A Study to Evaluate the Safety, Reactogenicity, and Acceptability of a Placebo Microneedle Patch in Healthy Infants and Young Children
Phase: NA
Conditions: Vaccination, Skin Absorption
Sponsor: Emory University

 
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 ____________________________________________________________________________________________ 
 
 
A Study to Evaluate the Safety, Reactogenicity, and 
Acceptability of a Placebo Microneedle Patch in Healthy 
Infants and Young Children 
 
 
Sponsored by: 
Micron Biomedical, Inc. 
 
 
Principal Investigator: 
Evan J. Anderson, MD 
 
 
Draft or Version Number: 5.0 
 
Day Month Year 
18 January 2019 
 
 
NCT Number: 
NCT03207763 
 
 

 
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Statement of Compliance 
The study will be carried out in accordance with Good Clinical Practice (GCP) as required by the 
following: 
 
• 
United States Code of Federal Regulations (CFR) applicable to clinical studies (45 CFR Part 
46; 21 CFR Part 50, 21 CFR Part 54, 21 CFR Part 56, and 21 CFR Part 312); 
• 
International Conference on Harmonization (ICH) E6; 62 Federal Register 25691 (1997); 
 
Compliance with these standards provides public assurance that the rights, safety and well-
being of study subjects are protected, consistent with the principles that have their origin in the 
Declaration of Helsinki. 
All key personnel (all individuals responsible for the design and conduct of this study) have 
completed Human Subjects Protection Training. 

 
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SIGNATURE PAGE 
The signature below constitutes the approval of this protocol and the attachments, and provides 
the necessary assurances that this trial will be conducted according to all stipulations of the 
protocol, including all statements regarding confidentiality, and according to local legal and 
regulatory requirements and applicable US federal regulations and ICH guidelines. 
 
Site Investigator: Evan J. Anderson, MD 
 
Signed: 
 
Date: 
 
 
Evan J. Anderson, MD 
 
 
 
 
 
 

 
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Table of Contents 
 
 
Page 
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iii 
Statement of Compliance ............................................................................................................. i 
Signature Page ........................................................................................................................... ii 
List of Abbreviations ................................................................................................................... vi 
Protocol Summary ...................................................................................................................... 1 
 
1 
Key Roles ........................................................................................................................... 4 
2 
Background Information and Scientific Rationale................................................................ 5 
2.1 
Background Information .......................................................................................... 5 
2.2 
Rationale ................................................................................................................ 6 
2.3 
Potential Risks and Benefits ................................................................................... 7 
2.3.1 
Potential Risks ............................................................................................ 7 
2.3.2 
Known Potential Benefits ............................................................................ 9 
3 
Objectives ........................................................................................................................ 10 
3.1 
Study Objectives ................................................................................................... 10 
3.1.1 
Primary Objectives .................................................................................... 10 
3.1.2 
Secondary Objectives ............................................................................... 10 
3.2 
Study Endpoints.................................................................................................... 10 
3.2.1 
Primary Endpoints ..................................................................................... 10 
3.2.2 
Secondary Endpoints ................................................................................ 10 
4 
Study Design .................................................................................................................... 12 
5 
Study Population .............................................................................................................. 14 
5.1 
Selection of the Study Population ......................................................................... 14 
5.2 
Subject Inclusion Criteria ...................................................................................... 14 
5.3 
Subject Exclusion Criteria ..................................................................................... 14 
5.4 
Treatment Assignment Procedures ....................................................................... 16 
5.4.1 
Subject Identification Procedure ................................................................ 16 
5.4.2 
Reasons for Withdrawal ............................................................................ 16 
5.4.3 
Handling of Withdrawals ............................................................................ 16 
5.4.4 
Termination of Study ................................................................................. 17 
6 
Study Intervention/Investigational Product ........................................................................ 18 
6.1 
Study Product Description .................................................................................... 18 
6.1.1 
Acquisition ................................................................................................. 18 
6.1.2 
Formulation, Packaging, and Labeling....................................................... 18 
6.1.3 
Product Storage and Stability .................................................................... 18 
6.2 
Dosage, Preparation and Administration of Study Intervention/Investigational 
Product ................................................................................................................. 18 
6.3 
Accountability Procedures for the Study Intervention/Investigational Product(s) ... 19 
7 
Study Schedule ................................................................................................................ 20 
7.1 
Visit 1: Enrollment/Application of Placebo Microneedle Patch, Day 1 .................... 20 

 
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7.2 
Visit 2:  Day 2 (+1) Clinic Visit ............................................................................... 20 
7.3 
Visit 3: Day 8 (+2), Clinic Visit ............................................................................... 21 
7.4 
Visit 4:  Day 9 (+2) Clinic Visit (Only in those with Placebo Microneedle Patches 
2/3 placement) ...................................................................................................... 22 
7.5 
Visit 5: Day 15 (+3), Clinic Visit (Only in those with Placebo Microneedle Patches 
2/3 placement) ...................................................................................................... 22 
7.6 
Final Visit: Day 27 - 38, Telephone Call ................................................................ 23 
7.7 
Premature Discontinuation Visit (if applicable) ...................................................... 23 
7.8 
Unscheduled Visit (if needed) ............................................................................... 23 
8 
Study Procedures/Evaluations.......................................................................................... 25 
8.1 
Clinical Evaluations ............................................................................................... 25 
8.1.1 
Medical History .......................................................................................... 25 
8.1.2 
Concomitant Medications .......................................................................... 25 
8.1.3 
Vital Signs ................................................................................................. 26 
8.1.4 
Physical Examination ................................................................................ 26 
8.1.5 
Reactogenicity........................................................................................... 26 
8.1.6 
Acceptability Assessments: ....................................................................... 27 
9 
Safety assessment and reporting ..................................................................................... 28 
9.1 
Definitions ............................................................................................................. 28 
9.1.1 
Definition of an Adverse Event (AE) .......................................................... 28 
9.1.2 
Definition of a Serious Adverse Event (SAE) ............................................. 28 
9.2 
Methods and Timing for Assessing, Recording, and Analyzing Safety Parameters
 ............................................................................................................................. 29 
9.2.1 
Adverse Events ......................................................................................... 29 
9.2.2 
Reactogenicity........................................................................................... 29 
9.2.3 
Serious Adverse Events ............................................................................ 30 
9.2.4 
Procedures to be followed in the Event of Abnormal Laboratory Test Values 
or Abnormal Clinical Findings .................................................................... 30 
9.3 
Reporting Procedures ........................................................................................... 30 
9.3.1 
Serious Adverse Event Detection and Reporting ....................................... 30 
9.3.2 
Reporting to IRB ........................................................................................ 31 
9.3.3 
Type and Duration of the Follow-up of Subjects After Adverse Events ...... 31 
9.4 
Individual Halting Rules ........................................................................................ 31 
9.5 
Study Halting Rules .............................................................................................. 32 
10 
Clinical Monitoring Structure ............................................................................................. 33 
10.1 
Study Documentation............................................................................................ 33 
10.2 
Data Collection and Data Management ................................................................ 33 
10.3 
Data Quality Control/Quality Assurance ................................................................ 33 
10.4 
Site Monitoring Plan .............................................................................................. 34 
10.5 
Timing/Reports ..................................................................................................... 34 

 
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10.6 
Study Records Retention ...................................................................................... 34 
10.7 
Protocol Deviations ............................................................................................... 34 
11 
Statistical Considerations ................................................................................................. 36 
11.1 
Study Outcome Endpoints .................................................................................... 36 
11.2 
Sample Size Considerations ................................................................................. 36 
11.3 
Analysis Plan ........................................................................................................ 36 
12 
Ethics/Protection of Human Subjects................................................................................ 38 
12.1 
Ethical Standard ................................................................................................... 38 
12.2 
Institutional Review Board .................................................................................... 38 
12.3 
Informed Consent Process ................................................................................... 38 
12.4 
Subject Confidentiality .......................................................................................... 39 
12.5 
Study Discontinuation ........................................................................................... 39 
13 
Literature References ....................................................................................................... 40 
14 
SUPPLEMENTS/APPENDICES ....................................................................................... 41 
14.1 
Appendix A: Study Schedule................................................................................. 41 
14.2 
Appendix B: Adverse Event & Reactogenicity Grading - LOCAL SITE REACTIONS
 ............................................................................................................................. 42 
14.3 
Appendix C: Adverse Event & Reactogenicity Grading - GENERAL ADVERSE 
REACTIONS ......................................................................................................... 43 
 

 
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List of Abbreviations 
 
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vi 
AE 
Adverse Event 
CFR 
Code of Federal Regulations 
CRF 
Case Report Form 
FDA 
Food and Drug Administration 
GCP 
Good Clinical Practice 
GRAS 
Generally Recognized as Safe 
ICF 
Informed Consent Form 
ICH 
International Conference on Harmonisation 
IRB 
Institutional Review Board 
LAR 
Legally Authorized Representative 
MedDRA 
Medical Dictionary for Regulatory Activities 
MOP 
Manual of Procedures 
N 
Number (typically refers to subjects) 
NOMC 
New-Onset Medical Conditions 
PI 
Principal Investigator 
SAE 
Serious Adverse Event 
SOP 
Standard Operating Procedure 
USP 
United States Pharmacopeia 
 
 

 
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Title:  
 
A Study to Evaluate the Safety, Reactogenicity and  
Acceptability of a Placebo Microneedle Patch in Healthy    
Infants and Young Children 
 
Population: 
Healthy infants and children, 6 weeks – 24 months inclusive  
 
Number of Sites: 
One  
 
Study Duration: 
Approximately 5 months 
 
Subject Duration: 
Approximately 4 – 5 weeks 
 
 
Objectives: 
 
Primary: 
• 
To evaluate the safety and reactogenicity following application of a placebo 
microneedle patch topically.  
 
