second; pred = predicted 
* Determined from participant recall, based on the 2-week interval directly preceding the study visit. 
**Predicted references are provided in the Protocol ICAC-28 MOP. 
*** Defined as a prescription of a course of systemic steroids by a clinician or initiation of a course of systemic steroids by a 
participant to prevent a serious asthma outcome. If a participant initiates and completes a course of systemic steroids without 
clinician involvement, this course will be counted only if it meets the following dosage: the course for prednisone, prednisolone, or 
methylprednisolone will be 2 mg/kg/day as a single daily dose for 4 days with a maximum dose of 60 mg per day. The course for 
dexamethasone will be 0.3 to 0.6 mg/kg/day as a single daily dose for 2 days with a maximum dose of 16 mg per day. If a 
corticosteroid burst for the treatment of an asthma exacerbation is prescribed by a non-ICAC clinician, it will be counted regardless 
of dose. 
 
Next, the study clinician will determine the current level of controller therapy that the participant is 
using. Table 7.1.1.1b shows the asthma regimens that will be used during the treatment phase of 
Protocol ICAC-28 CRITICAL. If the participant is currently on one of the therapies below, then the step 
level of that therapy will be noted. Otherwise, the study clinician must refer to the Protocol ICAC-28 
MOP for equivalency tables for other asthma therapies. From the information in the Protocol ICAC-28 
MOP, the study clinician will determine the corresponding step level of therapy that the participant is 
currently using. For example, if the participant is currently taking Flovent® Diskus® 250 mcg twice per 
day (bid), then he/she is receiving Step 3 therapy. 
Table 7.1.1.1b Asthma Regimen by Step Level of Therapy 
Step 
Medication Equivalent* 
0 
No controller medication; albuterol or levalbuterol prn 
1 
fluticasone 50 mcg bid 
2 
fluticasone 100 mcg bid 
3 
fluticasone 250 mcg bid 
4 
fluticasone 250 mcg bid plus LABA 
5 
fluticasone 500 mcg bid plus LABA 
bid = twice per day; LABA = long-acting beta agonist 
*Equivalent medication covered by participant’s insurance formulary – see Protocol ICAC-28 MOP.   
 
Based on the participant’s current control level (from Table 7.1.1.1a) and the participant’s current step 
level of therapy (from Table 7.1.1.1b and the Protocol ICAC-28 MOP), the study clinician will find the 
corresponding row in Table 7.1.1.1c below that includes both the current regimen and the current 
control level. The last column of that row gives the corresponding regimen as a step level, which refers 
back to Table 7.1.1.1b. The study clinician will prescribe this regimen.  
Continuing the example from above, since the participant is taking Step 3 therapy and is at control level 
3, the regimen assigned would be Step 4 (fluticasone 250 mcg bid with LABA). 

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Table 7.1.1.1c Algorithm for Prescribing Treatment Regimen at Screening 
Current Regimen 
Current Control Level 
Regimen Assigned 
Regimen equivalent to Step 0 
(or 1-3 days/week of a regimen 
equivalent to Step 1) 
Control level 1 
Control level 2 
Control level 3 
Control level 4 
Step 0 
Step 1 
Step 1 
Step 2 (and may also need prednisone 
burst) 
Regimen equivalent to Step 1 
(or 1-3 days/week of a regimen 
equivalent to Step 2) 
Control level 1 
Control level 2 
Control level 3 
Control level 4 
Step 1 
Step 2 
Step 2 
Step 3 (and may also need prednisone 
burst) 
Regimen equivalent to Step 2 
(or 1-3 days/week of a regimen 
equivalent to Step 3) 
Control level 1 
Control level 2 
Control level 3 
Control level 4 
Step 2 
Step 3 
Step 3 
Step 4 (and may also need prednisone 
burst) 
Regimen equivalent to Step 3 
(or 1-3 days/week of a regimen 
equivalent to Step 4) 
Control level 1 
Control level 2 
Control level 3 
Control level 4 
Step 3 
Step 4 
Step 4 
Step 5 (and may also need prednisone 
burst) 
Regimen equivalent to Step 4 
(or 1-3 days/week of a regimen 
equivalent to Step 5) 
Control level 1 
Control level 2 
Control level 3 
Control level 4 
Step 4 
Step 5 
Step 5 
Step 5 (and may also need prednisone 
burst) 
Regimen equivalent to Step 5 
 
Control level 1 
Control level 2 
Control level 3 
Control level 4 
Step 5 
Step 5 
Step 5 (and may also need prednisone 
burst) 
Step 5 (and may also need prednisone 
burst) 
Note: Shading in the table corresponds to the example described in the text. 
In addition to the controller regimen assigned above, all participants will be prescribed albuterol by 
metered-dose inhaler beta-agonist or nebulizer (per clinician discretion) to be used as needed and will 
be provided oral prednisone to be used as per protocol – see Section 7.4.1 and the Protocol ICAC-28 
MOP. The study clinician will prescribe enough medication to last until the next E&M visit. If a 
participant is not eligible to continue, the study clinician may prescribe an appropriate treatment 
regimen based on clinical judgment. 
7.1.1.2 
Study Period Treatment Regimen  
At Randomization and every 2 months during treatment, an asthma Evaluation and Management (E&M) 
process will occur where participants’ asthma medication regimen will be adjusted based on symptoms, 
albuterol/levalbuterol use, FEV1, recent exacerbations, and their current level of therapy.  
Participants may be stepped down from controller medications if their control level is equal to 1 at 
Screening, Asthma Control Visits, and at some E&M visits while the participant is in maintenance (see 
Appendix B: Study Restrictions Due to COVID-19). Participants may not be stepped down from controller 

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medications at Randomization or during Dose Escalation. Participants may be stepped up as per the 
protocol algorithm at any visit where indicated.  
Participants will undergo pre-bronchodilator spirometry and an assessment of symptoms, rescue 
bronchodilator usage, recent exacerbations and medication adherence. Bronchodilator use as a 
preventive measure prior to exercise will not count toward the assessment of rescue bronchodilator 
use. Based on these data, a study clinician will determine the participant’s current control level from 
Table 7.1.1.2a below. The control levels originated from the published national guidelines, Guidelines for 
the Diagnosis and Management of Asthma.28 
For all participants, the highest control level for days with symptoms or albuterol/levalbuterol use, 
nights with symptoms or albuterol/levalbuterol use, percent personal best FEV1, and exacerbation 
history will be determined by the study clinician. The day and night symptoms, albuterol/levalbuterol 
use, adherence to prescribed asthma controller medications by self-report, and exacerbation history will 
be determined from questionnaires. The FEV1 personal best is defined in the Protocol ICAC-28 MOP. If 
the quality of the spirometry maneuver at the current visit is unacceptable according to the technician’s 
judgment, FEV1 in Table 7.1.1.2a will not be used, and the control level will be based on day and night 
symptoms, albuterol/levalbuterol use, and exacerbation history. For example, if a participant has 0 days 
with symptoms (control level 1), 4 nights with symptoms (control level 3), FEV1 at 85% of personal best 
(control level 1), and 1 exacerbation (control level 2), then the participant’s overall control level is 3 
because that is the maximum value of control levels 1, 3, 1, and 2.  
Table 7.1.1.2a Control Levels of Symptoms, Bronchodilator Usage, FEV1 (% personal best), and 
Exacerbations 
Control 
Level 
Maximum of 1) # days with asthma 
symptoms/ 2 weeks and 2) # days 
with rescue albuterol/levalbuterol 
use/ 2 weeks* 
Maximum of 1) # nights of sleep 
disruption due to asthma/ 2 
weeks and 2) # nights use of 
albuterol/levalbuterol for 
awakening/ 2 weeks* 
FEV1 
(% personal 
best) 
Courses of 
Systemic 
Steroids since 
the Last 
Medication 
Management 
Visit** 
1 
0-3 days 
0-1 night 
 85 
0 
2 
4-9 days 
2 nights 
80-84 
1 
3 
10-13 days 
3-4 nights 
70-79 
- 
4 
14 days 
5-14 nights 
 70 
- 
FEV1 = forced expiratory volume in 1 second 
* Determined from participant recall, based on the 2-week interval directly preceding the study visit. 
**Defined as a prescription of a course of systemic steroids by a clinician or initiation of a course of systemic steroids by a participant to prevent 
a serious asthma outcome. If a participant initiates and completes a course of systemic steroids without clinician involvement, this course will 
be counted only if it meets the following dosage: the course for prednisone, prednisolone, or methylprednisolone will be 2 mg/kg/day as a 
single daily dose for 4 days with a maximum dose of 60 mg per day. The course for dexamethasone will be 0.3 to 0.6 mg/kg/day as a single daily 
dose for 2 days with a maximum dose of 16 mg per day. If a corticosteroid burst for the treatment of an asthma exacerbation is prescribed by a 
non-ICAC clinician, it will be counted regardless of dose. 
Note: Shading in the table corresponds to the example described in the text above. 
 

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Based on the overall control level and the participant’s estimated level of adherence, the study clinician 
will use Table 7.1.1.2b below to determine how the participant’s current therapy should be modified. At 
E&M Visits, the participant will be considered to have acceptable adherence if he/she reports having 
taken 50% or more of the prescribed doses in the last 2 weeks. Participants with unacceptable 
adherence will not be stepped up in the same way as those with acceptable adherence. Continuing with 
the same example, since this participant is at control level 3 and assuming he/she has acceptable 
adherence, the study clinician would recommend a 2-step increase in therapy (or an increase to Step 5 if 
on Step 4 or maintenance on Step 5 if already on Step 5). In all cases, consideration will be given to a 
burst of prednisone according to the suggestions in the table. 
Table 7.1.1.2b Treatment Adjustment Based on Control Levels and Adherence 
Control 
Level 
Treatment Algorithm for Participants 
with Unacceptable Adherence 
Treatment Algorithm for Participants with Acceptable 
Adherence 
1 
If on Step 0, maintain at Step 0  
If on Steps 1-5, decrease controller 
regimen by 1 step 
** Do not decrease controller regimen at 
Randomization or during Dose Escalation 
If on Step 0, maintain at Step 0  
If on Steps 1-5, decrease controller regimen by 1 step 
** Do not decrease controller regimen at 
Randomization or during Dose Escalation 
2 
Continue same controller regimen or 
place on Step 2 therapy, whichever is 
higher 
Increase controller regimen by 1 step, or continue Step 
5 therapy if already on Step 5 
3 
Continue same controller regimen or 
place on Step 2 therapy, whichever is 
higher 
No systemic steroids since the Last Medication 
Management visit* 
If on Steps 0-4 increase controller regimen by 1 step 
If on Step 5 continue Step 5 or treat with Step 5 and a 4 
day burst of prednisone or equivalent; 
≥1 course(s) of systemic steroids since the last E&M 
visit*  
If on steps 0-3 increase controller regimen by 2 steps 
If on treatment Step 4 increase controller regimen to 
Step 5 or treat with Step 5 and a 4 day burst of 
prednisone or equivalent 
If on treatment Step 5 continue Step 5 or treat with 
Step 5 and a 4 day burst of prednisone or equivalent 
4 
Continue same controller regimen or 
place on Step 3 therapy, whichever is 
higher 
OR 
Treat with 4-day prednisone burst and 
continue same controller regimen or place 
on Step 3 therapy, whichever is higher  
If on Steps 0-3 increase controller regimen by 2 steps 
If on Step 4, increase to Step 5 or treat with Step 5 and 
a 4-day prednisone burst or equivalent 
If already on Step 5, continue on Step 5 or treat with 
Step 5 and a 4-day burst of prednisone or equivalent 
*Defined as a prescription of a course of systemic steroids by a clinician or initiation of a course of systemic steroids by a 
participant to prevent a serious asthma outcome. If a participant initiates and completes a course of systemic steroids 
without clinician involvement, this course will be counted only if it meets the following dosage: the course for prednisone, 
prednisolone, or methylprednisolone will be 2 mg/kg/day as a single daily dose for 4 days with a maximum dose of 60 mg 
per day. The course for dexamethasone will be 0.3 to 0.6 mg/kg/day as a single daily dose for 2 days with a maximum dose 
of 16 mg per day. 
Note: Shading in the table corresponds to the example described in the text above. 
 

