Conditions: Eczema Atopic Dermatitis
Allocation: NA | Intervention model: SINGLE_GROUP
Enrollment: 28
Healthy volunteers: no

Brief summary:
An open-label, multicenter, Phase Ib study of B244 delivered as a topical spray to assess safety in pediatric subjects aged 2 to 17 years with atopic dermatitis

Condition or disease Intervention/treatment Phase Atopic Dermatitis (Eczema) Biological: B244 Phase 1b

Detailed description:
This is a Phase 1b, open-label, single arm, multiple site study assessing twice daily B244 application for 28 days in pediatric subjects with mild to moderate atopic dermatitis.

Number of Subjects:

The study will enroll 36 subjects in 3 cohorts of 12 subjects:

* Cohort 1: subjects aged 2 to 5 years.
* Cohort 2: subjects aged 6 to 11 years.
* Cohort 3, subjects aged 12 to 17 years.

At Screening and Baseline, all subjects must have confirmed diagnosis of atopic dermatitis, as defined by the Hanifin and Rajka criteria, which involves a minimum of 10% but no more than 60% body surface area and a Validated Investigator Global Assessment for Atopic Dermatitis (vIGA-AD) scale of 2 or 3.

The duration of the study will be approximately 7 weeks. Subjects will attend for a Screening visit between Days -21 and -14. If all eligibility criteria and none of the exclusion criteria are met, subjects will be enrolled into the study and will be required to undergo a 14 day washout period (Days-14 to -1). Subjects will attend the study center on Day 1 and the Baseline assessments will be performed before application of the first dose.

On confirmation of continued eligibility the subject and parent or guardian of the subject will be coached on how to apply medication, depending on the affected areas. They will be instructed to apply B244 twice daily (approximately 12 hours apart) for 28 days.

The first dose will be applied in the clinic under the supervision of clinical staff. Details of dose administration will be recorded in the study diary provided. The subjects with their parent or guardian will return to the study center on Days 7, 14, and 21 for completion of study assessments.

There will be a final study visit on Day 28, this will be defined as the end of the study for the subjects. A time window of ±2 day will be permitted for these 4 visits. There will not be a period of confinement in the study center all visits will be outpatient visits. Safety monitoring will include review of TEAEs, vital signs and physical examination. Efficacy will be assessed using EASI, vIGA-AD scale, POEM and ItchMan scores.

Arms:
arm 1: B244 suspension in 30ml/bottle

Interventions: intervention 1: Experimental: B244
Intervention descriptions: intervention 1: B244 suspension in 30ml/bottle

Protocol document:
Prot_000.pdf: 
CONFIDENTIAL 
Protocol ADB244-002 – Amendment 1 
Confidential| ADB244-002| Amendmen1| Date:  25 FEB 2019 
1 
TITLE PAGE 
Protocol Title: 
An open-label, multicenter, Phase Ib study of B244 delivered as a topical spray to assess safety in 
pediatric subjects aged 2 to 17 years with atopic dermatitis 
Protocol Number: ADB244-002 
Amendment Number: Amendment 1 
Product: B244 4 ×109 cells/mL (OD600 2.0 ± 0.4) 
Study Phase: Ib 
Sponsor Name: AOBiome Therapeutics 
Legal Registered Address: 125 Cambridgepark Drive, Cambridge, MA 02140 
Regulatory Agency Identifying Number(s): IND 17485 
 
Date of Amendment 1: February 25, 2019 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Any and all information presented in this document shall be treated as confidential and shall remain the exclusive 
property of AOBiome LLC (or any of its affiliated companies).  The use of such confidential information must be 
restricted to the recipient for the agreed purpose and must not be disclosed, published or otherwise communicated to 
any unauthorized persons, for any reasons, in any form whatsoever without the prior written consent of AOBiome 
LLC (or the concerned affiliated company) 
NCT03775434


J§
Cents
25
Feb
2019


CONFIDENTIAL 
Protocol ADB244-002 – Amendment 1 
Confidential| ADB244-002| Amendmen1| Date:  25 FEB 2019 
3 
PROTOCOL AMENDMENT 1 SUMMARY OF CHANGES 
Section 
Description of Changes 
 
 
Sections 1.1; 1.2; 1.3; 4.0; 8.2.2 
 
This section of the protocol is being clarified to allow a 
-1 to 1 window for subjects to complete the Baseline 
(Day 1) visit.  This clarification applies to all sections 
of the protocol discussing and describing the washout 
period  
Section 5.3.1 
Clarification is being added that subjects may use their 
own shampoo while in the study. 
Section 6.1.1 
Subjects will be dispensed up to 6 bottles of study 
medication for the duration of the trial. Actual number 
will depend upon the number of lesions and sprays of 
IP to be applied.  
Section 6.5.2 
This section of the protocol is being clarified to read: 
Sites will be provided scales, which will be “Tared” 
(set to “0”) prior to each use. 
Section 6.7 
This section clarifies that subject may use up to 16 
sprays per application, however this will depend on the 
number of lesions.  
Section 8.2.2 
Wording around timing of Washout period is being 
added for further clarification.  
Section 9.3.5 
This section of the protocol is being clarified that, as 
per the Schedule of Activities (Section 1.3), the first 
investigational product application will happen in the 
study center under clinical staff supervision, after the 
completion of the baseline assessments.  All 
subsequent study application will be administered by 
the parent/guardian or by the subject in the setting of 
subject’s home. 
Section 9.4.2 
There was a typo in this section of the protocol and it is 
being clarified that, as per Inclusion Criteria (Section 
5.1) Number 8: Female subjects aged ≥11 years old, or 
female patients <11 years old who have started 
menstruating, will have urinary pregnancy test 
performed at all visits.  The Baseline result must be 
available and must be negative before the subject apply 
the first application of IP.  Positive pregnancy test will 


CONFIDENTIAL 
Protocol ADB244-002 – Amendment 1 
Confidential| ADB244-002| Amendmen1| Date:  25 FEB 2019 
4 
disqualify the subject from the participation in the 
study. 
Section 9.4.4 
This section of the protocol is being clarified that, as 
per the Schedule of Activities (Section 1.3), Body 
weight and height will be measured at Screening and at 
Day 28/Final Visit (or at Early Termination Visit, as 
applicable). 
Appendix 5 
This section of the protocol is being clarified that, as 
per Inclusion Criteria (Section 5.1) Number 8, females 
must either practice abstinence from heterosexual 
contact or use one (1) of the highly effective 
contraceptive options described in the Appendix 5.  
Females are not required to use two (2) highly 
effective methods of contraception 
 
Administrative changes: Minor changes involving grammar, wordsmithing, punctuation, and 
other editorial changes have been made throughout the document.  All are clearly identified in the 
track-changes version of the amendment. 
 
Additional formatting and stylistic adjustments have been made to facilitate the reading process. 
 
 
 
 
 


CONFIDENTIAL 
Protocol ADB244-002 – Amendment 1 
Confidential| ADB244-002| Amendmen1| Date:  25 FEB 2019 
5 
TABLE OF CONTENTS 
1.0 
PROTOCOL SUMMARY ...................................................................................... 9 
1.1 
Synopsis .............................................................................................. 9 
1.2 
Schema ...............................................................................................11 
1.3 
Schedule of Activities ........................................................................12 
2.0 
INTRODUCTION ..................................................................................................15 
2.1 
Study Rationale .................................................................................15 
2.2 
Background .......................................................................................15 
2.3 
Benefit/Risk Assessment ...................................................................16 
3.0 
OBJECTIVES AND ENDPOINTS .......................................................................18 
4.0 
STUDY DESIGN ....................................................................................................19 
4.1 
Overall Design ...................................................................................19 
4.2 
Scientific Rationale for Study Design ...............................................20 
4.3 
Justification for Dose ........................................................................20 
4.4 
End of Study Definition ....................................................................20 
4.5 
Dose Escalation Criteria ...................................................................20 
4.6 
Study Stopping Criteria ....................................................................20 
5.0 
STUDY POPULATION .........................................................................................22 
5.1 
Inclusion Criteria ..............................................................................22 
5.2 
Exclusion Criteria .............................................................................22 
5.3 
Lifestyle Considerations ....................................................................23 
5.3.1 
Use of Cleanser and Moisturizer During the Study..........................23 
5.4 
Screen Failures ..................................................................................24 
6.0 
INVESTIGATIONAL PRODUCT TREATMENT AND APPLICATION .........25 
6.1 
Study Treatment(s) Administered ....................................................25 
6.1.1 
Investigational Product ...................................................................25 
6.2 
Preparation/Handling/Storage .........................................................28 
6.3 
Accountability, Destruction and Return of Study Supplies .............28 
6.4 
Measures to Minimize Bias: Randomization and Blinding .............29 
6.5 
Study Treatment Compliance ...........................................................29 
6.5.1 
Study Diary Compliance Review ....................................................29 
6.5.2 
Treatment Compliance ....................................................................30 
6.6 
Concomitant Therapy .......................................................................30 
6.7 
Dose Modification .............................................................................30 
6.8 
Rescue Medication Permitted During the Study ..............................31 
6.9 
Treatment after the End of the Study ..............................................32 


CONFIDENTIAL 
Protocol ADB244-002 – Amendment 1 
Confidential| ADB244-002| Amendmen1| Date:  25 FEB 2019 
6 
7.0 
DISCONTINUATION OF STUDY TREATMENT AND SUBJECT 
DISCONTINUATION/WITHDRAWAL ..............................................................33 
7.1 
Discontinuation of Study Treatment ................................................33 
7.2 
Subject Discontinuation/Withdrawal from the Study .....................33 
7.3 
Lost to Follow-up ..............................................................................33 
8.0 
STUDY ASSESSMENTS AND PROCEDURES ..................................................35 
8.1 
Administrative Procedures ...............................................................35 
8.1.1 
Subject Informed Consent ...............................................................35 
8.2 
Study Procedures ..............................................................................35 
8.2.1 
Visit 1- Screening Visit (Day -21 to Day -14) .................................35 
8.2.2 
Washout Phase (Day -14 to Day -1) ................................................36 
8.2.3 
Unscheduled Visit ..........................................................................36 
8.2.4 
Day 1 (Baseline) .............................................................................36 
8.2.5 
OutPatient, Days 1 to 6, Days 8 to 14, and Days 15 to 20 ................37 
8.2.6 
Study Center Visit, Day 7, Day 14 and Day 21 ...............................37 
8.2.7 
Final Visit (Day 28) or Early Termination Visit ..............................37 
9.0 
METHODS OF ASSESSMENT ............................................................................39 
9.1 
Subject Demographics ......................................................................39 
9.2 
Concomitant Medication Recording.................................................39 
9.3 
Efficacy Assessments .........................................................................39 
9.3.1 
Validated Investigator Global Assessment for Atopic 
Dermatitis (vIGA-AD) Scale ..........................................................39 
9.3.2 
Atopic Dermatitis Eczema Area Severity Index ..............................40 
9.3.3 
Patient Oriented Eczema Measure...................................................41 
9.3.4 
Burn Man Itch Scale .......................................................................41 
9.3.5 
Application Site Assessment ...........................................................41 
9.4 
Safety Assessments ............................................................................41 
9.4.1 
Physical Examinations ....................................................................42 
9.4.2 
Pregnancy Test ...............................................................................42 
9.4.3 
Medical History ..............................................................................42 
9.4.4 
Vital Signs ......................................................................................42 
9.5 
Adverse Events ..................................................................................42 
9.5.1 
Time Period and Frequency for Collecting AE and SAE 
Information .....................................................................................43 
9.5.2 
Method of Detecting AEs and SAEs ...............................................43 
9.5.3 
Follow-up of AEs and SAEs ...........................................................43 
9.5.4 
Regulatory Reporting Requirements for SAEs ................................43 
9.5.5 
Pregnancy .......................................................................................44 
9.6 
Treatment of Overdose .....................................................................44 
9.7 
Pharmacodynamics ...........................................................................44 
9.8 
Genetics .............................................................................................44 
9.9 
Biomarkers ........................................................................................44 
9.10 
Health Economics/Medical Resource Utilization and Health 
Economics ..........................................................................................45 


CONFIDENTIAL 
Protocol ADB244-002 – Amendment 1 
Confidential| ADB244-002| Amendmen1| Date:  25 FEB 2019 
7 
10.0 
STATISTICAL CONSIDERATIONS...................................................................45 
10.1 
Statistical Hypotheses .......................................................................45 
10.2 
Sample Size Determination ...............................................................45 
10.3 
Populations for Analyses ...................................................................45 
10.4 
Statistical Analyses ............................................................................45 
10.4.1 
Efficacy Analyses ...........................................................................46 
10.4.2 
Safety Analyses ..............................................................................46 
10.4.3 
Missing Data ..................................................................................47 
10.5 
Interim Analyses ...............................................................................47 
10.6 
Monitoring Committee......................................................................47 
11.0 
REFERENCES.......................................................................................................48 
Appendix 1 Abbreviations ....................................................................................49 
Appendix 2 Regulatory, Ethical, and Study Oversight Considerations ..............50 
Regulatory and Ethical Considerations .........................................................50 
Adequate Resources .....................................................................................50 
Financial Disclosure .....................................................................................51 
Insurance ......................................................................................................51 
Informed Consent Process ............................................................................51 
Data Protection .............................................................................................51 
Medical Monitor ...........................................................................................52 
Dissemination of Clinical Study Data ...........................................................52 
Data Quality Assurance ................................................................................52 
Source Documents ........................................................................................52 
Study and Study Center Closure ...................................................................53 
Publication Policy.........................................................................................53 
Appendix 3 Adverse Events: Definitions and Procedures for Recording, 
Evaluating, Follow-up, and Reporting .............................................55 
Appendix 4 Excluded Medications/Therapy ........................................................59 
Appendix 5 Contraceptive Guidance and Collection of Pregnancy 
Information .......................................................................................60 
Appendix 6 Body Surface Area and Investigational Medicinal Product 
Application ........................................................................................63 
Appendix 7 Signature of Investigator ..................................................................64 
 
 
 


CONFIDENTIAL 
Protocol ADB244-002 – Amendment 1 
Confidential| ADB244-002| Amendmen1| Date:  25 FEB 2019 
8 
Table of Tables 
Table 1.1 
Schedule of Assessments ..............................................................................12 
Table 3.1 
Study Objectives and Endpoints ...................................................................18 
Table 6.1 
Number of Bottles of B244 Issued to the Subject and Parent or 
Guardian.......................................................................................................26 
Table 6.2 
Body Surface Area and Application of Investigational Product .....................26 
Table 6.3 
Permitted Rescue Medication .......................................................................31 
Table 9.1 
Validated Investigator Global Assessment for Atopic Dermatitis Scale .........40 
Table 10.1 
Analysis Sets ................................................................................................45 
 
Table of Figures 
Figure 1 
Study Schema ...............................................................................................11 
 


CONFIDENTIAL 
Protocol ADB244-002 – Amendment 1 
Confidential| ADB244-002| Amendmen1| Date:  25 FEB 2019 
9 
1.0 PROTOCOL SUMMARY 
1.1 
Synopsis 
Protocol Title: An open-label, multicenter, Phase Ib study of B244 delivered as a topical spray to assess 
safety in pediatric subjects aged 2 to 17 years with atopic dermatitis 
Rationale: 
Clinical studies with topical administration of B244 have been conducted in subjects with acne, 
hypertension, atopic dermatitis, and rosacea. There have been no safety signals observed to date. 
The aim of this study is to assess the safety of B244 in pediatric subjects aged 2 to 17 years with atopic 
dermatitis. 
Objectives and Endpoints 
Objectives 
Endpoints 
Primary 
 
• 
Assessment of the safety and tolerability of B244 
in pediatric subjects with atopic dermatitis. 
• 
Incidence of treatment-emergent adverse events 
(TEAEs).  
• 
Change from Baseline in physical examination at 
each post baseline visit. 
• 
Change from Baseline in vital signs at each 
post baseline visit. 
Exploratory 
 
• 
Efficacy of B244 on signs and symptoms of atopic 
dermatitis. 
 
 
 
 
• 
Efficacy of B244 on patient oriented measure of 
atopic dermatitis. 
 
 
• 
Efficacy of B244 on patient reported assessment of 
atopic dermatitis. 
• 
Changes from Baseline to post baseline visits in: 
- 
Validated Investigator Global Assessment for 
Atopic Dermatitis (vIGA-AD) scale. 
- 
Area Severity Index (EASI) score and each 
component of EASI from Baseline to 
post baseline visits. 
 
• 
Changes is Patient Oriented Eczema Measure 
(POEM total score and each of the 7 components) 
from Baseline to post baseline visits. 
 
• 
Changes in patient reported outcome (self-reported 
ItchMan questionnaire).from Baseline to 
post baseline visits. 
 
Overall Design: 
This is a Phase 1b, open-label, multiple site study assessing twice daily B244 application for 28 days in 
pediatric subjects with atopic dermatitis. 
The study will enroll 36 subjects in 3 cohorts of 12 subjects: 
• 
Cohort 1: subjects aged 2 to 5 years. 
• 
Cohort 2: subjects aged 6 to 11 years. 
• 
Cohort 3: subjects aged 12 to 17 years. 