Secondary: 
• 
To evaluate unsolicited adverse events following application of a placebo 
microneedle patch topically. 
• 
To evaluate new-onset medical conditions (NOMC) following application of a 
placebo microneedle patch topically.  
• 
To evaluate the suitability of application of a placebo microneedle patch to 
different body locations. 
• 
To evaluate the acceptability to the Legally Authorized Representative (LAR) of 
applying a placebo microneedle patch topically.  
 
 
Endpoints 
Primary:  
Safety: 
• 
Occurrence of placebo microneedle patch-related serious adverse events from 
Day 1 through the Final Study Visit (Day 27 – 38). 
• 
Occurrence of Grade 3 placebo microneedle patch-related solicited adverse 
events for the 8 days following application of the patch. 
 
Reactogenicity: 
• 
Occurrence of solicited application site reactogenicity (e.g., erythema, 
induration, bruising, itching) for the 8 days following application of the patch.  

 
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Secondary: 
• 
Occurrence of Grade 3 placebo microneedle patch-related unsolicited adverse 
events from Day 1 through the Final Study Visit (Day 27 – 38). 
• 
Occurrence of new-onset medical conditions (NOMC) from Day 1 through the 
Final Study Visit (Day 27 – 38). 
• 
Occurrence of solicited and unsolicited adverse events described at the site at 
which the placebo microneedle patch was applied.  
• 
Quantitative and qualitative description of LAR responses to survey questions.  
 
 
Schematic of Study Design: 
 
This is a single-center, unblinded, study in which healthy infants and children (6 weeks – 
24 months inclusive) will have placebo microneedle patches applied to the skin.  This 
study is designed to investigate the safety, reactogenicity, and acceptability of a placebo 
microneedle patch. 
 
Infants and children will be enrolled into one of two possible cohorts that will have 
placebo microneedle patches administered topically for up to approximately 20 minutes. 
Cohort 1 will assess one formulation of the microneedle patch (Microneedle Formulation 
1).  If the Microneedle Formulation 1 is well tolerated in Cohort 1, Cohort 2 may be 
enrolled using a different formulation of the microneedle patch if available (Microneedle 
Formulation 2). Infants and children will be enrolled by sequential age groups using an 
age de-escalation approach (Table 1). At least 4 infants or children from each Group 
must complete Day 8 without halting criteria having been met (as detailed in Section 9.5) 
before subjects will be enrolled into the next younger age group within a Cohort.  For 
Cohort 1, at least the first 2 children in each Group will have a microneedle patch initially 
applied to the skin overlying the shoulder blade. If this site is well tolerated without 
halting criteria having been met (as detailed in Section 9.5), additional microneedle 
patches may be applied to the same participants and in subsequent participants to the 
upper arm, forearm, wrist, thigh, shin, and/or foot.  For Cohort 2, microneedle patches 
may be applied to the shoulder blade, upper arm, forearm, wrist, thigh, shin, and/or foot.  
If the first site is well tolerated in the first two children without halting criteria having been 
met (as detailed in Section 9.5), additional microneedle patches may be applied to the 
same participants and in subsequent participants. 
 
 
 
 

 
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Table 1: Cohorts and Groups of Enrolled Infants and Young Children 
Cohort Group Age Range* Number
** 
Study Product (administered Day 1 
and possibly Day 8) 
1 
12 – 24 months 
Up to 7 
Microneedle formulation 1 
1 
5 – 11 months 
Up to 6 
Microneedle formulation 1 
1 
6 weeks – 4 months Up to 12 
Microneedle formulation 1 
2 
12 – 24 months 
Up to 12 
Microneedle formulation 2 
2 
5 – 11 months 
Up to 12 
Microneedle formulation 2 
2 
6 weeks – 4 months Up to 12 
Microneedle formulation 2 
*All age ranges are inclusive. 4 children from each age group must complete Day 
8 without halting criteria having been met (as detailed in Section 9.5) before 
subjects will be enrolled into the next younger age group.  
** Total number enrolled into each Cohort will be ≤25. 
 
Subjects will have an initial microneedle patch placed on Day 1.  At Day 8, the LARs of 
subjects who have no ongoing solicited or unsolicited general AEs or local AEs will have 
the opportunity to decide to have second and third placebo microneedle patches placed 
at different body sites from the initial location. 
 
Each subject will receive up to three placebo microneedle patches.  Subjects will receive 
a first placebo microneedle patch on Day 1 and be assessed on Day 2 (+1 day), and 
Day 8 (+2 days).  If the first patch is well tolerated without halting criteria having been 
met on Day 8 (+2 days), then the LAR will be provided the opportunity to have the 
subjects receive a second and third placebo microneedle patch on Day 8 and be 
assessed on Day 9 (+2 days) and Day 15 (+3 days).  All subjects will have an end of 
study telephone call that will occur D27 – Day 38. 
 
Safety will be measured by the occurrence of solicited application site and systemic 
reactogenicity on the day of microneedle patch administration through Day 8 for the first 
patch and through Day 15 (+3 days) for those that receive a second and third patch. If 
symptoms persist, clinic staff will attempt to follow up with the subject daily until two days 
symptom-free. Maximum severity post Day 8 (Day 15 in those that receive a second and 
third patch) and stop date of the symptoms will be recorded by clinic staff on the 
Solicited Events eCRF.  Unsolicited AE, and serious adverse events (SAEs) and new-
onset medical conditions (NOMC) will be collected through Day 27 and Day 38 after 
microneedle patch administration.  
 
The acceptability of applying a microneedle patch topically will be assessed by LAR 
survey completed before each microneedle patch application, after microneedle patch 
removal, Day 2, and at Day 8 (+2 days) (and at Days 9 and 15 (+3 days) in those having 
an additional application).  
 

 
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1 
 
KEY ROLES 
Individuals: Principal Investigator: Evan J. Anderson, MD 
 
Institution: 
 
Emory University School of Medicine 
 
 
 
Emory Children’s Center 
 
 
            2015 Uppergate Drive 
 
 
            Atlanta, GA 30322 
 
Contact:  
 
Evan J. Anderson, MD 
 
 
 
(p) 404-727-1746 
 
 
 
(f) 404-727-9223 
 
 
 
evanderson@emory.edu 
 

 
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2 
BACKGROUND INFORMATION AND SCIENTIFIC 
RATIONALE 
2.1 
Background Information 
Available vaccine delivery methods include intramuscular or subcutaneous injection 
using hypodermic needle which is limited by patient needle phobia (Hamilton 1995) and 
the need for trained medical personnel. Alternative routes of vaccination that avoid 
hypodermic needles have previously been poorly immunogenic, require live vaccines, 
utilize bulky devices and/or are unsuitable for self-administration (Mitragotri 2005, Kersten 
2007).  Novel vaccine delivery methods such as microneedles can render vaccination 
easier and more acceptable to the public by simplifying vaccine access, and can confer 
equal or superior immunological responses to that induced by hypodermic needle through 
conventional intramuscular administration (Kim 2012).  
Microneedles are micron-scale needles that administer vaccine directly into the skin 
using a simple minimally invasive approach without generating sharps waste. The 
microneedles are solid conical structures made of water-soluble excipients that can 
encapsulate a vaccine. Excipients used will be on the Food and Drug Administration’s 
(FDA) Generally Recognized as Safe (GRAS) list and/or on FDA’s list of inactive 
ingredients in approved products. The microneedles that are used in the study are 
painlessly inserted into the skin as a patch with a hypoallergenic adhesive bandage 
backing. The microneedles are left in place for up to 20 minutes. During this time, the 
microneedles dissolve in the skin, so that upon removal of the patch, the microneedles 
have disappeared and the sharps-free patch backing can be discarded as non-sharps 
medical waste. Therefore, microneedle patch application can be carried out as simply as 
applying a Band-Aid® adhesive bandage. 
Microneedles have been studied for vaccines including influenza, rabies, Bacillus 
Calmette- Guerin (BCG), West Nile virus, and Human Papilloma Virus (HPV) (Kim 2012). 
There are a number of approved medical and cosmetic products using microneedles 
currently sold around the world. Soluvia® is a single hollow microneedle that is 1.5 mm 
long and is attached to a syringe (http://www.bd.com/pharmaceuticals/products/ 
microinjection.asp). It is marketed worldwide prefilled with influenza vaccine for 
intradermal 
vaccination 
as 
IDflu®, 
Intanza® 
and 
Fluzone 
Intradermal® 

 
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(http://www.fluzone.com/fluzone-intradermal-quadrivalent-vaccine.cfm). Also MicronJet 
600® received FDA clearance as a device (http://www.nanopass.com/product/).  
Vaccination by microneedles is designed to increase patient compliance and 
access to immunization. In focus group studies of the public and healthcare professionals, 
microneedle patches were generally viewed positively compared to hypodermic needle 
injections (Birchall 2011). Perceived benefits included reduced pain, tissue damage and 
risk of infections, as well as possibility for self-administration. Concerns focused on 
delayed onset, cost, accurate and reliable dosing and the potential for misuse. In separate 
vaccination surveys associated with hollow microneedle injection of influenza vaccine, 
most physicians and the general public preferred microneedles over conventional 
intramuscular injection largely due to the smaller needle size, as well as the increased 
immunogenicity of intradermal vaccination (Arnou 2011). Physicians and patients alike 
thought that microneedle-based vaccination could increase vaccination coverage rates. 
 