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Based on the participant’s step level assigned at the last E&M visit and the change in steps determined 
above, the new regimen will be prescribed according to Table 7.1.1.2b above. In the example above, if 
the participant were currently on Step 2 and having no problems with adherence, then the 
recommended new treatment step based on symptoms, albuterol/levalbuterol use, FEV1, and 
exacerbations is Step 4.  
7.1.1.3 
Final Study Visit 
At the Final Study Visit (12-month Visit), the final treatment regimen prescribed will be based on the 
protocol-based medications management algorithm or the discretion of the study clinician who 
examines the participant. The study clinician will base the treatment on factors such as symptoms, 
albuterol use, spirometry, adherence, and the participant’s current level of therapy. The participant’s 
care will then be transferred back to their primary care provider (PCP) and/or asthma specialist. 
7.1.1.4 
Asthma Action Plan 
Clinical research staff will provide a written Asthma Action Plan consistent with NAEPP guidelines for the 
participant at all E&M visits. This plan describes a Green, Yellow, and Red Zone for the participant based 
on his/her symptoms. In the Green Zone, the participant has no symptoms of an asthma episode and is 
directed to use his/her usual asthma medications. In the Yellow Zone, the participant is experiencing 
asthma, allergy, or cold symptoms, and is directed to increase rescue medication use until the symptoms 
have been resolved. In the Red Zone, the participant is having persistent symptoms that cannot be 
controlled. The participant is instructed to contact a study clinician or go to the emergency department 
(ED) if unable to contact a study clinician. 
7.1.1.5 
Asthma Education 
As part of the meeting at E&M visits with a clinical research staff member for asthma education, 
participants will be educated on topics related to asthma. These topics include background on asthma as 
a disease, use of the Asthma Action Plan (see Section 7.1.1.4), adherence to medications, using 
medications at school (when applicable), and allergen and irritant avoidance. Handouts will be provided 
and the education content will be tailored to each participant. For example, the allergen avoidance 
education will be based on the participant’s aeroallergen skin test/serum IgE results. The participant will 
receive education about the allergens to which he/she is sensitive. The information contained in the 
handouts will be based on the EPR-3: Guidelines for the Diagnosis and Management of Asthma and on 
experience from previous ICAC clinical trials.  
7.1.2 
 Other permitted concomitant medications 
During the study, after the initial skin testing, rhinitis and asthma medications will be permitted along 
with other maintenance medications, aside from those excluded in Section 4.3, Exclusion Criteria.  Short 
courses of oral corticosteroids or doses of greater than 500 mcg of fluticasone per day or the equivalent 
of another inhaled corticosteroid may be used short-term (not to exceed 6 months) to control an 
asthma exacerbation.  
7.2 Prophylactic Medications 
Pre-treatment with antihistamines can be used before immunotherapy injection at the study clinician’s 
discretion. 

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7.3 Prohibited Medications 
1. A regular dose of greater than 500 mcg of fluticasone per day or the equivalent of another 
inhaled corticosteroid for a duration of ≥ 6 months 
2. Allergen immunotherapy (SLIT or SCIT) 
3. Biologic therapies (e.g., anti-IgE, anti-IL-4, anti-IL-5)  
4. Tricyclic antidepressants  
5. Beta-adrenergic blocker drugs (both oral and topical) 
6. Any investigational drug  
7.4 Rescue Medications  
Participants may use antihistamines as needed for large local reactions to the injections.  
Participants may use antihistamines and/or a nasal steroid as needed for persistent nasal and/or ocular 
symptoms following the NAC. If at any time during the NAC a participant experiences asthma symptoms 
or anaphylaxis, treatment with inhaled short-acting bronchodilators, corticosteroids and epinephrine 
will be immediately available to treat the reaction. Participants will be instructed to bring an albuterol 
inhaler to any visit in which a NAC will be performed and carry it with them for the first 24 hours after 
the NAC. Participants who do not bring an albuterol inhaler to a NAC visit will be provided one. 
7.4.1 
Definition and Management of Acute Exacerbations 
Consistent with NAEPP 2007 guidelines, study clinicians caring for participants in the Protocol ICAC-28 
CRITICAL study will start a course of corticosteroids for severe and/or unresponsive exacerbations of 
asthma. For the purposes of the proposed analyses, an asthma exacerbation is defined as a prescription 
of a course of systemic steroids by a clinician or initiation of a course of systemic steroids by a 
participant or a hospitalization to prevent a serious asthma outcome. If a participant initiates and 
completes a course of systemic steroids without clinician involvement, this course will be counted only if 
the study clinician agrees the treatment was warranted and it meets the following dosage: the course 
for prednisone, prednisolone, or methylprednisolone will be at least 20 mg daily for 3 of 5 consecutive 
days. The course for dexamethasone will be a single daily dose. Study clinicians will strongly consider 
initiation of corticosteroids if:  
• 
Albuterol is needed by inhaler (with or without a spacer) or by nebulization for more than 6 
individual treatments in 24 hours; or 
• 
Moderate-severe wheeze, cough, shortness of breath, and/or chest tightness or pain occurs for 
at least 5 of the preceding 7 days; or 
• 
Symptoms of wheeze, cough, shortness of breath, and/or chest tightness or pain severe enough 
to place a participant in his or her “Red Zone” on their Asthma Action Plan (see Section 7.1.1.4) 
do not significantly improve after 3 doses of albuterol. (In such situations, in addition to the 
initiation of oral corticosteroids, the study clinician should consider directing the participant to 
the nearest ED.); or  
• 
There is an unscheduled visit for acute asthma care requiring repeated doses of albuterol 
(clinician office, urgent care, ED); or 
• 
Hospitalization is needed for asthma. 
Permissible drugs for systemic corticosteroid treatment of asthma exacerbations include: prednisone, 
prednisolone, methylprednisolone, and dexamethasone. The course for prednisone, prednisolone, or 

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methylprednisolone will be 2 mg/kg/day as a single daily dose for 4 days with a maximum dose of 60 mg 
per day. The course for dexamethasone will be 0.3 to 0.6 mg/kg/day as a single daily dose for 2 days 
with a maximum dose of 16 mg per day. Failure to respond to initial treatment will result in additional 
evaluation and possible hospitalization for further management. This management approach has been 
applied to previous ICAC clinical trials and is consistent with asthma specialist usual care practices. 
8 Study Procedures 
Detailed instructions for all procedures are provided in the Protocol ICAC-28 MOP. Please see Appendix 
B for information regarding institutional or ICAC-wide restrictions on study activities due to COVID-19.  
8.1 Study Assessments  
8.1.1 
Vital Signs and Growth Parameters 
The following vital signs and growth parameters will be collected at all E&M visits unless otherwise 
noted:  
• 
Weight in kilograms 
• 
Height (using a calibrated stadiometer) at all visits when spirometry is performed 
• 
Pulse rate 
• 
Respiratory rate 
• 
Blood pressure 
• 
Chest auscultation,  
• 
Influenza vaccine - All participants will be recommended to receive an annual flu vaccine.  
8.1.2 
Medical History and Physical Examination 
The participant’s medical history will be obtained and a study clinician will perform a physical 
examination at the Screening Visit. A chest auscultation and current asthma symptom assessment will 
be performed at all injection visits. An abbreviated physical examination will be performed at all E&M 
visits. Additional examinations may be completed at the study clinician’s discretion. 
Significant findings that are present prior to the start of the study must be included on the appropriate 
case report form (CRF). Significant findings that meet the definition of an adverse event (AE) must also 
be recorded on the AE form. 
If the participant is currently having an asthma exacerbation or other symptoms that the study nurse or 
study clinician feel may compromise the participant’s ability to complete the study procedures safely, a 
physical exam may be performed, and the study visit may be rescheduled. If the study clinician observes 
any AEs during the study visit, a targeted physical exam may be performed. Additional details regarding 
AE assessment are outlined in Section 12, Safety Monitoring and Reporting. 
8.1.3 
Aeroallergen Skin Testing 
The participant’s atopic status will be assessed with skin prick tests to assess allergy to dust mites, 
cockroaches and other aeroallergens relevant to an urban environment and the local area. Participants 
will be asked to stop taking antihistamines for 5 days prior to the visit at which the skin test is performed 
to limit interference with the results of the skin test. 

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Skin testing will be done by the prick technique using the GreerPick system (Stallergenes Greer; Lenoir, 
NC). Testing will be performed by certified clinical research staff according to the instructions in the 
Protocol ICAC-28 MOP. Tests will be read after 15 minutes by measuring the wheal for each antigen and 
for the controls. 
Acceptable skin testing completed as part of a participant’s participation in other ICAC protocols within 
12 months will meet the requirement for this procedure. In this situation, the skin testing results 
documentation from the previous study will be added to the participant’s study file, and the skin testing 
procedure will not be repeated, with the exception of the German cockroach test for study eligibility. 
8.1.4 
Measurement of Pulmonary Function 
Spirometry will be conducted following the ATS and European Respiratory Society guidelines. For 
children under 8 years of age, ATS Preschool Guidelines will be used for spirometry acceptance 
evaluation. This procedure has been successfully implemented in previous DAIT NIAID-sponsored ICAC 
trials. Details regarding pulmonary function testing (PFT) are provided in the Protocol ICAC-28 MOP. All 
PFTs will be performed by certified clinical research staff. 
Peak flow will be measured with the participant sitting upright in a chair as described in the Protocol 
ICAC-28 MOP.  
8.1.5 
Nasal Allergen Challenge 
The NAC must be rescheduled if the participant meets the following criteria: 
 
Has uncontrolled asthma at the time of the NAC, as defined by an FEV1 < 80% predicted or an 
ACT score < 20.  
 
Has active rhinitis symptoms at the time of the NAC, defined as a Baseline TNSS > 3, or any 
individual symptom score > 1. 
 
Is currently using oral or nasal antihistamines, nasal corticosteroids, nasal decongestants, nasal 
anticholinergics, biologic therapies, prednisone, or cromolyn, which cannot be suspended for 
the required washout periods. 
Baseline peak flow (PEF) and TNSS will be measured before the start of the challenge.  Nasal lavage will 
be performed as described in Section 8.1.6.  
Increasing doses of allergen will be administered in defined time intervals (every 10-20 minutes) up to a 
specified maximum dose or symptom level, will be given as described in an accompanying MOP for 
Protocol ICAC-28. Briefly, one spray (100mcL) of diluent or diluted allergen solution is applied to each of 
the participant’s nostrils using a nasal drug delivery system (LMA/Teleflex, San Diego, CA) while the 
participant breath-holds at TLC. After the dose is delivered, the participant is asked to exhale through 
the nose and then to avoid sniffing or swallowing in the immediate 1 minute after application. For the 
baseline NAC, the challenge will begin with a 0 mcg/ml of Bla g 1 [negative control – 50% glycerin, 50% 
COCAS with 0.2% phenol (Stallergenes Greer, Lenoir, NC)] dose followed by up to 8 doses of increasing 
concentration, until the participant reaches a TNSS of 6 or more, has a sneezing score of 3, or their 
symptoms become intolerable. Collection of TNSS and PEF will be done 10 minutes after each diluent or 
allergen dose is administered.  