CONFIDENTIAL 
Protocol ADB244-002 – Amendment 1 
Confidential| ADB244-002| Amendmen1| Date:  25 FEB 2019 
10 
Number of Investigators and Study Centers: 
Approximately 6 Investigators and study centers are expected to participate in this study. 
Number of Subjects: 
The study will enroll 36 subjects in 3 cohorts of 12 subjects: 
• 
Cohort 1: subjects aged 2 to 5 years. 
• 
Cohort 2: subjects aged 6 to 11 years. 
• 
Cohort 3, subjects aged 12 to 17 years. 
Treatment Groups and Duration: 
Subjects will attend for a Screening visit between Days -21 and -14. If all eligibility criteria and none of 
the exclusion criteria are met, subjects will be enrolled into the study and will be required to undergo a 
14 day washout period (Days-14 to -1). Subjects will attend the study center on Day 1(-1 to 1) and the 
Baseline assessments will be performed before application of the first dose. On confirmation of continued 
eligibility the subject and parent or guardian of the subject will be coached on how to apply medication, 
depending on the affected areas. They will be instructed to apply B244 twice daily (approximately 
12 hours apart) for 28 days. The first dose will be applied in the clinic under the supervision of clinical 
staff. Details of dose administration will be recorded in the study diary provided. 
The subjects with their parent or guardian will return to the study center on Days 7, 14, and 21 for 
completion of study assessments. There will be a final study visit on Day 28, this will be defined as the 
end of the study for the subjects. A time window of ±2 day will be permitted for these 4 visits. There will 
not be a period of confinement in the study center all visits will be outpatient visits. 
Safety monitoring will include review of TEAEs, vital signs and physical examination. 
Efficacy will be assessed using EASI, vIGA-AD scale, POEM and ItchMan scores. 
Statistical Methods: 
All subjects who are enrolled and take at least 1 dose of study treatment will be included in the Intent to 
Treat (ITT) population. The ITT population will be the primary population for safety and efficacy 
assessments. 
All subjects in the ITT population without any protocol deviations that may have an impact on the 
efficacy assessments will be included in the Per Protocol (PP) population. The PP population will be the 
supportive population for efficacy assessments. 
The sample size is not based on statistical considerations but is typical for studies of this nature, and is 
considered adequate to characterize the distribution of the planned endpoints. Any statistical testing will 
be considered exploratory and descriptive. 
Data Monitoring Committee: No 
 


CONFIDENTIAL 
Protocol ADB244-002 – Amendment 1 
Confidential| ADB244-002| Amendmen1| Date:  25 FEB 2019 
11 
1.2 
Schema 
Figure 1 
Study Schema 
Study Center Visit 
Screening assessments 
(Day -21 to Day -14) 
 
 
 
 
 
 
Washout period 
(Day -14 to Day -1, predose) 
 
 
 
 
 
Study Center visit 
Baseline assessments 
(Day -1 to Day 1, predose) 
 
 
 
 
 
 
Cohort 1: 
2 to 5 years old 
male and female 
subjects 
(N = 12) 
Cohort 2: 
6 to 11 years old 
male and female 
subjects 
(N = 12) 
Cohort 3: 
12 to 17 years old 
male and female 
subjects 
(N = 12) 
 
Days 1 to 28  
(Dose administration) 
 
 
 
Twice daily topical applications of B244 
 
 
 
 
Days 7, 14 and 21  
(Study Center visit) 
 
 
 
Study assessments 
 
 
 
 
Day 28  
(End of study, Study Center 
visit) 
 
 
 
End of study assessments 
 
 
 
 
 
 


CONFIDENTIAL 
Protocol ADB244-002 – Amendment 1 
Confidential| ADB244-002| Amendmen1| Date:  25 FEB 2019 
12 
1.3 
Schedule of Activities 
Table 1.1 
Schedule of Assessments 
Visit Name 
Screening 
Washout 
Baseline 
(Day 1) 
Day 
7 
Day 
14 
Day 
21 
Day 28 
Final 
Visit 
Early 
Termination 
Visit 
 
Study Center Visit 
1 
 
2 
3 
4 
5 
6 
 
Visit Window in 
Days 
-21 to -14 
-14 to -1 
-1 to 1 
±2 
±2 
±2 
±2 
 
Informed Consent 
X 
 
 
 
 
 
 
 
Inclusion/Exclusion 
Criteria 
Х 
 
X 
 
 
 
 
 
Demographics 
Х 
 
 
 
 
 
 
 
Medical History 
Х 
 
 
 
 
 
 
 
Hanifin and Rajka 
Criteria 
X 
 
X 
 
 
 
 
 
Physical Examination 
X 
 
Х 
Х 
Х 
Х 
X 
X 
Urine Pregnancy 
Test1 
X 
 
X 
 
 
 
X 
X 
Body Weight 
X 
 
 
 
 
 
X 
X 
Height 
X 
 
 
 
 
 
X 
X 
Vital Signs2 
X 
 
X 
X 
X 
X 
X 
X 
Validated 
Investigator Global 
Assessment for 
Atopic Dermatitis 
(vIGA-AD) Scale 
X 
 
X 
X 
X 
X 
X 
X 
Eczema Area 
Severity Index 
(EASI) 
X 
 
X 
X 
X 
X 
X 
X 
Patient Oriented 
Measure (POEM)3 
X 
 
X 
X 
X 
X 
X 
X 
ItchMan 
Questionnaire 
X 
 
X 
X 
X 
X 
X 
X 
Dispense 
Investigational 
Product to Subject4 
 
 
X 
Х 
X 
Х 
 
 


CONFIDENTIAL 
Protocol ADB244-002 – Amendment 1 
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13 
Visit Name 
Screening 
Washout 
Baseline 
(Day 1) 
Day 
7 
Day 
14 
Day 
21 
Day 28 
Final 
Visit 
Early 
Termination 
Visit 
 
Study Center Visit 
1 
 
2 
3 
4 
5 
6 
 
Visit Window in 
Days 
-21 to -14 
-14 to -1 
-1 to 1 
±2 
±2 
±2 
±2 
 
Investigational 
Product Application5 
 
 
Х 
Х 
X 
Х 
X 
 
Collect 
Investigational 
Product from 
Subject6 
 
 
 
Х 
X 
Х 
X 
 
Investigational 
Product Compliance6 
 
 
 
Х 
X 
Х 
X 
X 
Counseling7 
 
 
X 
Х 
X 
Х 
 
 
Study Cleanser8 
X 
X 
X 
X 
X 
X 
Х 
X 
Moisturizer8 
X 
X 
X 
X 
X 
X 
Х 
X 
Study Diary9 
 
 
X 
X 
X 
X 
Х 
X 
Adverse Events 
Recording10 
X 
X 
X 
Х 
X 
Х 
X 
X 
Concomitant 
Medications 
Х 
 
X 
Х 
X 
Х 
X 
X 
 
1. Urine pregnancy test will be administered to females 11 years of age or older. 
2. Pulse rate, temperature and blood pressure will be obtained. Subject should be allowed to rest for >5 minutes 
sitting, then a single blood pressure and pulse rate measurement will be performed, using the non-dominant arm 
with a calibrated electronic sphygmomanometer. 
3. Patient Oriented Measure questionnaire is to be filled out by the subject or the parent or guardian. 
4. At Baseline, depending on the age of the participant, 1 or 2 bottles will be supplied. Total number of bottles to be 
dispensed to the subjects for the duration of the study will depend upon the body surface area affected by atopic 
dermatitis (Section 6.1). At each visit, study staff will determine each subject’s usage and supply additional 
investigational product if necessary. 
5. The first investigational product application will happen in the study center under clinical staff supervision after 
completion of the baseline assessments. Subjects and parent or guardian will be coached on how to apply the 
study treatment depending on the affected area and will be asked to apply the study treatment twice daily. 
6. Weight of an investigational product kit will be obtained at the at the Baseline visit. Study staff will be asked to 
weigh dispensed bottles PRE FIRST DOSE. Weight will be recorded in grams. Subjects will be asked to bring 
their bottles back for every visit. Upon return for the study visit, bottles will be weighed again. 


CONFIDENTIAL 
Protocol ADB244-002 – Amendment 1 
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14 
7. Subjects will be counseled on the use of the study treatment, study diary and any questions the subject, parent or 
guardian may have will be answered. 
8. The Sponsor will provide a biome friendly, preservative-free moisturizer and cleanser to be used as needed, at 
the discretion of the parent or guardian. Any remaining moisturizer or cleanser will be returned to the 
Investigator at the Final Visit (Day 28) or the Early Termination Visit. 
9. The subject, parent or guardian will be asked to fill out a daily study diary. 
10. Adverse events will be monitored throughout the trial, starting with the time informed consent form has been 
signed. 
 


CONFIDENTIAL 
Protocol ADB244-002 – Amendment 1 
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15 
2.0 INTRODUCTION 
2.1 
Study Rationale 
AOBiome Therapeutics has isolated a purified strain of Nitrosomonas eutropha, designated 
Nitrosomonas eutropha D23, from soil samples. Sequencing of the Nitrosomonas eutropha D23 
genome revealed a distinct genetic profile from that of other published Nitrosomonas strains and 
ammonia (NH3) oxidizing bacteria (AOB) genomes. The unique metabolic and antimicrobial 
activity of Nitrosomonas, in combination with their complete lack of virulence, render these 
bacteria as attractive candidates for topical delivery of nitrite (NO2) and nitric oxide (NO) on 
human skin. This has potential to improve health in both normal and abnormal skin conditions 
(including wound sites). The drug product has been designated the code B244. 
Clinical studies with topical administration of B244 have been conducted in subjects with acne. 
In addition, other clinical studies, either ongoing or completed, have included the investigation of 
the efficacy of B244 in subjects with hypertension, atopic dermatitis, and rosacea. The results of 
these studies have indicated efficacy of B244 with no unexpected safety signals. The aim of this 
study is to assess the safety of B244 in pediatric subjects aged 2 to 17 years with atopic 
dermatitis. 
2.2 
Background 
Ammonia oxidizing bacteria are ubiquitous in the environment and are essential for the initial 
step in nitrification processes, specifically the oxidation of NH3 to NO. They are found in all 
soils and water sources (fresh, ground, and seawater). Nitrosomonas, as AOBs, are 
gram-negative chemolithoautotrophic betaproteobacteria that obtain energy solely from NH3 
oxidation, while fixing carbon dioxide (CO2) for their carbon needs [Arp and Sayavedro-Soto, 
2001]. 
It is hypothesized that there may be regulation of basal NO levels by AOB on the skin. In acne, 
for example, Nitrosomonas eutropha might be expected to down regulate androgen levels. Low 
NO causes high androgen levels. Increasing NO/NO2 by the oxidation of NH3 in sweat by 
Nitrosomonas eutropha may decrease androgen levels. Androgens, the male hormones present in 
men and women, can contribute to acne flares by over stimulating the oil glands and altering the 
development of skin cells that line hair follicles in the skin. Increasing NO/NO2 production may 
therefore have a critical role in controlling the signs and symptoms of acne vulgaris. In this 
regard, the disruption of the normal AOB component of the human microbiome has the potential 
to disrupt the feedback regulation between acne, NO, and androgens. Nitrogen oxide releasing 
drugs or NO donors have also shown activity against Propionibacterium acnes and other 
pathogenic bacteria, anti-inflammatory activity, and inhibition of lipogenesis by 
insulin-stimulated immortal sebocytes (Weller and Price, 2001, Rico et al, 2014). 


CONFIDENTIAL 
Protocol ADB244-002 – Amendment 1 
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16 
Other important potential mechanisms through which Nitrosomonas eutropha D23 could 
positively effect acne and other skin diseases include an anti-inflammatory and antimicrobial 
effects 
Clinical studies with topical application of B244 have been conducted, or are planned, include 
studies in subjects with clinical diagnosis of facial acne vulgaris (Investigational New Drug 
[IND] 16487) hypertension (IND 17086), atopic dermatitis (IND 17485) and mild to moderate 
rosacea (IND 18086). Overall, there have been no serious adverse events (SAE) or unexpected 
safety signals observed following treatment with B244. 
Efficacy was supported by statistically significant 2-point reduction in Investigator Global 
Assessment (IGA) with B244 and a trend in the reduction of the number of inflammatory lesions 
compared with vehicle in the study conducted in subjects with facial acne vulgaris (IND16487). 
B244 is comprised of Nitrosomonas eutropha D23 diluted in storage solution (50 mM Na2HPO4 
and 2 mM MgCl2, pH 7.6 ± 0.2). The B244 drug product is provided as a mist formulation in 
sterilized 7.5 or 30 mL plastic containers with appropriate sized and intended use designed spray 
nozzles. There are 3 concentrations, measured by optical density (OD), of the drug product: high 
dose (OD600 4.0 ± 0.8 equivalent to 8 × 109 cells/mL), middle dose (OD600 2.0 ± 0.4 equivalent to 
4 × 109 cells/mL), and low dose (OD600 1.0 ± 0.2 equivalent to 2 × 109 cells/mL). 
A detailed description of the chemistry, pharmacology, efficacy, and safety of B244 is provided 
in the current Investigator’s Brochure. 
2.3 
Benefit/Risk Assessment 
To date, there have been no reported infections or health risks associated with topical application 
or ingestion of Nitrosomonas species. The absence of any known illnesses attributed to these 
bacteria despite widespread human exposure suggests that they are unlikely to pose significant 
health risk. Infection or tissue damage by Nitrosomonas is unlikely, because the sequenced 
genomes of several Nitrosomonas and other AOB lack genes encoding cytotoxins, or other 
known bacterial virulence factors. Further, AOB are slow growing, as compared to most 
heterotrophic bacteria, with optimum doubling times of 8 hours or higher. In particular, 
Nitrosomonas growth is rate limited by the availability of ammonia requiring the oxidation of 27 
moles NH3/mole CO2 fixed. Due to their dependence on ammonia for their growth, the numbers 
of Nitrosomonas on the skin will be necessarily limited and naturally regulated by the amount of 
ammonia produced in sweat. This would ensure that the amount of nitrite and NO generated 
would be relatively low, mitigating the risk of adverse effects due to high NO/NO2 low without 
any adverse effects. 
The Sponsor will immediately notify the Principal Investigator if any additional safety or 
toxicology information becomes available during the study. 


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This study will be performed in compliance with the protocol, International Council on 
Harmonisation of Technical Requirements for Registration of Pharmaceuticals for Human Use 
(ICH) Good Clinical Practice (GCP) and applicable regulatory requirements. Aspects of the 
study concerned with the investigational product (IP) will meet the requirements of Good 
Manufacturing Practice (GMP). 


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3.0 OBJECTIVES AND ENDPOINTS 
Table 3.1 
Study Objectives and Endpoints 
Objectives 
Endpoints 
Primary 
 
• 
Assessment of the safety and tolerability of B244 
in pediatric subjects with atopic dermatitis. 
• 
Incidence of treatment-emergent adverse events 
(TEAEs).  
• 
Change from Baseline in physical examination at 
each post baseline visit. 
• 
Change from Baseline in vital signs at each 
post baseline visit. 
Exploratory 
 
• 
Efficacy of B244 on signs and symptoms of atopic 
dermatitis. 
 
 
 
 
• 
Efficacy of B244 on patient oriented measure of 
atopic dermatitis. 
 
 
• 
Efficacy of B244 on patient reported assessment of 
atopic dermatitis. 
• 
Changes from Baseline to post baseline visits in: 
- 
Validated Investigator Global Assessment for 
Atopic Dermatitis (vIGA-AD) scale. 
- 
Area Severity Index (EASI) score and each 
component of EASI from Baseline to 
post baseline visits. 
 
• 
Changes is Patient Oriented Eczema Measure 
(POEM total score and each of the 7 components) 
from Baseline to post baseline visits. 
 
• 
Changes in patient reported outcome (self-reported 
ItchMan questionnaire) from Baseline to post 
baseline visits. 
 


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4.0 STUDY DESIGN 
4.1 
Overall Design 
This is a Phase 1b, open-label, multiple site study assessing twice daily B244 application for 
28 days in pediatric subjects with atopic dermatitis. 
The study will enroll 36 subjects in 3 cohorts of 12 subjects: 
• Cohort 1: subjects aged 2 to 5 years. 
• Cohort 2: subjects aged 6 to 11 years. 
• Cohort 3: subjects aged 12 to 17 years. 
At Screening and Baseline, all subjects must have confirmed diagnosis of atopic dermatitis, as 
defined by the Hanifin and Rajka criteria, which involves a minimum of 10% but no more than 
60% body surface area and a Validated Investigator Global Assessment for Atopic Dermatitis 
(vIGA-AD) scale of 2 or 3. 
Subjects will attend for a Screening visit between Day -21 and -14. If all eligibility criteria and 
none of the exclusion criteria are met, subjects will be enrolled into the study and will be 
required to undergo a 14 day washout period (Day-14 to -1). The washout period is to ensure the 
subjects do not have any active systemic infections (including but not limited to, ear infections, 
upper respiratory tract infections, throat infections) and that they comply with the withdrawal of 
medications included in Exclusion Criterion 7. On completion of the washout period and 
confirmation of continued eligibility the subjects will be assigned to one of the cohorts based on 
the age of the subject. 
Subjects will attend the study center on Day 1 (-1 to 1) and the Baseline assessments listed in 
Table 1.1 will be conducted. On confirmation of continued eligibility, the subject and parent or 
guardian of the subject will be coached on how to apply medication, depending on the affected 
areas. They will be instructed to apply B244 twice daily (approximately 12 hours apart) for 28 
days and record the details of the application in the study diary provided. They will also be 
provided guidance on the storage of the study treatment. Guidance for the application of B244 is 
provided in Section 6.1. The first dose will be administered on Day 1 in the clinic, under the 
supervision of clinical staff, subsequent doses can be applied outside of the clinic. The 
importance of adherence to the medication schedule will be reinforced at each study visit. 
The subjects with their parent or guardian will return to the study center on Days 7, 14 and 21 
when the assessments listed in Table 1.1 will be conducted. There will be a final study visit on 
Day 28, this will be defined as the end of the study for the subjects. A time window of ±2 day 
will be permitted for these visits. 
Safety monitoring will include review of TEAEs, vital signs and physical examinations as 
indicated in Table 1.1. 