2.2 
Rationale 
Vaccines are typically injected using a hypodermic needle, a cost efficient, rapid 
and direct way for vaccine delivery. However, hypodermic needles cannot be easily used 
by patients themselves and patient willingness to receive vaccination is limited by pain 
and by needle-phobia experienced by many patients (Hamilton 1995). Spread of blood 
borne pathogens by needle re-use is also a major concern, especially in developing 
countries (Drucker 2001).  Microneedles can be prepared as a low-cost patch that is 
simple for patients to apply for vaccine delivery targeting the many antigen-presenting 
cells present in the skin. A recent study at Emory University evaluated the safety, 
reactogenicity, acceptability, and immunogenicity of administration of influenza vaccine by 
microneedle patch in comparison to hypodermic needle injection. Data from this study 
demonstrated an excellent profile of the microneedle patch.   
Data regarding the safety, reactogenicity, tolerability, and acceptability of a 
microneedle patch in children are lacking.  The goal of this study is to evaluate the safety, 
reactogenicity, and acceptability of placement of a placebo microneedle patch to the skin 
of children. Twenty-five to 50 children healthy children between the ages of 6 weeks and 
24 months will be enrolled in the study. Subjects will be recruited from the general 
population of metro Atlanta, GA and enrolled at the Emory Children’s Center, located on 
Emory University campus in Atlanta, GA.  

 
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2.3 
Potential Risks and Benefits 
2.3.1 Potential Risks 
 
Pain 
The most significant parameter associated with pain is the microneedle length. However, 
microneedles shorter than ~1,000 μm are generally considered painless. Microneedles 
have induced significantly less pain than hypodermic needle controls. Pain from hollow 
microneedles can be caused by microneedle insertion as well as liquid infusion during 
injection (Kaushik 2001 and Gill 2008). The patch used in this study has conical solid 
microneedles with a width of 300 µm at the base without a liquid infusion. In a Phase I 
study of influenza vaccination, when pain was sometimes reported, it was mild in 
severity (Rouphael unpublished data).  Pain in this study of placebo microneedle patch 
is thus possible, but is not expected.  
 
 
Skin irritation 
Microneedles can cause mild, transient skin irritation, primarily in the form of highly 
localized, mild and often punctuate erythema that disappears within hours or, in some 
cases, days. Erythema varies depending on length of microneedles. Bleeding is not 
characteristically seen. Itching has also been observed. Influenza vaccination using 
hollow microneedles has shown more local inflammatory reactions than hypodermic 
injection in human subjects. This may be due to inflammatory reactions being more 
easily visible in the skin than those that may occur after intramuscular injection (Arnou 
2009). 
 
Skin infection 
There have been no reports of skin infection with microneedle insertions in thousands of 
people and animals (Kim 2012). 
 
Adhesive backing component 
The adhesive backing component is made from hypoallergenic material (commercial 3M 
medical tapes designed to adhere to skin).  Local reactions (e.g., erythema, itching) can 
occur rarely, particularly with removal of the adhesive from the skin.   
 

 
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Placebo Microneedle Patch and Excipients 
Excipients (inactive ingredients) used to make the microneedles will be USP-grade and 
listed on FDA’s database of  Inactive Ingredients for Approved Drug Products. The final 
composition of the patch for Cohort 1 and Cohort 2 has not been finalized but all 
excipients are already in use in FDA-approved drug products (and usually at a much 
higher dose than will be used in the microneedle patch). Excipients are expected to 
include trehalose, sorbitol, histidine, maltodextrin, sodium carboxymethylcellulose, 
polysorbate, xylitol, polyvinyl alcohol, and/or glycerol.  The total mass of excipients 
delivered by placebo microneedle patch will be <1.5 mg.  
 
The microneedle patches used in the placebo study will be manufactured under low 
bioburden conditions and in compliance with cGMP requirements for Phase 1 clinical 
trials according to the FDA’s Guidance for Industry 2008: CGMP for Phase 1 
Investigational Drugs.  This will be the same process and same controls as those used 
in the manufacture of microneedle patches investigated in the Phase 1 clinical trial of the 
microneedle patch for influenza vaccination carried out by Georgia Tech and the Hope 
Clinic. 
 
The microneedle patch has a history of safe use in human subjects.  It has been used in 
several IRB-approved studies at Georgia Tech in adults and has always exhibited a safe 
profile that typically consists of itching and/or mild erythema that subsides after a few 
days.  Similarly, the Phase 1 trial of the microneedle patch for influenza vaccination 
showed that the microneedle patch was safe with no serious adverse events (SAEs) 
reported. No new chronic medical illnesses or influenza-like illnesses were reported with 
the patch.  
 
Although the composition of the microneedle patches used in these studies was different 
from that of the patches for the proposed placebo study in infants and young children, 
the microneedle patches were made of excipients that had the same safety profile as 
those that will be used in this placebo study. The controls that will be used to make the 
infant and young children placebo patches will be at least as strict as those that were 
used to make the patches used in the Georgia Tech IRB studies and the initial Phase 1 
clinical trial of influenza vaccine administration by microneedle patch. 

 
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2.3.2 Known Potential Benefits 
The knowledge gained from this study will facilitate the design of more effective and 
acceptable methods for administering vaccines in children by use of a microneedle patch.  
A future clinical trial of the microneedle patch for inactivated poliovirus (IPV) vaccination 
in infants is planned to occur in 2018, and the results from this IRB study will inform the 
design of this future clinical trial and others. There is no direct benefit to study participants.  
 
 
 
 
 
 
 
 
 
 
 
 
 
 

 
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3 
OBJECTIVES 
3.1 
Study Objectives 
3.1.1 Primary Objectives 
• 
To evaluate the safety and reactogenicity following application of a placebo 
microneedle patch topically.  
3.1.2 Secondary Objectives 
• 
To evaluate unsolicited adverse events following application of a placebo 
microneedle patch topically. 
• 
To evaluate new-onset medical conditions (NOMC) following application of a 
placebo microneedle patch topically.  
• 
To evaluate the suitability of application of a placebo microneedle patch to 
different body locations. 
• 
To evaluate the acceptability to the Legally Authorized Representative (LAR) of 
applying a placebo microneedle patch topically.  
 
3.2 
Study Endpoints 
3.2.1 Primary Endpoints 
Safety: 
• 
Occurrence of placebo microneedle patch-related serious adverse events from 
Day 1 through the Final Study Visit (Day 27 – 38). 
• 
Occurrence of Grade 3 placebo microneedle patch-related solicited adverse 
events for the 8 days following application of the patch. 
 
Reactogenicity: 
• 
Occurrence of solicited application site reactogenicity (e.g., erythema, 
induration, bruising, itching) for the 8 days following application of the patch.  
3.2.2 Secondary Endpoints 
• 
Occurrence of Grade 3 placebo microneedle patch-related unsolicited adverse 
events from Day 1 through the Final Study Visit (Day 27 – 38). 

 
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• 
Occurrence of new-onset medical conditions (NOMC) from Day 1 through the 
Final Study Visit (Day 27 – 38). 
• 
Occurrence of solicited and unsolicited adverse events described at the site at 
which the placebo microneedle patch was applied.  
• 
Quantitative and qualitative description of LAR responses to survey questions.  
 

