Clinical trial NCT02404103
Conditions: Childhood Asthma
Sponsor: University of Louisville
Start date: 2015-03-01; Completion date: 2017-06-01
Enrollment: 26 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
The purpose of this study is to see how two doses of Flunisolide HFA (an FDA approved inhaled medication to treat asthma) affect the small airways in children with asthma.

Detailed description:
This is a prospective, randomized, parallel, open label study. The primary aim is to compare the average change in spirometric values (Forced expiratory volume 1 (FEV1) and Forced Expiratory Flow 25-75% (FEF 25-75%) and Impulse Oscillometry System (IOS) values (Resistance at 5 Hz (R5), Resistance at 20 Hz (R20), Area of reactance (AX), Resonant frequency (Fres)) from baseline to week 6 from participants randomized flunisolide hydrofluoroalkane (HFA) 1 inhalation BID and to flunisolide HFA 2 inhalations BID. The change in scores from baseline to six week follow up will initially be compared using paired t-tests and Chi-squared tests for trend. Repeated measurements will be analyzed using generalized linear mixed-effects regression modeling (GLMM) techniques. For continuous outcomes (e.g. FEV1, FEF 25-75%, Fres, reactance at 5 Hz (X5), AX, R5-R20). The identity link function and normal distribution will be used. For count data (e.g., use of Beta-agonists, episodes of coughing, episodes of wheezing, etc.) the log link function and the Poisson distribution will be used. If we dichotomize outcomes (e.g., a Beta-agonist was used, coughing occurred, etc.) the logit link function and Bernoulli distribution will be used.

Arms: arm 1: Patients will receive inhaled Flunisolide HFA 80 mcg twice per day for a total of 160 mcg per day over the 6 week study period arm 2: Patients will receive inhaled Flunisolide HFA 160 mcg twice per day for a total of 320 mcg per day over the 6 week study period
Interventions: intervention 1: Flunisolide HFA
Intervention descriptions: intervention 1: None

Protocol documents:
ICF_000.pdf: 
Flunisolide HFA in Children with Small Airway Disease
2/1/2017
Page 1 of 10
INFORMED CONSENT AND RESEARCH AUTHORIZATION 
Flunisolide HFA in Children with Small Airway Disease
Industry Contracts number: OICB1500055
Sponsor(s) name & address: MEDA Pharmaceuticals, 1265 Davidson Ave, Sorensen, NJ 08873
Investigator(s) name, Degree, University Department, & address:
Scott Bickel, MD, and Nemr Eid, MD
Division of Pediatric Pulmonology
University of Louisville
571 S Floyd St., Suite 414
Louisville, KY 40202
Site(s) where study is to be conducted:
University of Louisville Pediatric Pulmonology Clinic
210 E. Gray St.
Suite 802
Louisville, Kentucky 40202
Phone number for subjects to call for questions: 502-588-4940
Introduction and Background Information
You/Your child (referred to as you in the rest of this document) are invited to take part in a research 
study because you have been diagnosed with asthma and have not been on inhaled medication for at 
least the past four weeks. The study is being conducted under the direction of Scott Bickel, MD, and 
Nemr Eid, MD, at the University of Louisville.  About 50 local subjects will be invited to take part in 
this research. 
Purpose
The purpose of this study is to see how Flunisolide HFA (an FDA approved inhaled medication to 
treat asthma) affects the lungs in asthma, especially the small airways deeper in the lungs as 
measured by tests that are commonly used in the day-to-day care of patients with asthma.
Procedures
To participate in this study, you must meet certain criteria that will be evaluated and determined by 
the study doctor and/or study staff.  Your medical history and current medical condition will be 
reviewed.  You will be asked for personal information, such as your date of birth and race/ethnicity. 
The study doctor in charge of this study or a member of the study doctor’s staff will discuss with you 
all requirements for participation in this study.
Your participation in this study will last for up to 14 weeks.  If you consent to participate, you will have 
the following procedures while you are in this study.   
UofL Institutional Review Boards
IRB NUMBER: 14.1024
IRB APPROVAL DATE: 02/26/2017
IRB EXPIRATION DATE: 02/25/2018


Flunisolide HFA in Children with Small Airway Disease
2/1/2017
Page 2 of 10
Visit 1: (1 hour)
At this visit you can expect us to do the following:

Ask you to review and sign this informed consent and HIPAA document

Obtain your past medical history and any medications you have taken in the past 4 weeks or 
are currently taking

Ask you to fill out a simple questionnaire to help show how well your asthma has been 
controlled.

Measure oxygen saturation on room air

Perform a physical exam (weight, height, blood pressure, heart rate, temperature, etc)

Collect urine to preform a pregnancy test if you are a female who could be pregnant

Require that you have the following procedures:
o
Spirometry  - a breathing test where you will be asked to take a very deep breath and 
blow out as hard and quick as you can into a mouthpiece connected to a computer
o
Impulse oscillometry - a test where you will be asked to sit up straight and breathe 
normally for about 30 seconds while you have a mouthpiece in place.  You will hear a 
quiet “ticking” sound during the procedure but it is painless and does not require 
significant effort.  
This visit will determine if you are eligible to be enrolled in the study.  If you meet the study criteria, 
we will ask you to continue in the study and schedule a second visit.
Visit 2: (1 hour; 1 to 56 days after visit 1))
At this visit you can expect us to do the following:

Ask you to fill out a simple questionnaire to help show how well your asthma has been 
controlled

Review your health status/medical history

Review any medications you are taking

Obtain vital signs (heart rate, temperature, respiratory rate and blood pressure)

Measure your oxygen saturation on room air

Measure your height and weight

Perform a short physical exam

Perform pre-bronchodilator impulse oscillometry

Perform pre-bronchodilator spirometry

Receive bronchodilator (albuterol, 4 puffs via spacer, or ProAir if you are currently using it)

Perform post-bronchodilator impulse oscillometry

Perform post-bronchodilator spirometry

Randomly assign you (a process like flipping a coin) to a one of two doses of flunisolide (either 
80 mcg 1 puff twice a day or 80 mcg 2 puffs twice a day)

Provide you with flunisolide and teach you how to use the study drug device, per 
manufacturer’s instructions

Provide you with albuterol sulfate for breakthrough symptoms.
Visit 3: (1 hour; 6 weeks after visit 2)
At this visit you can expect us to do the following:

Review your health status/medical history
UofL Institutional Review Boards
IRB NUMBER: 14.1024
IRB APPROVAL DATE: 02/26/2017
IRB EXPIRATION DATE: 02/25/2018


Flunisolide HFA in Children with Small Airway Disease
2/1/2017
Page 3 of 10

Review any medications you are taking

Obtain vital signs (heart rate, temperature, respiratory rate and blood pressure)

Measure your oxygen saturation on room air

Measure your height and weight

Perform a short physical exam

Perform pre-bronchodilator impulse oscillometry

Perform pre-bronchodilator spirometry

Receive bronchodilator (albuterol, 4 puffs via spacer)