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Efficacy will be assessed using EASI, vIGA-AD scale, POEM, and ItchMan scores Table 1.1. 
4.2 
Scientific Rationale for Study Design 
AOBiome Therapeutics has developed B244 as a topical application of a natural source of AOB 
and NO/NO2 to the human skin. B244 for topical delivery has the potential to improve health in 
both normal and abnormal skin conditions or wound sites. 
A standard parallel-group, open-label design is used for this study to evaluate the safety and 
tolerability of B244 in pediatric subjects with atopic dermatitis. 
The study will be conducted in pediatric subjects with atopic dermatitis because they are a target 
population. 
The sample size for each cohort is based on the desire to obtain adequate safety and tolerability 
data to achieve the objectives of the study while exposing as few subjects as possible to B244 and 
study procedures. 
This study will be performed in compliance with the protocol, the ICH GCP, GMP, and 
applicable regulatory requirements. 
4.3 
Justification for Dose 
There are 3 concentrations of the drug product available: high dose (OD600 4.0 ± 0.8 equivalent 
to 8 × 109 cells/mL), middle dose (OD600 2.0 ± 0.4 equivalent to 4 × 109 cells/mL) and low dose 
(OD600 1.0 ± 0.2 equivalent to 2 × 109 cells/mL). 
The middle dose has been selected for this study to minimize the exposure while ensuring 
administration of a dose considered likely to show improvement in symptoms of atopic 
dermatitis. 
4.4 
End of Study Definition 
The end of the study is defined as the date of last scheduled procedure shown in the Table 1.1 for 
the last subject in the study. 
4.5 
Dose Escalation Criteria 
There will not be any dose escalation in this study. 
4.6 
Study Stopping Criteria 
Dosing for any individual subject will be stopped if: 
• The subject experiences a possibly drug-related SAE. 
• The subject experiences a possibly drug-related significant non-serious adverse event (AE), 
which in the opinion of the Principal Investigator, Chief Investigator, Medical Monitor, or 


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Sponsor’s medical representative, warrants discontinuation from the study for that subject’s 
wellbeing. The occurrence of significant non-serious AEs as described above will require 
that further dosing of other subjects be evaluated by the Chief Investigator, the Medical 
Monitor and the Sponsor’s Medical Advisor to determine study discontinuation. 
• The subject’s atopic dermatitis worsens and requires alternative or supplemental medication 
during the study (see Section 6.8 for allowed treatments). 
• The subject or his/her parent or guardian choose to discontinue for any reason. 
Dosing for a cohort will be stopped if: 
• A subject experiences a possibly drug-related SAE. 
• More than 2 subjects experiences a possibly drug-related significant non-serious AE, which 
in the opinion of the Principal Investigator, Chief Investigator, Medical Monitor, or 
Sponsor’s medical representative, warrants discontinuation from the study for that subject’s 
wellbeing. The occurrence of significant non-serious AEs as described above will require 
that further dosing of other subjects be evaluated by the Chief Investigator, the Medical 
Monitor and the Sponsor’s Medical Advisor to determine study discontinuation. 
The study will be stopped if: 
• More than 1 subject experiences a drug-related SAE. 


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5.0 STUDY POPULATION 
Prospective approval of protocol deviations to recruitment and enrollment criteria, also known as 
protocol waivers or exemptions, is not permitted. 
5.1 
Inclusion Criteria 
Subjects are eligible to be included in the study only if all of the following criteria apply: 
1. Male and female subjects 2 to 17 years of age, inclusive. 
2. Confirmed diagnosis of atopic dermatitis according to the Hanifin and Rajka criteria. 
3. A minimum of 10% but no more than 60% of the subjects' body surface area (see Appendix 6 
for guidance) is affected by atopic dermatitis (affected is defined by physical examination 
findings: erythema, edema, scaling, lichenification, and excoriation; with the excoriation 
serving as the physical examination correlate of pruritus). 
4. A vIGA-AD scale of 2 or 3 at Screening and Baseline. 
5. Subject, or the parent or guardian, to provide written informed consent and authorization for 
protected health information disclosure. 
6. Subjects must be generally in good health based on Investigator’s assessment (other than 
atopic dermatitis). 
7. Normal vital signs, or with no clinically significant vital signs that in the opinion of the 
Investigator, would place the subject at increased risk or would confound the objectives of 
the study. 
8. Females must not be pregnant, as confirmed by negative urine pregnancy testing. Female 
subjects aged ≥11 years old, or female patients <11 years old who have started menstruating, 
will have urinary pregnancy test performed at Screening and prior to the first dose with 
negative results in order to participate in the study. Females must either practice abstinence 
from heterosexual contact or use one of the highly effective contraceptive options described 
in the Appendix 5. 
9. Male subjects of reproductive potential, must be willing to practice effective contraception 
during the study while receiving study treatment from Day 1 and for 7 days after the last 
study visit (Day 28). 
10. Ability to comprehend and comply with study procedures. 
11. Agree to commit to participate in the current protocol. 
12. Provide written informed consent prior to any study procedure being performed. 
5.2 
Exclusion Criteria 
Subjects are excluded from the study if any of the following criteria apply: 
1. Clinically significant physical or mental disorder which, in the opinion of the Investigator, 
would place the subject at increased risk or would confound the objectives of the study. 
2. Subjects with atopic dermatitis on the face only. 


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3. Active cutaneous bacterial, viral or fungal infection in any treatment area at Baseline (eg, 
clinically infected atopic dermatitis). 
4. History or presence of immunological deficiencies or diseases, organ transplant, human 
immunodeficiency virus (HIV), diabetes, malignancy, malignant or pre-malignant skin 
conditions, serious active or recurrent infection, systemic immunosuppressive regimens, 
clinically significant renal disease severe hepatic disorders, or other severe uncontrolled 
conditions (eg, drug or alcohol abuse), that are significant and/or that may pose a health risk 
to the subject in the study or may have an impact on the study assessments. 
5. Unstable atopic dermatitis or a consistent requirement for high-potency corticosteroids (class 
I-III steroids). 
6. Active systemic or localized infection (including infected AD). 
7. Subjects unable to comply with the excluded medication/therapy restriction listed in 
Appendix 4. 
8. Known hypersensitivity to the study treatment. 
9. Known to have hepatitis B, hepatitis C or HIV I or II tests. Details will be recorded in 
medical history, a blood sample will not be collected for confirmation. 
10. Female subject who is pregnant, breastfeeding, or considering pregnancy during the study. 
11. Any skin condition which in the Investigator's opinion may interfere with the evaluation of 
atopic dermatitis. 
12. Use of any investigational drugs within the previous 30 days prior to dosing or within a 
period of less than 5 times the drug's half-life, whichever is longer. 
13. Use of any biologic within a period of 5 times its half-life. 
14. Children or relatives of the Sponsor, clinical research organization, or the Study Site 
personnel are excluded from participating in the study. 
5.3 
Lifestyle Considerations 
There are no dietary or activity related restrictions for this study. 
5.3.1 
Use of Cleanser and Moisturizer During the Study 
At the beginning of the study, subjects will be provided with cleanser and moisturizer to use for 
the duration of the stud as needed.  
Subject should be advised to apply moisturizer 10 minutes after the application of the B244. 
Subjects may not use other cleansers to wash their body for the duration of the trial. Subjects 
may use their preferred shampoo for the duration of the trial.  
During Day 28 visit (End of B244 application) subjects will be asked to return cleanser and 
moisturizer that was provided to them by the Sponsor and will be asked to go back to their 
regular regimen and use their preferred cleanser and moisturizer. 


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Subjects will be encouraged not to use sunscreen during participation in the study. Sunscreen 
should be used minimally or used sparingly while in the active phase (Baseline to Day 28) of the 
study. 
Subjects who do not have atopic dermatitis on their face may apply makeup as needed. However, 
those subjects who have atopic dermatitis on their face and require to use makeup will be advised 
to use it minimally. 
5.4 
Screen Failures 
Screen failures are defined as subjects who consent/assent to participate in the clinical study but 
are not subsequently assigned to study treatment. A minimal set of screen failure information is 
required to ensure transparent reporting of screen failure subjects to meet the Consolidated 
Standards of Reporting Trials (CONSORT) publishing requirements and to respond to queries 
from regulatory authorities. Minimal information includes demography, screen failure details, 
eligibility criteria, and any SAE. 
Individuals who do not meet the criteria for participation in this study (screen failure) may be 
rescreened on 1 occasion. Rescreened subjects should not be assigned the same subject number 
as for the initial screening. 


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6.0 INVESTIGATIONAL PRODUCT TREATMENT AND 
APPLICATION 
Study treatment is defined as any investigational treatment(s), marketed product(s), placebo, or 
medical device(s) intended to be administered to a subject according to the study protocol. 
6.1 
Study Treatment(s) Administered 
6.1.1 
Investigational Product 
Under normal conditions of handling and administration, the Investigational Product (IP) is not 
expected to pose significant safety risks to site staff. A Material Safety Data Sheet describing the 
occupational hazards and recommended handling precautions will be provided to site staff if 
required by local laws or will otherwise be available from the Sponsor upon request. 
The IP must be stored in a secure area under the appropriate physical conditions for the product. 
Access to and administration of the IP will be limited to the Investigator and authorized site staff. 
The IP must be dispensed or administered only to participants enrolled in the study and in 
accordance with the protocol. 
The Investigator is responsible for IP accountability, reconciliation, and record maintenance. The 
Investigator or designated site personnel must maintain IP accountability records throughout the 
course of the study. The responsible person(s) will document the amount of IP received from and 
returned to the Sponsor and the amount administered to subjects. The required accountability 
unit for this study will be the bottle. Discrepancies are to be reconciled or resolved. 
Product name: 
B244, 30 mL/bottle 
Dosage form: 
B244 suspension 
Unit dose strength: 
4x109 cfu/mL 
Route/administration/duration: 
Topical application twice daily for 4 weeks 
Physical description: 
Odorless, cloudy, light pink suspension 
Manufacturer/source of procurement: 
AOBiome Therapeutics 
 
Up to 6 bottles total will be dispensed to the subjects and will depend upon the body surface area 
affected by atopic dermatitis (Appendix 6) and the age of the subject (Table 6.1). 


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Table 6.1 
Suggested Number of Bottles of B244 Issued to the Subject and Parent or 
Guardian 
BSA (%) 
2 to 5 years old 
6 to 11 years old 
12 to17 years old 
10 
1 bottle 
1 bottle 
2 bottles 
20 
1 bottle 
2 bottles 
3 bottles 
30 
2 bottles 
2 bottles 
4 bottles 
50 
2 bottles 
3 bottles 
5 bottles 
 
Table 6.2 
Body Surface Area and Suggested Application of Investigational Product 
Affected Body Surface Area 
Approximate Number of Pumps per application 
2 to 5 years old 
6 to 11 years old 
12 to- 17 years old 
10% 
2 
2 
3 
20% 
3 
4 
7 
30% 
4 
6 
10 
50% 
7 
10 
16 
 
At Baseline visit (Day1), all subjects will be dispensed up to 2 bottles of IP, depending on the 
number of lesions. Upon examining the subject, study staff will instruct the patient on the 
number of pumps to be applied per application for the duration of the treatment.  If during the 
study participation subject develops new lesions, those should be treated as well.  
It is suggested that subjects will use up to the number of bottles indicated in Table 6.1 during 
participation in the trial, however this number should not exceed 6 bottles per subject per study. 
Study staff should monitor usage at every study visit and determine whether more IP should be 
dispensed to the subject based on age and usage, where the total number of pumps per 
application should not exceed 16.  
Subjects and their guardians should use the details in Table 6.2 to guide the suggested number of 
pumps to be applied on each application. Subjects will apply 1 pump (0.14 mL) of B244 (OD600 
2.0 ± 0.4 equivalent to 4 × 109 cells/mL) per 200 cm2 (approximately one adult palm size) of the 
affected area, twice a day approximately 12 hours apart, for 28 days (Day 1 to 28). 
One pump should cover the surface area of skin the approximate size of one adult sized palm. 
One pump will be applied directly to the skin for each atopic dermatitis area that is the size of a 
palm of 1 adult sized hand.  


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The total number of bottles to be dispensed to the subjects will depend upon the body surface 
area affected by atopic dermatitis (Appendix 6), age of the subject and the number of areas 
affected by the disease. 
The subject and parent or guardian of each subject will be instructed by clinical staff regarding 
the use of the spray pump and application of the dose to the area of atopic dermatitis. The first 
dose will be applied by the subject, parent or guardian in the study center under the supervision 
of the clinical staff. 
For each dosing period, the subject under the supervision of the parent or guardian, or the parent 
or guardian, will dispense the required amount of study treatment using the pump. Whether the 
subject is likely to be able to apply the study treatment will be decided by the Investigator, or 
delegate, during the training session. If the subject is considered to be too young, or would be 
unreliable, to apply the study treatment the application will be done by the parent or guardian. 
Whenever the study treatment is applied by the subject the application must be under the 
supervision of the parent or guardian. 
• The person applying the study treatment should wash his/her hands before and after applying 
study treatment. 
• Subject should shake the bottle before each application and then saturate the application area 
well, holding the bottle approximately 6 inches away from the skin. 
• Subjects will be asked to let the product air dry. 
• Subjects may not wash for 2 hours post morning application of the IP. 
• It is recommended that subjects may not bathe, shower or wash until the morning after the 
evening application of B244. For younger subjects who need cleaning related to diaper 
changes this is acceptable. 
• While in use, one spray bottle may be stored at ambient temperature. 
• DO NOT FREEZE 
• The Sponsor will provide a biome friendly, preservative-free moisturizer and cleanser to be 
used as needed, at the discretion of the parent or guardian to clean the area of application 
before application of the treatment. 
• The subject or parent or guardian will apply the study treatment to the affected area twice 
daily (approximately 12 hours apart) for 28 consecutive days. 
• The parent or guardian will verify if the study treatment was applied as directed. Application 
details will be recorded in the study diary provided. 
• Subjects will be asked not to expose the treatment kit to conditions which are unnatural or 
harmful to the product, such as excessive heat (temperatures over 77°F [25°C] and freezing 
temperatures [at 0°C]). Subjects may travel with their study medication but should not leave 
it in the hot car, outside in the cold temperatures etc. Subjects will also be asked not to 
tamper or cause damage to IP bottle. 


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6.2 
Preparation/Handling/Storage 
All investigational drug supplies in the study will be stored in a secure, refrigerated (2 to 8°C) 
safe place, under the responsibility of the Investigator or other authorized individual. 
The Investigator, or designee will maintain temperature monitoring of the IP with daily 
temperature readings. All temperature excursions must be reported to the Sponsor using the 
Temperature Excursion log. If the IP was exposed to the temperature excursion outside the range 
of 2 to 8°C, but for the period greater than 24 hours, the IP must be quarantined until the 
Sponsor’s approval on future use. 
The Investigator or designee must confirm appropriate temperature conditions have been 
maintained during transit for all study treatment received and any discrepancies are reported and 
resolved before use of the study treatment. 
The Investigator or designee must provide instruction to the subject, and parent or guardian, on 
the storage requirements for the study treatment. 
Only subjects enrolled in the study may receive study treatment and only authorized study center 
staff may supply study treatment. All study treatments must be stored in a secure, 
environmentally controlled, and monitored (manual or automated) area in accordance with the 
labeled storage conditions with access limited to the Investigator and authorized study center 
staff. 
The Investigator, institution, or the head of the medical institution (where applicable) is 
responsible for study treatment accountability, reconciliation, and record maintenance (ie, 
receipt, reconciliation, and final disposition records). 
Further guidance and information for the final disposition of unused study treatment will be 
provided. 
6.3 
Accountability, Destruction and Return of Study Supplies 
In accordance with federal and local regulatory requirements, the Investigator and designated site 
personnel must document the amount of IP dispensed to study subjects, the amount returned by 
study subjects, and amount received and returned to the Sponsor, when applicable. Product 
accountability records must be maintained throughout the course of the trial. Any quality issue 
noticed with the receipt or use of an IP (deficient IP in condition, appearance, pertaining 
documentation, labeling, expiry date, etc.) should be promptly reported to the Sponsor, who will 
initiate a complaint procedure. 
All IP must be stored in a secure locked room with access limited to the Investigator and 
designated site personnel. Study product is to be stored in a refrigerator between 2 to 8°C. 
Maintenance of a temperature log is required. 