 
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4 
STUDY DESIGN 
This is a single-center, unblinded, study in which healthy infants and children (6 weeks – 
24 months inclusive) will have placebo microneedle patches applied to the skin.  This 
study is designed to investigate the safety, reactogenicity, and acceptability of a placebo 
microneedle patch. 
Infants and children will be recruited from metropolitan Atlanta and will be enrolled at 
Emory Children’s Center. Approximately 25 to 50 infants and young children will be 
enrolled into one of two possible cohorts that will have placebo microneedle patches 
administered topically for up to approximately 20 minutes. Cohort 1 will assess one 
formulation of the microneedle patch (Microneedle Formulation 1).  If the Microneedle 
Formulation 1 is well tolerated in Cohort 1, Cohort 2 may be enrolled using a different 
formulation of the microneedle patches if available (Microneedle Formulation 2).  
After informed consent is obtained, subjects will be screened by history and physical 
examination at screening. Collected data will include demographic information, medical 
history, list of current and recent medications, and vaccination history. The placebo 
microneedle patch will be administered on Day 1 to subjects meeting enrollment criteria.  
Each subject will have 3 clinic visits: Day 1, Day 2 (+1 day), and Day 8 (+2 days).  One 
telephone call will occur (Day 29 +/- 3 days). In those that receive additional microneedle 
patches on Day 8 (+2 days), follow-up visits will also occur at Day 9 (+2 days) and Day 15 
(+3 days). Refer to the Appendix A for a detailed listing of study days and procedures. 
Safety will be measured by the occurrence of solicited application site and systemic 
reactogenicity on the day of microneedle patch administration through Day 8 (+2 days) for 
the first patch and through Day 15 (+3 days) for the second and third patch. Unsolicited 
AE, and serious adverse events (SAEs) and new-onset medical conditions (NOMC) will 
be collected through Day 29 and Day 38 after microneedle patch administration. The 
acceptability of applying a microneedle patch topically will be assessed by LAR survey 
completed before microneedle patch application on Day 1, after microneedle patch 
removal on Day 1, at Day 2 (+1 day), Day 8 (+2 days), and the Final Study Visit (Day 27 
– 38) in everyone.  In those that receive additional microneedle patches, it will be also be 
repeated at Day 9 (+2 days) and Day 15 (+3 days).  
 
Infants and children will be enrolled by sequential age groups using an age de-escalation 
approach (Table 1). At least 4 infants or children from each Group must complete Day 8 
without halting criteria having been met (as detailed in Section 9.5) before subjects will be 
enrolled into the next younger age group within a Cohort.  For Cohort 1, at least the first 2 
children in each Group will have the microneedle patch applied to the skin overlying the 
shoulder blade. If this site is well tolerated without halting criteria having been met (as 
detailed in Section 9.5), additional microneedle patches may be applied at a different 
location on the same participant and in subsequent participants to the upper arm, forearm, 
wrist, thigh, shin, and/or foot. For Cohort 2, microneedle patches may be applied to the 

 
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shoulder blade, upper arm, forearm, wrist, thigh, shin, and/or foot.  If the first site is well 
tolerated in the first two children without halting criteria having been met (as detailed in 
Section 9.5), additional microneedle patches may be applied to the same participants and 
in subsequent participants. 
 
 
Table 1: Cohorts and Groups of Enrolled Infants and Young Children 
Cohort Group Age Range* Number
** 
Study Product (administered Day 1 
and possibly Day 8) 
1 
12 – 24 months 
Up to 7 
Microneedle formulation 1 
1 
5 – 11 months 
Up to 6 
Microneedle formulation 1 
1 
6 weeks – 4 months Up to 12 
Microneedle formulation 1 
2 
12 – 24 months 
Up to 12 
Microneedle formulation 2 
2 
5 – 11 months 
Up to 12 
Microneedle formulation 2 
2 
6 weeks – 4 months Up to 12 
Microneedle formulation 2 
*All age ranges are inclusive. 4 children from each age group must complete Day 
8 without halting criteria having been met (as detailed in Section 9.5) before 
subjects will be enrolled into the next younger age group.  
** Total number enrolled into each Cohort will be ≤25. 
 
 
 
 

 
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5 
STUDY POPULATION 
5.1 
Selection of the Study Population 
Approximately 25 or 50 healthy male and female infants and young children will be 
enrolled.  The study will be conducted at a single site.  Subjects will be recruited from the 
community at large. 
Only infants and young children who meet the inclusion/exclusion criteria will be eligible 
for enrollment into this study. 
5.2 
Subject Inclusion Criteria 
A subject must meet all the following criteria to be eligible to participate in this study: 
1. LAR provides written informed consent prior to any study procedures being 
performed. 
2. Subject is between the ages of 6 weeks and 24 months, inclusive, on the day of 
signing informed consent. 
3. Subject is in good health as determined by vital signs, medical history, and a 
targeted physical examination.  
4. LAR is able to understand and comply with required study procedures. 
5.3 
Subject Exclusion Criteria 
A subject will not be eligible to participate in this study if any the following criteria apply: 
1. Subject has an acute illness with fever (temperature >100.4 °F) within 72 hours 
prior to enrollment. 
2. Subject has a known chronic medical problem. 
3. Subject has known immunosuppression due to underlying illness or treatment, 
including (but not limited to): Human Immunodeficiency Virus (or birth to a HIV-
positive mother), hepatitis B or C; organ transplant; active cancer or any history 

 
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of hematologic cancer; receipt of chemotherapy or radiation therapy; congenital 
immunodeficiency, anatomical or functional asplenia. 
4. Subject has used long-term* high-dose** oral or parenteral glucocorticoids, or 
high-dose inhaled steroids.*** 
* Long term is defined as taken for 2 weeks or more in total at any time 
during the past 2 months.  
** High dose defined as prednisone ≥ 20 mg total daily dose, or 
equivalent dose of other glucocorticoids.   
*** High dose defined as >800 mcg/day of beclomethasone dipropionate 
or equivalent. 
5. Subject has a history of an underlying skin condition (e.g., eczema, atopic 
dermatitis) or an open lesion (e.g., laceration, abrasion), scar, or rash in the 
areas of the planned microneedle patch administration which will interfere with 
the assessment of reactogenicity. 
6. Subject or family members have a history of keloid formation. 
7. Subject has any condition that, in the opinion of the investigator, may put the 
subject at increased risk of harm, may cause the subject to be unable to meet the 
requirements or might otherwise interfere with evaluations required by the study. 
8. Subject has received any experimental products within 30 days before study 
entry or plan to receive experimental products at any time during the study. 
9. Subject has received a vaccine within 7 days of enrollment or plans to receive a 
vaccine within 7 days after enrollment. 
10. Subject has previously received immunoglobulin or blood products. 
 

 
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5.4 
Treatment Assignment Procedures 
5.4.1 Subject Identification Procedure 
All subjects who are screened for the study (i.e., LAR signing the informed consent) will 
be assigned a subject identification number and will be included on the Screening and 
Enrollment Log.  Subject identification numbers will be assigned sequentially starting 
with:  ECCMN-001.  If a subject does not meet eligibility criteria, that subject is 
considered a screen failure. 
5.4.2 Reasons for Withdrawal 
Subjects may by voluntarily withdrawn by their LAR from the study for any reason at any 
time.  A subject may also be withdrawn from the study for one of the following reasons: 
• 
The Investigator deems it is in the subject’s best interest, or in the interest of study 
data integrity, to discontinue the subject from the study for clinical, safety, non-
adherence or other reason. 
• 
The subject is lost to follow up. 
• 
New information becomes available that makes further participation unsafe. 
• 
The study is terminated by the Investigator or Sponsor. 
5.4.3 Handling of Withdrawals 
The LAR(s) of an infant or young child will be informed that they have the right to 
discontinue their child’s study participation at any time without prejudice.  Although the 
LAR(s) are not obligated to state the reason for withdrawal, every attempt should be made 
to establish if the reason for discontinuation is due to the study product or an AE. LAR(s) 
who withdraw their child for any reason should be asked to complete an Early Termination 
Visit. 
Ongoing AEs or reactogenicity should be followed to resolution if the LAR is agreeable to 
continued phone contact by the study staff. Subjects who are withdrawn from the study 

 
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for any reason will not be replaced, unless there are fewer than 4 subjects who have 
reached Day 8 for any given age group. 
5.4.4 Termination of Study  
The study may be terminated at any time by the Sponsor for clinical, safety or 
administrative reasons. 
 

 
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6 
STUDY INTERVENTION/INVESTIGATIONAL 
PRODUCT 
6.1 
Study Product Description 
6.1.1 Acquisition 
Microneedle patches will be provided by Micron Biomedical.  
6.1.2 Formulation, Packaging, and Labeling 
Microneedle patches will be manufactured by Micron Biomedical. Microneedle patches 
will be made of excipients that are expected to include trehalose, sorbitol, histidine, 
maltodextrin, sodium carboxymethylcellulose, polysorbate, xylitol, polyvinyl alcohol, 
and/or glycerol.  The total mass of excipients delivered by placebo microneedle patch will 
be <1.5 mg. The microneedle patches used in the placebo study will be manufactured 
under low bioburden conditions and in compliance with cGMP requirements for Phase 1 
clinical trials according to the FDA’s Guidance for Industry 2008: CGMP for Phase 1 
Investigational Drugs.  The adhesive backing component is made from hypoallergenic 
material (commercial 3M medical tapes designed to adhere to skin). 
6.1.3 Product Storage and Stability 
Microneedle patches will be stored at room temperature (i.e. 200C - 250C). 
 
6.2 
Dosage, Preparation and Administration of Study 
Intervention/Investigational Product 
Microneedle patches will be administered topically by manual application to the skin. The 
sites of microneedle patch application will be cleaned with an alcohol swab and allowed 
to dry before the microneedle patch is applied.  The microneedle patches will be 
packaged and provided as single patches. 
 
 

 
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6.3 
Accountability Procedures for the Study 
Intervention/Investigational Product(s) 
The Principal Investigator is responsible for study investigational product accountability, 
reconciliation, and record maintenance. In accordance with all applicable regulatory 
requirements, the Principal Investigator or designated study center personnel must 
maintain accountability records throughout the study.   