Perform post-bronchodilator impulse oscillometry

Perform post-bronchodilator spirometry

Record any adverse events you may have experienced 
 
Potential Risks
The following table details the known risks related to Flunisolide HFA and how often they may occur. 
Very Common
Greater than 10%
Common
Between 1% and 10%
Uncommon 
Between 0.1% and 1%

Sore throat

Runny nose

Headache
Fever
Allergic reaction
Infection
Back pain
Vomiting
Upset stomach
Cough
Sinus infection
Nose bleed
Rash

Urinary tract infection
The following table details the know risks related to albuterol and how often they occur.
Very Common
Greater than 10%
Common
Between 1% and 10%
Uncommon 
Between 0.1% and 1%
Asthma worsening
Ear infection
Allergic reaction
Dry mouth and throat

Diarrhea
Cough, hoarseness, sore 
throat, runny or stuffy nose
Swollen lymph nodes
Muscle pain
Skin infection
Hives
Migraine headache
Chest pain

Bronchitis
Heart rhythm 
abnormality
Bronchospasm 
(wheezing, chest 
tightness, trouble 
breathing), especially 
after starting a new 
canister of this medicine
Chest pain and fast, 
pounding, or uneven 
heart beats
Tremor, nervousness
Low potassium 
(confusion, uneven 
UofL Institutional Review Boards
IRB NUMBER: 14.1024
IRB APPROVAL DATE: 02/26/2017
IRB EXPIRATION DATE: 02/25/2018


Flunisolide HFA in Children with Small Airway Disease
2/1/2017
Page 4 of 10

Nausea

Vomiting
heart rate, extreme 
thirst, increased 
urination, leg 
discomfort, muscle 
weakness or limp 
feeling)
Dangerously high blood 
pressure (severe 
headache, blurred 
vision, buzzing in your 
ears, anxiety, 
confusion, chest pain, 
shortness of breath, 
uneven heartbeats, 
seizure)
There may also be other procedures required as part of the study.  The risks associated with Impulse 
oscillometry and spirometry include becoming short of breath when asked to inhale and exhale 
deeply and quickly.  
In addition, you may suffer harms that we have not seen before. 
Possible Pregnancy Risks 
You should discuss pregnancy risks with your doctor before signing this consent form. Women who 
are pregnant or breast feeding may not participate in this research study.  If you are pregnant or 
become pregnant, your unborn child may suffer harms that we have not seen before. If you (or your 
partner) become pregnant while in this study, the sponsor may ask to follow the outcome of the 
pregnancy.  If you agree to allow the study doctor to follow your pregnancy, you will be asked to read 
and sign a separate consent form for permission to follow the outcome of your pregnancy.  
If you are a man taking part in the study and your partner becomes pregnant, the study doctor may 
ask you to ask your partner for permission to follow her pregnancy.  If she agrees, she will be asked 
to sign a separate consent form mentioned above.
Before starting this research study, females able to have children will have a pregnancy test.  Talk to 
your doctor about the best method of birth control to use while you are in this study.  It is important 
that you call your study doctor at 502-588-4940 right away if you become pregnant or father a child 
during the course of this study.  If you or your partner becomes pregnant, a decision may have to be 
made whether or not to end the pregnancy.  
We do not know the effects of flunisolide on an unborn baby.  There is a risk that your unborn baby 
could be harmed if you become pregnant during your participation in the study.  (If you ask, your 
study doctor will discuss the possible risks to your unborn child and your options should you become 
pregnant while in this study.)
UofL Institutional Review Boards
IRB NUMBER: 14.1024
IRB APPROVAL DATE: 02/26/2017
IRB EXPIRATION DATE: 02/25/2018


Flunisolide HFA in Children with Small Airway Disease
2/1/2017
Page 5 of 10
Benefits
The possible benefits of this study include improving your asthma control and having access to an 
inhaler device that may be easier to use than others (as it does not require a separate spacer).
Alternatives
Instead of taking part in this study, you could choose to not to participate in this study. You can 
discuss other medications and/or methods with your doctor to bring your asthma symptoms under 
control.
Research Related Injury 
If you are injured by being in this research study, the study doctor will arrange for you to get medical 
treatment. The sponsor will pay for any reasonable medical costs related to the treatment of your 
injury. If you are injured, there is no money set aside for lost wages, discomfort, disability, etc. You do 
not give up your legal rights by signing this form. If you think you have a research related injury, 
please call your study doctor, Dr. Bickel at 502-588-4940.
Compensation
You will be paid $50 by Visa gift card for your time, inconvenience, or expenses while you are in this 
study. Because you will be paid to be in this study the University of Louisville may collect your name, 
address, social security number, and keep records of how much you are paid.  You may or may not 
be sent a Form 1099 by the University.  This will only happen if you are paid $600 or more in one 
year by the University. This will not include payments you may receive as reimbursement, for 
example mileage reimbursement. We are required by the Internal Revenue Service to collect this 
information and you may need to report the payment as income on your taxes.  
Costs
You will not be billed for the following office visits, tests, medications, and procedures that are done 
for this research study that are done for the research study: Flunisolide HFA, spirometry and impulse 
oscillometry.  The charges for these items will be paid for by the Sponsor.  
You or your insurance company will be billed for all office visits, tests, medications and procedures 
that are part of your routine medical care outside of this research study.  You will be responsible for 
paying your co-pay that is associated with any office visit, test, medication or procedure.  Some 
insurance companies will not pay for medical bills for people who participate in a research study.   It is 
your responsibility to find out what costs, if any, your insurance company will cover before taking part 
in the study. If you need help finding out what your insurance company will cover, please ask your 
study doctor for assistance. If your insurance company does not pay for your bills associated with this 
study, you will be responsible for paying them.”   
UofL Institutional Review Boards
IRB NUMBER: 14.1024
IRB APPROVAL DATE: 02/26/2017
IRB EXPIRATION DATE: 02/25/2018


Flunisolide HFA in Children with Small Airway Disease
2/1/2017
Page 6 of 10
HIPAA Research Authorization 
The Health Insurance Portability and Accountability Act of 1996 (HIPAA) provides federal safeguards 
for your protected health information (PHI).   Examples of PHI are your name, address, and birth date 
together with your health information.  PHI may also include your medical history, results of health 
exams and lab tests, drugs taken and results of this research study.  Your PHI may not be used or 
shared without your agreement, unless it meets one of the HIPAA exceptions. 
State and federal privacy laws protect your health information.  In most cases, health information that 
identifies you can be used or shared by the research team only if you give your permission by signing 
this form.   
If you sign this form your health information will be used and shared to answer the research questions 
described above and to make sure that the research was done correctly. The time period when 
information can be used or shared ends when all activities related to this study are completed.  
Your access to your health information will not be limited during this study
You do not have to sign this form.  If you do not sign this form you may not participate in the study 
and health information that identifies you will not be shared with the research team.  
Site(s) where health information about you will be used or shared for this research:
In our research, the research team will look at and may share information about you and your health.  
Federal law requires that health care providers and researchers protect the privacy and security of 
health information that identifies you.  We may ask for your health information from the following:
Faculty Practice Group Sites:
University of Louisville Pediatric Pulmonology Clinic
Protected health information (PHI) that will be used or shared for research 
Consultation reports
Healthcare Provider orders
History and physical exams
Laboratory, x-ray and other tests
Records about the study drug and other drugs you may be taking
Revocation of Research Authorization
You may cancel the permission you have given to use and share your protected health information at 
any time.  This means you can tell us to stop using and sharing your protected health information.  If 
you cancel your permission:

We will stop collecting information about you.