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Under no circumstances will the Investigator or designees allow IP to be used other than as 
directed by this Clinical Study Protocol, or dispose of investigational product without Sponsor 
direction. 
The Sponsor will supply sufficient quantities of the IP for the completion of this study. 
The study pharmacist or designated study personnel will maintain an Investigational Materials 
Accountability Record and a Subject IP Accountability Log itemizing all IP received, dispensed 
to and returned from each subject during the study. All dispensed bottles must be accounted for, 
and any discrepancies explained. Study site should contact site Clinical Research Associate 
(CRA) or designee in case of any dispensing errors or if discrepancies are discovered. 
Prior to site closure and at appropriate intervals during the study, site CRA will perform IP 
accountability and reconciliation. At the end of the study, the Investigator or designee will retain 
all the original documentation regarding IP accountability, return, and copies will be sent to the 
Sponsor. 
All unused and used IP tubes will be returned to the Sponsor or its designee for destruction at the 
end of the study. 
6.4 
Measures to Minimize Bias: Randomization and Blinding 
Not applicable, this is an open-label study. 
6.5 
Study Treatment Compliance 
The prescribed dosage, timing, and mode of administration may not be changed. Any departures 
from the intended regimen must be recorded in the electronic case report forms (CRFs). 
At each visit, prior to dispensing study treatment, previously dispensed study treatment will be 
retrieved by the Investigator or designee and compliance assessed. Subjects exhibiting poor 
compliance as assessed by the returned IP and the study diary should be counseled on the 
importance of good compliance to the study dosing regimen. 
6.5.1 
Study Diary Compliance Review 
The subject will be given a study diary at each study visit of the treatment period to record date 
and time of applications, any adverse events, and quality of life assessments. Subjects will record 
every application during the treatment period and will bring the subject diary to each of the 
post baseline study visits for compliance review. The Investigator or designee will verify that the 
subject complied with the application requirements and will file the completed subject diary in 
the study files at each study visit until the Final/Early Termination visit. Any missed application 
notations will be clarified with the subject and documented in the subject’s CRF. 


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6.5.2 
Treatment Compliance 
Each site participating in the trial will be instructed to assess subject’s compliance by weighing 
the IP and obtaining the weight of the bottles in grams pre- and post-application. Study personnel 
will be asked to weigh dispensed bottle(s) and record the weight pre first application. At each 
subsequent visit and then Day 28 visit, study personnel will need to weigh bottle(s) and record 
the weight. This procedure should be followed every time study medication is dispensed and 
returned. Sites will be provided scales, which will be tared prior to each use. Study personnel 
will be instructed to record measurements into the eCRF. 
6.6 
Concomitant Therapy 
Any medication or vaccine (including over-the-counter or prescription medicines, vitamins, 
and/or herbal supplements) that the subject is receiving within 30 days prior to the start of the IP 
and through the final study visit will be recorded on the appropriate CRF) along with: 
• Reason for use. 
• Dates of administration including start and end dates. 
• Dosage information including dose and frequency. 
Any medications started during the study (including “as needed” medications) will be recorded 
in the concomitant medication list as soon as the Investigational Site will become aware of the 
medication being added. 
The subject, or parent or guardian, will be instructed to record the details of any medication 
taken by the subject outside of the study center in the study diary provided. The details will be 
reviewed by the Investigator or designee on each study center visit. 
The Medical Monitor should be contacted if there are any questions regarding concomitant or 
prior therapy. 
A list of excluded medications/therapy is provided in Appendix 4. 
Previous treatment of atopic dermatitis must be recorded irrespectively of the term it was given. 
Acetaminophen, at doses approved for the age of the subject, is permitted for use any time during 
the study. Other concomitant medication may be considered on a case-by-case basis by the 
Investigator in consultation with the Medical Monitor. 
6.7 
Dose Modification 
The study treatment will be administered as described in this protocol. Up to 16 pumps per 
application may be administered, depending on the number of lesions subject has. Number of 
applications will be documented in each subject’s chart. Any AEs or circumstances that impact 
the dosing of the IP will be documented and reported to the Medical Monitor. 


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6.8 
Rescue Medication Permitted During the Study 
Over the course of the study, the Investigator will monitor and evaluate subject’s condition and 
determine whether rescue therapy may be necessary. The use of medications to treat a subject’s 
atopic dermatitis during the study will be permitted if the parent, guardian or medical 
professional determines that it becomes medically necessary. Such rescue treatment should not 
exceed 7 days. If a subject requires treatment for more than 7 days or requires systemic therapy, 
they should be discontinued from the study. Medications permitted are listed in Table 6.3. 
Study staff must be notified of the use of any medication as soon as feasible. The details of the 
medication should be recorded in the study diary and transferred to the CRF. Details recorded 
should include medication name, date of administration, dosage, and number of applications. 
Table 6.3 
Permitted Rescue Medication 
Class 4 – Mid-strength  
Clocortolone pivalate (0.1%) 
Cloderm® Cream 
Mometasone furoate (0.1%) 
Elocon® Cream 
Triamcinolone acetonide (0.1%) 
Aristocort® A Cream, Kenalog® Ointment 
Betamethasone valerate (0.1%) 
Valisone Ointment 
Fluocinolone acetonide (0.025%) 
Synalar® Ointment 
Class 5 – Lower Mid-strength 
Fluticasone propionate (0.05%) 
Cutivate® Cream/Cutivate Lotion 
Prednicarbate (0.1%) 
Dermatop® Cream 
Hydrocortisone probutate (0.1%) 
Pandel® Cream 
Triamcinolone acetonide (0.1%) 
Aristocort A Cream, Kenalog Lotion 
Fluocinolone acetonide (0.025%) 
Synalar Cream 
Class 6 – Mild 
Alclometasone dipropionate (0.05%) 
Aclovate® Cream/Ointment 
Desonide (0.05%) 
Verdeso™ Foam, Desonate Gel™ 
Triamcinolone acetonide (0.025%) 
Aristocort A Cream, Kenalog Lotion 
Hydrocortisone butyrate (0.1%) 
Locoid Cream/Ointment 
Fluocinolone acetonide (0.01%) 
Derma-Smoothe/FS® Scalp Oil, Synalar Topical 
Solution 
Class 7 – Least potent 
Hydrocortisone (2%/2.5%) 
Nutracort® Lotion, Synacort Cream 
Hydrocortisone (0.5 to 0.1%) 
Cortaid® Cream/Spray/Ointment and many other over-
the-counter products 
 


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6.9 
Treatment after the End of the Study 
The Sponsor will not provide any additional care to subjects after they leave the study because 
such care should not differ from what is normally expected for subjects with atopic dermatitis. 


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7.0 DISCONTINUATION OF STUDY TREATMENT AND 
SUBJECT DISCONTINUATION/WITHDRAWAL 
7.1 
Discontinuation of Study Treatment 
The stopping criteria for the study are described in Section 4.6. 
If a subject who does not meet enrollment criteria is inadvertently enrolled, that subject must be 
discontinued from study treatment and the Sponsor or Sponsor designee must be contacted. An 
exception may be granted in rare circumstances for which there is a compelling safety reason to 
allow the subject to continue. In these rare cases, the Investigator must obtain documented 
approval from the Sponsor or Sponsor designee to allow the subject to continue in the study. 
Subjects who discontinue study treatment will not be replaced. 
7.2 
Subject Discontinuation/Withdrawal from the Study 
• A subject may withdraw from the study at any time at his/her own request, or at the request 
of their parent or guardian, or may be withdrawn at any time at the discretion of the 
Investigator for safety, behavioral, compliance, or administrative reasons. 
• If the subject, or their parent or guardian, withdraws consent for disclosure of future 
information, the Sponsor may retain and continue to use any data collected before such a 
withdrawal of consent. 
• If a subject withdraws from the study, he/she or their parent or guardian, may request 
destruction of any samples taken and not tested, and the Investigator must document this in 
the study center study records. 
• See the schedule of assessments (SoA) Table 1.1 for data to be collected at the time of study 
discontinuation and follow-up and for any further evaluations that need to be completed. 
Should a subject, or their parent or guardian request or decide to withdraw from the study, all 
efforts must be made to complete and report the observations as thoroughly as possible up to 
the date of withdrawal. Subjects withdrawing due to an AE should be followed up according 
to the follow-up visit. 
7.3 
Lost to Follow-up 
A subject will be considered lost to follow-up if he or she repeatedly fails to return for scheduled 
visits and is unable to be contacted by the study center. 
The following actions must be taken if a subject fails to return to the study center for a required 
study visit: 
• The study center must attempt to contact the subject or their parent or guardian, and 
reschedule the missed visit as soon as possible and counsel the subject on the importance of 


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maintaining the assigned visit schedule and ascertain whether or not the subject wishes to 
and/or should continue in the study. 
• Before a subject is deemed lost to follow-up, the Investigator or designee must make every 
effort to regain contact with the subject, or their parent or guardian (where possible, 
3 telephone calls and, if necessary, a certified letter to the subject’s last known mailing 
address or local equivalent methods). These contact attempts should be documented in the 
subject’s CRF. 
• Should the subject continue to be unreachable, he/she will be considered to have withdrawn 
from the study. 
Discontinuation of specific study centers or of the study as a whole are handled as part of 
Appendix 2. 
 


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8.0 STUDY ASSESSMENTS AND PROCEDURES 
• Study procedures and their timing are summarized in the SoA (Table 1.1). 
• Protocol waivers or exemptions are not allowed. 
• Immediate safety concerns should be discussed with the Medical Monitor immediately upon 
occurrence or awareness to determine if the subject should continue or discontinue study 
treatment. 
• Any serious or non-serious adverse event will be appropriately reported and documented. 
• Adherence to the study design requirements, including those specified in the SoA, is essential 
and required for study conduct. 
• All screening evaluations must be completed and reviewed to confirm that potential subjects 
meet all eligibility criteria. The Investigative site will record and document as applicable 
either confirmation of subject eligibility or screen failure for each subject within the CRF. 
• Basic demographic information, including date of birth, gender, ethnicity, and race will be 
recorded at the Screening Visit. 
8.1 
Administrative Procedures 
8.1.1 
Subject Informed Consent 
A signed and dated, study-specific, approved by Institutional Review Board (IRB and applicable 
regulatory authorities informed consent form must be obtained from each subject, or their parent 
or guardian, prior to performing any study-related procedures. No study related procedures or 
activities may be performed until each subject is fully informed and the consent form is signed and 
dated. 
8.2 
Study Procedures 
8.2.1 
Visit 1- Screening Visit (Day -21 to Day -14) 
The following assessments will be performed and recorded by the Investigator or Designee: 
• Informed Consent 
• Evaluation of Inclusion/Exclusion Criteria. 
• Review and record demographic information. 
• Medical history. 
• Hanifin and Rajka criteria. 
• Collect concomitant medication details. 
• Physical examination. 
• Vital signs. 
• Body weight and height measurement. 
• Urine pregnancy test for female subjects ≥11 years old, or female patients <11 years old who 
have started menstruating. 
• vIGA-AD scale. 


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• EASI. 
• POEM. 
• ItchMan Questionnaire. 
• Provide study cleanser and moisturizer. 
• Start AE collection and assessment. 
8.2.2 
Washout Phase (Day -14 to Day -1) 
Washout phase may be initiated after Screening procedures have been completed. Every effort 
should be made for subjects to complete a 14-day Washout period. If absolutely necessary subjects 
may undergo Baseline on Day -1, which is also the 13th day of Washout.  
The Investigator or designee will provide the subject and parent or guardian with study cleanser 
and moisturizer and will provide instructions for the use. Adverse event and concomitant 
medication will be recorded. 
8.2.3 
Unscheduled Visit 
If an event arises that requires subject to come in to the study center, subjects should be scheduled 
for the unscheduled visit and assessments performed based on Investigator discretion. 
Subjects will be encouraged to report any complications or adverse effects during their 
participation. Investigator may evaluate the subject at an unscheduled visit, if subject’s condition 
will be considered as worsening. 
8.2.4 
Day 1 (Baseline) -1 to 1 day 
Baseline assessments to be completed before dose administration: 
• Review Inclusion/Exclusion Criteria. 
• Hanifin and Rajka criteria. 
• Collect concomitant medication details. 
• Vital signs. 
• Urine pregnancy test for female subjects ≥11 years old, or female patients <11 years old who 
have started menstruating. 
• Physical examination 
• vIGA-AD scale. 
• EASI. 
• POEM. 
• ItchMan Questionnaire. 
• Adverse event collection and assessment. 
On completion of Baseline assessments: 
• Dispense IP to Subject and parent or guardian. 
• Provide study diary 


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• Provide counseling on the use of the study treatment, study diary and any questions the 
subject, parent or guardian may have will be answered. 
• Provide study cleanser and moisturizer. 
• Administer the IP under supervision of clinical staff. 
 
8.2.5 
Out Patient, Days 1 to 6, Days 8 to 14, and Days 15 to 20 
The subject, or their parent or guardian, will be instructed by the Investigator or designee to: 
• Administer the IP twice a day (only PM on Day 1). 
• Complete the study diary. 
• Use study cleanser and moisturizer as instructed. 
• Record and review AEs. 
• Record and review concomitant medications. 
8.2.6 
Study Center Visit, Day 7, Day 14 and Day 21 
• The subject or parent or guardian may apply the IP at home and use study cleanser and 
moisturizer as instructed. The diary card should be completed as instructed. 
The following assessments will be conducted by the Investigator or designee 
• Vital signs. 
• vIGA-AD scale. 
• EASI. 
• POEM. 
• ItchMan questionnaire. 
• Physical examination 
• Dispense IP to Subject as necessary. 
• Collect IP from Subject as necessary. 
• Review IP compliance. 
• Provide study cleanser. 
• Provide study moisturizer. 
• Provide counseling on the continued use of the study treatment, study diary and any 
questions the subject, parent or guardian may have will be answered. 
• Review study diary entries. 
• Record and review AEs. 
• Record and review concomitant medications. 
8.2.7 
Final Visit (Day 28) or Early Termination Visit 
Every attempt should be made to complete all visits during the defined window periods. Subjects 
who do not complete all required study visits and withdraw from the study before Day 28 final 
visit, will be asked to complete the Early Termination Visit. 


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• The subject or parent or guardian may apply the IP at home (not applicable for an Early 
Termination Visit). 
The following assessments will be performed by the Investigator or designee: 
• Physical examination. 
• Record and review concomitant medication details. 
• Record of vital signs. 
• Body weight and height. 
• Urine pregnancy test for female subjects ≥11 years old, or female patients <11 years old who 
have started menstruating. 
• vIGA-AD scale. 
• EASI. 
• POEM. 
• ItchMan questionnaire. 
• Review IP compliance 
• Record and review AE details. 
• Review study diary entries. 
• Collect used and unused IP containers, study cleanser and moisturizer. 


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9.0 METHODS OF ASSESSMENT 
9.1 
Subject Demographics 
Basic demographic information, including date of birth, gender, ethnicity, and race will be 
recorded at the Screening Visit. 
9.2 
Concomitant Medication Recording 
All medications (both prescription and nonprescription, and including vitamins, herbals, topicals, 
inhaled, and intranasal) taken within 30 days prior to the start of the IP and through the final study 
visit will be recorded on the appropriate CRF (using their generic and brand name, if known) with 
the corresponding indication, start and stop dates. At each study visit, subjects will be asked 
whether they have started or discontinued any medication since their previous study visit. This 
includes single use or PRN (as needed) medication use. 
Previous treatment of atopic dermatitis must be recorded irrespectively of the term it was given. 
Corresponding condition shall be captured in the subject’s medical history. 
9.3 
Efficacy Assessments 
Planned timepoints for all efficacy assessments are provided in the SoA (Table 1.1). 
The Investigator or designee will be responsible for providing the subjects and parent or guardian 
with an explanation of the purpose of the POEM and Itch assessments and training for the 
completion of the assessments. The Investigator or designee will provide the relevant documents 
for completion and assessments will be completed during visits to the clinic. 
9.3.1 
Validated Investigator Global Assessment for Atopic Dermatitis (vIGA-AD) 
Scale 
The Investigator or designee will select the vIGA-AD scale that best describes the overall 
appearance of the atopic dermatitis lesions at each of the assessment timepoints during the study. 
The vIGA-AD scale allows for an assessment of overall disease severity at a specified timepoint, 
based on a 5 point scale. The vIGA-AD scale evaluates clinical characteristics of erythema, 
infiltration, papulation, oozing, and crusting as a guideline for the overall severity assessment 
(Table 9.1). 


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Table 9.1 
Validated Investigator Global Assessment for Atopic Dermatitis Scale 
Score 
Grade 
Definition 
0 
Clear 
No inflammatory signs of atopic dermatitis (no erythema, no 
induration/papulation, no lichenification, no oozing/crusting). 
Post inflammatory hyperpigmentation and/or hypopigmentation may be 
present. 
1 
Almost Clear 
Barely perceptible erythema, barely perceptible induration/papulation, 
and/or minimal lichenification. No oozing or crusting. 
2 
Mild 
Slight but definite erythema (pink), slight but definite induration/papulation, 
and/or slight but definite lichenification. No oozing or crusting. 
3 
Moderate  
Clearly perceptible erythema (dull red), clearly perceptible 
induration/papulation, and/or clearly perceptible lichenification. Oozing and 
crusting may be present. 
4 
Severe 
Marked erythema (deep or bright red), marked induration/papulation, and/or 
marked lichenification. Disease is widespread in extent. Oozing or crusting 
may be present. 
 