 
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7 
STUDY SCHEDULE 
Procedures to be performed at each study visit are detailed below.  Refer also to 
Appendix A: Study Schedule. 
7.1 
Visit 1: Enrollment/Application of Placebo Microneedle 
Patch, Day 1 
The following assessments will be performed on the day of enrollment prior to 
administration of the placebo microneedle patch. 
• 
Informed Consent obtained. 
• 
The optional consent for the optional placebo microneedle patches 2/3 
may be signed. 
• 
Inclusion/Exclusion criteria review. 
• 
Complete medical history via interview with LAR including vaccination 
history. 
• 
Record medications administered within the past 30 days and any 
concomitant medications. 
• 
Vital signs: temperature and pulse. 
• 
Complete physical examination.  
• 
Height and weight. 
• 
Baseline acceptability questionnaire. 
The following procedures will be performed after subject eligibility has been verified: 
• 
Subject enrolled. 
• 
A baseline photograph of the area of application may be obtained.  
• 
Application of placebo microneedle patch to the skin by a trained study 
nurse. The microneedle patch will remain in place for up to 20 minutes. 
The patch will then be removed and the used patch will be saved.  
• 
The memory aid, thermometer and ruler will be provided to the LAR and 
instructions will be provided. 
• 
The site of the placebo microneedle patch removal will be assessed at 
least 15 minutes and 30 minutes post-placebo microneedle patch 
removal. Per investigator discretion, photographic documentation (refer to 
MOP) and dermatologic referrals may be obtained.  
• 
Study personnel will assess and record all AE/SAEs that occur after 
enrollment. 
• 
The acceptability questionnaire will be completed by the LAR.  
 
7.2 
Visit 2:  Day 2 (+1) Clinic Visit  
The following assessments will be performed. 

 
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• 
Obtain interim medical history and note any changes since the last visit. 
• 
Record concomitant medications. 
• 
Symptom-directed physical examination, if needed.   
• 
Vital signs: temperature and pulse. 
• 
Examine placebo microneedle patch application site. Subjects with 
localized rash, scarring or evidence of infection at placebo microneedle 
patch application site are to be evaluated by a study investigator. Per 
investigator discretion, photographic documentation (refer to MOP) and 
dermatologic referrals may be obtained. 
• 
Study personnel will review the memory aid information with the LAR and 
record all AE/SAEs. 
• 
The follow-up acceptability questionnaire will be completed by the LAR. 
 
7.3 
Visit 3: Day 8 (+2), Clinic Visit 
The following assessments will be performed. 
• 
Obtain interim medical history and note any changes since the last visit. 
• 
Record concomitant medications. 
• 
Symptom-directed physical examination, if needed.   
• 
Vital signs: temperature and pulse. 
• 
Examine placebo microneedle patch application site. Subjects with 
localized rash, scarring or evidence of secondary infection at microneedle 
patch application site are to be evaluated by a study investigator. Per 
investigator discretion, photographic documentation (refer to MOP) and 
dermatologic referrals may be initiated for subjects with localized 
reactions. 
• 
Study personnel will review the memory aid information with the LAR and 
record all AE/SAEs. If symptoms persist, clinic staff will attempt to follow 
up with the subject daily until two days symptom-free. Maximum severity 
post Day 8 and stop date of the symptoms will be recorded by clinic staff 
on the Solicited Events eCRF. 
• 
The follow-up acceptability questionnaire will be completed by the LAR. 
The LARs of subjects who have no ongoing solicited or unsolicited 
general AE or local AEs will have the opportunity to decide to have 
second and third placebo microneedle patches placed at different body 
sites from the initial location. 
• 
Subjects with solicited or unsolicited general AE or local AEs or declining 
the optional microneedle patch 2/3 will then proceed to the Final Study 
Visit (Days 27 – 38).  
 
Optional Microneedle Patch 2/3 Study Events Day 8 (+2 days) 
• 
The optional consent for the optional placebo microneedle patches 2/3 
will be signed before additional study procedures occur on Day 8 (if not 
already signed). 
• 
Inclusion/Exclusion criteria review. 
• 
A baseline photograph of the area of application may be obtained.  

 
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• 
Application of placebo microneedle patches 2/3 to the skin in a different 
location than previously by a trained study nurse. The placebo 
microneedle patches will remain in place for up to 20 minutes. The 
patches will then be removed and the used patch will be saved.  
• 
The memory aid, thermometer and ruler will be provided to the LAR and 
instructions will be provided. 
• 
The site of the placebo microneedle patches removal will be assessed at 
least 15 minutes and 30 minutes post-placebo microneedle patch 
removal. Per investigator discretion, photographic documentation (refer to 
MOP) and dermatologic referrals may be obtained.  
• 
Study personnel will assess and record all AE/SAEs that occur after 
enrollment. 
• 
The acceptability questionnaire will be completed by the LAR.  
7.4 
Visit 4:  Day 9 (+2) Clinic Visit (Only in those with Placebo 
Microneedle Patches 2/3 placement) 
The following assessments will be performed. 
• 
Obtain interim medical history and note any changes since the last visit. 
• 
Record concomitant medications. 
• 
Symptom-directed physical examination, if needed.   
• 
Vital signs: temperature and pulse. 
• 
Examine placebo microneedle patch application sites. Subjects with 
localized rash, scarring or evidence of infection at placebo microneedle 
patch application site are to be evaluated by a study investigator. Per 
investigator discretion, photographic documentation (refer to MOP) and 
dermatologic referrals may be obtained. 
• 
Study personnel will review the memory aid information with the LAR and 
record all AE/SAEs. 
• 
The acceptability questionnaire will be completed by the LAR.  
 
7.5 
Visit 5: Day 15 (+3), Clinic Visit (Only in those with Placebo 
Microneedle Patches 2/3 placement) 
The following assessments will be performed. 
• 
Obtain interim medical history and note any changes since the last visit. 
• 
Record concomitant medications. 
• 
Symptom-directed physical examination, if needed.   
• 
Vital signs: temperature and pulse. 
• 
Examine placebo microneedle patch application site. Subjects with 
localized rash, scarring or evidence of secondary infection at placebo 
microneedle patch application site are to be evaluated by a study 
investigator. Per investigator discretion, photographic documentation 
(refer to MOP) and dermatologic referrals may be obtained. 

 
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• 
Study personnel will review the memory aid information with the LAR and 
record all AE/SAEs. If symptoms persist, clinic staff will attempt to follow 
up with the LAR daily until the child is symptom-free for 2 days. Maximum 
severity post Day 15 in those that receive a second and third patch and 
stop date of the symptoms will be recorded by clinic staff on the Solicited 
Events eCRF. 
• 
The follow-up acceptability questionnaire will be completed by the LAR. 
7.6 
Final Visit: Day 27 - 38, Telephone Call 
The following assessments will be performed. 
• 
Obtain interim medical history and note any changes since the last visit. 
• 
Record concomitant medications. 
• 
Study personnel will review the memory aid information with the LAR (if 
ongoing symptoms were noted at Day 8 for placebo microneedle patch 1 
and Day 15 for placebo microneedle patch 2/3) and record all AE/SAEs. 
• 
The final acceptability questionnaire will be completed by the LAR.  
7.7 
Premature Discontinuation Visit (if applicable) 
The following activities will be performed (if the LAR agrees) should a premature 
discontinuation occur: 
• 
Obtain interim medical history and note any changes since the last visit. 
• 
Record concomitant medications. 
• 
Symptom-directed physical examination, if needed.   
• 
Vital signs: temperature and pulse. 
• 
Examine placebo microneedle patch application site. Subjects with 
localized rash, scarring or evidence of secondary infection at placebo 
microneedle patch application site are to be evaluated by a study 
investigator. Per investigator discretion, photographic documentation 
(refer to MOP) and dermatologic referrals may be obtained. 
• 
Study personnel will review the memory aid information with the LAR and 
record all AE/SAEs. 
• 
The follow-up acceptability questionnaire will be completed by the LAR.  
7.8 
Unscheduled Visit (if needed) 
The following activities will be performed should an unscheduled visit occur: 
• 
Obtain interim medical history and note any changes since the last visit. 
• 
Record concomitant medications. 
• 
Symptom-directed physical examination, if needed.   
• 
Vital signs: temperature and pulse. 

 
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• 
Examine placebo microneedle patch application site. Subjects with 
localized rash, scarring or evidence of secondary infection at placebo 
microneedle patch application site are to be evaluated by a study 
investigator. Per investigator discretion, photographic documentation 
(refer to MOP) and dermatologic referrals may be obtained. 
• 
Study personnel will review the memory aid information with the LAR and 
record all AE/SAEs. 
• 
The follow-up acceptability questionnaire will be completed by the LAR. 
 