You may not withdraw information that we had before you told us to stop.
UofL Institutional Review Boards
IRB NUMBER: 14.1024
IRB APPROVAL DATE: 02/26/2017
IRB EXPIRATION DATE: 02/25/2018


Flunisolide HFA in Children with Small Airway Disease
2/1/2017
Page 7 of 10
o
We may already have used it or shared it.
o
We may need it to complete the research.

Staff may ask your permission to follow-up with you if there is a medical reason to do so.
To cancel your permission, you will be requested to complete a written “Revocation of Research 
Authorization” form located at the end of this document.  You may also obtain a copy from your study 
doctor, designated personnel or from the Human Subjects Protections Program Office website 
(http://louisville.edu/research/humansubjects/links-to-forms). 
Information Available on ClinicalTrials.gov
A description of this clinical trial will be available on http://www.ClinicalTrials.gov, as required by U.S. 
Law.  This website will not include information that can identify you. At most, the website will include a 
summary of the results. You can search this website at any time.
Confidentiality
Total privacy cannot be guaranteed.  We will protect your privacy to the extent permitted by law.  If 
the results from this study are published, your name will not be made public. Once your information 
leaves our institution, we cannot promise that others will keep it private.  
Your information may be shared with the following:

The sponsor (MEDA Pharmaceuticals) and others hired by the sponsor to oversee the 
research

The University of Louisville Institutional Review Board, Human Subjects Protection Program 
Office, Privacy Office and others involved in research administration at the University

The local research team

People responsible for billing, sending and receiving payments related to your participation in 
the study 

Government agencies, such as: 
o
Office for Human Research Protections 
o
Office of Civil Rights
o
Food and Drug Administration 
Security 
The data collected about you will be kept private and secure in the UL Pediatric Pulmonology Clinic in 
a locked office.  Data stored on a computer will be kept in a secured, password protected location 
which will be accessible only by those authorized by the study.
 
Conflict of Interest 
This study involves a conflict of interest because: the institution and investigator will be compensated 
for your participation.  The investigator may also receive compensation from the sponsor in exchange 
for sharing your study results and your protected health information with the sponsor.  This 
UofL Institutional Review Boards
IRB NUMBER: 14.1024
IRB APPROVAL DATE: 02/26/2017
IRB EXPIRATION DATE: 02/25/2018


Flunisolide HFA in Children with Small Airway Disease
2/1/2017
Page 8 of 10
compensation is used to pay for the costs of doing this study.  If you want to know, please ask the 
investigator how the institution and investigator will benefit by your participation in the study.
Voluntary Participation
Taking part in this study is completely voluntary. You may choose not to take part at all.  If you decide 
not to be in this study, you won’t be penalized or lose any benefits for which you qualify. If you decide 
to be in this study, you may change your mind and stop taking part at any time. If you decide to stop 
taking part, you won’t be penalized or lose any benefits for which you qualify.  You will be told about 
any new information learned during the study that could affect your decision to continue in the study.
Termination
Your study doctor or the study sponsor has the right to stop this study at any point. Your study doctor 
may take you out of this study with or without your okay.  Reasons why this may occur include: 

The study doctor believes it is best for you to stop being in the study.

You are a female and become pregnant

You do not follow directions about the study.

The sponsor stops the study for any reason. 
Participation in Other Research Studies
You may take part in this study if you are currently in another research study.  It is important to let 
your doctor know if you are in another research study.
Contact Persons
If you have any questions, concerns, or complaints about the research study, please contact Dr. 
Bickle at 502-588-4940.
UofL Institutional Review Boards
IRB NUMBER: 14.1024
IRB APPROVAL DATE: 02/26/2017
IRB EXPIRATION DATE: 02/25/2018


Flunisolide HFA in Children with Small Airway Disease
2/1/2017
Page 9 of 10
Research Subject’s Rights
If you have any questions about your rights as a research subject, you may call the Human Subjects 
Protection Program Office at (502) 852-5188.  You may discuss any questions about your rights as a 
research subject, in private, with a member of the Institutional Review Board (IRB).  You may also call 
this number if you have other questions about the research, and you cannot reach the study doctor, 
or want to talk to someone else. The IRB is an independent committee made up of people from the 
University community, staff of the institutions, as well as people from the community not connected 
with these institutions.  The IRB has approved the participation of human subjects in this research 
study. 
  
Concerns and Complaints
If you have concerns or complaints about the research or research staff and you do not wish to give 
your name, you may call the toll free number 1-877-852-1167.  This is a 24 hour hot line answered by 
people who do not work at the University of Louisville.  
Acknowledgment and Signatures
This informed consent document is not a contract.  This document tells you what will happen during 
the study if you choose to take part.  Your signature indicates that this study has been explained to 
you, that your questions have been answered, and that you agree to take part in the study.  You are 
not giving up any legal rights to which you are entitled by signing this informed consent document.  
You will be given a copy of this consent form to keep for your records. 
_______________________________________
__________________________________________
Subject Name (Please Print)
Signature of Subject
   Date Signed
___________________________________________
______________________________________________
Printed Name of Legal Representative (if applicable)
Signature of Legal Representative   
    Date Signed
    
___________________________________________      
Relationship of Legal Representative to Subject
_________________________________________
______________________________________________
Printed Name of PersonExplaining Consent Form
Signature of Person Explaining 
Date Signed
Consent Form (if other than the Investigator)
 
___________________________________________
______________________________________________
Printed Name of Investigator
Signature of Investigator
Date Signed
______________________________________________________________________________________________
List of Investigators:
Phone Numbers:
Nemr Eid, MD
502-852-3772
Scott Bickel, MD
502-558-4940 
UofL Institutional Review Boards
IRB NUMBER: 14.1024
IRB APPROVAL DATE: 02/26/2017
IRB EXPIRATION DATE: 02/25/2018