9.3.2 
Atopic Dermatitis Eczema Area Severity Index 
The EASI is a validated scoring system used to grade the physical signs of atopic dermatitis and 
eczema. The Investigator or designee will select the appropriate score at each of the assessment 
timepoints during the study. 
The EASI evaluation assesses the extent of disease (% involvement) at 4 body sites: 
• Head and neck. 
• Trunk. 
• Upper extremities. 
• Lower extremities. 
and measures 4 clinical signs: 
• Erythema. 
• Edema/papulation. 
• Excoriation. 
• Lichenification. 
graded on a severity scale of 0 to 3 (half points may be used): 
• 0 = None. 
• 1 = Mild. 
• 2 = Moderate. 
• 3 = Severe. 


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Scoring information for each of the above measures will be recorded on paper. 
9.3.3 
Patient Oriented Eczema Measure 
The POEM is a tool developed by the University of Nottingham, United Kingdom, for 
monitoring atopic dermatitis severity. The subject or the parent or guardian of the subject, will 
complete the questionnaire at each of the assessment timepoints. 
Each of the 7 questions in the POEM questionnaire carries equal weight and is scored from 
0 to 4: 
• No days = 0. 
• 1 to 2 days = 1. 
• 3 to 4 days = 2. 
• 5 to 6 days = 3. 
• Every day = 4. 
Scores are then added to yield a total score of 0 to 28; higher scores mean the greater the severity 
of atopic dermatitis. 
9.3.4 
ItchMan Questionnaire 
The ItchMan Questionnaire will be used for the subject, or the parent or guardian, to indicate 
how itchy the area of atopic dermatitis feels at the timepoints during the study. Pictures to guide 
in the grading will be included in the subject diary. 
• 0 = Comfortable, no itch. 
• 1 = Itches a little; does not interfere with activity. 
• 2 = Itches more; sometimes interferes with activity. 
• 3 = Itches a lot difficult to sit still, concentrate. 
• 4 = Itches most terribly; impossible to sit still, concentrate. 
9.3.5 
Application Site Assessment 
The study treatment application sites will be evaluated at each visit, preferably by the same 
assessor. The first investigational product application will happen in the study center under 
clinical staff supervision, after the completion of the baseline assessments.  All subsequent study 
application will be administered by the parent/guardian or by the subject in the setting of 
subject’s home. Skin irritation will be recorded as an adverse event and followed until resolution 
(or stabilization, as applicable) 
9.4 
Safety Assessments 
Planned timepoints for all safety assessments are provided in the SoA (Table 1.1). 


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9.4.1 
Physical Examinations 
A complete physical examination will include, at a minimum, assessments of the cardiovascular, 
respiratory, and gastrointestinal systems. Height and weight will also be measured and recorded. 
9.4.2 
Pregnancy Test 
Female subjects aged ≥11 years old, or female patients <11 years old who have started 
menstruating, will have urinary pregnancy test performed at all visits.  The Baseline result must 
be available and must be negative before the subject apply the first application of IP.  Positive 
pregnancy test will disqualify the subject from the participation in the study. 
 
9.4.3 
Medical History 
A complete medical history included evaluation (past or present) of the following: general, head 
and neck, eyes, ears, nose throat, chest/respiratory, heart/cardiovascular, gastrointestinal/liver, 
gynecological/urogenital, musculoskeletal/extremities, skin, neurological/psychiatric, 
endocrine/metabolic, hematologic/lymphatic, allergies/drug sensitivities, past surgeries, 
substance abuse, or any other diseases or disorders. 
The details of the subject’s atopic dermatitis history will be recorded. 
9.4.4 
Vital Signs 
• Blood pressure, pulse and body temperature measurements will be assessed in the sitting 
position with a completely automated device. Manual techniques will be used only if an 
automated device is not available or the subject is uncomfortable or distressed with the use of 
an automated device. 
• Blood pressure and pulse measurements should be preceded by at least 5 minutes of rest for 
the subject in a quiet setting without distractions (eg, television, cell phones, use of electronic 
games). 
• Vital signs will consist of single measurement. 
• Body weight and height will be measured at Screening and at Day 28/Final Visit (or at Early 
Termination Visit, as applicable). 
9.5 
Adverse Events 
The definitions of an AE or SAE can be found in Appendix 3. 
Adverse events will be reported by the subject, parent or guardian. 
The Investigator and any designees are responsible for detecting, documenting, and recording 
events that meet the definition of an AE or SAE and remain responsible for following up AEs 
that are serious, considered related to the study treatment or study procedures, or that caused the 
subject to discontinue the study (see Section 7.0). 


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9.5.1 
Time Period and Frequency for Collecting AE and SAE Information 
All SAEs will be collected from the signing of the informed consent form (ICF) until the final 
visit (or Early Termination Visit), at the timepoints specified in the SoA (Table 1.1). 
All AEs will be collected from the signing of the ICF until the final visit (or Early Termination 
Visit), at the timepoints specified in the SoA (Table 1.1). 
All SAEs will be recorded and reported to the Sponsor or designee within 24 hours, as indicated 
in Appendix 3. The Investigator or designee will submit any updated SAE data to the Sponsor 
within 24 hours of it being available. 
Investigators or designees are not obligated to actively seek AE or SAE after conclusion of the 
study participation. However, if the Investigator or designee learns of any SAE, including a 
death, at any time after a subject has been discharged from the study, and he/she considers the 
event to be reasonably related to the study treatment or study participation, the Investigator or 
designee must promptly notify the Sponsor. 
The method of recording, evaluating, and assessing causality of AEs and SAEs and the 
procedures for completing and transmitting SAE reports are provided in Appendix 3. 
9.5.2 
Method of Detecting AEs and SAEs 
Care will be taken not to introduce bias when detecting AEs and/or SAEs. Open-ended and 
non-leading verbal questioning of the subject is the preferred method to inquire about 
AE occurrences. 
9.5.3 
Follow-up of AEs and SAEs 
After the initial AE/SAE report, the Investigator or designee is required to proactively follow 
each subject at subsequent visits/contacts. All SAEs, will be followed until resolution, 
stabilization, the event is otherwise explained, or the subject is lost to follow-up (as defined in 
Section 7.3). Further information on follow-up procedures is given in Appendix 3. 
9.5.4 
Regulatory Reporting Requirements for SAEs 
• Prompt notification by the Investigator or designee to the Sponsor of an SAE is essential so 
that legal obligations and ethical responsibilities toward the safety of subjects and the safety 
of a study treatment under clinical investigation are met. 
• The Sponsor has a legal responsibility to notify both the local regulatory authority and other 
regulatory agencies about the safety of a study treatment under clinical investigation. The 
Sponsor will comply with country-specific regulatory requirements relating to safety 
reporting to the regulatory authority, IRBs, and Investigators. 


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• Investigator safety reports must be prepared for suspected unexpected serious adverse 
reactions (SUSARs) according to local regulatory requirements and Sponsor policy and 
forwarded to Investigators as necessary. 
• An Investigator who receives an Investigator safety report describing an SAE or other 
specific safety information (eg, summary or listing of SAEs) from the Sponsor will review 
and then file it along with the Investigator’s Brochure and will notify the IRB, if appropriate 
according to local requirements. 
9.5.5 
Pregnancy 
• Details of all pregnancies in female subjects will be collected after the start of study 
treatment and until 1 month after the last dose. 
• If a pregnancy is reported, the Investigator should inform the Sponsor within 24 hours of 
learning of the pregnancy and should follow the procedures outlined in Appendix 6. 
• Abnormal pregnancy outcomes (eg, spontaneous abortion, fetal death, stillbirth, congenital 
anomalies, and ectopic pregnancy) are considered SAEs. 
9.6 
Treatment of Overdose 
The Sponsor does not recommend specific treatment for an overdose. Washing with 
conventional cleanser and water will remove the product. 
The subject, or the parent or guardian, should notify the Investigator of any overdose. 
In the event of an overdose, the Investigator should: 
1. Contact the Medical Monitor immediately. 
2. Closely monitor the subject for any AE/SAE. 
3. Document the quantity of the excess dose as well as the duration of the overdose in the CRF. 
Decisions regarding dose interruptions will be made by the Investigator in consultation with the 
Medical Monitor based on the clinical evaluation of the subject. 
9.7 
Pharmacodynamics 
Pharmacodynamics parameters are not evaluated in this study. 
9.8 
Genetics 
Genetics are not evaluated in this study. 
9.9 
Biomarkers 
Biomarkers are not evaluated in this study. 


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9.10 Health Economics/Medical Resource Utilization and Health Economics 
Health Economics/Medical Resource Utilization and Health Economics parameters are not 
evaluated in this study. 
10.0 STATISTICAL CONSIDERATIONS 
10.1 Statistical Hypotheses 
No formal statistical hypothesis testing is planned for this study. All analyses will be considered 
exploratory and descriptive. 
10.2 Sample Size Determination 
The study will enroll and dose 36 subjects, in 3 age cohorts of 12 subjects: 
• Cohort 1: subjects aged 2 to 5 years old. 
• Cohort 2: subjects aged 6 to 11 years old. 
• Cohort 3: subjects aged 12 to 17 years old. 
The sample size is not based on statistical considerations but is typical for studies of this nature, 
and is considered adequate to characterize the distribution of the planned endpoints. Any 
statistical testing will be considered exploratory and descriptive. 
10.3 Populations for Analyses 
For purposes of analysis, the analysis sets in Table 10.1 are defined. 
Table 10.1 
Analysis Sets 
Analysis Set 
Description 
Intent to Treat (ITT) population 
All subjects who are enrolled and take at least 1 dose of study treatment. The 
ITT population will be the primary population for safety and efficacy 
assessments. 
Per Protocol (PP) population 
All subjects in the ITT population without any protocol deviations that may 
have an impact on the efficacy assessments. The PP population will be the 
supportive population for efficacy assessments. 
10.4 Statistical Analyses 
The Statistical Analysis Plan will be developed and finalized before database lock and will 
describe the subject analysis sets to be included in the analyses, and procedures for accounting 
for missing, unused, and spurious data. This section is a summary of the planned statistical 
analyses of the primary and secondary endpoints. 


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All analyses, summaries, and listings will be performed using SAS® software (version 9.3 or 
higher). 
The following descriptive statistics will be used as applicable to summarize the study data unless 
otherwise specified: 
• Continuous variables: sample size (n), mean, standard deviation, median, minimum (min), 
and maximum (max). 
• Categorical variables: frequencies and percentages. 
Individual subject data will be presented in listings. 
10.4.1 
Efficacy Analyses 
All efficacy analyses will be performed on the ITT and PP populations, for overall and by age 
cohorts (2 to 5 years, 6 to 11 years, and 12 to 17 years). 
Summary statistics will be provided for the vIGA-AD scale, EASI score (total and by 
component), POEM score (total and by component) and the ItchMan scale, and changes from 
baseline at each visit. The frequency and percentage of subjects who have achieved clear (0) or 
almost clear (1) on the vIGA-AD scale will also be provided at each visit. 
10.4.2 
Safety Analyses 
All safety analyses will be performed on the ITT population. 
All safety assessments, including TEAEs, vital signs and weight, physical examinations, medical 
examination pregnancy test results and concomitant medication will be listed and as appropriate 
summarized with descriptive statistics. 
Treatment-emergent adverse events are defined as AEs that first occurred or worsened in 
severity after the first administration of study treatment. 
Adverse events will be coded using the Medical Dictionary for Regulatory Activities 
(MedDRA). The numbers of TEAEs and incidence rates will be tabulated by preferred term and 
system organ class, for overall and by cohort. 
Treatment-emergent AEs by maximum severity, TEAEs by relationship to study treatment, 
SAEs, TEAEs leading to death, and TEAEs leading to discontinuation of study treatment will be 
tabulated for overall and by age cohort. 
All vital signs measurements, weight, and body mass index will be summarized for overall and 
by age cohort, using descriptive statistics at each visit for raw numbers and change from 
Baseline. The incidence of abnormal physical examination results will also be summarized using 
descriptive statistics. 


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10.4.3 
Missing Data 
Data from subjects who withdraw from the study, including AEs and any follow-up, will be 
included in the analyses of all outcomes. 
Missing data will not be imputed. 
10.5 Interim Analyses 
No interim analysis is planned. 
10.6 Monitoring Committee 
A Safety Monitoring Committee will not be established. 
 


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11.0 REFERENCES 
1. Arp DJ, Sayavedra-Soto LA, Hommes NG. Molecular biology and biochemistry of ammonia 
oxidation by Nitrosomonas europaea. Arch Microbiol 2002: 178. 250-255. 
2. Rico J, Quiring J, Hollenbach S, Enloe C, Stasko N. Phase 2 study of efficacy and safety of 
SB204 in the treatment of acne vulgaris. Novan Therapeutics, Poster Presentation, Annual 
Meeting of the Society for Investigative Dermatology (SID) May 7-10, 2014, Albuquerque, 
New Mexico. 
3. Weller R, Price R. Antimicrobial effect of acidified nitrite on dermatophyte fungi, Candida 
and bacterial skin pathogens. J Appl Microbiol 2001: 648-652. Appendices. 
4. Investigator Brochure 


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Appendix 1 
Abbreviations 
Abbreviation 
Definition 
AE 
Adverse event 
AOB 
Ammonia oxidizing bacteria 
CRA 
Clinical Research Associate 
CRF 
Case report form (electronic or paper) 
CRO 
Clinical research organization 
EASI 
Eczema Area Severity Index 
GCP 
Good Clinical Practice 
GMP 
Good Manufacturing Practice 
HIV 
Human immunodeficiency virus 
ICF 
Informed consent form 
ICH 
International Council for Harmonisation 
IRB 
Institutional Review Board 
vIGA-AD 
Validated Investigator Global Assessment for Atopic Dermatitis 
ITT 
Intent To Treat 
IP 
Investigational product 
IND 
Investigational New Drug 
IRB 
Institutional Review Board 
NO 
nitrite 
NO2 
nitric oxide 
OD 
Optical density 
POEM 
Patient Oriented Measure 
PP 
Per Protocol 
SAE 
Serious adverse event 
SoA 
Schedule of assessments 
TEAE 
Treatment-emergent adverse events 
 


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Appendix 2 
Regulatory, Ethical, and Study Oversight Considerations 
Regulatory and Ethical Considerations 
• This study will be conducted in accordance with the protocol and with the following: 
- Consensus ethical principles derived from international guidelines including the 
Declaration of Helsinki and Council for International Organizations of Medical 
Sciences (CIOMS) International Ethical Guidelines. 
- Applicable ICH GCP Guidelines. 
- Applicable laws and regulations. 
• The protocol, protocol amendments, ICF, Investigator Brochure’s, and other relevant 
documents (eg, advertisements) must be submitted to an IRB by the Investigator and 
reviewed and approved by the IRB before the study is initiated. 
• Any amendments to the protocol will require IRB and regulatory authority approval, when 
applicable, before implementation of changes made to the study design, except for changes 
necessary to eliminate an immediate hazard to subjects. 
• The Investigator will be responsible for the following: 
- Providing written summaries of the status of the study to the IRB annually or more 
frequently in accordance with the requirements, policies, and procedures established 
by the IRB. 
- Notifying the IRB of SAEs or other significant safety findings as required by IRB 
procedures. 
- Providing oversight of the conduct of the study at the study center and adherence to 
requirements of 21 Code of Federal Regulations (CFR), ICH guidelines, the IRB, 
European regulation 536/2014 for clinical studies (if applicable), and all other 
applicable local regulations. 
• After reading the protocol, each Investigator will sign the protocol signature page and send a 
copy of the signed page to the Sponsor or representative (Appendix 7). The study will not 
start at any study center at which the Investigator has not signed the protocol. 
Adequate Resources 
The Investigator is responsible for supervising any individual or party to whom the Investigator 
delegates study-related duties and functions conducted at the study center. 
If the Investigator/institution retains the services of any individual or party to perform 
study-related duties and functions, the Investigator/institution should ensure this individual or 
party is qualified to perform those study-related duties and functions and should implement 
procedures to ensure the integrity of the study-related duties and functions performed and any 
data generated. 


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Financial Disclosure 
Investigators and sub-Investigators will provide the Sponsor with sufficient, accurate financial 
information as requested to allow the Sponsor to submit complete and accurate financial 
certification or disclosure statements to the appropriate regulatory authorities. Investigators are 
responsible for providing information on financial interests during the course of the study and for 
1 year after completion of the study. 
Insurance 
Sponsor will provide insurance in accordance with local guidelines and requirements as a 
minimum for the subjects in this study. The terms of the insurance will be kept in the study files. 
Informed Consent Process 
• The Investigator or his/her representative will explain the nature of the study to the subject 
and their parent or guardian, and answer all questions regarding the study. 
• Subjects and their parent or guardian, must be informed that their participation is voluntary. 
Subjects or their parent or guardian, will be required to sign a statement of informed consent 
that meets the requirements of 21 CFR 50, local regulations, ICH guidelines, Health 
Insurance Portability and Accountability Act (HIPAA) requirements, where applicable, and 
the IRB or study center. 
• The medical record must include a statement that written informed consent was obtained 
before the subject was entered in the study and the date the written consent was obtained. 
The authorized person obtaining the informed consent must also sign the ICF. 
• Subjects, and their parent or guardian, must be re-consented to the most current version of 
the ICF(s) during their participation in the study. 
• A copy of the ICF(s) must be provided to the subject or the subject’s parent or guardian. 
If a subject is rescreened the subject, or their parent or guardian, are required to sign a new ICF. 
Data Protection 
• Subjects will be assigned a unique identifier by the Sponsor. Any subject records or datasets 
that are transferred to the Sponsor will contain the identifier only; subject names or any 
information which would make the subject identifiable will not be transferred. 
• The subject must be informed that his/her personal study-related data will be used by the 
Sponsor in accordance with local data protection law. The level of disclosure must also be 
explained to the subject. 
• The subject must be informed that his/her medical records may be examined by Clinical 
Quality Assurance auditors or other authorized personnel appointed by the Sponsor, by 
appropriate IRB members, and by inspectors from regulatory authorities. 