 
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8 
STUDY PROCEDURES/EVALUATIONS 
8.1 
Clinical Evaluations 
8.1.1 Medical History 
A complete medical history will be obtained by direct interview with the LAR.  
LAR(s) will be asked about any history in their infant or young child of significant medical 
disorders of the head, eyes, ears, nose, throat, mouth, cardiovascular system, 
respiratory system, gastrointestinal tract, liver, pancreas, kidney, urologic system, 
nervous system, blood and lymphatics, endocrine system, musculoskeletal system, skin 
and genial/reproductive tract.  A history of any allergies or hypersensitivities, cancer, 
immunodeficiency, and autoimmune diseases will be solicited. Interim medical history is 
also obtained at each clinic visit.  
8.1.2 Concomitant Medications 
All medications including prescriptions, over-the-counter medications, vitamins and 
supplements taken by the subject in the 30 days prior to enrollment should be recorded 
at the screening visit. Assessment of eligibility will also include a review of permitted and 
prohibited medications per the exclusion criteria. At subsequent visits, LAR(s) will be 
queried about changes in their infant or young child’s medications.  Each new 
concomitant medication or change to existing medication will be recorded through the 
Final Study Visit (Day 27 – 38).  
Medications which may interfere with the evaluation of the investigational product should 
not be used during the study unless absolutely necessary.  Medications or treatments 
which are prohibited include: 
• 
Vaccines (unless clinically necessary, vaccines should be avoided within 
7 days of enrollment. Live vaccines should not be administered during the 
study).  
• 
Oral, parenteral or high-dose inhaled steroids. 
• 
Immunosuppressive or cytotoxic therapy. 
• 
Blood products or immunoglobulins. 
• 
Experimental products. 

 
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8.1.3 Vital Signs 
Vital sign assessments including pulse and temperature will be taken at each in-clinic 
visit through Day 8 (+2 days) (Day 15 +3 days in those having placebo microneedle 
patches 2/3 placed).   
8.1.4 Physical Examination 
A complete physical examination (PE) will be performed at the Day 1 visit. A symptom-
directed PE will be performed at all other in-clinic study visits.  All PEs will be performed 
by a clinician licensed to make medical diagnoses and listed on the Form 1572 as the site 
principal investigator or sub-investigator.  
8.1.5 Reactogenicity 
The LAR will be provided with a memory aid, thermometer and ruler and will be 
instructed to record the presence of solicited symptoms and oral temperature through 
the Day 8 (+2 days) (Day 15 +3 days in those having microneedle patches 2/3 placed)..  
If a symptom is still present at that time, the LAR will continue to follow that symptom 
until two days symptom-free.  Memory aids will be reviewed and collected by study staff 
at follow-up visits.  
Solicited local microneedle patch application site symptoms include: 
• 
Pain  
• 
Erythema 
• 
Ecchymosis (bruising) 
• 
Induration/swelling 
• 
Pruritus (itching) 
• 
Tenderness 
Solicited systemic reactions include: 
• 
Fever 
• 
Irritability (fussiness) above baseline 
• 
Lethargy (drowsiness) 
• 
Decreased appetite 
• 
Vomiting 
The LAR will use the following grading scale for describing symptoms: 

 
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Grade 0: Not present 
Grade 1: Mild (present but easily tolerated) 
Grade 2: Moderate (able to tolerate routine activity with effort) 
Grade 3: Severe (unable to continue routine activity) 
8.1.6 Acceptability Assessments:  
To gauge LAR acceptability of vaccination using a microneedle patch, the LAR will 
complete a survey at Days 1, 2 (+1 day), 8 (+2 days), and Day 27 - 38 (Day 9 (+2 days) 
and Day 15 (+3 days) in those having placebo microneedle patches 2/3) including items 
that assess vaccination acceptability items (outcomes) via continuous scales (0-10 
likelihood) and vaccination knowledge, attitudes, perceptions, and beliefs using Likert-type 
measurement (1-5 agreement levels) for multiple time point ANOVA and correlational 
analyses. The LAR will report on absolute and relative scores of ease of use, pain, product 
apprehension, comparative product utility, and overall preference comparing placebo 
microneedle patch application to previous experience with needle and syringe injection 
(Day 1); preference comparing the post-patch period to prior experience with vaccination 
(Day 8 (+2 days), and 27 – 38; also Day 9 (+2 days) and Day 15 (+3 days) in those having 
placebo microneedle patches 2/3); and perception of ease with which they might 
administer a microneedle patch in the future. The same LAR will complete the survey at 
all follow-up time points whenever possible. Basic sociodemographic characteristics will 
also be included, such as race/ethnicity, healthcare utilization/access, parental 
educational attainment, healthcare experience including previous immunization history, 
and socioeconomic indicators (household income, education).  

 
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9 
SAFETY ASSESSMENT AND REPORTING 
9.1 
Definitions 
9.1.1  Definition of an Adverse Event (AE) 
An AE is any untoward or unfavorable medical occurrence in a human subject, 
including any abnormal sign (e.g., abnormal physical exam or laboratory finding), 
symptom, or disease temporally associated with the use of study treatment, whether or 
not considered related to the study treatment. 
9.1.2 Definition of a Serious Adverse Event (SAE) 
A “Serious Adverse Event” (SAE) is defined in 21 CFR 312.32.  An SAE is any 
adverse event that meets at least one of the following criteria 
• 
Death; 
• 
Life-threatening; 
Life-threatening:  an adverse event is considered “life-threatening” if, in 
the view of either the investigator or sponsor, its occurrence places the 
subject at immediate risk of death.  It does not include an adverse event 
that, had it occurred in a more severe form, might have caused death. 
• 
Hospitalization (initial or prolonged); 
• 
Disability or permanent damage; 
• 
Other important medical event. 
Important Medical Event: Events which do not fit the other outcomes, but 
may jeopardize the subject and may require medical or surgical 
intervention (treatment) to prevent one of the other outcomes. Examples 
include allergic bronchospasm (a serious problem with breathing) 
requiring treatment in an emergency room, serious blood dyscrasias 
(blood disorders) or seizures/convulsions that do not result in 
hospitalization.  

 
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9.2 
Methods and Timing for Assessing, Recording, and 
Analyzing Safety Parameters 
All safety parameters will be graded using the scales listed in the Appendices B and C. 
9.2.1 Adverse Events 
All AEs occurring while on study during the AE reporting period must be 
documented appropriately regardless of seriousness, severity, or causal relationship to 
study produce administration. AEs will be recorded on the AE page of the CRF.  
Solicited AEs will be collected from Day 1 (after placebo microneedle placement) 
through Day 8 following placebo microneedle administration (Day 15 in those receiving 
placebo microneedle patches 2/3). Unsolicited AEs and SAEs will be collected from Day 
1 (after placebo microneedle placement) through the Day 27 – 38 end of study visit.  AE 
details will be collected via interview with the subject LAR.  Information to be collected 
includes event description, date of onset, severity and date of resolution/stabilization of 
the event. Severity and relationship to study product (either “related” or “unrelated”) must 
be assessed by the Investigator or sub-investigator.  Signs and symptoms due to a 
single diagnosis will be reported as the diagnosis.  For example, cough, pharyngitis, 
rhinitis would be reported as “upper respiratory infection”.  If multiple signs/symptoms 
presenting simultaneously cannot be attributed to the same etiology, then each symptom 
should be reported separately. 
Any medical condition present at the time the subject is screened, or occurring 
prior to placebo microneedle placement will not be considered an AE, but will be 
captured in the medical history form.  If a preexisting condition worsens (changes in 
severity or quality, not consistent with the subject’s reported past history of the condition) 
at any time during the study, this change should be captured as an AE. 
9.2.2 Reactogenicity  
Reactogenicity events are reactions that are common and known to or expected 
to occur following the administration of the study product. Subjects LAR will be provided 
with a memory aid, thermometer and ruler and will be instructed to record the presence 
of solicited symptoms and oral temperature through Day 8 after placebo microneedle 

 
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placement (Day 15 in those receiving placebo microneedle patches 2/3). If a symptom is 
still present at Day 8 (Day 15 in those receiving placebo microneedle patches 2/3), the 
subject LAR will continue to follow that symptom until two days symptom-free.  Memory 
aids will be reviewed and collected by study staff at follow up visits.  Reactogenicity 
event details will be collected via review of the subject’s memory aid and by interview 
with the subject LAR. Memory aid will not be considered source. The subject memory 
aid will be reviewed with the subject LAR at subsequent visits.  Reactogenicity will be 
analyzed using Appendices B + C.  
9.2.3 Serious Adverse Events 
 
SAEs will be collected from Day 1 (after placebo microneedle administration) 
through the end of study participation. Any suspected SAE that occurs outside of the 
protocol-specified follow-up period and considered to be caused by the study placebo 
microneedle must be reported.  
9.2.4 Procedures to be followed in the Event of Abnormal 
Laboratory Test Values or Abnormal Clinical Findings 
AEs/SAEs will be followed until resolved or stable even if this extends beyond the 
study-reporting period.  Resolution of an AE/SAE is defined as the return to pretreatment 
status or stabilization of the condition with the expectation that it will remain chronic. 
9.3 
Reporting Procedures 
Related AE grade 3 and above will be reported to the Sponsor within 5 business 
days.   
9.3.1 Serious Adverse Event Detection and Reporting 
The following procedures will apply to all events meeting the definition of SAE as 
described in Section 9.1.2 SAEs:  
The site Investigator must submit an initial SAE report immediately (within 24 
hours of site awareness) to the Sponsor. 