Flunisolide HFA in Children with Small Airway Disease
2/1/2017
Page 10 of 10
REVOCATION OF AUTHORIZATION FOR USE AND DISCLOSURE OF YOUR HEALTH 
INFORMATION FOR RESEARCH
Return To:
To Whom It May Concern:
I would like to discontinue my participation in the research study noted above. I understand that health 
information already collected will continue to be used as discussed in the Authorization I signed when joining 
the study.
Your options are (choose one):
□Withdraw from Study & Discontinue Authorization:
Discontinue my authorization for the future use and disclosure of protected health information. In some 
instances, the research team may need to use your information even after you discontinue your 
authorization, for example, to notify you or government agencies of any health or safety concerns that were 
identified as part of your study participation. 
□Withdraw from Study, but Continue Authorization:
Allow the research team to continue collecting information from me and my personal health information. 
This would be done only as needed to support the goals of the study and would not be used for purposes 
other than those already described in the research authorization.
____________________
___
_____
________
Printed Name and Signature of Subject
Date Signed
____________________
___
_____
________
Signature of Subject’s Legal Representative (if subject is unable to sign)
Date Signed
___________________
___
_____
________
Printed Name of Subject’s Legal Representative 
Birthdate of Subject
_________________________________________________
Relationship of Legal Representative to Subject
____________________
___
_____
________
Subject’s Address
Subject’s Phone Number
Optional:
I am ending my participation in this study because: _
_____
__
___________________
___
_____
________
PI Address:
571 S Floyd St., Suite 414
Louisville, KY 40202
Phone: 502-588-4940
Institutional Review Board
MedCenter One, Suite 200
501 E. Broadway
Louisville, KY 40202
OR
Do not sign this letter unless you are withdrawing from this research.   You will be 
sent confirmation that this notice was received.
UofL Institutional Review Boards
IRB NUMBER: 14.1024
IRB APPROVAL DATE: 02/26/2017
IRB EXPIRATION DATE: 02/25/2018

Prot_SAP_003.pdf: 
IRB Number 14.1024 
Confidential 
 
Version #: 2.0 
Version Date:  6/15/2015 
Page 1 of 36 
 
 
Clinical Research Protocol 
FLUNISOLIDE HFA IN CHILDREN WITH SMALL AIRWAY DISEASE 
Protocol Number:  2.0, IRB 14.1024 
Version Date: 6/15/2015 
Investigational Product: 
Flunisolide HFA 
Funding Agency:                       MEDA Pharmaceuticals 
                                                    265 Davidson Ave.  
                                                    Somerset, NJ 08873-4120   
Principal Investigators: 
Nemr Eid, MD 
571 S. Floyd St., Suite 414 
University of Louisville 
Louisville, KY 40202 
Voice: (502) 852-3772 
Fax: 
(502) 852-4051 
Nemr.eid@louisville.edu 
 
Co-investigators: 
 
Scott Bickel, MD 
571 S. Floyd St., Suite 414 
University of Louisville 
Louisville, KY 40202 
Voice: (502) 852-3772 
Fax: 
(502) 852-4051 
Scott.bickel@louisville.edu 
 
John Myers, PhD 
Department of Pediatrics 
University of Louisville 
 
 
 
571 South Floyd St, Suite 404 
 
 
 
Louisville, KY 40202 
Medical Monitors: 
 
Nemr Eid, MD and Scott Bickel, MD  
 
 
 
 
Clinic: (502) 629-8830 
 
 
 
 
Fax: 
(502) 852-4051 


IRB Number 14.1024 
Confidential 
 
Version #: 2.0 
Version Date:  6/15/2015 
Page 2 of 36 
 
 
Clinical Management:  
University of Louisville Physicians – Pediatric Pulmonology 
 
 
 
 
Louisville, KY 40202 
 
 
 
 
Voice: (502) 629-8830 
 
 
 
 
Fax: 
(502) 852-4051 
Data Coord. Center (DCC): 
University of Louisville Physicians – Pediatric Pulmonology (Academic 
Office) 
 
 
 
 
Louisville, KY 40202 
 
 
 
 
Voice: (502) 852-3772 
 
 
 
 
Fax: 
(502) 852-4051 
Approval: 
 
 
 
Principal Investigator Sponsor Signature  
 
Date 
This confidential information about an investigational drug is provided for the exclusive use of 
investigators of this drug and is subject to recall at any time.  The information in this document may 
not be disclosed unless federal or state law or regulations require such disclosure.  Subject to the 
foregoing, this information may be disclosed only to those persons involved in the study who have a 
need to know, with the obligation not to further disseminate this information.  These restrictions on 
disclosure will apply equally to all future oral or written information. 


IRB Number 14.1024 
Confidential 
 
Version #: 2.0 
Version Date:  6/15/2015 
Page 3 of 36 
 
 
PROTOCOL AGREEMENT 
 
I have read the protocol specified below. In my formal capacity as Investigator, my duties include ensuring the safety of the study subjects 
enrolled under my supervision.  It is understood that all information pertaining to the study will be held strictly confidential and that this 
confidentiality requirement applies to all study staff at this site. Furthermore, on behalf of the study staff and myself, I agree to maintain the 
procedures required to carry out the study in accordance with accepted GCP principles and to abide by the terms of this protocol. 
 
Protocol Number: 14.1024 
 
Protocol Title: Flunisolide HFA in Children with Small Airway Disease 
 
Protocol Date: 6/15/15 
 
 
 
 
Investigator Signature  
 
Date 
 
Print Name and Title 
Site # 
 
 
Site Name 
 
Address 
 
 
 
 
 


IRB Number 14.1024 
Confidential 
 
Version #: 2.0 
Version Date:  6/15/2015 
Page 4 of 36 
 
 
 
 
Phone Number 
 


IRB Number 14.1024 
Confidential 
 
Version #: 2.0 
Version Date:  6/15/2015 
Page 5 of 36 
 
 
TABLE OF CONTENTS 
 
1 
BACKGROUND 
14 
1.1 
Prevalence and Impact of Asthma ...................................................................................... 14 
1.2 
ICS Therapy in Asthma ...................................................................................................... 15 
1.3 
CFC and HFA Flunisolide .................................................................................................. 15 
1.4 
Clinical Pharmacology ....................................................................................................... 15 
1.5 
Pediatric Use of Flunisolide: .............................................................................................. 17 
1.6 
Efficacy of Flunisolide HFA: ............................................................................................. 18 
1.7 
Rational for lung function as primary endpoint ................................................................. 19 
1.8 
Secondary endpoints ........................................................................................................... 19 
2 
STUDY RATIONALE 
19 
3 
STUDY OBJECTIVES 
19 
3.1 
Primary Objective ............................................................................................................... 19 
4 
STUDY DESIGN 
20 
4.1 
Study Overview .................................................................................................................. 20 
4.2 
Primary Efficacy Endpoint ................................................................................................. 20 
4.3 
Secondary Efficacy Endpoints ........................................................................................... 20 
4.4 
Safety Evaluations .............................................................................................................. 20 
5 
SUBJECT SELECTION 
20 
5.1 
Study Population ................................................................................................................ 20 
5.2 
Subject Eligibility Criteria .................................................................................................. 21 
6 
CONCURRENT MEDICATIONS 
21 
6.1 
Allowed .............................................................................................................................. 21 
6.2 
Prohibited ........................................................................................................................... 22 
7 
STUDY TREATMENTS 
22 
7.1 
Method of Assigning Subjects to Treatment Groups ......................................................... 22 
7.2 
Test Formulation ................................................................................................................ 22 
7.3 
Study Medication Accountability ....................................................................................... 23 