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The follow-up challenge at 12 months will be performed as described above, except the challenge will 
continue until the participant reaches at least the dose that elicited a positive response at the baseline 
NAC or the participant reaches a TNSS of 12 or their symptoms become intolerable.  If a participant 
reaches the dose that elicited a positive response at the baseline NAC without having a TNSS of 6 or 
more or a sneezing score of 3, dosing will continue until the participant reaches a TNSS of 6 or more, has 
a sneezing score of 3, or symptoms become intolerable.  
If a participant begins exhibiting asthma symptoms during the NAC, or the PEF is reduced by more than 
20% from baseline, the challenge will be suspended, and the participant will be evaluated by the study 
clinician. If it is determined treatment is needed based on clinical judgment, then the challenge will not 
be continued.  In the absence of an immediate need for treatment, spirometry will be performed to 
confirm a change in lung function. If the FEV1 is < 85% of baseline value, the challenge will be stopped. If 
spirometry is performed because of a low PEF and the FEV1 is ≥ 85% of baseline value, the challenge can 
continue at the clinician’s discretion.  
The day after the NAC is performed, the participant will receive a follow-up phone call to assess if he or 
she is experiencing any late-onset respiratory symptoms. Participants will be given the peak flow meter 
they used during the challenge and will be asked to record two PEF measurements, one 4-8 hours after 
the completion of the challenge and one 24 hours after the completion of the challenge (or as soon as 
possible after the school day, if applicable). AEs and concomitant medications will also be assessed. 
Participants who report significant asthma symptoms will receive additional follow-up to assess safety.  
For further details, please refer to the Investigator Brochure for German Cockroach Allergenic Extract for 
Nasal Allergen Challenge. 
8.1.6 
Nasal Lavage 
Each NAC will accompanied by collection of nasal lavage samples. Samples will be collected prior to the 
challenge and approximately 3 hours from initiation of the challenge as specified in the Protocol ICAC-28 
MOP. Nasal lavage samples will be collected by instilling preservative-free buffered saline into the 
nostrils and allowing fluid to return passively into collection vessels. If the nostrils are occluded, a nasal 
decongestant may be administered at the discretion of the study clinician. Samples will be split and 
processed for both cell differentials and RNA extraction. Site clinical research staff who are trained, 
study-authorized, and certified will perform the nasal lavage and processing procedure as specified in 
the Protocol ICAC-28 MOP. 
8.1.7 
Dust Sample Collection 
The caretaker or participant will be given a dust collection kit, which includes instructions on how to 
collect a dust sample (Refer to the MOP for Protocol ICAC-28 for detailed instructions). A combined dust 
sample from the participant's bed and the participant's bedroom floor will be collected. The room where 
the participant sleeps most nights will be considered the participant's bedroom. Measuring templates 
will be used to delineate the areas to be vacuumed. Dust will be collected using a vacuum cleaner with a 
special dust collection filter attached. The dust collector will be placed into a sealable plastic bag and 
returned to the study center for temporary storage (frozen). Crude samples will be batched and shipped 
to a central laboratory by express mail for sieving, extraction, and analysis. The dust specimens will be 
assayed to measure the concentration of cockroach allergens such as: Bla g 1, Bla g 2, and Bla g 5. 
Additional allergens of interest and markers of fungal and microbial exposure may be measured.  In 

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addition, the caretaker/participant will complete a dust collection questionnaire, which will be returned 
with the dust sample. 
The caretaker or participant will be given the dust collection kit at the Randomization Visit and will be 
asked to return the dust sample and questionnaire either by mail or by bringing it to the next visit.  
8.1.8 
Questionnaire Assessments 
Questionnaires administered by site staff will collect inclusion/exclusion criteria information, participant 
contact information, demographic characteristics, asthma and allergy history and medication use, 
asthma exacerbation history, asthma symptoms and health care utilization, concomitant medications, 
and AE information.  
8.2 Clinical and Research Laboratory Evaluations and Specimen Collection 
8.2.1 
Blood Sample Collection 
Whole blood will be collected by venipuncture at Screening to determine eligibility. Blood collected prior 
to Randomization and at 12 months of treatment will be tested for assessment of biomarkers of allergen 
immunotherapy, such as cockroach-specific IgE and IgG4 antibodies. Mechanistic studies are described 
in Section 9. 
8.2.2 
Urine Pregnancy Testing 
All females who have reached menarche will be required to have a urine pregnancy test before 
completing study activities at Screening, Randomization, 12-month visit, visits where the NAC is 
performed, monthly during the escalation phase, and at each Evaluation and Management Visit (E&M) 
during maintenance. Results of all pregnancy tests will be given to the participant or caretaker as per 
site-specific guidelines and relevant state laws. 
8.3 Recruitment 
The study center may use any IRB-approved means to identify potential participants. Examples include 
hospital, clinic, or emergency department admission records; investigators’ specialty clinic records; and 
advertising (in public locations and on the radio). Potential participants will be screened and recruited 
using a standardized questionnaire that collects contact information and inclusion/exclusion criteria 
information. Participants may be recruited by phone or in person. 
Retention methods involve a number of different approaches.  We will use an appointment reminder 
system that consists of phone calls several days and one day prior to scheduled appointments for 
confirmation. To facilitate telephone contact with subjects whose phone service may change during the 
study, up to three telephone contact numbers (relatives, neighbors, friends) will be collected for each 
subject.  This has proven to be an effective strategy in previous DAIT NIAID-sponsored ICAC studies. 
Those who have no obvious characteristics making them ineligible and who are interested will be invited 
to the clinic for a Screening Visit. 
8.4 Screening Procedures 
8.4.1 
Screening Eligibility Visit 
This research study will be explained in lay terms to the parent/legal guardian of each potential research 
participant. Written informed consent and Health Insurance Portability and Accountability Act (HIPAA) 

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authorization will be obtained from all parents/legal guardians at the beginning of this visit and before 
the child undergoes any screening study procedures. Children (age dependent on local IRB guidelines) 
will sign a written assent form. When the informed consent has been signed, the participant is 
considered enrolled in the study and will be assigned a unique participant number. Study procedures 
will be stopped and the participant will be deemed ineligible for the study at any point during the 
Screening Visit if and when they fail to meet eligibility criteria.  
After the consent (and assent, if applicable) is signed, participants will undergo screening study 
procedures, including prick skin tests with German cockroach to ensure participants are sensitive to the 
test product, since those who do not react to German cockroach are excluded from the remainder of the 
study. In addition, participants will undergo prick skin tests to a panel of allergens detailed in the MOP 
for Protocol ICAC-28 to characterize the study population. Participants will not need additional skin 
testing if they have a positive skin test result using the same lot of non-standardized German cockroach 
extract used for Protocol ICAC-28 immunotherapy within the previous year.  If a different German 
cockroach extract was used for skin testing, the participant will have a repeat skin test of German 
cockroach, histamine, and diluent control to confirm eligibility.  
A urine pregnancy test will be performed on all female participants that have reached menarche. A 
medical history will also be taken and a physical examination will be performed to verify the 
participant’s suitability for inclusion in the study. Participants will be encouraged to receive a flu vaccine 
during each flu season.  
Spirometry will be performed by all participants to verify the participant’s suitability for inclusion in the 
study.  
For participants with a positive skin prick test to cockroach, blood will be collected by venipuncture for 
cockroach-specific IgE antibody testing to determine study eligibility.  Participants who have valid IgE 
test results within the previous year under another ICAC protocol will not need to be re-tested.  
The study clinician will assign the participant to the appropriate asthma treatment step based on the 
participant’s current asthma medications and symptoms according to the treatment algorithm (see 
Section 7.1.1.1), write an appropriate prescription, and provide an asthma action plan (see Section 
7.1.1.4). Participants will receive basic asthma education (see Section 7.1.1.5). 
8.4.2 
Screening Nasal Allergen Challenge 
The NAC will be performed on all participants. The NAC can be performed as part of a separately 
scheduled visit, if necessary.  
Each NAC will be accompanied by collection of nasal lavage samples. Samples will be collected prior to 
the challenge and approximately 3 hours from initiation of the challenge as described in Section 8.1.6 
and the Protocol ICAC-28 MOP.  
A urine pregnancy test will also be performed on all female participants that have reached menarche. 
Blood samples will be collected prior to the NAC for mechanistic studies (see Section 9). Blood will also 
be evaluated for baseline assessment of biomarkers of allergen immunotherapy, such as cockroach-

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specific IgE and IgG4 antibodies. Total IgE and specific IgE to a panel of additional allergens detailed in 
the Protocol ICAC-28 MOP will also be measured.  
Participants who have:  
 
a positive German cockroach skin prick test,  
 
German cockroach-specific IgE ≥0.35 kUA/L,  
 
reached the TNNS of ≥ 6 or a sneeze score of 3 at doses 2-9,  
 
FEV1 is at least 80% of predicted normal, and 
 
an Asthma Control Test/Childhood Asthma Control Test score ≥ 20 
are considered eligible for the study, and at the discretion of the study clinician, will be invited to 
proceed to Randomization. 
Candidates whose FEV1 is less than 80% of predicted normal or with an Asthma Control Test/Childhood 
Asthma Control Test score  20 will enter a run-in period, as described in Section 8.4.3 below.  
Participants may also qualify for rescreening if they are ineligible due to reversible illness if their 
condition improves while recruitment is ongoing. 
8.4.3 
Asthma Control Optional Visits 
Participants whose FEV1 is less than 80% of predicted normal or whose Asthma Control Test/Childhood 
Asthma Control Test score is  20 may have their asthma managed by a study clinician for up to four 
months in an attempt to get their asthma under control. Participants will return to the clinic for visits 
approximately every two weeks to report on their asthma symptoms and medication use, and have their 
medication adjusted if indicated. When control has been established based on the Asthma Control 
Test/Childhood Asthma Control Test, the participant may proceed in the study. If control cannot be 
established, the participant’s care will then be transferred back to their primary care provider (PCP) 
and/or asthma specialist. The participant will be provided with a summary of their treatment plan, 
which can be shared with their PCP. 
8.5 Randomization 
At randomization, the study clinician will review all inclusion and exclusion criteria to confirm the 
participant’s eligibility. Blood will be drawn, if needed, for tests described in Section 8.4.2. A dust sample 
collection kit will be provided (see Section 8.1.7). 
The study clinician will adjust the participant’s asthma medications as necessary according to the 
treatment algorithm (see Section 7.1.1.2), write an appropriate prescription, and provide a new asthma 
action plan (see Section 7.1.1.4). Participants will receive basic asthma education (see Section 7.1.1.5). 
Study participants will be randomized (see Section 13.3) to one of two groups: 1) cockroach SCIT or 2) 
placebo SCIT (1:1).  
8.6 Follow-up 
8.6.1 
SCIT Dose Escalation 
The dose escalation of glycerinated German cockroach allergenic extract or placebo is detailed in the 
Dose Escalation Table 8.6.1. Each injection will be administered by the trained research staff under the 

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supervision of the study clinician along with any rescue medications, as required. Refer to the ICAC-28 
Reaction Orders on handling treatment-related reactions.  
During the dose escalation phase, all females who have reached menarche will be required to have a 
urine pregnancy test monthly.  
Prior to the administration of each dose of allergenic extract or placebo, pre-assessment will be 
completed to assess the eligibility of the participant to receive the allergenic extract injection.  
Post-assessment of participants, 30 minutes after each injection, will be completed for symptoms or 
changes.   
During all dosing visits, a study clinician and appropriate emergency supplies will be readily available to 
treat any adverse reactions.  
Participants will receive weekly injections during escalation (Table 8.6.1). From Dose 1 through Dose 20, 
injections must be separated by a minimum of 2 days. From Dose 21 through Dose 26, injections must 
be separated by a minimum of 5 days. To maximize flexibility during dose escalation, injections can be 
given once weekly, and can be delayed at any point if there are systemic reactions, local reactions or 
other concerns. To continue on to maintenance, each subject will need to reach the minimum 
maintenance dose in a maximum of 40 weeks (see Appendix B: Study Restrictions Due to COVID-19).   
Dose escalation will be conducted by the following schedule(s): 
 
 
Table 8.6.1 SCIT Dose Escalation 
All participants will start SCIT with Dose 1. Doses -1 and -2 are included for participants who 
experience a reaction at Doses 1 or 2 that require dosage reductions. 
Dose # 
Concentration 
Volume 
-2 
1:10,000 
0.03 ml 
-1 
1:10,000 
0.04 ml 
1 
1:10,000 
0.05 ml 
2 
1:10,000 
0.1 ml 
3 
1:10,000 
0.2 ml 
4 
1:10,000 
0.3 ml 
5 
1:10,000 
0.4 ml 
6 
1:1,000 
0.05 ml 
7 
1:1,000 
0.1 ml 
8 
1:1,000 
0.2 ml 
9 
1:1,000 
0.3 ml 
10 
1:1,000 
0.4 ml 
11 
1:100 
0.05 ml 
12 
1:100 
0.1 ml 
13 
1:100 
0.2 ml 
14 
1:100 
0.3 ml 
15 
1:100 
0.4 ml 
16 
1:10 
0.05 ml 
17 
1:10 
0.1 ml 

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18 
1:10 
0.2 ml 
19 
1:10 
0.3 ml 
20 
1:10 
0.4 ml 
21 
1:1 
0.05 ml 
22 
1:1 
0.1 ml 
23 
1:1 
0.15 ml 
24 
1:1 
0.2 ml 
25 
1:1 
0.3 ml 
26 
1:1 
0.4 ml 
 