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Medical Monitor 
Dr. James Milbauer 
Phone:  973-265-4431 
Office:  973-335-1516 
Cell:  973-727-7969 
Fax:  973-335-5417 
Dissemination of Clinical Study Data 
The results of the study should be reported within 1 year from the end of the clinical study. 
Irrespective of the outcome, the Sponsor will submit to the European Union database a summary 
of the results of the clinical study within 1 year from the end of the clinical study. It shall be 
accompanied by a summary written in a manner that is understandable to laypersons. 
Data Quality Assurance 
• All subject data relating to the study will be recorded on printed or CRFs unless transmitted 
to the Sponsor or designee electronically (eg, laboratory data). The Investigator is responsible 
for verifying that data entries are accurate and correct by physically or electronically signing 
the CRF. 
• The Investigator must maintain accurate documentation (source data) that supports the 
information entered in the CRF. 
• The Investigator must permit study-related monitoring, audits, IRB review, and regulatory 
agency inspections and provide direct access to source data documents. 
• The Sponsor or designee is responsible for the data management of this study including 
quality checking of the data. 
• Study monitors will perform ongoing source data verification to confirm that data entered 
into the CRF by authorized study center personnel are accurate, complete, and verifiable 
from source documents; that the safety and rights of subjects are being protected; and that the 
study is being conducted in accordance with the currently approved protocol and any other 
study agreements, ICH GCP, and all applicable regulatory requirements. 
• Records and documents, including signed ICFs, pertaining to the conduct of this study must 
be retained by the Investigator for 15 years after study completion unless local regulations or 
institutional policies require a longer retention period. No records may be destroyed during 
the retention period without the written approval of the Sponsor. No records may be 
transferred to another location or party without written notification to the Sponsor. 
Source Documents 
The Investigator/institution should maintain adequate and accurate source documents and study 
records that include all pertinent observations on each of the study center’s subjects. Source data 
should be attributable, legible, contemporaneous, original, accurate, and complete. Changes to 


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source data should be traceable, should not obscure the original entry, and should be explained if 
necessary (eg, via an audit trail). 
• Source documents provide evidence for the existence of the subject and substantiate the 
integrity of the data collected. Source documents are filed at the Investigator’s study center. 
• Data reported on the CRF or entered in the CRF that are transcribed from source documents 
must be consistent with the source documents or the discrepancies must be explained. The 
Investigator may need to request previous medical records or transfer records, depending on 
the study. Also, current medical records must be available. 
• Source documents will include, but are not limited to, screening logs, questionnaires and 
forms completed by the clinical staff and the subjects, or their parent or guardian. 
Study and Study Center Closure 
The Sponsor designee reserves the right to close the study center or terminate the study at any 
time for any reason at the sole discretion of the Sponsor. Study centers will be closed upon study 
completion. A study center is considered closed when all required documents and study supplies 
have been collected and a study center closure visit has been performed. 
The Investigator may initiate study center closure at any time, provided there is reasonable cause 
and sufficient notice is given in advance of the intended termination. 
Reasons for the early closure of a study center by the Sponsor or Investigator may include but 
are not limited to: 
• Failure of the Investigator to comply with the protocol, the requirements of the IRB or local 
health authorities, the Sponsor’s procedures, or GCP guidelines. 
• Inadequate recruitment of subjects by the Investigator. 
• Discontinuation of further study treatment development. 
Publication Policy 
The data generated by this study are confidential information of the Sponsor. The Sponsor will 
make the results of the study publicly available. The publication policy with respect to the 
Investigator and study center will be set forth in the Clinical Trial Agreement. 
• The results of this study may be published or presented at scientific meetings. If this is 
foreseen, the Investigator agrees to submit all manuscripts or abstracts to the Sponsor before 
submission. This allows the Sponsor to protect proprietary information and to provide 
comments. 
• The Sponsor will comply with the requirements for publication of study results. In 
accordance with standard editorial and ethical practice, the Sponsor will generally support 
publication of multicenter studies only in their entirety and not as individual study center 
data. In this case, a Coordinating Investigator will be designated by mutual agreement. 


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• Authorship will be determined by mutual agreement and in line with International Committee 
of Medical Journal Editors authorship requirements. 


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Appendix 3 
Adverse Events: Definitions and Procedures for Recording, 
Evaluating, Follow-up, and Reporting 
Definition of AE 
AE Definition 
• 
An AE is any untoward medical occurrence in a patient or subject, temporally associated with the use 
of study treatment, whether or not considered related to the study treatment. 
• 
NOTE: An AE can therefore be any unfavorable and unintended sign (including an abnormal 
laboratory finding), symptom, or disease (new or exacerbated) temporally associated with the use of 
study treatment. 
 
Events Meeting the AE Definition  
• 
Any abnormal laboratory test results (hematology, clinical chemistry, or urinalysis) or other safety 
assessments (eg, electrocardiogram, radiological scans, and vital signs measurements), including those 
that worsen from Baseline, considered clinically significant in the medical and scientific judgment of 
the Investigator (ie, not related to progression of underlying disease). 
• 
Exacerbation of a chronic or intermittent pre-existing condition including either an increase in 
frequency and/or intensity of the condition. 
• 
New conditions detected or diagnosed after study treatment administration even though it may have 
been present before the start of the study. 
• 
Signs, symptoms, or the clinical sequelae of a suspected drug-drug interaction. 
• 
Signs, symptoms, or the clinical sequelae of a suspected overdose of either study treatment or a 
concomitant medication. Overdose per se will not be reported as an AE/SAE unless it is an intentional 
overdose taken with possible suicidal/self-harming intent. Such overdoses should be reported 
regardless of sequelae. 
 
Events NOT Meeting the AE Definition  
• 
Any clinically significant abnormal laboratory findings or other abnormal safety assessments which are 
associated with the underlying disease, unless judged by the Investigator to be more severe than 
expected for the subject’s condition. 
• 
The disease/disorder being studied or expected progression, signs, or symptoms of the disease/disorder 
being studied, unless more severe than expected for the subject’s condition. 
• 
Medical or surgical procedure (eg, endoscopy, and appendectomy): the condition that leads to the 
procedure is the AE. 
• 
Situations in which an untoward medical occurrence did not occur (social and/or convenience 
admission to a hospital). 
• 
Anticipated day-to-day fluctuations of pre-existing disease(s) or condition(s) present or detected at the 
start of the study that do not worsen. 
 


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Definition of SAE 
If an event is not an AE per definition above, then it cannot be an SAE even if serious conditions 
are met (eg, hospitalization for signs/symptoms of the disease under study, death due to 
progression of disease). 
An SAE is defined as any untoward medical occurrence that, at any dose: 
a) Results in death. 
b) Is life-threatening 
The term ‘life-threatening’ in the definition of “serious” refers to an event in which the subject was at risk 
of death at the time of the event. It does not refer to an event, which hypothetically might have caused 
death, if it were more severe. 
c) Requires inpatient hospitalization or prolongation of existing hospitalization 
In general, hospitalization signifies that the subject has been detained (usually involving at least an 
overnight stay) at the hospital or emergency ward for observation and/or treatment that would not have 
been appropriate in the physician’s office or outpatient setting. Complications that occur during 
hospitalization are AEs. If a complication prolongs hospitalization or fulfills any other serious criteria, the 
event is serious. When in doubt as to whether “hospitalization” occurred or was necessary, the AE should 
be considered serious. 
Hospitalization for elective treatment of a pre-existing condition that did not worsen from Baseline is not 
considered an AE. 
d) Results in persistent disability/incapacity 
• 
The term disability means a substantial disruption of a person’s ability to conduct normal life 
functions. 
• 
This definition is not intended to include experiences of relatively minor medical significance such as 
uncomplicated headache, nausea, vomiting, diarrhea, influenza, and accidental trauma (eg, sprained 
ankle) which may interfere with or prevent everyday life functions but do not constitute a substantial 
disruption. 
e) Is a congenital anomaly/birth defect 
f) 
Other (important medical events): 
• 
Medical or scientific judgment should be exercised in deciding whether SAE reporting is appropriate 
in other situations such as important medical events that may not be immediately life-threatening or 
result in death or hospitalization but may jeopardize the subject or may require medical or surgical 
intervention to prevent 1 of the other outcomes listed in the above definition. These events should 
usually be considered serious. 
Examples of such events include invasive or malignant cancers, intensive treatment in an emergency 
room or at home for allergic bronchospasm, blood dyscrasias or convulsions that do not result in 
hospitalization, or development of drug dependency or drug abuse. 


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Recording and Follow-up of AE and/or SAE 
AE and SAE Recording 
• 
When an AE/SAE occurs, it is the responsibility of the Investigator to review all documentation (eg, 
hospital progress notes, laboratory reports, and diagnostics reports) related to the event. 
• 
The Investigator or designee will then record all relevant AE/SAE information in the CRF. Each event 
must be recorded separately. 
• 
It is not acceptable for the Investigator to send photocopies of the subject’s medical records in lieu of 
completion of the AE/SAE CRF page. 
• 
There may be instances when copies of medical records for certain cases are requested by the Sponsor. 
In this case, all subject identifiers, with the exception of the subject number, will be redacted on the 
copies of the medical records before submission to the Sponsor. 
• 
The Investigator will attempt to establish a diagnosis of the event based on signs, symptoms, and/or 
other clinical information. Whenever possible, the diagnosis (not the individual signs/symptoms) will 
be documented as the AE/SAE. 
Assessment of Intensity 
The Investigator will make an assessment of intensity for each AE and SAE reported during the study and 
assign it to 1 of the following categories: 
• 
Mild: An event that is easily tolerated by the subject, causing minimal discomfort and not interfering 
with everyday activities. 
• 
Moderate: An event that causes sufficient discomfort and interferes with normal everyday activities. 
• 
Severe: An event that prevents normal everyday activities. An AE that is assessed as severe should not 
be confused with an SAE. Severe is a category utilized for rating the intensity of an event; and both 
AEs and SAEs can be assessed as severe. 
An event is defined as ‘serious’ when it meets at least 1 of the predefined outcomes as described in the 
definition of an SAE, NOT when it is rated as severe. 
 
Assessment of Causality 
• 
The Investigator is obligated to assess the relationship between study treatment and each occurrence of 
each AE/SAE. The AE must be characterized as unrelated, unlikely to be related, or possibly related. 
o 
“Unrelated” is used if there is not a reasonable possibility that the study treatment caused the 
AE. 
o 
“Unlikely to be related” suggests that only a remote connection exists between the study 
treatment and the AE. Other conditions, including chronic illness, progression or expression 
of the disease state or reaction to concomitant therapy, appear to explain the reported AE. 
o 
“Possibly related” suggests that the association of the AE with the study treatment is 
unknown; however, the AE is not reasonably supported by other conditions. 
o 
“Probably related” conveys that there are facts, evidence, and/or arguments to suggest a 
causal relationship, rather than a relationship cannot be ruled out. 
• 
The Investigator will use clinical judgment to determine the relationship. 
• 
Alternative causes, such as underlying disease(s), concomitant therapy, and other risk factors, as well 
as the temporal relationship of the event to study treatment administration will be considered and 
investigated. 
• 
The Investigator will also consult the Investigator’s Brochure and/or Product Information, for 
marketed products, in his/her assessment. 


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• 
For each AE/SAE, the Investigator must document in the medical notes that he/she has reviewed the 
AE/SAE and has provided an assessment of causality. 
• 
There may be situations in which an SAE has occurred and the Investigator has minimal information to 
include in the initial report to the Sponsor. However, it is very important that the Investigator always 
make an assessment of causality for every event before the initial transmission of the SAE data to the 
Sponsor. 
• 
The Investigator may change his/her opinion of causality in light of follow-up information and send a 
SAE follow-up report with the updated causality assessment. 
• 
The causality assessment is one of the criteria used when determining regulatory reporting 
requirements. 
 
Follow-up of AEs and SAEs 
• 
The Investigator is obligated to perform or arrange for the conduct of supplemental measurements 
and/or evaluations as medically indicated or as requested by the Sponsor to elucidate the nature and/or 
causality of the AE or SAE as fully as possible. This may include additional laboratory tests or 
investigations, histopathological examinations, or consultation with other health care professionals. 
• 
New or updated information will be recorded in the originally completed CRF. 
• 
The Investigator will submit any updated SAE data to the Sponsor within 24 hours of receipt of the 
information. 
 
Reporting of SAEs 
SAE Reporting via Paper SAE form 
• 
Reporting will be via paper as standard for the site. This will be using Novella template reporting form. 
• 
To report a Safety Event, please contact the main Safety Management phone/fax/email (or your 
applicable country specific toll-free numbers): 
Phone:  919.313.7111 (US Toll-free: 1-866-758-2798) 
Fax:  919.313.1412 (US Toll-free: 1-866-761-1274) 
Email:  Safety-Inbox@novellaclinical.com 


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Appendix 4 
Excluded Medications/Therapy 
Excluded medication/therapy is listed below. The use of an excluded medication/therapy is a 
protocol violation and must be recorded in the CRF. 
Within 4 weeks prior to Baseline 
• Systemic immunosuppressive/immunomodulating drugs (ie, methotrexate, cyclosporine, etc). 
• Immunoglobulin or blood products. 
Within 2 weeks prior to Baseline 
• High, or mid or low -potency topical corticosteroids. The use of inhaled or intranasal 
corticosteroids will be alloweda. 
• Systemic anti-inflammatory products. 
• Use of crisaborole ointment. 
• Systemic antibiotics. 
• Bleach baths or topical coal tar. 
• Topical calcineurin inhibitor use. 
• New onset use of systemic antihistamines. 
• Topical antihistamines. 
• The use of intranasal antihistamines will be alloweda. 
a Subjects following stable regimens (≥2 weeks consistent use before study baseline) with systemic antihistamines 
or oral corticosteroids are permitted to continue use but should not alter the dose or stop the regimen while in the 
study within 1 week prior to Baseline. 
Biologics 
• Cell-depleting agents, including but not limited to rituximab: within 6 months of baseline. 
• Infliximab, adalimumab, golimumab, certolizumab pegol, abatacept, etanercept, anakinra, 
and dupilumab: within 12 weeks of baseline, or 5 half-lives, whichever is longer. 
• Other biologics: within 12 weeks of Baseline, or 5 half-lives (if known), whichever is longer. 


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Appendix 5 
Contraceptive Guidance and Collection of Pregnancy 
Information 
Definitions: 
Contraception Guidance 
Male subjects 
• Male subjects with female partners of childbearing potential are eligible to participate if they 
agree to ONE of the following [during the protocol-defined time frame in Section 5.1]: 
- Are abstinent from penile-vaginal intercourse and agree to remain abstinent for 
duration of study and for 3 months after the final study treatment days. 
- Agree to use a male condom and have their partner use of a contraceptive method 
with a failure rate of <1% per year as described in the table below when having 
penile-vaginal intercourse with a female. 
• In addition, male subjects must refrain from donating sperm for the duration of the study and 
for 3 months after the last dose of study treatment. 
• Male subjects with a pregnant or breastfeeding partner must agree to remain abstinent from 
penile-vaginal intercourse or use a male condom during each episode of penile penetration 
during the protocol-defined time frame. 
Female subjects 
Female subjects of childbearing potential are eligible to participate if they practice abstinence or 
agree to use a highly effective method of contraception consistently and correctly as described in 
the table below. 


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Highly Effective Contraceptive Methods 
Highly Effective Contraceptive Methods That Are User Dependent a 
Failure rate of <1% per year when used consistently and correctly.  
Sexual Abstinence 
Sexual abstinence is considered a highly effective method only if defined as refraining from heterosexual 
intercourse during the entire period of risk associated with the study treatment. The reliability of sexual abstinence 
needs to be evaluated in relation to the duration of the study and the preferred and usual lifestyle of the subject. 
Combined (estrogen and progestogen containing) hormonal contraception associated with inhibition of ovulationb 
• 
Oral. 
• 
Intravaginal. 
• 
Transdermal. 
Progestogen only hormonal contraception associated with inhibition of ovulation 
• 
Oral. 
• 
Injectable. 
Highly Effective Methods That Are User Independent a  
Implantable progestogen only hormonal contraception associated with inhibition of ovulationb 
• 
Intrauterine device (IUD). 
• 
Intrauterine hormone-releasing system (IUS). 
• 
Bilateral tubal occlusion. 
Vasectomized Partner 
A vasectomized partner is a highly effective birth control method provided that the partner is the sole male sexual 
partner of the Women of child-bearing potential and the absence of sperm has been confirmed. If not, an additional 
highly effective method of contraception should be used. 
NOTES: 
a Typical use failure rates may differ from those when used consistently and correctly. Use should be consistent with 
local regulations regarding the use of contraceptive methods for subjects participating in clinical studies. 
b Hormonal contraception may be susceptible to interaction with the study treatment, which may reduce the efficacy 
of the contraceptive method. Females must either practice abstinence from heterosexual contact or use one (1) of the 
highly effective contraceptive options described in the Appendix 5.  Females are not required to use two (2) highly 
effective methods of contraception. 
 