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7.4 
Measures of Treatment Compliance ................................................................................... 23 
8 
STUDY PROCEDURES AND GUIDELINES 
23 
8.1 
Overview of Evaluations and Visits ................................................................................... 23 
8.2 
Clinical Assessments .......................................................................................................... 24 
9 
EVALUATIONS BY VISIT 
25 
9.1 
Visit 1 (Screening) (Day -1 to -56) ..................................................................................... 25 
9.2 
Visit 2 (Baseline) (Day 0) ................................................................................................... 25 
9.3 
Visit 3 (Week 6 ± 3 days) ................................................................................................... 26 
10 ADVERSE EXPERIENCE REPORTING AND DOCUMENTATION 
27 
10.1 Adverse Events ................................................................................................................... 27 
10.2 Serious Adverse Experiences (SAE) .................................................................................. 29 
10.3 Medical Monitoring ............................................................................................................ 30 
11 SCREEN FAILURES AND RE-SCREENING OF SUBJECTS 
30 
12 SUSPENSION OF STUDY DRUG, WITHDRAWALS, EARLY TERMINATION PROCEDURES, AND SUBJECT REPLACEMENT
 
30 
12.1 Discontinuation of Study Drug, Subject Withdrawals, Early Termination Procedures ..... 30 
12.2 Replacement of Subjects .................................................................................................... 31 
13 PROTOCOL VIOLATIONS 
31 
14 DATA SAFETY MONITORING 
31 
15 STATISTICAL METHODS AND CONSIDERATIONS 
31 
15.1 Analysis of Physiologic Effects (Lung Function) .............................................................. 31 
15.2 Sample Size ........................................................................................................................ 32 
16 DATA COLLECTION, RETENTION AND MONITORING 
32 
16.1 Data collection .................................................................................................................... 32 
16.2 Availability and Retention of Investigational Records ...................................................... 32 
17 ADMINISTRATIVE, ETHICAL, REGULATORY CONSIDERATIONS 
33 
 
REFERENCES 
 
 
 
 
 
 
 
 
 
31 
 
 


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List of Abbreviations 
AE 
adverse experience 
CFR 
Code of Federal Regulations 
CF 
cystic fibrosis 
CRF 
case report form 
FDA 
Food and Drug Administration 
FEF25-75 
Forced expiratory flow between the 25th and 75th percent of vital 
capacity 
FEV1 
forced expiratory volume in one second 
FRC 
Functional residual capacity 
FVC 
forced vital capacity 
GCP 
Good Clinical Practice 
HIPAA 
Health Insurance Portability and Accountability Act of 1996 
ICF 
informed consent form 
ICH 
IOS 
International Conference on Harmonisation 
Impulse Oscillometry  
IRB 
MDI 
Institutional Review Board 
Metered Dose Inhaler 
PI 
Principal Investigator 
SAE 
serious adverse experience 
 
 
 
 
 
 
 
 
 
 
 
 


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PROTOCOL SYNOPSIS 
TITLE 
Flunisolide HFA in Children with Small Airway Disease 
FUNDING AGENCY 
MEDA Pharmaceuticals  
PRINCIPAL 
INVESTIGATORS  
Nemr Eid, MD 
University of Louisville 
Louisville, KY  
 
 
Scott Bickel, MD 
University of Louisville 
Louisville, KY  
 
 
PRINCIPAL 
INVESTIGATOR 
SPONSOR 
 MEDA Pharmaceuticals 
DATA 
COORDINATING 
CENTER 
University of Louisville Physicians – Pediatric Pulmonology (Academic 
Office) 
NUMBER OF SITES 
One 
STUDY DESIGN 
Prospective, randomized, parallel, open label study 
OBJECTIVE 
To assess whether there is a dose-related difference with flunisolide 
HFA in pediatric patients with small airway obstruction based on 
pulmonary function parameters specifically designed to measure 
changes in small airway function.  
NUMBER OF 
SUBJECTS 
50 


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SUBJECT 
ELIGIBILITY 
CRITERIA 
Inclusion Criteria: 
1. Diagnosis of asthma by pediatrician or asthma specialist  
2. Informed consent by parent or legal guardian 
3. 6 years to 21 years of age at Screening Visit 
4. Ability to comply with medication use, study visits and study 
procedures as judged by the site investigator  
5. FEF25-75% < 65% of predicted as a marker for small airway disease 
Exclusion Criteria: 
1. Acute wheezing at Screening visit or at Baseline visit 
2. Acute intercurrent respiratory infection, defined as an increase in 
cough, wheezing, or respiratory rate with onset in 1 week 
preceding Screening visit or 3 weeks preceding Baseline visit 
3. Oxygen saturation < 94% at Screening visit or at Baseline visit 
4. Clinically significant upper airway obstruction as determined by 
the Site Investigator (e.g. severe laryngomalacia, markedly 
enlarged tonsils, significant snoring, diagnosed obstructive sleep 
apnea) 
5. Severe gastroesophageal reflux, defined as persistent frequent 
emesis despite anti-reflux therapy 
6. Physical findings that would compromise the safety of the subject 
or the quality of the study data as determined by site investigator 
7. ICS use within 7 days of Baseline visit, systemic steroid use 
within 30 days of Baseline visit 
8. CF, ILD, history of severe BPD or other underlying significant 
respiratory disease apart from asthma  
9. Patients who are pregnant may not enroll in this study 
 
TEST DRUG, DOSE 
AND MODE OF 
ADMINISTRATION 
Flunisolide HFA (Aerospan™, MEDA Pharmaceuticals, Somerset, 
NJ) 1 or 2 inhalations administered via MDI twice daily for 6 weeks.   


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DURATION OF 
SUBJECT 
PARTICIPATION AND 
DURATION OF STUDY 
Study visits will occur at screening, baseline, and 6 weeks (± 1 
week). Total duration of subject participation will be up to 8 weeks.  
As enrollment will occur over approximately 12 months, total 
duration of the study is expected to be up to 14 months (12 months 
enrollment plus about 2 months for the last subjects to complete 
treatment). 
Screening, enrollment, 
randomization and 
treatment 
Screening: At the Screening visit, a focused, standardized history and 
physical exam will be conducted by one of the physicians on the 
research team.  Patients will also undergo pre and post bronchodilator 
spirometry.  Spirometry values prior to the administration of 
bronchodilator will be used to assess patient’s enrollment status. 
Enrollment and Randomization: At the Baseline visit, patients will 
undergo a repeat focused, standardized history and physical exam.  
Spirometry and IOS will both be undertaken pre and post 
bronchodilator (in this order: IOS, spirometry, bronchodilator, IOS, 
spirometry). 
Treatment: Subjects will receive treatments twice per day for 6 ± 3 
days. 
CONCOMITANT 
MEDICATIONS 
Allowed: All standard therapies 
Prohibited: Other forms of ICS, LABAs  
Efficacy Evaluations 
Physiologic effects (change in lung function between baseline and end 
of treatment) and Clinical Effects (number of asthma exacerbations, 
asthma control scores) will be compared between subjects randomized 
to flunisolide HFA 1 inhalation BID and to flunisolide HFA 2 
inhalations BID. 
Primary endpoint 
The average change in FEV1, FEF25-75% , R5, R5-R20, AX, Fres and 
X5 measured by spirometry and IOS during from baseline to end of 
treatment (6 ± 3 days) between subjects randomized to flunisolide 
HFA 1 inhalation BID and to flunisolide HFA 2 inhalations BID. 
SECONDARY 
The number of protocol-defined asthma exacerbations requiring 