 
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• 
Complete an initial SAE report form, reviewed and signed by PI or 
physician sub-investigator 
• 
Initial report submitted by the PI on an expedited basis to the Sponsor 
• 
SAEs must be reviewed and followed to resolution by a study physician 
• 
Follow up reports submitted to document additional pertinent information 
and resolution of the event 
9.3.2 Reporting to IRB 
The PI is responsible for reporting AEs to the site IRB in accordance with the IRB’s 
requirements for expedited reporting and continuing review reporting. 
9.3.3 Type and Duration of the Follow-up of Subjects After Adverse 
Events 
AEs and SAEs will be followed until resolution or stability even if this extends beyond the 
study reporting period.  Resolution is defined as when the condition resolves (either with 
or without residual effects), returns to baseline for a pre-existing condition or has 
stabilized and is expected to remain chronic. 
9.4 
Individual Halting Rules 
Enrolled subjects will not be eligible to receive placebo microneedle patches 2/3 placement at 
Day 8 (+2 days) if any of the following occur: 
• 
An ongoing ≥Grade 1 local site reaction (see Appendix B). 
• 
An ongoing ≥Grade 1 solicited general AE (see Appendix C) or 
unsolicited AE. 
Subjects unable to receive placebo microneedle patches 2/3 due to meeting an individual 
halting rule will continue to follow up according to the protocol through Day 27 – 38.  
 

 
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9.5 
Study Halting Rules 
Further enrollment and placebo microneedle patch application (e.g., placebo 
microneedle patch 2/3 placement) to subjects will be halted if any of the following occur: 
• 
Any death following placebo microneedle patch application. 
• 
Any subject develops erosion, ulceration, or abscess at the administration 
site related to study product administration. 
• 
Any subject develops laryngospasm, bronchospasm or anaphylaxis within 
24 hours of placebo microneedle patch administration. 
• 
Any subject experiences a placebo microneedle patch-related SAE. 
• 
Any Grade 3 AEs or an SAE that cannot be clearly attributed to another 
cause. 
If the study is halted, the site will immediately notify the Sponsor and the Emory IRB. Prior to 
recommencing enrollment, all available safety data will be reviewed by the site Investigator 
and the Sponsor.   

 
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10 
CLINICAL MONITORING STRUCTURE 
10.1 Study Documentation 
The Principal Investigator will maintain appropriate medical and research records for this 
trial, in compliance with ICH-GCP, regulatory and institutional requirements for the protection of 
confidentiality of subjects. Source documents are the original data source used by the 
Investigator that allow verification of the study data collected, captured on CRFs and entered 
into the study database.  Source documents may include but are not limited to: clinical charts 
and progress notes, memoranda, pharmacy dispensing records and other research records 
maintained for the clinical trial.  Study CRFs may serve as the original source document. 
The Investigator will permit authorized representatives of the Sponsor and regulatory 
agencies to examine (and when required by applicable law, to copy) clinical records for the 
purposes of quality assurance reviews, audits and evaluation of the study safety and progress. 
10.2 Data Collection and Data Management  
The Investigator and designated study staff will keep accurate records to ensure that the 
conduct of the study is fully documented. The investigator will ensure that all CRFs and subject 
study files are legible and complete for every subject. A detailed description of each of the forms 
and the procedures required for forms completion and submission can be found in the MOP. 
The Investigator or designee must record all required subject data, and an explanation must be 
documented for any missing data. 
Clinical research data will be collected and recorded in a timely fashion in a secure 
electronic web-based database (e.g., REDCap).  Extracted data will be sent to the statisticians 
for statistical analysis as needed. The final study database and statistical evaluations will be 
transferred to the Sponsor at the study completion. 
10.3 Data Quality Control/Quality Assurance  
 
The Principal Investigator, through the use of an internal Quality Management Plan and 
appropriate internal site monitoring staff, will be responsible for the regular review of the conduct 
of the trial, for verifying adherence to the protocol, and for confirming the completeness, 

 
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consistency, and accuracy of all documented data and accuracy of source documentation 
verification.  
10.4 Site Monitoring Plan 
The study data integrity and compliance with the protocol will be assured by the 
monitoring of the study documentation and study conduct by an internal monitor.  Routine data 
monitoring and protocol compliance will be performed by the site investigators, study 
coordinator and quality assurance staff on an ongoing basis. The study clinical monitoring plan 
and the data quality monitoring plan will be developed and followed by the study site. 
10.5 Timing/Reports 
A cumulative report of related AE grade 3, major deviations and subject terminations is 
sent to sponsor on a monthly basis. SAEs are reported within 24 hours to the IRB and the 
sponsor.  
10.6 Study Records Retention 
Study records including source documentation, CRFs, informed consent documents, 
laboratory report forms, study product accountability records and regulatory files will be retained 
for a period of 18 years after the submission of the final report and closeout procedures on the 
research project for which the clinical trials records were prepared or termination of the study, 
unless a longer retention period is specified by Emory policy, the sponsor, or regulation. In 
addition, records must be maintained for at least 2 years after a marketing application is 
approved for the study product (i.e. microneedle patch). The Investigator must notify the study 
Sponsor prior to destroying any study records.  Consent forms for future use samples must be 
maintained as long as the sample exists. 
10.7 Protocol Deviations 
A protocol deviation is any change, deviation or departure from the study design or 
procedures of the research protocol that is not approved by the Sponsor and/or IRB prior to its 
initiation or implementation, or deviation from standard operating procedures, Good Clinical 
Practices (GCPs), federal state or local regulations.  These protocol violations may be major or 

 
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minor violations.  The Investigator and study staff will have ongoing monitoring to identify any 
protocol deviations during the conduct of the study and to report any deviations to the Sponsor 
or Emory IRB as appropriate.  
Minor protocol deviations are deviations from the research protocol that do not (a) 
adversely affect the rights, welfare or safety of subjects; (b) adversely affect the integrity of 
research data; (c) adversely affect the subjects’ willingness to continue participation in the 
research; or (d) were not undertaken to prevent immediate hazard to a human subject.  A minor 
protocol deviation or protocol non-compliance will be reported to the Sponsor on an ongoing 
basis. Minor deviations do not require reporting to the Emory IRB for review unless subject 
safety is a concern.  A major protocol deviation must be reported to the Sponsor and Emory IRB 
(per IRB reporting guidelines) immediately upon discovery of the deviation and no later than 10 
days after site awareness. 

 
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11 
STATISTICAL CONSIDERATIONS 
11.1 Study Outcome Endpoints 
Primary:  
Safety: 
• 
Occurrence of placebo microneedle patch-related serious adverse events from 
Day 1 through the Final Study Visit (Day 27 – 38). 
• 
Occurrence of Grade 3 placebo microneedle patch-related solicited adverse 
events for the 8 days following application of the patch. 
 
Reactogenicity: 
• 
Occurrence of solicited application site reactogenicity (e.g., erythema, 
induration, bruising, itching) for the 8 days following application of the patch.  
 
Secondary: 
• 
Occurrence of Grade 3 placebo microneedle patch-related unsolicited adverse 
events from Day 1 through the Final Study Visit (Day 27 – 38). 
• 
Occurrence of new-onset medical conditions (NOMC) from Day 1 through the 
Final Study Visit (Day 27 – 38). 
• 
Occurrence of solicited and unsolicited adverse events described at the site at 
which the placebo microneedle patch was applied.  
• 
Quantitative and qualitative description of LAR responses to survey questions.  
 
11.2 Sample Size Considerations 
For sample size calculation and statistical analysis plan the primary and secondary 
endpoints will mainly be addressed. The small numbers in this study allow only rough estimates 
of safety. With 25 subjects per cohort, if the true event rate is 5%, we will have 34% chance to 
observe one AE and 12% chance to observe more. If the true event rate is 10%, the chance to 
observe one AE is 38%, and the chance to observe more than one AEs is 34%.  
11.3 Analysis Plan 
The safety population includes all subjects who receive the placebo microneedle patch. 
The safety population will be the primary analysis population for safety analyses. AEs will be 
analyzed using the safety population. Subjects will be analyzed as treated. 

 
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Primary Outcome Endpoints 
AEs, reactogenicity events and SAEs will be recorded throughout the study. AEs will be 
coded using the Medical Dictionary for Regulatory Activities (MedDRA) dictionary. AE summary 
tables will be based on treatment-emergent AEs for the safety population. Descriptive statistics 
(e.g., number and percentage of subjects) will be used for each treatment group. AEs will be 
summarized by severity, relationship to treatment, and AEs leading to discontinuation. SAEs will 
also be tabulated by overall and treatment related events. 
Secondary Outcome Endpoints 
Unsolicited AEs and new-onset medical conditions (NOMC) will be recorded. AEs will be 
coded using the Medical Dictionary for Regulatory Activities (MedDRA) dictionary. AE summary 
tables will be based on treatment-emergent AEs for the safety population. Descriptive statistics 
(e.g., number and percentage of subjects) will be used for each treatment group. AEs will be 
summarized by severity, relationship to treatment, and AEs leading to discontinuation. NOMC will 
also be tabulated by overall and treatment related events. 