Dose escalation will continue according to the schedule unless there are lapses in dosing or reactions 
occur.  Dosing modifications as a result of reaction or lapse in dosing during dose escalation are detailed 
in the MOP for Protocol ICAC-28.  
Participants who are unable to reach the minimum maintenance dose (the highest volume of the 1:10 
concentration; Dose 20 in Table 8.6.1) by 40 weeks following the start of dose escalation will be unable 
to proceed to the maintenance period and will have their study therapy stopped (see Section 11.2.1; see 
Appendix B Study Restrictions Due to COVID-19).  
8.6.2 
Maintenance Visits 
Participants who have completed dose escalation will receive one injection of investigational agent 
every 2 weeks for 3 doses, followed by maintenance injections every 4 weeks to complete a maximum 
of 12 months of treatment.  
During the maintenance phase, a urine pregnancy test will be performed at the E&M visits (every two 
months) on all female participants that have reached menarche. 
Dosing modifications as a result of reaction or lapse in dosing for the three, initial, maintenance-level 
injections, planned at two week intervals, are detailed in the MOP for Protocol ICAC-28. Additionally, 
dosing modifications as a result of reaction or lapse in dosing for the subsequent maintenance level 
injections planned at four-week intervals are detailed in the MOP for Protocol ICAC-28.  
Participants will be instructed to immediately report any severe sign or symptom possibly related to the 
subcutaneous administration of the investigational agent and to contact the study site when they need 
medical advice. At each visit, participants will be queried regarding any delayed reactions or side effects 
experienced. For those participants with asthma, exacerbations will be handled through an approach 
consistent with standard clinical practice as described in the Protocol ICAC-28 MOP.  
8.7 Asthma Evaluation and Management (E&M) Visits 
Every two months, an asthma E&M process will occur where participants’ asthma medication regimen 
will be adjusted based on symptoms, albuterol/levalbuterol use, FEV1, recent exacerbations, and their 
current level of therapy (see Section 7.1.1.2).  At these visits, asthma and rhinitis endpoints, including 
the CASI (see Section 3) will also be measured.   The E&M Visits will include: 
 
Pregnancy test (post-menarcheal females) 
 
Physical exam and AE assessment 
 
Vital signs, with height and weight 

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 
Spirometry and peak flow 
 
CASI and other symptom measurements 
 
Assignment of asthma medication regimen by study clinician (see Section 7.1.1) 
 
Asthma education/counseling (see Section 7.1.1.5) 
8.8 12-Month Visit  
The 12-Month Visit is the final visit and will include: 
 
Pregnancy test (post-menarcheal females) 
 
Final physical exam and AE assessment 
 
Vital signs, with height and weight 
 
Blood draw 
 
Allergen skin test for German cockroach 
 
Spirometry and peak flow 
 
CASI and other symptom measurements 
 
Targeted pulmonary exam 
 
NAC 
 
Nasal lavage, before and after NAC 
8.9 Early Termination Visit  
Participants who withdraw from the study or are dropped from the study will be invited to the study 
center for an Early Termination Visit as specified in the Protocol ICAC-28 MOP. The Early Termination 
Visit can include: 
 
Pregnancy test (post-menarcheal females) 
 
Final physical exam and AE assessment 
 
Vital signs, with height and weight 
 
Blood draw  
 
Allergen skin test for German cockroach 
 
Spirometry and peak flow 
 
CASI and other symptom measurements 
Procedures contraindicated by the medical condition of the participant will not be conducted at the 
discretion of the study clinician. For participants who refuse or are unable to come to the clinic, the final 
clinical assessment as described above may be conducted over the phone. Besides this visit, no further 
follow-up will be made, except for participants who are discontinued due to pregnancy or SAEs. These 
participants will be contacted to determine the outcome of the pregnancy or the SAE. Refer to Section 
12.6, Pregnancy Reporting, for more information on AE reporting for pregnancy. 
8.10 Unscheduled Visits  
Participants who experience asthma-related problems (not requiring emergency room care) or concerns 
between scheduled study visits will be seen by a study clinician as warranted by the situation. If the site 
staff are notified by the participant, his/her family, an ED, a hospital, or clinic that the participant was 
seen for an unscheduled visit elsewhere, the site staff will contact the participant within 2 weeks of 
discharge to obtain an update on the participant’s clinical status.  A follow-up visit at the study center 

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will be scheduled if needed. For details on the management plan, please refer to Section 7.1.1 and the 
Protocol ICAC-28 MOP. 
Participants who are at Control Level 4 at a study visit will either be seen in the clinic or will receive a 
follow-up phone call within 1-2 weeks of the visit to check the status of their symptoms.   
Participants who have 2 exacerbations within a 1-month period must be seen in a face-to-face visit to 
determine if continuation in the study is in the best interest of the participant. 
8.11 Visit Windows 
During dose escalation, 1-2 injections will be given each week separated by at least 2 days. Dose 
escalation must be completed over a maximum of 40 weeks (See Appendix B: Study Restrictions Due to 
COVID-19). Bi-weekly and monthly maintenance injections should be scheduled as close as possible to 
the every 2-week or every-4-week target dates.  
See the Protocol ICAC-28 MOP for details regarding visit scheduling and Appendix A for the Table of 
Events. 
9 Mechanistic Assays 
Exploratory objectives will be addressed using mechanistic assays to evaluate biological responses to CR 
immunotherapy. Detailed descriptions of the methodology for biological sample collection and 
processing and for assay implementation are described in the ICAC-28 MOP and in separate mechanistic 
study proposals.  
Whole blood will be collected by venipuncture according to the visit activity schedule (see Appendix A) 
prior to Randomization and at the 12-Month Visit or the Early Termination Visit. Nasal lavage samples 
will be collected prior to each NAC and at approximately 3 hours after the initiation of each NAC.  
9.1 Antibody Assays 
Serum processed from study blood draws will be tested for biomarkers of allergen immunotherapy, such 
as cockroach-specific IgE and IgG4 antibodies to cockroach component allergens. These include, but may 
not be limited to, Bla g 1, Bla g 2, Bla g 4, Bla g 5 and Per a 7.  
Serum from these blood draws will also be used to measure in-vitro cockroach antigen binding to B-
cells. 
9.2 Cellular Assays 
Peripheral blood mononuclear cells (PBMCs) will be separated from study blood draws and used to 
measure the magnitude and phenotype of the CR-specific T cell response to CR immunotherapy.  
9.3 Gene Expression 
Blood drawn at each study blood draw will be used to extract RNA samples for whole transcriptome RNA 
sequencing to identify the changes in PBMC gene expression response to CR stimulation over time and 
compare those changes between the treated group and the untreated group. Significant differences will 
allow the identification of mechanisms of immune tolerance in CR SCIT. 

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Nasal lavage samples collected before and after each NAC will be used to compare gene expression by 
RNA-sequencing in nasal lavage samples pre-CR NAC with samples post-CR NAC. Samples collected at 12 
months will be used to identify the changes in nasal lavage gene expression in response to CR 
immunotherapy between the treated group and the untreated group. 
10 Biospecimen Storage 
Unused samples of biological specimens collected during the course of the study will be stored 
(described in the Protocol ICAC-28 MOP) for future use for tests that may or may not be planned. These 
tests may or may not be related to the study of asthma and allergy and may include genetic studies such 
as DNA. Participants will be asked to give permission for long-term storage and future use during the 
consent process.  With the participant’s approval and as approved by the central IRB, de-identified 
biological samples will be stored indefinitely at the DAIT NIAID central repository (Eminent Services 
Corporation, Frederick, MD). 
11 Criteria for Participant and Study Completion and Premature Study Termination 
11.1 Participant Completion 
Participants are considered to have completed the study once they have completed the final visit (12-
month Visit). 
11.2 Participant Stopping Rules and Withdrawal Criteria 
11.2.1 Discontinuation of Study Therapy 
Study therapy may be prematurely discontinued for any participant for any of the following reasons: 
1. SAE related to investigational agent.      
2. Systemic reaction grade 3 or 4 (see Table 12.3.1.1c, WAO Systemic Reaction Grading System).  
3. Failure to reach the minimum maintenance dose in a forty-week period (See Appendix B: Study 
Restrictions Due to COVID-19).  
4. Development of any serious medical illness whose natural history, sequela, or treatment would be 
worsened or impaired by continuation in the protocol. 
5. The participant has a need to start immunotherapy or any chronic immunosuppressive medications. 
6. The participant has a need for a dose of greater than 500 mcg of fluticasone per day, or the 
equivalent of another inhaled corticosteroid, to maintain asthma control for greater than 6 months. 
11.2.2 Discontinuation of Study Participation 
Participants may additionally be prematurely terminated from the study for the following reasons: 
1. Pregnancy  
2. The participant elects to withdraw consent from all future study activities, including follow-up. 
3. The participant is “lost to follow-up” as defined in the Protocol ICAC-28 MOP. 
4. The participant dies.  
5. The Investigator no longer believes participation is in the best interest of the participant. 
6. The participant has a need for > 3 bursts of systemic corticosteroids for asthma exacerbations 
during the treatment period OR has a need for > 2 bursts of systemic corticosteroids for asthma 

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exacerbations within 6 months during the treatment period. If prescribed by an ICAC study 
clinician, a burst is defined as a course for prednisone, prednisolone, or methylprednisolone 
will be 2 mg/kg/day as a single daily dose for 4 days with a maximum dose of 60 mg per day. 
The course for dexamethasone will be 0.3 to 0.6 mg/kg/day as a single daily dose for 2 days 
with a maximum dose of 16 mg per day. If a corticosteroid burst for the treatment of an 
asthma exacerbation is prescribed by a non-ICAC clinician, it will be counted regardless of dose.  
11.3 Participant Replacement 
Participants who are discontinued prior to completing the study may be replaced as long as 
randomization for the study is still ongoing. All reasons for withdrawal will be captured on the 
appropriate electronic case report form (eCRF). 
11.4 Follow-up after Study Therapy Discontinuation 
Participants who discontinue study therapy after receiving one dose of investigational product will be 
asked to continue study follow-up for the remainder of the treatment period, using an altered visit 
schedule. 
11.5 Study Stopping Rules 
Study enrollment and treatment will be suspended pending expedited review of all pertinent data for 
the following reasons: 
1) One death if at least possibly related to the investigational agent 
2) Two Grade 4 systemic reactions possibly related to the injection of the investigational agent (see 
Table 12.3.1.1c)  
3) One local Grade 4 reaction (see Table 12.3.1.1a) or Grade 4 systemic reaction (see Table 12.3.1.1c) 
possibly related to the NAC  
a) The study will be halted for this occurrence pending review of pertinent data by DAIT/NIAID 
Medical Monitor (MM) and the NIAID Asthma and Allergy DSMB 
 
If the study enrollment is stopped due to meeting the above criteria, it may not be resumed until all 
pertinent information is discussed with DAIT/NIAID, NIAID Asthma and Allergy DSMB, and the Central 
IRB, and all parties concur with the resumption of the study. The FDA will be notified if stopping rules 
are met and also on resumption of the study. 
The study may be terminated by the IND sponsor (DAIT/NIAID) or the NIAID Allergy and Asthma DSMB 
upon review of any observations, events, or new information that merits such action. 
12 Safety Monitoring and Reporting 
12.1 Overview 
This section defines the types of safety data that will be collected under this protocol and outlines the 
procedures for appropriately collecting, grading, recording, and reporting those data. Adverse events 
that are classified as serious according to the definition of health authorities must be reported promptly 
(per Section 12.5, Reporting of Serious Adverse Events and Adverse Events) to the IND sponsor (DAIT 
NIAID).  Appropriate notifications will also be made to site Principal Investigators, Institutional Review 
Boards (IRBs), and appropriate Health Authorities. 