 
Pregnancy Testing: 
Pregnancy testing (urine) will be performed at times shown in Table 1.1 for all female subjects 
≥11 years, or female patients <11 years old who have started menstruating. 


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Collection of Pregnancy Information 
Male subjects with partners who become pregnant 
• After obtaining the necessary signed informed consent from the pregnant female partner 
directly, the Investigator will record pregnancy information on the appropriate form and 
submit it to the Sponsor within 24 hours of learning of the partner’s pregnancy. The female 
partner will also be followed to determine the outcome of the pregnancy. Information on the 
status of the mother and child will be forwarded to the Sponsor. Generally, the follow-up will 
be no longer than 6 to 8 weeks following the estimated delivery date. Any termination of the 
pregnancy will be reported regardless of fetal status (presence or absence of anomalies) or 
indication for the procedure. 
Female Subjects who become pregnant 
• The Investigator will collect pregnancy information on any female subject who becomes 
pregnant while participating in this study. Information will be recorded on the appropriate 
form and submitted to the Sponsor within 24 hours of learning of a subject’s pregnancy. The 
subject will be followed to determine the outcome of the pregnancy. The Investigator will 
collect follow-up information on the subject and the neonate and the information will be 
forwarded to the Sponsor. Generally, follow-up will not be required for longer than 6 to 
8 weeks beyond the estimated delivery date. Any termination of pregnancy will be reported, 
regardless of fetal status (presence or absence of anomalies) or indication for the procedure. 
• While pregnancy itself is not considered to be an AE or SAE, any pregnancy complication or 
elective termination of a pregnancy will be reported as an AE or SAE. A spontaneous 
abortion is always considered to be an SAE and will be reported as such. 
• Any post study pregnancy related SAE considered reasonably related to the study treatment 
by the Investigator will be reported to the Sponsor as described in Section 9.5.4. While the 
Investigator is not obligated to actively seek this information in former subjects, he or she 
may learn of an SAE through spontaneous reporting. 
• Any female subject who becomes pregnant while participating in the study will discontinue 
study treatment. 
 
 


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Appendix 6 
Body Surface Area and Investigational Medicinal Product 
Application 
 
 


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Appendix 7 
Signature of Investigator 
PROTOCOL TITLE: An open-label, multicenter, Phase Ib study of B244 delivered as a topical 
spray to assess safety in pediatric subjects aged 2 to 17 years with atopic dermatitis  
PROTOCOL NO: 
ADB244-002  
VERSION:  
 
Amendment 1 
This protocol is a confidential communication of [Sponsor]. I confirm that I have read this 
protocol, I understand it, and I will work according to this protocol. I will also work consistently 
with the ethical principles that have their origin in the Declaration of Helsinki and that are 
consistent with GCP and the applicable laws and regulations. Acceptance of this document 
constitutes my agreement that no unpublished information contained herein will be published or 
disclosed without prior written approval from the Sponsor. 
Instructions to the Investigator: Please SIGN and DATE this signature page. PRINT your name, title, and the name of the study 
center in which the study will be conducted. Return the signed copy to [Sponsor or CRO]. 
 
I have read this protocol in its entirety and agree to conduct the study accordingly: 
 
Print Name 
 
Title 
 
Address of Institution / 
Site: 
__________________________________________________ 
__________________________________________________ 
__________________________________________________ 
__________________________________________________ 
Telephone Number: 
 
Investigator Signature: _______________________________ Date: _______________ 
 
 


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SAP_001.pdf: 
NCT03775434


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Table of Contents 
Table of Contents ...........................................................................................................................2
List of Abbreviations and Definitions of Terms ..........................................................................4
1. STUDY SYNOPSIS ...............................................................................................................5
2. INTRODUCTION ..................................................................................................................9
3. STUDY OBJECTIVES ..........................................................................................................9
4. STUDY DESIGN ....................................................................................................................9
5. HARDWARE AND SOFTWARE ......................................................................................10
6. DATABASE CLOSURE .....................................................................................................10
7. RANDOMIZATION ............................................................................................................10
8. SAMPLE SIZE DETERMINATION .................................................................................11
9. ANALYSIS POPULATIONS .............................................................................................11
10. HANDLING OF MISSING DATA ....................................................................................11
11. INTERIM ANALYSIS ........................................................................................................11
12. DATA CONVENTIONS FOR ANALYSIS .......................................................................12
12.1General Statistical Principles ..............................................................................................12
12.2Study Day ..............................................................................................................................12
12.3Baseline and Change from Baseline ...................................................................................12
12.4Analysis Visit Window .........................................................................................................12
13. STATISTICAL EVALUATION .........................................................................................12
13.1Subject Disposition ...............................................................................................................12
13.2Protocol Deviation ................................................................................................................13
13.3Demographic and Baseline Characteristics .......................................................................13
13.4Study Medication Exposure and Compliance ...................................................................13
13.5Prior and Concomitant Medications ..................................................................................14
13.6Medical History and Concurrent Procedures ...................................................................15
13.7Efficacy Endpoints ...............................................................................................................15
13.8Efficacy Analyses .................................................................................................................16
13.9Safety Analyses .....................................................................................................................16
13.9.1
Adverse Events ...........................................................................................................16
13.9.2
Clinical Laboratory Testing ......................................................................................17
13.9.3
Vital Signs ...................................................................................................................17


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13.9.4
Physical Examination ................................................................................................18
14. CHANGES FROM THE PROTOCOL AND PLANNED ANALYSES .........................18
15. FORMATTING ....................................................................................................................18
16. ARCHIVING AND RETENTION OF DOCUMENTS ....................................................18
17. OUTLINE OF PROPOSED TABLES, LISTINGS AND FIGURES ..............................19
 


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Protocol No. ADB244-002 
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IQVIA Biotech No. BZA46494                                                                                             SAP version 1.0 
List of Abbreviations and Definitions of Terms 
Abbreviation 
Definition 
ADaM 
Analysis dataset model 
AE 
Adverse event 
ATC 
Anatomical Therapeutic Chemical Classification System 
BMI 
Body mass index 
BSA 
Body surface area 
EASI 
Eczema Area Severity Index 
eCRF 
Electronic Case Report Form 
EOS 
End of study 
ETV 
Early termination visit 
ITT 
Intent To Treat 
vIGA-AD 
Validated Investigator Global Assessment for Atopic Dermatitis 
IP 
Investigational product 
MedDRA 
Medical Dictionary for Regulatory Activities 
POEM 
Patient Oriented Eczema Measure 
PP 
Per protocol 
PT 
Preferred Term 
SAE 
Serious adverse event 
SAP 
Statistical analysis plan 
SD 
Standard deviation 
SDTM 
Study data tabulation model 
SOC 
System Organ Class 
TEAE 
Treatment-emergent adverse event 


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Protocol No. ADB244-002 
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IQVIA Biotech No. BZA46494                                                                                             SAP version 1.0 
1. STUDY SYNOPSIS 
Protocol Title: An open-label, multicenter, Phase Ib study of B244 delivered as a topical spray 
to assess safety in pediatric subjects aged 2 to 17 years with atopic dermatitis 
Rationale: 
Clinical studies with topical administration of B244 have been conducted in subjects with acne, 
hypertension, atopic dermatitis, and rosacea. There have been no safety signals observed to date. 
The aim of this study is to assess the safety of B244 in pediatric subjects aged 2 to 17 years with 
atopic dermatitis. 
Objectives and Endpoints 
Objectives 
Endpoints 
Primary 
 
x 
Assessment of the safety and tolerability of B244 
in pediatric subjects with atopic dermatitis. 
x 
Incidence of treatment-emergent adverse events 
(TEAEs).  
x 
Change from Baseline in physical examination at 
each post baseline visit. 
x 
Change from Baseline in vital signs at each 
post baseline visit. 
Exploratory 
 
x 
Efficacy of B244 on signs and symptoms of atopic 
dermatitis. 
 
 
 
 
x 
Efficacy of B244 on patient oriented measure of 
atopic dermatitis. 
 
 
x 
Efficacy of B244 on patient reported assessment of 
atopic dermatitis. 
x 
Changes from Baseline to post baseline visits in: 
 
Validated Investigator Global Assessment for 
Atopic Dermatitis (vIGA-AD) scale. 
 
Area Severity Index (EASI) score and each 
component of EASI from Baseline to 
post baseline visits. 
 
x 
Changes is Patient Oriented Eczema Measure 
(POEM total score and each of the 7 components) 
from Baseline to post baseline visits. 
 
x 
Changes in patient reported outcome (self-reported 
ItchMan questionnaire).from Baseline to 
post baseline visits. 
 
Overall Design: 
This is a Phase 1b, open-label, multiple site study assessing twice daily B244 application for 28 
days in pediatric subjects with atopic dermatitis. 
The study will enroll approximately 36 subjects in 3 cohorts of 12 subjects: 


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Protocol No. ADB244-002 
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IQVIA Biotech No. BZA46494                                                                                             SAP version 1.0 
• 
Cohort 1: subjects aged 2 to 5 years. 
• 
Cohort 2: subjects aged 6 to 11 years. 
• 
Cohort 3: subjects aged 12 to 17 years. 
Number of Investigators and Study Centers: 
Approximately 6 Investigators and study centers are expected to participate in this study. 
Number of Subjects: 
The study will enroll approximately 36 subjects in 3 cohorts of 12 subjects: 
• 
Cohort 1: subjects aged 2 to 5 years. 
• 
Cohort 2: subjects aged 6 to 11 years. 
• 
Cohort 3, subjects aged 12 to 17 years. 
Treatment Groups and Duration: 
Subjects will attend a Screening visit between Days -21 and -14. If all eligibility criteria and 
none of the exclusion criteria are met, subjects will be enrolled into the study and will be 
required to undergo a 14 day washout period (Days-14 to -1). Subjects will attend the study 
center on Day 1 (-1 to 1) and the Baseline assessments will be performed before application of 
the first dose. On confirmation of continued eligibility the subject and parent or guardian of the 
subject will be coached on how to apply medication, depending on the affected areas. They will 
be instructed to apply B244 twice daily (approximately 12 hours apart) for 28 days. The first 
dose will be applied in the clinic under the supervision of clinical staff. Details of dose 
administration will be recorded in the study diary provided. 
The subjects with their parent or guardian will return to the study center on Days 7, 14, and 21 
for completion of study assessments. There will be a final study visit on Day 28, this will be 
defined as the end of the study for the subjects. A time window of ±2 day will be permitted for 
these 4 visits. There will not be a period of confinement in the study center all visits will be 
outpatient visits. 
Safety monitoring will include review of TEAEs, vital signs and physical examination. 
Efficacy will be assessed using EASI, vIGA-AD scale, POEM and ItchMan scores. 
Statistical Methods: 
All subjects who are enrolled and take at least 1 dose of study treatment will be included in the 
Intent to Treat (ITT) population. The ITT population will be the primary population for safety 
and efficacy assessments. 


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Protocol No. ADB244-002 
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IQVIA Biotech No. BZA46494                                                                                             SAP version 1.0 
All subjects in the ITT population without any protocol deviations that may have an impact on 
the efficacy assessments will be included in the Per Protocol (PP) population. The PP population 
will be the supportive population for efficacy assessments. 
The sample size is not based on statistical considerations but is typical for studies of this nature 
and is considered adequate to characterize the distribution of the planned endpoints. Any 
statistical testing will be considered exploratory and descriptive. 
Data Monitoring Committee: No 
Table Error! No text of specified style in document..1 
Schedule of Assessments 
Visit Name 
Screening 
Washout 
Baseline
(Day 1) 
Day 
7 
Day 
14 
Day 
21 
Day 28 
Final 
Visit 
Early 
Termination 
Visit 
 
Study Center Visit 
1 
 
2 
3 
4 
5 
6 
 
Visit Window in 
Days 
-21 to -14 
-14 to -1 
-1 to 1 
±2 
±2 
±2 
±2 
 
Informed Consent 
X 
 
 
 
 
 
 
 
Inclusion/Exclusion 
Criteria 
O 
 
X 
 
 
 
 
 
Demographics 
O 
 
 
 
 
 
 
 
Medical History 
O 
 
 
 
 
 
 
 
Hanifin and Rajka 
Criteria 
X 
 
X 
 
 
 
 
 
Physical Examination 
X 
 
O 
O 
O 
O 
X 
X 
Urine Pregnancy 
Test1 
X 
 
X 
 
 
 
X 
X 
Body Weight 
X 
 
 
 
 
 
X 
X 
Height 
X 
 
 
 
 
 
X 
X 
Vital Signs2 
X 
 
X 
X 
X 
X 
X 
X 
Validated 
Investigator Global 
Assessment for 
Atopic Dermatitis 
(vIGA-AD) Scale 
X 
 
X 
X 
X 
X 
X 
X 
Eczema Area 
Severity Index 
X 
 
X 
X 
X 
X 
X 
X 


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Protocol No. ADB244-002 
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IQVIA Biotech No. BZA46494                                                                                             SAP version 1.0 
Visit Name 
Screening 
Washout 
Baseline
(Day 1) 
Day 
7 
Day 
14 
Day 
21 
Day 28 
Final 
Visit 
Early 
Termination 
Visit 
 
Study Center Visit 
1 
 
2 
3 
4 
5 
6 
 
Visit Window in 
Days 
-21 to -14 
-14 to -1 
-1 to 1 
±2 
±2 
±2 
±2 
 
(EASI) 
Patient Oriented 
Measure (POEM)3 
X 
 
X 
X 
X 
X 
X 
X 
ItchMan 
Questionnaire 
X 
 
X 
X 
X 
X 
X 
X 
Dispense 
Investigational 
Product to Subject4 
 
 
X 
O 
X 
O 
 
 
Investigational 
Product Application5 
 
 
O 
O 
X 
O 
X 
 
Collect 
Investigational 
Product from 
Subject6 
 
 
 
O 
X 
O 
X 
 
Investigational 
Product Compliance6 
 
 
 
O 
X 
O 
X 
X 
Counseling7 
 
 
X 
O 
X 
O 
 
 
Study Cleanser8 
X 
X 
X 
X 
X 
X 
O 
X 
Moisturizer8 
X 
X 
X 
X 
X 
X 
O 
X 
Study Diary9 
 
 
X 
X 
X 
X 
O 
X 
Adverse Events 
Recording10 
X 
X 
X 
O 
X 
O 
X 
X 
Concomitant 
Medications 
O 
 
X 
O 
X 
O 
X 
X 

1. Urine pregnancy test will be administered to females 11 years of age or older. 
2. Pulse rate, temperature and blood pressure will be obtained. Subject should be allowed to rest for >5 minutes 
sitting, then a single blood pressure and pulse rate measurement will be performed, using the non-dominant arm 
with a calibrated electronic sphygmomanometer. 
3. Patient Oriented Measure questionnaire is to be filled out by the subject or the parent or guardian. 


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IQVIA Biotech No. BZA46494                                                                                             SAP version 1.0 
4. At Baseline, depending on the age of the participant, 1 or 2 bottles will be supplied. Total number of bottles to be 
dispensed to the subjects for the duration of the study will depend upon the body surface area affected by atopic 
dermatitis. At each visit, study staff will determine each subject’s usage and supply additional investigational 
product if necessary. 
5. The first investigational product application will happen in the study center under clinical staff supervision after 
completion of the baseline assessments. Subjects and parent or guardian will be coached on how to apply the 
study treatment depending on the affected area and will be asked to apply the study treatment twice daily. 
6. Weight of an investigational product kit will be obtained at the at the Baseline visit. Study staff will be asked to 
weigh dispensed bottles PRE FIRST DOSE. Weight will be recorded in grams. Subjects will be asked to bring 
their bottles back for every visit. Upon return for the study visit, bottles will be weighed again. 
7. Subjects will be counseled on the use of the study treatment, study diary and any questions the subject, parent or 
guardian may have will be answered. 
8. The Sponsor will provide a biome friendly, preservative-free moisturizer and cleanser to be used as needed, at 
the discretion of the parent or guardian. Any remaining moisturizer or cleanser will be returned to the 
Investigator at the Final Visit (Day 28) or the Early Termination Visit. 
9. The subject, parent or guardian will be asked to fill out a daily study diary. 
10. Adverse events will be monitored throughout the trial, starting with the time informed consent form has been 
signed. 
2. INTRODUCTION 
This Statistical Analysis Plan (SAP) is based on the study Protocol Amendment 1 dated  
February 25, 2019 .   
This document provides additional details concerning the statistical analyses outlined in the 
protocol and reflects any changes to the protocol from any amendments. This plan will not repeat 
all the definitions given in the protocol but will provide further details of the summaries and 
analyses planned therein.     
3. STUDY OBJECTIVES 
The primary objectives:  
x To assess the safety and tolerability of B244 in pediatric subjects with atopic dermatitis. 
The exploratory objectives: 
x To assess the efficacy of B244 on signs and symptoms of atopic dermatitis. 
x To assess the efficacy of B244 on patient oriented measure of atopic dermatitis. 
x To assess the efficacy of B244 on patient reported assessment of atopic dermatitis. 
4. STUDY DESIGN 
This is a Phase 1b, open-label, multiple site study assessing twice daily B244 application for 
28 days in pediatric subjects with atopic dermatitis. 