 
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12 
ETHICS/PROTECTION OF HUMAN SUBJECTS 
12.1 Ethical Standard 
This study will be conducted in accordance with the protocol, the Declaration of Helsinki, 
ICH E6 GCP and local regulations. 
12.2 Institutional Review Board 
Prior to initiating any study procedures, the Investigator will submit the following 
documents to the Emory IRB for review and approval:  protocol and any amendments, informed 
consent, any documents to be given to the subject (e.g., memory aid), recruitment materials, 
and any other documents as requested by the IRB.  A copy of the IRB approval will be 
submitted to the Sponsor. 
Any amendments to the protocol or changes to the consent form must be submitted and 
approved by the IRB prior to implementation at the site. The Investigator will also ensure the 
timely dissemination of SAE and study safety reporting to the IRB in accordance with local IRB 
regulations and guidance. 
12.3 Informed Consent Process 
Voluntary written informed consent must be obtained before any study-related 
procedures are performed in accordance with International Conference on Harmonization (ICH) 
guidelines and the requirements of informed consent (Title 21 Code of Federal Regulations 
(CFR) Parts 50.20 and 50.25). Consent must be documented by the use of a written consent 
form approved by the site’s institutional review board (IRB) in accordance with Title 21 CFR Part 
50.27.   
Subject’s LAR will be given an adequate amount of time to read the consent and ask any 
questions prior to signing the document.  A copy of the signed informed consent will be provided 
to the subject LAR signing the form and the original retained in the source documents of the 
study subject. 

 
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12.4 Subject Confidentiality 
The investigational site participating in this study will maintain the highest degree of 
confidentiality for the clinical and research information obtained from the subjects in this clinical 
trial.  Medical and research records will be maintained at each site in the strictest confidence.  
However, as a part of the quality assurance and legal responsibilities of an investigation, the 
investigational site will permit authorized representatives of FDA and health authorities to examine 
(and when required by applicable law, to copy) clinical records for the purpose of quality 
assurance reviews, audits, and evaluations of the study safety and progress.  Unless required by 
the laws that permit copying of records, only the coded identity associated with documents or with 
other subject data may be copied (and all personally identifying information will be removed).  
Authorized representatives as noted above are bound to maintain the strict confidentiality of 
medical and research information that is linked to identify individuals.   
A subject’s privacy and confidentiality will be respected throughout the study.  Each 
subject will be assigned a sequential identification number, and these numbers, rather than 
names, will be used during collection, storage, and reporting of subject information. 
12.5 Study Discontinuation 
If the study is discontinued, enrolled subjects will continue to be followed for safety 
assessments as specified in the protocol.   

 
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13 
LITERATURE REFERENCES 
Arnou, R. et al. Intradermal influenza vaccine for older adults: A randomized controlled 
multicenter phase III study. Vaccine 27, 7304-12 (2009). 
 
Arnou Ret al. Willingness to vaccinate/get vaccinated with an intradermal seasonal influenza 
vaccine: a survey of general practitioners and the general public in France and Germany, Adv. 
Ther. 28 555–565 (2011). 
 
Birchall JC et al. Microneedles in clinical practice — an exploratory study into the opinions of 
healthcare professionals and the public, Pharm. Res. 28 95–106 (2011) 
 
Drucker E et al. The injection century: massive unsterile injections and the emergence of human 
pathogens, Lancet 358 1989–1992 (2001). 
 
Gill, H.S., Denson, D.D., Burris, B.A. & Prausnitz, M.R. Effect of microneedle design on pain in 
human volunteers. Clin J Pain 24, 585-94 (2008). 
 
Kaushik, S. et al. Lack of pain associated with microfabricated microneedles. Anesth. Analg. 92, 
502- 504 (2001). 
 
Kersten, G. & Hirschberg, H. Needle-free vaccine delivery. Expert Opin Drug Deliv 4, 459-74 
(2007). 
 
Kim YC, Park JH, Prausnitz MR. Microneedles for drug and vaccine delivery. Adv Drug Deliv 
Rev.;64(14):1547-68 (2012).  
 
Mitragotri, S. Immunization without needles. Nat Rev Immun 5, 905-16 (2005). 
 

 
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14 
SUPPLEMENTS/APPENDICES 
14.1 Appendix A: Study Schedule 
 
 
 
 
Visit # 
1 
2 
3 
4& 
5& 
Fin
al* 
 
 
Procedures 
D
1 
D2 
+1 
D8 
+2 
D9 
+2 
D15 
+3 
D27
- 
D38 
Unscheduled 
Visit (If 
needed) 
Premature 
Discontinuation 
Signed Consent Form 
X 
 
 
 
 
 
 
 
Inclusion/Exclusion Review 
X 
 
 
 
 
 
 
 
Complete Medical History 
X 
 
 
 
 
 
 
 
Concomitant Medications  
X 
X 
X 
X& 
X& 
X 
X 
X 
Interim Medical History 
 
 
X 
X 
X& 
X& 
X 
X 
X 
Sign Optional Consent For 
Microneedle Patch 2/3 
(X
) 
 
(X) 
 
 
 
 
 
Application of microneedle 
patch 
X 
 
X& 
 
 
 
 
 
Distribute memory aid, ruler 
& thermometer 
X 
 
X& 
 
 
 
 
 
Review memory aid 
 
X 
X 
X&  
X& 
(X) 
(X) 
(X) 
Physical Exam 
Complete Physical 
Exam 
X 
 
 
 
 
 
 
 
Assessment of 
microneedle patch 
application site 
X*
* 
X 
X*
*& 
X& 
X& 
 
X 
X 
Symptom-Directed 
Physical Exam 
 
(X) 
(X) 
(X)& 
(X) & 
 
(X) 
(X) 
Height and weight 
X 
 
 
 
 
 
 
 
Vital Signs^ 
X 
X 
X 
(X)& 
(X)& 
 
X 
X 
Photograph site of placebo 
microneedle patch 
(X
) 
(X) 
(X) 
(X) 
(X) 
(X) 
(X) 
(X) 
Assessment of Adverse 
Events and SAEs 
X*
* 
X 
X 
(X)& 
(X)& 
X 
X 
X 
Acceptability Questionnaire 
X 
X 
X 
(X)& 
(X)& 
X 
X 
X 
* The final study visit will be a telephone call at D27 – D38 
** Occurring 15 minutes and 30 minutes after microneedle patch removal.  
& At Day 8 the LARs of subjects who no ongoing solicited or unsolicited general AE or local AEs will have the opportunity to decide 
to have second and third placebo microneedle patches placed at different body sites from the initial location. In those that elect to 
have a second/third placebo microneedle patch placed, they will return for clinic visits on Day 9 and Day 15.  
^ Vital signs will include temperature and pulse.  
(X) – As indicated/appropriate. 
 
 
 

 
 
 
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14.2 Appendix B: Adverse Event & Reactogenicity Grading - LOCAL 
SITE REACTIONS 
 
LOCAL SITE REACTIONS 
 
Grade 
 
0 
1 
2 
3 
Induration/ Swelling * 
None to 
less than 
2.5 cm 
2.5 – 5 cm and 
does not interfere  
with activity  
5.1 – 10 cm or  
interferes with  
activity  
> 10 cm or  
prevents daily  
activity, erosion, or 
ulceration  
Erythema** 
None to 
less than 
2.5 cm 
2.5 – 5 cm  
 
5.1 – 10 cm  
 
> 10 cm, 
erythroderma, or a 
diffuse rash >15% of 
the body surface area  
 
Ecchymosis 
None 
2.5 – 5 cm  
 
5.1 – 10 cm  
 
> 10 cm  
 
Tenderness 
None 
Mild discomfort to 
touch 
Discomfort with 
movement  
Significant  
discomfort at rest  
Pain  
None 
Does not interfere  
with activity  
Repeated use of 
non-narcotic pain 
reliever > 24 hours or 
interferes with activity 
Any use of narcotic 
pain reliever or 
prevents daily  
activity  
Pruritus (Itching) 
None 
Mild 
Moderate itching; 
limiting instrumental 
activities of daily 
living 
Severe itching; limiting 
self-care activities of 
daily living 
*Induration/swelling should be evaluated and graded using the functional scale as well as the actual 
measurement 
**In addition to grading the measured local reaction at the greatest single diameter, the measurement 
should be recorded as a continuous variable. 
 
 

 
 
 
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14.3 Appendix C: Adverse Event & Reactogenicity Grading - 
GENERAL ADVERSE REACTIONS 
 
GENERAL ADVERSE REACTIONS 
 
Grade 
 
0  
1 
2 
3 
Irritability 
(fussiness) 
None 
No interference 
with 
activity  
Some interference  
with activity  
Significant;  
prevents daily  
activity  
Lethargy 
(drowsiness) 
None 
No interference 
with 
activity  
Some interference  
with activity  
Significant;  
prevents daily  
activity  
Decreased 
appetite  
None 
No interference 
with 
activity  
Some interference  
with activity  
Significant;  
prevents daily  
activity  
Vomiting 
None 
No interference  
with activity  
Some interference  
with activity  
Prevents daily  
activity, requires  
outpatient IV  
hydration  
Fever 
None 
100.4 – 101.1 F 
101.2 – 102.1 F 
>102.1 F