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ENDPOINTS 
treatment with oral steroids between subjects randomized to 
flunisolide HFA 1 inhalation BID and to flunisolide HFA 2 
inhalations BID. 
SAFETY 
EVALUATIONS 
Rates of adverse events, withdrawal, adherence to treatment, rate of 
asthma exacerbations will be monitored.  
SAFETY 
MONITORING 
As this is an FDA approved drug being used in approved populations 
at approved doses, the elements listed under “safety evaluations” as 
above will be tracked by the PIs but no formal data safety review 
board will be in place. 
STATISTICS 
Primary Analysis Plan 
The primary aim is to compare the average change in spirometric 
values (FEV1 and FEF25-75%) and IOS values (R5, R5-R20, AX, Fres) 
from baseline to Week 6 from participants randomized flunisolide 
HFA 1 inhalation BID and to flunisolide HFA 2 inhalations BID. The 
change in scores from baseline to six-week follow-up will initially be 
compared using paired t-tests and Chi-squared tests for trend. 
Repeated measurements will be analyzed using generalized linear 
mixed-effects regression modeling (GLMM) techniques. For 
continuous outcomes (e.g., FEV1, FEF 25-75%, Fres, X5, AX, R5-R20.) 
the identity link function and normal distribution will be used. For 
count data (e.g., use of Beta-agonists, episodes of coughing, episodes 
of wheezing, etc.) the log link function and the Poisson distribution 
will be used. If we dichotomize outcomes (e.g., a Beta-agonist was 
used, coughing occurred, etc.) the logit link function and Bernoulli 
distribution will be used. Statistical analyses will be performed using 
SAS® Version 9.3 (SAS Institute Inc., Cary, NC). 
Rationale for Number 
of Subjects 
Based on our preliminary studies, we anticipate that 10% of all 
potential participants will not be eligible and/or willing to participant; 
and that 10% of the eligible/willing participants will be lost to follow-
up. Therefore, we will recruit a total of n=50 individuals for the 
current study. This is a feasible sample size for the research team to 
recruit and enroll in the current study. Power calculations were based 


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on the anticipated total sample size (n=40) that will be available for 
complete analysis.  
 
We will develop separate mixed-effects general linear models for each 
of the continuous outcomes. From the anticipated sample size (n=40) 
the study has 86% power to detect a 10% main effect of each 
treatment for each outcome, our anticipated effect size given 
preliminary studies. When using count data the study has 94% power 
to detect a 10% decrease in the rate of outcomes (coughing, wheezing, 
etc.), our anticipated change in the rate. Using the dichotomized 
version of some outcomes, this study has 80% power to detect on 
odds ratio of 1.32 with a two sided α=0.05 (n=40). Therefore, we have 
more than sufficient numbers of participants in each comparison 
group. 
 


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1
BACKGROUND 
Flunisolide HFA is an inhaled corticosteroid that is a reformulated version of the older CFC preparation.  The CFC formulation was approved 
in 1981 and had been in use as an asthma controller since with good results.1  The HFA formulation, which is in solution as opposed to 
suspension, has superior lung deposition when compared to its CFC counterpart (68% versus 20%).1  Studies have demonstrated flunisolide 
HFA’s effectiveness with regards to controlling airway inflammation and improving lung function2,3 while maintaining an excellent side 
effect profile, including no measurable effect on growth over one year.4  These attributes make it ideal for use in pediatric patients in whom 
growth suppression is a common concern.  In addition, the current device used for delivery has a built-in spacer to ensure optimal lung 
deposition.   
 
It is known that flunisolide HFA is uniformly distributed throughout all airways, with deposition approaching 68% and less drug being 
deposited in the oral cavity than larger molecule inhaled corticosteroids.  Fluticasone, for example, has a larger particle size and results in 
about 20% lung deposition, mainly in the central airways. Despite this, there is little data that specifically examines the effect of flunisolide 
HFA on small airway parameters in children with asthma.  We propose a randomized parallel study between flunisolide HFA 80 mcg twice a 
day and 160 mcg twice a day to determine the effect of each dose on spirometry and impulse oscillometry (IOS) parameters.   
 
Based on the small molecule size and even lung deposition, we hypothesize that we will see a dose dependent significant improvement 
in small airway parameters (FEF 25-75%, AX, Fres, X5, R20-R5) with flunisolide.  Secondary outcome measures will include clinical 
effects such as frequency of coughing and wheezing, number of short acting beta agonists used, oral steroid doses required, emergency 
department visits, and hospitalizations.  If the results support our hypothesis this will address an important problem in the field and shift 
current clinical practice paradigms by a refinement in interventions.  It may also provide the foundation for future studies to directly compare 
flunisolide to other coarse molecules inhaled corticosteroids.  

Prevalence and Impact of Asthma 
Asthma is one of the most prevalent chronic diseases worldwide, with a substantial burden of disease in the United States.  The condition is 
characterized by extensive airway inflammation leading to variable airflow obstruction, airway hyperresponsiveness and symptoms of 
wheezing, coughing and dyspnea.  Asthma is responsible for an estimated 450,000 hospitalizations in the United States annually (nearly 
200,000 of these in children) at considerable cost.  Many efforts have been made in attempting to reduce this number.  Chronic therapies, 
consisting primarily of inhaled corticosteroids to reduce airway inflammation and beta-two agonists for acute symptoms, are well recognized 
by National Heart, Lung, and Blood Institute asthma guidelines for treatment.  Despite this, medication adherence remains a major barrier in 
care.5,6    


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ICS Therapy in Asthma 
As noted, chronic therapy with ICS is widely recongized as standard of care, first line therapy for patients with persistant asthma.  Compared 
with oral corticosteroids, ICS are effective, safe, and exert a local anti-inflammatory effect directly at the site of pathology.  ICS can be 
delivered by a number of mechanisms, the most common of which are pMDIs, dry powdered inhalers, and nebulizers.  Failure to correctly use 
these devices are a common cause of inadvertant non-adherance and is associated with poor asthma control.7-11  Nebulization may be an ideal 
delievery mechanism for very young or old patients, acutely ill patients, or those with neurologic or developmental impairments.12  Selection 
of ICS by a physician is an individulized process, with the focus on selecting a product with a delivery device that the patient will be able to 
use easily as well as a molocule with ideal pharmacokinetics and pharmacodyamics.  An ideal ICS would be one that has high lung 
deposition, prolonged pulmonary residency times and low systemic absoprtion (reflected by an excellent safetey profile).13  While beyond the 
scope of this discussion, comprehensive reviews comparing ICS molocules have been published and are of  great reference to the practioner.13  