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Protocol No. ADB244-002 
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IQVIA Biotech No. BZA46494                                                                                             SAP version 1.0 
The study will enroll approximately 36 subjects in 3 cohorts of 12 subjects: 
x Cohort 1: subjects aged 2 to 5 years. 
x Cohort 2: subjects aged 6 to 11 years. 
x Cohort 3: subjects aged 12 to 17 years. 
At Screening and Baseline, all subjects must have confirmed diagnosis of atopic dermatitis, as 
defined by the Hanifin and Rajka criteria, which involves a minimum of 10% but no more than 
60% body surface area and a Validated Investigator Global Assessment for Atopic Dermatitis 
(vIGA-AD) scale of 2 or 3. 
Subjects will attend a Screening visit between Day -21 and -14. If all eligibility criteria and none 
of the exclusion criteria are met, subjects will be enrolled into the study and will be required to 
undergo a 14 day washout period (Day-14 to -1). After that, subjects will be assigned to one of 
the cohorts based on their age. 
Subjects will attend the study center on Day 1 where the first dose will be administered and the 
Baseline assessments will be conducted. Subject and parent or guardian of the subject will be 
instructed to apply B244 twice daily (approximately 12 hours apart) for 28 days and record the 
details of the application in the study diary provided. They will return to the study center on 
Days 7, 14, 21 and end of the study (EOS) on Day 28. Subjects who do not complete all required 
study visits and withdraw from the study before Day 28 final visit, will be asked to complete the 
ETV (Early Termination Visit). 
5. HARDWARE AND SOFTWARE 
Statistical analysis will be performed following IQVIA Biotech standard operating procedures 
and on the IQVIA Biotech computer network. All statistical analysis will be performed using 
SAS Version 9.3 or higher with program code prepared specifically for the project by qualified 
IQVIA Biotech statisticians and SAS programmers. 
6. DATABASE CLOSURE 
After completion of all data review and cleaning procedures and approval of the sponsor, the 
clinical database will be closed. Any change to the clinical database after this time will require 
written authorization, with explanation, by the Sponsor and the Biostatistician.   
7. RANDOMIZATION 
Not applicable as this is an open-label study. 


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IQVIA Biotech No. BZA46494                                                                                             SAP version 1.0 
8. SAMPLE SIZE DETERMINATION 
The sample size is not based on statistical considerations but on the desire for each cohort to 
obtain adequate safety and tolerability data to achieve the objectives of the study while exposing 
as few subjects as possible to B244 and study procedures.  
No formal statistical hypothesis testing is planned for this study. All statistical analyses will be 
considered exploratory and descriptive. 
9. ANALYSIS POPULATIONS 
The following analysis sets/populations will be used in this trial: 
x ITT population: All subjects who are enrolled and take at least 1 dose of study cohort will 
be included in the Intent to Treat (ITT) population. The ITT population will be the 
primary population for safety and efficacy assessments. 
x Per Protocol (PP) population: All subjects in the ITT population without any protocol 
deviations that may have an impact on the efficacy assessments will be included in the 
Per Protocol (PP) population. The PP population will be the supportive population for 
efficacy assessments. Major protocol violations will include but not be restricted to the 
following: 
 Failure to meet the inclusion/exclusion criteria 
 Usage of any prohibited concomitant medications or procedures 
 Failure to be compliant with treatment regimen 
 Non-compliance with study drug application (applied <50% of the total number of 
expected applications) 
Additional criteria may be added to determine PP population.  
10. HANDLING OF MISSING DATA  
No imputation will be used.  
11. INTERIM ANALYSIS 
No interim analysis is planned. 


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Protocol No. ADB244-002 
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IQVIA Biotech No. BZA46494                                                                                             SAP version 1.0 
12. DATA CONVENTIONS FOR ANALYSIS 
12.1 
General Statistical Principles 
All observed and derived variables (e.g., change from baseline, percentage change from baseline, 
response status) used in the summaries of analyses will be presented in by-cohort and by-subject 
listings. Descriptive statistics will be used to provide an overview of the efficacy and safety 
results. For categorical parameters, the number and percentage of subjects in each category will 
be presented. The denominator for percentage will be based on the number of subjects 
appropriate for the purpose of analysis. For continuous parameters, descriptive statistics will 
include number of subjects (n), mean, standard deviation (SD), median, minimum (min), and 
maximum (max). 
12.2 
Study Day 
Day 1 is defined as the date of first study drug application. Study day is calculated relative to the 
date of Day 1. 
12.3 
Baseline and Change from Baseline 
Baseline value is defined as the last non-missing value prior to the first dose of study drug. 
Change from baseline is defined as: post-baseline value – baseline value.   
12.4 
Analysis Visit Window 
Where applicable, all efficacy and safety data will be analyzed according to the nominal study 
visits, for Baseline/Day 1, Day 7, Day 14, Day 21, Day 28 (excluding ETV), and EOS (including 
Day 28 and ETV).  
13. STATISTICAL EVALUATION  
13.1 
Subject Disposition 
The number and percentage of subjects screened, enrolled, included in each analysis population, 
completing the study, withdrawing from the study (together with the reasons for withdrawal), 
and subjects excluded from PP population (together with the reasons for exclusion) will be 
summarized using frequencies and percentages by Cohort and overall. A by-cohort and by-
subject listing will be presented for all subject enrollment and disposition. Screen failures will 
also be presented in by-cohort and by-subject listings.  


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IQVIA Biotech No. BZA46494                                                                                             SAP version 1.0 
13.2 
Protocol Deviation 
Protocol deviations will be logged into the IL2 database and displayed in a by-cohort and by-
subject listing.  
13.3 
Demographic and Baseline Characteristics 
Demographics and baseline characteristics will be summarized overall and by cohort and overall 
for the ITT and PP populations. The following demographic and baseline variables will be 
included:  
x Age 
x Gender 
x Race 
x Ethnicity 
x Weight 
x Height 
x BMI 
x Total Body Surface Area 
x Baseline vIGA-AD scale 
13.4 
Study Medication Exposure and Compliance 
Subjects will apply IP B244 suspension twice a day approximately 12 hours apart, for 28 days 
(Day 1 to 28) and record the date of each trial medication application in the subject diary. The 
Med ID (kit number), the corresponding date dispensed and returned will be recorded, the weight 
of the IP for each bottle in grams pre- and post-application at each visit will also be collected. 
The Investigator will review the completed subject diary and record number of missed 
applications at each visit.  
The following exposure and compliance parameters will be summarized for the ITT population 
by cohort and overall using descriptive statistics: 
x Total number of days of exposure to the study drug, defined as the date of last application 
of study drug minus date of first application plus one  
x Total number of applications taken during the treatment period, defined as the summation 
of number of applications used between each two visits, as reviewed and recorded on the 
CRF by the Investigator. If the number of applications between any two visits is missing, 
the subject will be assumed to have used 0 application. 
x Total amount of drug used (g), defined as the summation of amount of drug used per kit 
for all dispensed kits. Amount of drug used per kit is defined as the difference in weight 


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Protocol No. ADB244-002 
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IQVIA Biotech No. BZA46494                                                                                             SAP version 1.0 
between the returned and dispensed kits, where weight of dispensed kits is a unit value. 
Amount of drug used for sealed and unreturned kits will be assumed to be 0.0 g.  
x Percent compliance, defined as the total number of applications used divided by total 
number of expected applications times 100%. The total number of expected applications 
is defined as the total number of days of exposure times 2. 
x Percent study drug applied, defined as total amount of drug applied divided by the 
expected weight of study drug applied times 100%. The expected weight of study drug 
applied is calculated as number of pumps per day times 0.14g per pump and multiply by 
total number of days of exposure assuming that subject applies the same amount of 
pumps per day during the treatment period. Table 13.1 gives the suggested number of 
pumps to be applied on each application based on cohort and baseline affected body 
surface area. 
 Table 13.1 
Body Surface Area and Suggested Application of Investigational Product 
Affected Body Surface Area 
Approximate Number of Pumps per application 
2 to 5 years old 
6 to 11 years old 
12 to- 17 years old 
10% (>=10% - <20%) 
2 
2 
3 
20% (>=20% - <30%) 
3 
4 
7 
30% (>=30% - <50%) 
4 
6 
10 
50% (>=50% - <60%) 
7 
10 
16 
 
13.5 
Prior and Concomitant Medications 
Prior (within the previous 30 days and with stop dates prior to first dose of study drug) and 
concomitant (ongoing or with stop dates on or after first dose of study drug) medications or 
vaccines will be presented for the ITT population in a by-cohort and by-subject listing. If the 
medication is ongoing or the stop year is missing, the medication will be considered as received 
for the entire duration of the study. Medications will be coded using WHO-DD terminology.  
For the determination of prior vs concomitant medications, the following rules regarding the stop 
date will be applied:  
x If only year was recorded, and it is before Baseline, it is a prior medication; if year is 
same or after Baseline, it is assumed to be a concomitant medication.  
x If day is missing, but month and year are before Baseline, it is a prior medication; if 
month and year are the same as Baseline, it is assumed to be a concomitant medication; if 
month and year are after Baseline, it is a concomitant medication.  
x If start date is after Baseline, it is a concomitant medication regardless.  


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IQVIA Biotech No. BZA46494                                                                                             SAP version 1.0 
In addition, concomitant medications will be summarized by WHO-DD Anatomical-
Therapeutic-Chemical (ATC) classification and preferred term (PT) for each cohort and overall. 
The use of medications to treat a subject’s atopic dermatitis during the study will be permitted if 
deemed necessary and it will be indicated in the CRF. Rescue medication will be indicated in the 
concomitant medication listing. 
13.6 
Medical History and Concurrent Procedures 
Medical history (including previous and ongoing medical conditions) will be coded using 
MedDRA and presented in a by-cohort and by-subject listing.  
Concurrent procedures will be coded using MedDRA and presented in a by-cohort and by-
subject listing. 
13.7 
Efficacy Endpoints 
The efficacy assessments are as follows: 
x Changes from Baseline to post baseline visits in Validated Investigator Global 
Assessment for Atopic Dermatitis (vIGA-AD) scale. 
The vIGA-AD is a 5-point scale that evaluates overall severity assessment of AD: 
0=Clear, 1=Almost Clear, 2=Mild, 3=Moderate, and 4=Severe. 
x Number and proportion of subjects with a vIGA-AD of 0 (Clear) or 1 (Almost Clear) at 
each post baseline visit. 
x Changes from Baseline to post baseline visits in Area Severity Index (EASI) score (total 
and each component). 
The EASI assesses the extent of disease (% involvement) at 4 body sites (head/neck, 
trunk, upper extremities, and lower extremities) and measures 4 clinical signs: erythema, 
edema/papulation, excoriation, and lichenification, and is graded on a severity scale of 0 
to 3 (half points may be used): 0=None, 1=Mild, 2=Moderate, and 3=Severe. 
x Number and proportion of subjects with 30% EASI score reduction from Baseline to 
each post baseline visit 
x Changes from Baseline to post baseline visits in Patient Oriented Eczema Measure 
(POEM total score and each of the 7 components). 
The POEM consists of 7 questions and each question carries equal weight and is scored 
from 0 to 4, and yield a total score of 0 to 28; higher scores mean the greater the severity 
of atopic dermatitis. 
x Changes from Baseline to post baseline visits in self-reported ItchMan scale. 


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IQVIA Biotech No. BZA46494                                                                                             SAP version 1.0 
The ItchMan Scale ranges from 0 to 4: no itch to itches most terribly. 
x Number and proportion of subjects with 0, 1, 2, 3 grade reduction in ItchMan Scale 
from Baseline to each post baseline visit 
13.8 
Efficacy Analyses 
All efficacy analyses will be exploratory and performed on the ITT and PP populations, for 
overall and by age cohorts (2 to 5 years, 6 to 11 years, and 12 to 17 years).  
Summary statistics will be provided for scheduled visits (Baseline/Day 1, Day 7, Day 14, Day 
21, Day 28 [excluding ETV]) and the EOS visit (including Day 28 and ETV). Frequency counts 
and percentages will be provided for vIGA-AD Scale, POEM component scores, and ItchMan 
Scale, including absolute values and changes from baseline. The frequency and percentage of 
subjects who have achieved clear (0) or almost clear (1) on the vIGA-AD scale will also be 
provided at each post-baseline visit. Descriptive statistics for continuous parameters will be 
provided for EASI (total and by component), and POEM total score. 
13.9 
Safety Analyses 
All safety analyses will be performed on the ITT population. 
Safety endpoints include the following: 
x Incidence of treatment-emergent adverse events (TEAEs). 
x Change from Baseline in physical examination at each post baseline visit. 
x Change from Baseline in vital signs at each post baseline visit 
13.9.1 Adverse Events 
AE terms will be coded using MedDRA dictionary. Treatment-emergent adverse events (TEAEs) 
are defined as AEs that first occurred or worsened in severity after the first administration of 
study treatment. If relationship to treatment is missing, the event will be conservatively 
considered as being related to study drug. If severity is missing, a separate category of missing 
severity will be included in the summary table, and no imputation of severity will be performed.  
For the determination of TEAEs, the following rules regarding the start date will be applied:  
x If only year was recorded, and it is before Baseline, it is a non-TEAE; if year is same or 
after Baseline, it is assumed to be a TEAE.  
x If day is missing, but month and year are before Baseline, it is a non-TEAE; if month and 
year are the same as Baseline, it is assumed to be a TEAE; if month and year are after 
Baseline, it is a TEAE.  


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IQVIA Biotech No. BZA46494                                                                                             SAP version 1.0 
x If start date is after Baseline, it is a TEAE regardless.  
All AEs will be presented in a by-cohort and by-subject listing, detailing the verbatim term given 
by the investigator, the preferred term (PT), system organ class (SOC), onset date and time, end 
date and time, intensity, outcome, relationship to study drug, action taken with study drug, other 
action taken to treat the event, seriousness and criteria for seriousness. Serious AEs (SAEs), 
TEAEs leading to death, and TEAEs leading to discontinuation of study treatmentwill also be 
presented in a separate listing. An overall summary of AEs will be presented by age cohort and 
overall. The summary will include the total number of events, frequency counts and percentages 
for:
x Any AE  
x Any SAE 
x Any TEAE  
x Any TEAE leading to death 
x Any TEAE leading to discontinuation of study treatment 
The number of the TEAEs and the incidence rate of TEAEs will be displayed by cohort and 
overall according to the following:  
x 
All TEAEs by SOC in alphabetical order and PT in descending order of frequency (the 
frequency in the overall group)  
x 
All TEAEs by SOC, PT, and maximum severity (mild, moderate, or severe)  
x 
All TEAEs by SOC, PT, and maximum causality (not related, related) to the study drug  
x SAEs, TEAEs leading to death, and TEAEs leading to discontinuation of study treatment 
by SOC and PT 
At each level of summarization of incidence rates, a subject will be counted once if he/she 
reported one or more events. In the counts of subjects with TEAEs, each subject will contribute 
only once (maximum severity) regardless of the number of occurrences (events). 
13.9.2 Clinical Laboratory Testing 
A urine pregnancy test will be performed at all visits for females 11 years of age or older. The 
results will be presented in a by-cohort and by-subject listing.                                                                                  
13.9.3 Vital Signs 
Vital signs including blood pressure (systolic and diastolic), pulse rate, and body temperature 
will be presented in a by-cohort and by-subject listing. Absolute values and change from baseline 
value will be summarized by cohort using descriptive statistics for scheduled visits 
(Baseline/Day 1, Day 7, Day 14, Day 21, Day 28 [excluding ETV], and the EOS visit [including 
Day 28 and ETV]). 


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IQVIA Biotech No. BZA46494                                                                                             SAP version 1.0 
13.9.4 Physical Examination 
Number and frequency of subjects with abnormal findings for physical examination (including 
general appearance, dermatological, musculoskeletal, thyroid, HEENT, lymphatic, respiratory, 
gastrointestinal, cardiovascular, neurologic, extremities and Overall) will be summarized by-
cohort and overall for scheduled visits.  
The abnormality status will also be summarized in a shift table for all post-baseline visits by 
cohort and overall. 
All abnormal results (including verbatim comments) will be presented in a by-cohort and by-
subject listing.  
14. CHANGES FROM THE PROTOCOL AND PLANNED ANALYSES 
Not applicable. 
15. FORMATTING 
Each page of the analysis will show the sponsor’s name, the investigational product, and the 
protocol number. Report tables will be embedded in the MS Word report document from SAS 
program output without change. The footer of each table will show the name of the SAS program 
module which generated it, the names of all data sets providing input data in the program and the 
date and time the table was generated. 
The SAS programs will generate rich-text-formatted (RTF) output with the “RTF” extension 
using the SAS Output Delivery System (ODS). The summary tables and listings will be 
formatted using the Times New Roman 9-point font.  
Datasets will be created and taken as input to validated SAS programs to generate the report-
ready tables, listings, and figures. Each output display will show the names of the data sets and 
SAS program used to produce it.  
16. ARCHIVING AND RETENTION OF DOCUMENTS 
After finalization of the analysis, the following will be archived at IQVIA Biotech  and/or with 
the study sponsor: 
x SAP and any amendments 
x All SAS code used in the project for statistical analysis, report tables generation, and 
analysis data set creation 
x Tables, listings and figures as included in the clinical study report 
x SAS study data tabulation model (SDTM) and analysis dataset model (ADaM) datasets 


AOBiome Therapeutics  
                            Page 19 of 19 
Protocol No. ADB244-002 
April 8, 2019 
IQVIA Biotech No. BZA46494                                                                                             SAP version 1.0 
17. OUTLINE OF PROPOSED TABLES, LISTINGS AND FIGURES