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Information in this section complies with ICH Guideline E2A: Clinical Safety Data Management: 
Definitions and Standards for Expedited Reporting, ICH Guideline E-6: Guideline for Good Clinical 
Practice, 21CFR Parts 312 and 320, and applies the standards set forth in the National Cancer Institute 
(NCI), Common Terminology Criteria for Adverse Events (CTCAE), Version [enter 4.0 or correct version 
applicable to trial] : http://ctep.cancer.gov/reporting/ctc.html. 
12.2 Definitions 
12.2.1 Adverse Event (AE) 
Any untoward or unfavorable medical occurrence associated with the subject’s participation in the 
research, whether or not considered related to the subject’s participation in the research (modified 
from the definition of adverse events in the 1996 International Conference on Harmonisation E-6 
Guidelines for Good Clinical Practice) (from OHRP "Guidance on Reviewing and Reporting Unanticipated 
Problems Involving Risks to Subjects or Others and Adverse Events (1/15/07)" 
http://www.hhs.gov/ohrp/policy/advevntguid.html#Q2 )  
The following are adverse events associated with study therapy and study procedures:   
 
Study therapy regimen: German cockroach allergenic extract administered by the subcutaneous 
route  
 
Local Injection site reaction which requires a change in SCIT dose 
 
Systemic reactions such as, but not limited to, those listed below: 
 
Eye symptoms (itchy, runny, swelling) 
 
Nose symptoms (sneezing, itching, runny, stuffy) 
 
Mouth/ears/throat symptoms (itchy mouth, throat irritation, oral or throat angioedema, 
cough, itchy ears) 
 
Skin symptoms other than local injection site reactions (angioedema, urticaria, 
generalized itching, rash) 
 
Gastrointestinal symptoms (vomiting, diarrhea, cramps, nausea) 
 
Chest (cough, tightness, wheezing) 
 
Anaphylaxis (see Table 12.3.1.1b) 
 
Study procedures: AEs that occur due to a study procedure will be collected and recorded. The 
following clinical situations, when associated with study procedures, are defined as adverse events 
and will be recorded on the AE eCRF.   
Blood Draws 
 
Fainting/Vasovagal events 
 
Bruising at puncture site larger than 2 cm diameter 
 
Bleeding from puncture site lasting more than 30 minutes 
 
Swelling at puncture site larger than 2 cm 
 
Pulmonary Function Testing  
 
Wheezing or bronchoconstriction requiring treatment with bronchodilators within 30 
minutes from the procedure 

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 
Coughing requiring treatment with bronchodilators within 30 minutes from the 
procedure 
Nasal Allergen Challenge 
• 
Any clinical response requiring medication (see table 12.3.1.1a) 
Allergen Skin Testing 
 
Prolonged (> 24 hours) itching at test site 
 
Swelling (> 10 cm) at site of test lasting more than 24 hours 
 
Nasal allergic symptoms within 30 minutes of the procedure 
 
Fainting/vasovagal event within 30 minutes of the procedure 
 
Anaphylaxis 
12.2.2 Suspected Adverse Reaction (SAR)  
Any adverse event for which there is a reasonable possibility that the investigational drug [or 
investigational study therapy regimen] caused the adverse event. For the purposes of safety reporting, 
‘reasonable possibility’ means there is evidence to suggest a causal relationship between the drug and 
the adverse event. A suspected adverse reaction implies a lesser degree of certainty about causality 
than adverse reaction, which means any adverse event caused by a drug (21 CFR 312.32(a)). 
12.2.3 Unexpected Adverse Event  
An adverse event or suspected adverse reaction (SAR) is considered “unexpected” when its nature 
(specificity), or severity, or rate of occurrence is not consistent with the risk information described in the 
general investigational plan or elsewhere in the IND. 
 “Unexpected” also refers to adverse events or suspected adverse reactions that are mentioned in the 
package insert as occurring with a class of drugs or as anticipated from the pharmacological properties 
of the drug, but are not specifically mentioned as occurring with the particular drug under investigation 
(21 CFR 312.32(a)). 
12.2.4 Serious Adverse Event (SAE) 
An adverse event or suspected adverse reaction is considered “serious” if, in the view of either the 
investigator or the DAIT/NIAID Medical Monitor, it results in any of the following outcomes (21 CFR 
312.32(a)): 
1. Death. 
2. A life-threatening event: An AE or SAR is considered “life-threatening” if, in the view of either the 
Principal Investigator or IND Sponsor, its occurrence places the subject at immediate risk of 
death. It does not include an AE or SAR that, had it occurred in a more severe form, might have 
caused death.  
3. Inpatient hospitalization or prolongation of existing hospitalization. 
4. Persistent or significant incapacity or substantial disruption of the ability to conduct normal life 
functions. 
5. Congenital anomaly or birth defect.  
6. Important medical events that may not result in death, be life-threatening, or require 
hospitalization may be considered serious when, based upon appropriate medical judgment, 

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they may jeopardize the subject and may require medical or surgical intervention to prevent one 
of the outcomes listed above. 
Exacerbations of asthma are ordinary, anticipated complications of asthma observed in patients 
receiving standard of care. An asthma exacerbation that requires hospitalization and is determined to be 
a SAR (Section 12.2.1.1) will be considered a SAE. All other asthma hospitalizations will not be 
considered SAEs and will be entered only on the appropriate CRFs. The date of onset of the SAE will be 
the date of hospital admission and the date of resolution will be the discharge date. The underlying 
condition will be followed as per protocol. 
12.3 Grading and Attribution of Adverse Events 
Information in this section complies with ICH Guideline E-6: Guidelines for Good Clinical Practice; and 
applies the standards: 
 
Guidance for Industry: Toxicity Grading Scale for Healthy Adult and Adolescent Volunteers Enrolled in 
Preventive Vaccine Clinical Trials (published September 2007) for allergic local reactions to study 
procedures.  
 
The definition of anaphylaxis is described in Table 12.3.1.1b (Clinical Criteria for Diagnosing 
Anaphylaxis)29 
 
World Allergy Organization (WAO) Subcutaneous Immunotherapy Systemic Reaction Grading 
System.9 National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events Version 
4.03 (published June 14, 2010) for all other reactions. (This document is referred to herein as the 
“NCI-CTCAE manual.”)  
12.3.1 Grading Criteria 
12.3.1.1 Adverse Events Related to Nasal Allergen Challenge, Skin Testing and Immunotherapy 
Adverse events related to nasal allergen challenge, skin testing, and immunotherapy not associated with 
systemic signs or symptoms will be graded according to Table 12.3.1.1a below. All AEs should be 
recorded on the eCRF. 

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Table 12.3.1.1a Grading of Local Reactions to Study Procedures 
Grade 
1 
2 
3 
4 
 
Nasal allergen 
challenge 
 
Requiring 
antihistamines, 
decongestants or 
nasal steroids as 
rescue 
medication 
Requiring oral 
steroids as 
rescue 
medication  
Requiring a visit 
to a health care 
provider for 
treatment. 
Life-threatening 
and/or requiring 
hospitalization 
(e.g. upper 
airway 
obstruction) 
Skin testing 
Meets the 
minimum criteria 
listed in section 
12.2.1, but 
requiring no 
medication other 
than topical 
corticosteroids 
or 
antihistamines. 
Interfering with 
usual daily 
activities or sleep 
and requiring 
oral steroids. 
Requiring a visit 
to a health care 
provider  for 
treatment 
Not applicable 
Immunotherapy 
Requires a 
change in IT 
dosing, but 
requiring no 
medication other 
than topical 
corticosteroids 
or 
antihistamines. 
Interfering with 
usual daily 
activities or sleep 
and requiring 
oral steroids. 
Requiring a visit 
to a health care 
provider for 
treatment 
Not applicable 
 
Criteria from Sampson, et al.29 (Table 12.3.1.1b), will be used to determine whether systemic allergic 
reactions constitute anaphylaxis. To be considered anaphylaxis, the event must involve at least two 
organ systems (e.g. not be simply a skin reaction).  

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Table 12.3.1.1b Clinical Criteria for Diagnosing Anaphylaxis 
All anaphylaxis events, regardless of severity grade, and other systemic reactions will be recorded as 
Adverse Events and will be graded according to Table 12.3.1.1c World Allergy Organization 
Subcutaneous Immunotherapy Systemic Reaction Grading System.9 
 
 
Anaphylaxis is highly likely when any one of the following 3 criteria are fulfilled: 
1) Acute onset of an illness (minutes to several hours) with involvement of the skin, mucosal 
tissue, or both (e.g., generalized hives, pruritus or flushing, swollen lips-tongue-uvula) 
AND AT LEAST ONE OF THE FOLLOWING: 
a) Respiratory compromise (e.g., dyspnea, wheeze-bronchospasm, stridor, reducted PEF, 
hypoxemia 
b) Reduced BP or associated symptoms of end-organ dysfunction (e.g., hypotonia [collapse], 
syncope, incontinence) 
2) Two or more of the following that occur rapidly after exposure to a likely allergen for that 
patient (minutes to several hours): 
a) Involvement of the skin-mucosal tissue (e.g., generalized hives, itch-flush, swollen lips-
tongue-uvula) 
b) Respiratory compromise (e.g., dyspnea, wheeze-bronchospasm, stridor, reducted PEF, 
hypoxemia) 
c) Reduced BP or associated symptoms (e.g., hypotonia [collapse], syncope, incontinence) 
d) Persistent gastrointestinal symptoms (e.g., crampy abdominal pain, vomiting) 
3) Reduced BP after exposure to known allergen for that patient (minutes or several hours): 
a) Infants and children: low systolic BP (age specific) or greater than 30% decrease in systolic 
BP* 
b) Adults: systolic BP of less than 90 mm Hg or greater than 30% decrease from that person’s 
baseline 
PEF, Peak expiratory flow; BP, blood pressure. 
*Low systolic blood pressure for children is defined as less than 70 mm Hg from 1 month to 1 year, less than (70 
mm Hg + [2 x age]) from 1 to 10 years, and less than 90 mm Hg from 11 to 17 years.  

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Table 12.3.1.1c World Allergy Organization Subcutaneous Immunotherapy Systemic 
Reaction Grading System  
 
12.3.1.2 Grading and Attribution of All Other Adverse Events 
The study clinician will grade the severity of other adverse events experienced by the study participants 
according to the criteria set forth in the National Cancer Institute’s Common Terminology Criteria for 
Adverse Events (CTCAE) Version 4.0. This document (referred to herein as the NCI-CTCAE manual) 
provides a common language to describe levels of severity, to analyze and interpret data, and to 
articulate the clinical significance of all adverse events. The NCI-CTCAE has been reviewed by the 
Principal Investigators and has been deemed appropriate for the participant population to be studied in 
this protocol.  
Adverse events will be graded on a scale from 1 to 5 according to the following standards in the NCI-
CTCAE manual: 
Grade 1 = mild adverse event 
Grade 2 = moderate adverse event 
Grade 3 = severe and undesirable adverse event 
Grade 4 = life-threatening or disabling adverse event 
Grade 5 = death 
 
Events Grade 1 or higher will be recorded on the appropriate AE electronic case report form for this 
study. 

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During the course of the study, to determine if an abnormal value or a clinical or laboratory evaluation 
(including, but not limited to, a radiograph, an ultrasound, an electrocardiogram etc.), is an adverse 
event will rely on clinical judgment of the study clinician.  
For additional information and a printable version of the NCI-CTCAE manual, consult the NCI-CTCAE web 
site: http://ctep.cancer.gov/reporting/ctc.html. 
12.3.2 Attribution Definitions 
The relationship, or attribution, of an adverse event to the study therapy regimen or study procedure(s) 
will initially be determined by the study clinician and recorded on the appropriate AE/SAE eCRF.  Final 
determination of attribution for safety reporting will be determined by DAIT NIAID.  The relationship of 
an adverse event to study therapy regimen or procedures will be determined using the descriptors and 
definitions provided in Table 12.3.2.  
For additional information and a printable version of the NCI-CTCAE manual, consult the NCI-CTCAE web 
site: http://ctep.cancer.gov/reporting/ctc.html. 
Table 12.3.2 Attribution of Adverse Events 
Code 
Descriptor 
Relationship (to primary investigational product and/or 
other concurrent mandated study therapy or study 
procedure) 
UNRELATED CATEGORY 
1 
Unrelated 
The adverse event is clearly not related; there is insufficient 
evidence to suggest a causal relationship. 
RELATED CATEGORIES 
2 
Possible 
The adverse event has a reasonable possibility to be related; 
there is evidence to suggest a causal relationship. 
3 
Definite 
The adverse event is clearly related. 
 