CFC and HFA Flunisolide 
An excellent, comprehensive review of flunisolide was recently published by Melani.12  Flunisolide was first discovered in 1965 and 
approved for inhalation via a CFC-MDI in the United States in 1981.  Prior studies demonstrated a clinical profile similar to other CFC ICSs 
such as BDP, fluticasone and budesonide.  Lung deposition of this formulation was estimated to be 10% of the delivered dose.  Secondary to 
environmental concerns, CFC MDIs have been phased out with CFC flunisolide being removed from market in 2010.  Reformulated versions 
of these drugs have been developed with HFA MDIs.  While some versions of these reformulated drugs were created to match their previous 
CFC counterparts, others (including flunisolide) were formulated as solutions and deliver extrafine aerosols that have improved deposition 
even into the distal airways.  The mass median aerodynamic diameter of CFC funisolide was 3.8 µm while the HFA formulation has a 
MMAD of only 1.2 µm.  Studies have demonstrated that this smaller particle size results in significantly less deposition in the mouth, pharynx 
and GI tract and greater deposition in the peripheral lung with improved homogeneity of deposition throughout the respiratory tract.  This 
results in reduced local side effects such as thrush as well as less systemic bioavailability.  HFA flunisolide is FDA approved and has recently 
been marketed in the US at strength of 80 µg per dose.  The device has a 50 mL inhalation chamber attached to assist with medication 
delivery to the lungs.  The recommended starting dose in adults is 160 µg twice daily (recommended maximum dose 320 µg twice daily) and 
in children (ages 6-11) is 80 µg twice daily (recommended maximum dose 160 µg twice daily).   

Clinical Pharmacology 
This section (through 1.6) is derived from data directly from the package insert for flunisolide HFA:   
Mechanism of Action: Flunisolide has demonstrated marked anti-inflammatory activity in classical test systems. It is a corticosteroid that is 
several hundred times more potent than cortisol in animal anti-inflammatory assays, and several hundred times more potent than 
dexamethasone in anti-inflammatory effect as determined by the McKenzie skin blanching test. The clinical significance of these findings is 
unknown. The precise mechanism of corticosteroid action is unknown. Airway inflammation is an important component in the pathogenesis 


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of asthma. Corticosteroids have been shown to have a wide range of anti-inflammatory effects, inhibiting both inflammatory cells (e.g. mast 
cells, eosinophils, neutrophils, macrophages, and lymphocytes) and release of inflammatory mediators (e.g., histamine, eicosanoids, 
leukotrienes, and cytokines) involved in allergic and non-allergic mediated inflammation. These anti-inflammatory actions of corticosteroids 
may contribute to their efficacy in asthma. 
Pharmacokinetics: All the data described below is based on studies conducted in subjects 18 to 51 years of age.  
Absorption: Flunisolide is rapidly absorbed after oral inhalation. Mean values for the time to maximum concentration, Tmax, of flunisolide 
range from 0.09 to 0.17 hr after a single 320 mcg dose of AEROSPAN Inhalation Aerosol. The corresponding mean values for the maximum 
concentration, Cmax, of flunisolide vary from 1.9 to 3.3 ng/mL. Oral bioavailability is less than 7%. Over the dose range of 80 mcg to 320 
mcg of  
AEROSPAN Inhalation Aerosol, values for Cmax increase proportionately with dose after single as well as multiple dose administration.  
Distribution: Flunisolide is extensively distributed in the body, with mean values for apparent volume of distribution ranging from 170 to 
350 L after a single 320 mcg dose of AEROSPAN Inhalation Aerosol.  
Metabolism: Flunisolide is rapidly and extensively converted to 6ß-OH flunisolide and to water-soluble conjugates during the first pass 
through the liver. Conversion to 6ß-OH flunisolide, the only circulating metabolite detected in man, is thought to occur via the cytochrome 
P450 enzyme system, particularly the enzyme CYP3A4. 6ß-OH flunisolide has a low corticosteroid potency (ten times less potent than 
cortisol and more than 200 times less potent than flunisolide). Maximum levels of 6ß-OH flunisolide were 0.66 mcg/mL after a single 320 
mcg dose of AEROSPAN Inhalation Aerosol, and 0.71 mcg/mL after multiple doses of AEROSPAN Inhalation Aerosol.  
Excretion: Urinary excretion of flunisolide is low. Less than 1% of the administered dose of flunisolide is recovered in urine after inhalation. 
The half-life values for 6ß-OH flunisolide range from 3.1 to 5.1 hrs after administration of AEROSPAN Inhalation Aerosol in the dose range 
of 160 mcg to 320 mcg.  
Disposition and Elimination: Twice daily inhalation administration of flunisolide hemihydrate for up to 14 days did not result in appreciable 
accumulation of flunisolide. Upon multiple dosing with 160 mcg and 320 mcg, the Cmax values were 1.0 ng/mL and 2.1 ng/mL, respectively. 
The corresponding AUC0-12hr values were 1.2 ng.hr/mL and 2.5 ng.hr/mL.  
Flunisolide is rapidly cleared from the body, independent of route of administration or dose administered. Flunisolide is not detectable in 
plasma twelve hours post-dose. After administration of 320 mcg of AEROSPAN Inhalation Aerosol the elimination half-life ranges from 1.3 
to 1.7 hours. After a single 320 mcg dose, mean oral clearance values, not adjusted for bioavailability, range from 83 to 167 L/hr.  
Special Populations: There were no gender differences for flunisolide after single and multiple dose administration of the AEROSPAN 
Inhalation Aerosol. Formal pharmacokinetic studies using flunisolide were not carried out in any other special populations.  


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Pharmacodynamics: Dose finding for AEROSPAN Inhalation Aerosol was based on comparability of systemic exposure to flunisolide CFC 
inhalation aerosol. The effect of flunisolide CFC inhalation aerosol and AEROSPAN Inhalation Aerosol on pharmacokinetics and 12-hour 
plasma cortisol levels was investigated in two studies. In both studies, the Cmax and AUC of flunisolide, 6β-OH flunisolide, and 12-hour 
plasma cortisol measurements were comparable for 1000 mcg of flunisolide CFC inhalation aerosol and 320 mcg of AEROSPAN Inhalation 
Aerosol. The first was a parallel arm study in 31 subjects. Pharmacokinetics and plasma cortisol levels were determined after single and 
multiple doses of flunisolide CFC inhalation aerosol 1000 µg and AEROSPAN Inhalation Aerosol 160 µg or 320 µg administered twice daily 
for 13.5 days. At steady state, flunisolide mean peak plasma concentrations from flunisolide CFC inhalation aerosol 1000 mcg and 
AEROSPAN Inhalation Aerosol 320 mcg were found to be 2.6 ng/mL and 3.4 ng/mL, respectively. The corresponding mean AUC values for 
the 12-hr dosing interval were 5.7 ng.hr/mL and 4.7 ng.hr/mL, respectively. At steady state, the mean peak plasma concentrations of 6β-OH 
flunisolide from flunisolide CFC inhalation aerosol 1000 mcg and AEROSPAN Inhalation Aerosol 320 mcg were found to be 0.9 ng/mL and 
0.3 ng/mL, respectively. The corresponding mean AUC values for the 12-hr dosing interval were 3.8 ng.hr/mL and 1.1 ng.hr/mL, 
respectively. The second was a crossover study in 11 subjects after single doses of flunisolide CFC inhalation aerosol  
1000 mcg or AEROSPAN Inhalation Aerosol 320 mcg. The mean peak plasma concentrations of flunisolide from the flunisolide CFC 
inhalation aerosol 1000 mcg and AEROSPAN Inhalation Aerosol 320 mcg were found to be 2.5 ng/mL and 3.3 ng/mL, respectively. The 
corresponding mean AUC values were 5.1 ng.hr/mL and 5.8 ng.hr/mL, respectively. The mean peak plasma concentrations of 6β-OH 
flunisolide from flunisolide CFC inhalation aerosol 1000 mcg and AEROSPAN Inhalation Aerosol 320 μg were found to be 0.8 ng/mL and 
0.3 ng/mL, respectively. The corresponding mean AUC values were 3.8 ng.hr/mL and 2.3 ng.hr/mL, respectively. 