12.4 Collection and Recording of Adverse Events 
12.4.1 Collection Period 
Adverse events (including SAEs) will be collected from the time of consent until 30 days after a 
participant completes study participation or until 30 days after he/she prematurely withdraws (without 
withdrawing consent) or is withdrawn from the study. 
12.4.2 Collecting Adverse Events 
Adverse events (including SAEs) may be discovered through any of these methods: 
 
Observing the participant 
 
Interviewing the participant  
 
Receiving an unsolicited complaint from the subject 
 
In addition, an abnormal value or result from a clinical or laboratory evaluation can also 
indicate an adverse event, as defined in Section 12.3, Grading and Attribution of Adverse 
Events 

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12.4.3 Recording Adverse Events 
Throughout the study, the investigator will record adverse events and serious adverse events as 
described previously (Section 12.2, Definitions) on the appropriate AE/SAE eCRF regardless of the 
relationship to study therapy regimen or study procedure. 
Once recorded, an AE/SAE will be followed until it resolves with or without sequelae, or until 30 days 
after the end of study participation, or until 30 days after the subject prematurely withdraws (without 
withdrawing consent)/or is withdrawn from the study, whichever occurs first. The DAIT NIAID Medical 
Officer may request continued follow-up of an adverse event beyond the stated timeframe if deemed 
clinically important. 
12.5 Reporting of Serious Adverse Events and Adverse Events 
12.5.1 Reporting of Serious Adverse Events to the IND Sponsor (DAIT/NIAID) 
This section describes the responsibilities of the Principal Investigator to report serious adverse events 
to the IND sponsor via SAE eCRF. Timely reporting of adverse events is required by 21 CFR and ICH E6 
guidelines.  
Principal Investigators must report all serious adverse events (see Section 04, Serious Adverse Event), 
regardless of relationship or expectedness within 24 hours of becoming aware of the event. 
For serious adverse events, all requested information on the AE/SAE eCRF will be provided.  The 
following minimal criteria must be included in the initial SAE eCRF: 
 
AE Term 
 
Study Drug Treatment 
 
Relationship to study drug 
 
Reason why the event is serious 
However, unavailable details of the event will not delay submission of the known information.  As 
additional details become available, the AE/SAE eCRF will be updated and submitted. Every time the SAE 
eCRF is submitted, it should be electronically signed by the investigator or sub-investigator. 
12.5.2 Reporting to FDA 
After an adverse event requiring 24 hour reporting (per Section 12.5.1, Reporting of Serious Adverse 
Events to Sponsor) is submitted by the Principal Investigator and assessed by the IND sponsor (DAIT 
NIAID), the IND Sponsor (DAIT NIAID) must report the adverse event to the FDA using one of these two 
options: standard reporting (report in the IND annual report) and expedited safety reporting. 
12.5.2.1 Standard Reporting (Report in the IND Annual Report) 
This option applies if the AE is classified as one of the following: 
 
Serious, expected, suspected adverse reactions (see Section 12.2.2, Suspected Adverse 
Reaction, and Section 12.2.3, Unexpected Adverse Event). 
 
Serious and not a suspected adverse reaction (see Section 12.2.2, Suspected Adverse 
Reaction). 
 
Pregnancies. 

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Note that all adverse events (not just those requiring 24-hour reporting) will be reported in the IND 
Annual Report. 
12.5.2.2 Expedited Safety Reporting  
This option, with 2 possible categories, applies if the adverse event is classified as one of the following: 
Category 1:  Serious and unexpected suspected adverse reaction [SUSAR] (see Section 12.2.2, 
Suspected Adverse Reaction (SAR), and Section 12.2.3, Unexpected Adverse Event and 21 CFR 
312.32(c)(1)i).  
The sponsor must report any suspected adverse reaction that is both serious and unexpected.  The 
sponsor shall report an adverse event as a suspected adverse reaction only if there is evidence to 
suggest a causal relationship between the study drug and the adverse event, such as: 
1. One or more occurrences of an event that is not commonly associated with drug exposure, but 
is otherwise uncommon in the population exposed to the drug (e.g., tendon rupture); 
2. An aggregate analysis of specific events observed in a clinical trial (such as known consequences 
of the underlying disease or condition under investigation or other events that commonly occur 
in the study population independent of drug therapy) that indicates those events occur more 
frequently in the drug treatment group than in a concurrent or historical control group. 
Category 2: Any findings from studies that suggests a significant human risk  
The sponsor shall report any findings from other epidemiological studies, analyses of adverse events 
within the current study or pooled analysis across clinical studies or animal or in vitro testing (e.g. 
mutagenicity, teratogenicity, carcinogenicity) that suggest a significant risk in humans exposed to the 
drug that would result in a safety-related change in the protocol, informed consent, Investigator 
Brochure or Package Insert or other aspects of the overall conduct of the study.   
DAIT NIAID must report to the FDA and notify all participating investigators of expedited Safety Reports 
within 15 calendar days; unexpected fatal or immediately life-threatening suspected adverse reaction(s) 
must be reported as soon as possible or within 7 calendar days.  
12.5.3 Reporting of Adverse Events to IRBs 
All Principal Investigators must report adverse events, including expedited reports, in a timely fashion to 
the central IRB of record in accordance with applicable regulations and guidelines. All IND Safety Reports 
to the FDA shall be distributed by the IND sponsor (DAIT NIAID) or designee to all participating 
institutions for central IRB submission. 
12.6 Pregnancy Reporting 
The Principal Investigator shall be informed immediately of any pregnancy in a study participant 
occurring from time of consent through 30 days after the participant completes study participation. A 
pregnant participant shall be instructed to stop taking study medication. The investigator shall counsel 
the participant and discuss the risks of continuing with the pregnancy and the possible effects on the 
fetus. Monitoring of the pregnant participant shall continue until the conclusion of the pregnancy.   
The investigator shall report to the DAIT SACCC and the IND sponsor (DAIT NIAID) all pregnancies within 
1 business day of becoming aware of the event using the Pregnancy eCRF.  All pregnancies identified 
during the study shall be followed to conclusion and the outcome of each must be reported. The 

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Pregnancy eCRF shall be updated and submitted to the DAIT SACCC when details about the outcome are 
available.   
Information requested about the delivery shall include: 
 
Gestational age at delivery 
 
Birth weight, length, and head circumference 
 
Gender 
 
Appearance, pulse, grimace, activity, and respiration (APGAR) score at 1 minute, 5 minutes, 
and 24 hours after birth, if available 
 
Any abnormalities 
For all pregnancy complications that result in a congenital abnormality, birth defect, miscarriage, and 
medically indicated abortion, an SAE shall be submitted to the DAIT SACCC and the IND sponsor (DAIT 
NIAID) using the SAE reporting procedures described above.  
12.7 Reporting of Other Safety Information 
A Principal Investigator shall promptly notify the Central IRB as well as the DAIT SACCC and the IND 
sponsor (DAIT NIAID) via email when an “unanticipated problem involving risks to subjects or others” is 
identified, which is not otherwise reportable as an adverse event. 
12.8 Review of Safety Information 
12.8.1 Medical Monitor Review 
The DAIT NIAID Medical Monitor shall receive monthly reports from the DAIT SACCC compiling new and 
accumulating information on major protocol deviations, AEs, SAEs, and pregnancies recorded by the 
study sites on appropriate eCRFs. 
In addition, the DAIT NIAID Medical Monitor shall review and make decisions on the disposition of the 
SAE and pregnancy reports received by the DAIT SACCC (See Sections 12.5 and 12.6).   
12.8.2 DSMB Review  
12.8.2.1 Planned DSMB Reviews  
NIAID Asthma and Allergy Data and Safety Monitoring Board (DSMB) shall review safety data at least 
yearly during planned DSMB Data Review Meetings. Data for the planned safety reviews will include, at 
a minimum, a listing of all reported AEs and SAEs.   
The NIAID Asthma and Allergy DSMB will be informed of an Expedited Safety Report as determined by 
the DAIT NIAID Medical Monitor. An SAE which the DAIT NIAID Medical Monitor determines to be an 
unexpected safety risk will be sent to the DSMB immediately. 
12.8.2.2 Ad hoc DSMB Reviews  
In addition to the pre-scheduled data reviews and planned safety monitoring, the NIAID Asthma and 
Allergy DSMB may be called upon for ad hoc reviews. The NIAID Asthma and Allergy DSMB will review 
any event that potentially impacts safety at the request of the protocol chair or the IND sponsor (DAIT 
NIAID). In addition, occurrences described in Section 11.5 Study Stopping Rules will trigger an ad hoc 
comprehensive DSMB Safety Review. 

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After review of the data, the DSMB will make recommendations regarding study conduct and/or 
continuation. 
12.8.2.2.1 Temporary Suspension of enrollment and drug dosing for ad hoc DSMB Safety Review  
A temporary halt in both enrollment and drug dosing will be implemented if an ad hoc DSMB safety 
review is required. 
13 Statistical Considerations and Analytical Plan 
13.1 Overview  
The primary hypothesis to be tested by this study is whether nasal allergen challenge outcomes, in 
children with persistent, well-controlled asthma, will be affected by subcutaneous treatment with non-
standardized glycerinated German cockroach (B. germanica) allergenic extract.  Major secondary 
hypotheses are that subcutaneous treatment with German cockroach (B. germanica) extract can affect 
asthma severity measures as well as induce significant changes in immunologic biomarkers indicative of 
desensitization in children with persistent, well-controlled asthma.  
13.2 Endpoints 
The primary endpoint of the study is the average TNSS (total nasal symptom score) over the 9 protocol-
defined doses at the 12-month NAC. Secondary and exploratory endpoints include other NAC outcomes, 
safety, in vivo and in vitro biomarkers of immunotherapy, other asthma and rhinitis severity endpoints, 
and key mechanistic parameters.  
13.3 Measures to Minimize Bias  
To minimize bias, a randomization schedule will be generated by the DAIT SACCC and implemented in a 
validated system that will be used by site personnel to automate the random assignment of treatment 
groups to study participants.  The randomization scheme will be reviewed and approved by a statistician 
at the DAIT SACCC (Rho Federal) and will not be modified thereafter except to accommodate any 
changes required by amendments to the protocol. Participants will be randomized using a 1:1 ratio of 
active (German cockroach (B. germanica) extract) and control (placebo) participants. Randomization will 
be stratified by site. 
All laboratory assays for serum IgE and IgG antibodies and other parameters will be performed in a 
central laboratory by technicians who do not know the participants’ group assignments.  
13.4 Analysis Plan 
13.4.1 Analysis Populations 
The following groups of participants will define samples for endpoint analysis: 
 
Modified Intent-to-treat (ITT) sample:  All participants who are randomized, received at least one 
dose of study treatment, and receive at least one dose during the 12-month NAC. Participants will 
be analyzed according to the treatment arm to which they were randomized, regardless of the 
medication they actually received. 
 
Safety sample: All participants who sign consent and undergo study procedures at Screening. 
Participants will be analyzed according to the medication they actually received, regardless of the 

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treatment arm to which they were randomized. Non-treatment-emergent adverse events (e.g., any 
adverse event that occurs before the first injection) will be summarized in all participants who are 
enrolled, while treatment-emergent adverse events (e.g., any adverse event that occurs on or after 
the first injection) will be summarized in the safety sample.  
 
Per-protocol (PP) sample: All participants who are randomized, are escalated to 0.4 mL of the 1:10 
maintenance dose, and receive at least 66% of expected doses of maintenance.  
13.4.2 Primary Analysis of Primary Endpoint  
The primary outcome of the study is the average TNSS, calculated as the average TNSS over the 
observed doses. The comparison between arms will be conducted using an analysis of covariance 
(ANCOVA) model. The ANCOVA model will include fixed categorical effects for treatment and baseline 
TNSS score, with adjustment for site. Least square means (LSmeans), SE, LSmeans difference, 95% 
confidence interval (CI) and p-value will be presented. Further details regarding the analyses of the 12-
month TNSS will be provided in the Statistical Analysis Plan.  
13.4.3 Supportive Analyses of the Primary Endpoint  
13.4.3.1 Effects of Cockroach SCIT on TNSS  
Additionally, it will be possible to compare the responsive dose at the 12-month NAC (the dose which 
elicits the threshold response of a TNSS ≥ 6 or a sneeze score ≥ 3) at the 12-month NAC by treatment 
group, using discrete-time (discrete-dose) survival analyses as described by Chinchilli et al.30 and 
Sampson et al.31 This analysis, which will estimate a hazard ratio, is based on a model for the conditional 
probability of a subject reacting to a given dose, given that the subject has not reacted to previously 
administered doses. Details of right censoring, adjustment for the baseline NAC, imputation for missing 
12-month NAC observations, and evaluation of the proportional hazards assumption (and analytical 
options when the assumption is not met) will be provided in the Statistical Analysis Plan. 
13.4.3.2 Approaches for Missing Data 
The primary method of handling missing efficacy data will be the method of MCMC multiple imputation 
which does not rely on the assumption of data missing at random. After imputing with MCMC, each 
complete data set will be analyzed with an ANCOVA with factors for arm and site and the respective 
baseline TNSS as a covariate. Lastly, we will combine the sets of estimates (and their standard errors) 
generated from different ANCOVA multiply imputed datasets into one set of results. 
13.4.4 Analyses of Secondary and Other Endpoints 
13.4.4.1 Safety 
Safety will be summarized by arm in the safety sample by the number and percentage of serious and 
non-serious adverse events stratified by grade and relationship to treatment as well as the number and 
percentage of participants who have a serious and non-serious adverse event stratified by grade and 
relationship to treatment.   
13.4.4.2 German Cockroach-specific IgE and IgG4 
12-months log-transformed German cockroach-specific IgE and IgG4 will also be modeled as ANCOVA 
with factors for treatment arm, site and the respective log-transformed baseline as covariate. Similarly, 
Least square means (LSmeans), SE, LSmeans difference, 95% confidence interval (CI) and p-value will be 

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presented, modeled using a linear mixed model that will include a random intercept and fixed effects for 
each treatment arm, and an interaction term between treatment arm and time of measurement. 
13.4.5 Analyses of Exploratory Endpoints 
13.4.5.1 CASI outcome measures 
To account for the correlation among repeated measures within subject, the effect of cockroach SCIT on 
asthma severity will be analyzed using a mixed effect repeated measures model looking at the CASI 
assessments at 10 and 12 months of treatment.   
The mixed model will include fixed effects for treatment group, baseline CASI score at randomization, 
site as well as a within-subject random effects. Treatment group differences will be tested using the F 
statistics from the mixed model with Kenward-Roger degrees of freedom. Least squares estimates of the 
CASI for both of the study arms will be obtained from the model and presented. Ninety-five percent 
confidence intervals for the estimated treatment effect (LS Mean for the German Roach arm – LS Mean 
for the Placebo arm) will also be obtained using the fitted-regression model. The validity of model 
assumptions will be explored using regression diagnostics and may include separate models to assess 
possible modification of the treatment effect by CASI or other fixed effects. 
In addition, for each subject, the average CASI overall assessments will be computed and summarized by 
treatment group (mean, standard deviation, median, minimum and maximum).  For each visit where 
CASI is collected following the first injection of study drug, summary statistics will be presented by 
treatment arm.  
13.4.5.2 Rhinitis severity outcome measures 
The same mixed effect repeated measures model as used for the CASI outcomes, with the same 
covariates, will be used to examine treatment differences in the secondary rhinitis severity endpoints: 
1. Modified Rhinitis Symptom Utility Index 
2. Rhinitis treatment step (medication requirements) 
13.4.5.3 Additional asthma severity outcome measures 
The same mixed effect repeated measures model as used for the CASI, with the same covariates, will be 
used to examine treatment differences in the additional asthma severity endpoints: 
1. Number of days with asthma symptoms (wheezing or tightness in the chest or cough) 
2. Number of nights with asthma symptoms (waking up because of wheezing or tightness in the 
chest or cough) 
3. Number of days with albuterol use 
4. Number of nights with albuterol use 
5. Asthma treatment step (medication requirements) 
6. Asthma exacerbations 
7. FEV1 
13.4.5.4 Mechanistic Endpoints 
For continuous variables with baseline value and one post-baseline measurement (12-months), ANCOVA 
will be used, unless specified otherwise. Least square means (LSmeans), SE, LSmeans difference, 95% 

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confidence interval (CI) and p-value will be presented. Logistic regression analyses adjusted for baseline 
will be performed for the binary variables, and the odds ratio and 95% CI for the odds ratio of treatment 
group comparisons will be given. 
Analysis plans for other mechanistic endpoints, as described in Section 9, will be detailed in their 
respective mechanistic proposals.   
13.4.6 Descriptive Analyses  
Descriptive analyses will be reported separately for immunotherapy and placebo arms. Continuous 
baseline measures will be reported 1) means (or geometric means) with 95% confidence intervals, or 2) 
median with first and third quartiles, as appropriate. Categorical baseline and demographic 
characteristics and study disposition will be reported as frequencies and proportions.  
13.5 Interim Analyses  
13.5.1 Interim Analysis of Efficacy Data 
Not applicable. 
13.5.2 Interim Analysis of Safety Data 
Not applicable. 
13.5.3 Futility Analysis 
Not applicable. 
13.6 Sample Size Considerations  
Sample size calculations are based on the primary endpoint of the study, mean TNSS over the 9 
protocol-defined doses at the 12-month NAC following the primary analysis, modeled as ANCOVA with 
factors for treatment arm, site and TNSS baseline as covariate. For sample size calculations we assumed 
a mean TNSS score of 2.94 for the placebo group with varying effect sizes. A risk reduction of 0.30 is 
obtained as (2.94 – 2.94*(1-0.3)) / 2.94 = 0.30 and translates into an absolute difference of 2.94*0.3 = 
0.88. A mean squared error (pooled SD) of 1.09 was assumed for these sample sizes calculations. 
Assuming a risk reduction of 30%, absolute difference of 0.88 an ANCOVA with a total sample size of 54 
participants will provide 83% power for a 2-sided, 0.05 significance level test. 
 
 

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Table 13.6:  Power Calculations under different scenarios of total sample size. 
Risk Reduction 
Absolute Diff 
n = 44 
n = 54 
n = 64 
0.20 
0.59 
0.42 
0.50 
0.57 
0.25 
0.74 
0.59 
0.68 
0.76 
0.30 
0.89 
0.75 
0.83 
0.89 
0.35 
1.03 
0.87 
0.93 
0.96 
0.40 
1.18 
0.94 
0.97 
0.99 
0.45 
1.33 
0.98 
0.99 
1.00 
0.50 
1.48 
0.99 
1.00 
1.00 
Code for table: 
pacman::p_load(tidyverse, rio) 
pacman::p_load(arsenal, gt) 
nac_per <- import("S:/RhoFED/NIAID/DAIT/Allergy_Asthma/ICAC/CRITICAL/Statistics/Manuscripts/Baseline/Data/nac_per.rds") 
t1 <- tableby(nac_pos ~ tnss_mean, data = nac_per, digits = 2) %>%  
  summary() 
t1 
m1 <- lm(tnss_mean ~ 1, data = nac_per, subset = nac_pos == 1) 
summary(t1) 
anova(t1) 
# rr and abs diff 
(2.94 - 2.94*(1-0.3))/2.94 
(2.94 - 2.94*(1-0.3)) 
2.94*0.3 
#table 
crossing(  n = c(44, 54, 64)/2, 
                 sd = 1.09, 
                 m1 = 2.95, 
                 rr = seq(0.20, 0.50, 0.05)) %>%  
  mutate( m2 = m1*(1-rr), 
          d = m1-m2, 
          N = n*2) %>% 
  rowwise() %>%  
  mutate(pw = power.t.test(n = n, delta = d, sd = sd)$power %>%  
           round(2)) %>%  
  pivot_wider(id_cols = c(rr,d), 
              names_from = N, 
              values_from = pw, 
              names_prefix = "n_") %>%  
  gt() 
14 Identification and Access to Source Data 
14.1 Source Data 
Source documents and source data are considered to be the original documentation where subject 
information, visits consultations, examinations and other information are recorded.  Documentation of 
source data is necessary for the reconstruction, evaluation and validation of clinical findings, 
observations and other activities during a clinical trial.  All clinical site laboratory reports, spirometry 
reports, and any paper and electronic CRFs will be maintained as source data. 

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14.2 Access to Source Data 
The Principal Investigators and site staff will make all source data available to the IND sponsor (DAIT 
NIAID), as well as to the FDA.  Authorized representatives as noted above are bound to maintain the 
strict confidentiality of medical and research information that may be linked to identified individuals. 
15 Protocol Deviations 
15.1 Protocol Deviation Definitions 
15.1.1 Protocol Deviation 
The investigators and site staff will conduct the study in accordance to the protocol; no deviations from 
the protocol are permitted.  Any change, divergence, or departure from the study design or procedures 
constitutes a protocol deviation.  As a result of any deviation, corrective actions will be developed by the 
site and implemented promptly. 
15.1.2 Major Protocol Deviation (Protocol Violation)  
A Protocol Violation is a deviation from the IRB approved protocol that may affect the subject's rights, 
safety, or well-being and/or the completeness, accuracy and reliability of the study data.  In addition, 
protocol violations include willful or knowing breaches of human subject protection regulations, or 
policies, any action that is inconsistent with the NIH Human Research Protection Program’s research, 
medical, and ethical principles, and a serious or continuing noncompliance with federal, state, local or 
institutional human subject protection regulations, policies, or procedures.  
15.1.3 Non-Major Protocol Deviation 
A non-major protocol deviation is any change, divergence, or departure from the study design or 
procedures of a research protocol that does not have a major impact on the subject's rights, safety or 
well-being, or the completeness, accuracy and reliability of the study data. 
15.2 Reporting and Managing Protocol Deviations 
The Principal Investigator has the responsibility to identify, document and report protocol deviations as 
directed by the study Sponsor.  However, protocol deviations may also be identified during site 
monitoring visits or during other forms of study conduct review.  
Upon determination that a protocol deviation (major or minor) has occurred, the study staff will a) 
notify the Principal Investigator (PI), b) notify the DAIT SACCC, and c) complete the Protocol Deviation 
form. The Protocol Deviation form will document at a minimum the date the protocol deviation (PD) 
occurred, the date PD identified, a description of event, whether the deviation resulted in SAE/AE, the 
signature of PI, report to IRB, and documentation of a corrective action plan. The DAIT SACCC and the 
IND sponsor (DAIT NIAID) may request discussion with the PI to determine the effect of the protocol 
deviation on the study participant and his/her further study participation, the effect of the protocol 
deviation on the overall study, and corrective actions. The PI will complete and sign the Protocol 
Deviation form and submit it to the DAIT SACCC and to the Central IRB, per IRB regulations.  Major 
protocol deviations will be reviewed by the DSMB.   

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16 Ethical Considerations and Compliance with Good Clinical Practice 
16.1 Quality Control and Quality Assurance 
The Principal Investigator is required to keep accurate records to ensure that the conduct of the study is 
fully documented. The Principal Investigator is required to ensure that all CRFs are completed for every 
participant entered in the trial.  
The sponsor is responsible for regular inspection of the conduct of the trial, for verifying adherence to 
the protocol, and for confirming the completeness, consistency, and accuracy of all documented data.  
The CRFs will be completed online via a web-based electronic data capture (EDC) system that has been 
validated and is compliant with Part 11 Title 21 of the Code of Federal Regulations. Study staff at the site 
will enter information into the electronic CRFs, and the data will be stored remotely at a central 
database. Data quality will be ensured through the EDC system’s continuous monitoring of data and 
real-time detection and correction of errors. All elements of data entry (i.e., time, date, verbatim text, 
and the name of the person performing the data entry) will be recorded in an electronic audit trail to 
allow all changes in the database to be monitored and maintained in accordance with federal 
regulations. 
16.2 Statement of Compliance 
This clinical study will be conducted using good clinical practice (GCP), as delineated in Guidance for 
Industry: E6 Good Clinical Practice Consolidated Guidance, and according to the criteria specified in this 
study protocol.  Before study initiation, the protocol and the informed consent documents will be 
reviewed and approved by the IRB.  Any amendments to the protocol or to the consent materials will 
also be approved by the IRB before they are implemented. 
16.3 Informed Consent Process 
The consent process will provide information about the study to a prospective participant and 
parent(s)/legal guardian(s) and will allow adequate time for review and discussion prior to his/her 
decision.  The Principal Investigator or designee listed on the FDA 1572 will review the consent and 
answer questions. The consent designee must be listed on the delegation log and have knowledge of the 
study. The prospective participant and parent(s)/legal guardian(s) will be told that being in the trial is 
voluntary and that he or she may withdraw from the study at any time, for any reason.  All participants 
(or their legally acceptable representative) and parent(s)/legal guardian(s) will read, sign, and date a 
consent form before undergoing any study procedures.  Consent materials will be presented in 
participants’ primary language. A copy of the signed consent form will be given to the participant. 
Assent will also be obtained from children with due consideration for age-appropriate private 
conversations between study staff member and participant. 
The consent process will be ongoing.  The consent form will be revised when important new safety 
information is available, the protocol is amended, and/or new information becomes available that may 
affect participation in the study.  
16.4 Privacy and Confidentiality 
A participant’s privacy and confidentiality will be respected throughout the study.  Each participant will 
be assigned a unique identification number and these numbers rather than names will be used to 

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collect, store, and report participant information.  Site personnel will not transmit documents containing 
personal health identifiers (PHI) to the study sponsor or their representatives. 
17 Publication Policy 
Presentations and publication of the results of this trial will be governed by the ICAC Publication Policy. 

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18 References 
 
1. 
Rosenstreich DL, Eggleston P, Kattan M, Baker D, Slavin RG, Gergen P, et al. The role of 
cockroach allergy and exposure to cockroach allergen in causing morbidity among inner-city children 
with asthma. N Engl J Med 1997;336:1356-63. 
2. 
Morgan WJ, Crain EF, Gruchalla RS, O'Connor GT, Kattan M, Evans R, 3rd, et al. Results of a 
home-based environmental intervention among urban children with asthma. N Engl J Med 
2004;351:1068-80. 
3. 
Wood RA, Togias A, Wildfire J, Visness CM, Matsui EC, Gruchalla R, et al. Development of 
cockroach immunotherapy by the Inner-City Asthma Consortium. J Allergy Clin Immunol 2014;133:846-
52 e6. 
4. 
Bassirpour G, Zoratti E. Cockroach allergy and allergen-specific immunotherapy in asthma: 
potential and pitfalls. Curr Opin Allergy Clin Immunol 2014;14:535-41. 
5. 
Allergen immunotherapy: a practice parameter second update. J Allergy Clin Immunol 
2007;120:S25-85. 
6. 
Nelson HS. Allergen immunotherapy: where is it now? J Allergy Clin Immunol 2007;119:769-79. 
7. 
Abramson MJ, Puy RM, Weiner JM. Is allergen immunotherapy effective in asthma? A meta-
analysis of randomized controlled trials. Am J Respir Crit Care Med 1995;151:969-74. 
8. 
Abramson MJ, Puy RM, Weiner JM. Allergen immunotherapy for asthma. Cochrane database of 
systematic reviews (Online) 2003:CD001186. 
9. 
Cox L, Nelson H, Lockey R, Calabria C, Chacko T, Finegold I, et al. Allergen immunotherapy: a 
practice parameter third update. J Allergy Clin Immunol 2011;127:S1-55. 
10. 
Ross RN, Nelson HS, Finegold I. Effectiveness of specific immunotherapy in the treatment of 
hymenoptera venom hypersensitivity: a meta-analysis. Clin Ther 2000;22:351-8. 
11. 
Ross RN, Nelson HS, Finegold I. Effectiveness of specific immunotherapy in the treatment of 
asthma: a meta-analysis of prospective, randomized, double-blind, placebo-controlled studies. Clin Ther 
2000;22:329-41. 
12. 
Ross RN, Nelson HS, Finegold I. Effectiveness of specific immunotherapy in the treatment of 
allergic rhinitis: an analysis of randomized, prospective, single- or double-blind, placebo-controlled 
studies. Clin Ther 2000;22:342-50. 
13. 
Nelson HS. The use of standardized extracts in allergen immunotherapy. J Allergy Clin Immunol 
2000;106:41-5. 
14. 
Kang BC, Johnson J, Morgan C, Chang JL. The role of immunotherapy in cockroach asthma. J 
Asthma 1988;25:205-18. 
15. 
Srivastava D, Gaur SN, Arora N, Singh BP. Clinico-immunological changes post-immunotherapy 
with Periplaneta americana. Eur J Clin Invest 2011;41:879-88. 
16. 
Scadding GW, Eifan A, Penagos M, Dumitru A, Switzer A, McMahon O, et al. Local and systemic 
effects of cat allergen nasal provocation. Clin Exp Allergy 2014. 
17. 
Togias A, Corren J, Wagenmann M. Nasal Provocation Testing. In: Adkinson NF, Busse WW, 
Bochner BS, Holgate ST, Simons ER, Lemanske RFJ, eds. Middleton's Textbook of Allergy. 7th ed: Elsevier; 
2009:1281-94. 
18. 
Scadding GW, Eifan A, Penagos M, Dumitru A, Switzer A, McMahon O, et al. Local and systemic 
effects of cat allergen nasal provocation. Clin Exp Allergy 2015;45:613-23. 
19. 
Okuda M, Usami A, Itoh H, Ogino S. [Nationwide investigation of insect allergy in patients with 
allergic rhinitis]. Nihon Jibiinkoka Gakkai Kaiho 2002;105:1181-8. 
20. 
Wierzbicki DA, Majmundar AR, Schull DE, Khan DA. Multiallergen nasal challenges in nonallergic 
rhinitis. Ann Allergy Asthma Immunol 2008;100:533-7. 
21. 
Hosen H. Insects as a cause of inhalant respiratory allergy. Ann Allergy 1970;28:596-9. 
22. 
Tankersley MS, Butler KK, Butler WK, Goetz DW. Local reactions during allergen immunotherapy 
do not require dose adjustment. J Allergy Clin Immunol 2000;106:840-3. 

Inner-City Asthma Consortium 
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23. 
Lockey RF, Nicoara-Kasti GL, Theodoropoulos DS, Bukantz SC. Systemic reactions and fatalities 
associated with allergen immunotherapy. Ann Allergy Asthma Immunol 2001;87:47-55. 
24. 
Malling HJ. Minimising the risks of allergen-specific injection immunotherapy. Drug Saf 
2000;23:323-32. 
25. 
Baki A, Ucar B. Diagnostic value of the nasal provocation test with Dermatophagoides 
pteronyssinus in childhood asthma. Allergy 1995;50:751-4. 
26. 
Hervas D, Rodriguez R, Garde J. Role of aeroallergen nasal challenge in asthmatic children. 
Allergol Immunopathol (Madr) 2011;39:17-22. 
27. 
Pedroletti C, Lundahl J, Alving K, Hedlin G. Exhaled nitric oxide in asthmatic children and 
adolescents after nasal allergen challenge. Pediatr Allergy Immunol 2005;16:59-64. 
28. 
National Asthma E, Prevention P. Expert Panel Report 3 (EPR-3): Guidelines for the Diagnosis 
and Management of Asthma-Summary Report 2007. J Allergy Clin Immunol 2007;120:S94-138. 
29. 
Sampson HA, Munoz-Furlong A, Campbell RL, Adkinson NF, Jr., Bock SA, Branum A, et al. Second 
symposium on the definition and management of anaphylaxis: summary report--Second National 
Institute of Allergy and Infectious Disease/Food Allergy and Anaphylaxis Network symposium. J Allergy 
Clin Immunol 2006;117:391-7. 
30. 
Chinchilli VM, Fisher L, Craig TJ. Statistical issues in clinical trials that involve the double-blind, 
placebo-controlled food challenge. J Allergy Clin Immunol 2005;115:592-7. 
31. 
Sampson HA, Gerth van Wijk R, Bindslev-Jensen C, Sicherer S, Teuber SS, Burks AW, et al. 
Standardizing double-blind, placebo-controlled oral food challenges: American Academy of Allergy, 
Asthma & Immunology-European Academy of Allergy and Clinical Immunology PRACTALL consensus 
report. J Allergy Clin Immunol 2012;130:1260-74. 
32. 
Chow S, Shao J, Wang H. Sample Size Calculations in Clinical Research. 2nd ed: Chapman & Hall; 
2008. 
 

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Appendix A: Schedule of Procedures/Evaluations 
Visit  
Screening 
Eligibility 
Visit 
Screening 
NAC Visit 
Asthma  
Control 
Visits6 
Random-
ization 
Visit 
Dose 
Escalation 
Injection 
Visits5 
Maintenance 
Injection 
Visits 
Injection Visits 
with 
Evaluation and 
Management 
(E&M) 
12-Month 
Visit  
Early 
Termination 
Visit7 
Unscheduled 
Asthma 
Control 
Visits/ Phone 
Calls8  
Informed consent 
X 
 
 
 
 
 
 
 
 
 
Medical history 
X 
 
 
 
 
 
 
 
 
 
Physical exam1 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
Targeted Pulmonary Exam 
 
X 
 
 
 
 
 
X 
 
 
Vital signs and growth 
parameters2 
X 
X 
X 
X 
 
 
X 
X 
X 
X 
Asthma Evaluation & 
Management 
X 
 
X 
X 
 
 
X 
X 
X 
X 
Asthma Counseling 
X 
 
X 
X 
 
 
X 
X 
X 
X 
Spirometry 
X 
X 
X 
X 
 
 
X 
X 
X 
X 
Peak flow 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Adverse event assessment 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Concomitant medication 
assessment 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Symptom questionnaires 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
CASI 
X 
 
 
X 
 
 
X 
X 
X 
 
Allergen skin test3 
X 
 
 
 
 
 
 
X 
X 
 
Blood collection 
X 
X 
 
X 
 
 
 
X 
X 
 
Pregnancy test 
X 
X 
 
X 
X4 
 
X4 
X 
X 
 
Injection 
 
 
 
 
X 
X 
X 
 
 
 
Nasal allergen challenge 
 
X  
 
 
 
 
 
X 
 
 
Nasal lavage 
 
X 
 
 
 
 
 
X 
 
 
Dust sample collection 
 
 
 
X 
 
 
 
 
 
 
1A detailed physical exam will occur at Screening and 12 months. A more limited physical exam will be completed at other visits. 
2 Height will be assessed at Screening and at visits where spirometry is performed.  Weight will be assessed at screening and every 2 months at E&M Visits. 
3 Full panel of allergens at Screening, German cockroach only at 12 months and Early Termination. 
4 Pregnancy testing will be performed monthly during escalation and at E&M Visits during maintenance. 
5Dose Escalation will normally take 16-26 weeks, but can take place over up to 40 weeks, if needed. See Appendix B Study Restrictions Due to COVID-19. 
6 Visits occur approximately every two weeks until participant’s asthma is under control as defined by the ACT. 
7 An Early Termination Visit will be conducted for participants who withdraw from the study or are dropped from the study.    
8 Procedures, e.g. spirometry, can be performed at the discretion of the clinician.

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Appendix B: Study Restrictions Due to COVID-19 
In the event of institutional or ICAC-wide restrictions on certain types of procedures or certain classes of research, some 
study activities will be suspended. This includes certain visits and specific inhalation and nasal procedures, such as: 
 
In-person study visits, including injection visits 
 
Spirometry 
 
Nasal Allergen Challenges 
 
Nasal sampling, including nasal lavages 
 
Peak Expiratory Flow 
When all in-person study activities are suspended, study staff will continue to make contact with study participants over 
the phone and clinicians will continue to manage the participants’ asthma remotely. Prescriptions for asthma 
management medications can be sent to local pharmacies and additional prednisone, if needed, can be mailed to the 
participant. Should reconsenting be necessary, the consent process will occur remotely. 
Participants whose immunotherapy regimen was halted as a result of study activity restrictions will be asked to resume 
therapy once the site is able to administer injections. The initial restart dose for these participants will be dictated by the 
dose modification rules in the Protocol ICAC-28 MOP.  Re-escalation of immunotherapy will follow the rules referenced 
in Section 8.6 and in the Protocol ICAC-28 MOP, taking into account each participant’s total time off therapy and history 
of reactions. The 40-week requirement for reaching maintenance will be reset for participants whose immunotherapy 
was interrupted by the COVID-19 pandemic. 
While participants may typically be stepped down from controller medications during the maintenance phase, 
participants in this phase who had their therapy level modified as a result of the COVID-19 pandemic will not be stepped 
down in MEDS treatment level until they have successfully re-escalated to their original maintenance dose.