Pediatric Use of Flunisolide:  
The safety and effectiveness of AEROSPAN Inhalation Aerosol has been studied in children 4- 17 years of age. In clinical studies, the 
efficacy of AEROSPAN Inhalation Aerosol was not established in children 4-5 years of age, although the adverse reaction profile observed in 
patients exposed to AEROSPAN Inhalation Aerosol was similar between the 4-5 year age group (n=21), the 6-11 year age group (n=210), the 
12-17 year age group (n=30), and those patients 18 years of age and older (n=258). The safety and effectiveness of AEROSPAN Inhalation 
Aerosol has not been studied in patients less than 4 years of age.  
Effects on Growth: Controlled clinical studies have shown that orally inhaled corticosteroids may cause a reduction in growth velocity in 
pediatric patients. In these studies, the mean reduction in growth velocity was approximately one cm per year (range 0.3 to 1.8 cm per year) 
and appears to depend upon the dose and duration of exposure. This effect was observed in the absence of laboratory evidence of 
hypothalamic-pituitary-adrenal (HPA) axis suppression, suggesting that growth velocity is a more sensitive indicator of systemic 
corticosteroid exposure in pediatric patients than some commonly used tests of HPA axis function. The long-term effects of this reduction in 
growth velocity associated with orally inhaled corticosteroids, including the impact on final adult height, are unknown. The potential for 
“catch up” growth following discontinuation of treatment with orally inhaled corticosteroids has not been adequately studied. The growth of 
pediatric patients receiving orally inhaled corticosteroids, including AEROSPAN Inhalation Aerosol, should be monitored routinely (e.g., via 


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stadiometry). The potential growth effects of prolonged treatment should be weighed against clinical benefits obtained and the risks/benefits 
of treatment alternatives. To minimize the systemic effects of orally inhaled corticosteroids, including AEROSPAN Inhalation Aerosol, each 
patient should be titrated to the lowest dose that effectively controls his/her symptoms. The potential effect of AEROSPAN on growth rates in 
children was assessed in a 52 week randomized, placebo controlled study conducted in 242 prepubescent children age 4 to 9.5 years (145 
males, 97 females) with mild persistent asthma. Treatment groups were AEROSPAN 160 mcg twice daily and placebo. Growth velocity was 
estimated for each patient using the slope of the linear regression of height over time using observed data in the intent to treat population who 
had at least 3 height measurements. The mean growth velocities were 6.19 cm/year in the placebo group and 6.01 cm/year in the AEROSPAN 
treated group (difference from placebo -0.17 cm/year; 95% CI: -0.58, 0.24). 

Efficacy of Flunisolide HFA: 
The efficacy of AEROSPAN Inhalation Aerosol has been studied in two double-blind, parallel, placebo-and active-controlled clinical trials of 
12 weeks duration involving more than 1250 patients, one in adults and adolescents 12 years of age and older, and one in patients 4-11 years 
of age. In adults and adolescents, efficacy was evaluated in patients previously treated with inhaled corticosteroids. In children 6 to 11 years 
of age, efficacy was evaluated in patients previously treated with bronchodilators alone or inhaled corticosteroids. Both trials had a 2- week 
run-in period followed by a 12-week randomized treatment period. During the run-in period all patients received flunisolide CFC inhalation 
aerosol 500 mcg twice daily. Patients were then randomized to double-blind treatment with different doses of AEROSPAN Inhalation 
Aerosol or flunisolide CFC inhalation aerosol and monitored for lung function changes to see if they maintained, improved, or lost stability. 
Baseline was assessed at the end of the run-in period. The primary endpoint was the change from baseline in percent predicted FEV1 after 12 
weeks treatment.  
Adult and Adolescent Patients 12 Years of Age and Older: Efficacy was evaluated in 669 asthma patients, 12 to 78 years of age, including 
88 patients 12-17 years of age and 581 patients 18 years and older. Mean FEV1 at screening was 2.44 L and mean FEV1 at baseline was 2.72 
L following the 2-week run-in period. Patients were randomized to AEROSPAN Inhalation Aerosol 80 mcg, 160 mcg or 320 mcg twice daily, 
flunisolide CFC inhalation aerosol 250 mcg, 500 mcg, or 1000 mcg twice daily, or placebo. Change from baseline in percent predicted FEV1 
over 12 weeks treatment demonstrated that placebo patients deteriorated 4.3% from baseline after 12 weeks of treatment, whereas patients 
treated with AEROSPAN Inhalation Aerosol 160 mcg or 320 mcg twice daily maintained FEV1 over the course of the study. Results for the 
comparison to placebo were statistically significant for the 160 and 320 mcg twice daily AEROSPAN Inhalation Aerosol doses (see Figure 
1), but not for the 80 mcg dose. Secondary endpoints of AM peak expiratory flow rate, AM and PM asthma symptoms, nocturnal awakenings 
requiring a β2 agonist, and as needed use of inhaled β2 agonists showed differences from baseline favoring AEROSPAN Inhalation Aerosol 
over placebo. AEROSPAN Inhalation Aerosol and flunisolide CFC inhalation aerosol gave comparable results. 
Pediatric Patients 4 to 11 Years of Age: The trial enrolled 583 asthma patients, 4 to 11 years of age, although the primary efficacy 
parameter was evaluated only in the population of 513 patients 6 to 11 years of age. In these patients, the mean FEV1 at screening was 81.2% 
predicted, and the mean FEV1 at baseline following a two week run-in period was 87.5% predicted. Patients were randomized to 


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AEROSPAN Inhalation Aerosol 80 mcg or 160 mcg twice daily, flunisolide CFC inhalation aerosol 250 mcg or 500 mcg twice daily, or 
placebo. Change from baseline in percent predicted FEV1 over 12 weeks in patients 6 years of age and older demonstrated that placebo 
patients deteriorated 4.0% from baseline after 12 weeks of treatment; whereas patients treated with AEROSPAN Inhalation Aerosol 80 mcg 
or 160 mcg twice daily maintained FEV1 over the course of the study. Results for the comparison to placebo were statistically significant for 
the 80 mcg and 160 mcg doses of AEROSPAN Inhalation Aerosol, but there was no added benefit for the 160 mcg BID dose over the 80 mcg 
BID dose (see Figure 2). AEROSPAN Inhalation Aerosol and flunisolide CFC inhalation aerosol gave comparable results in patients 6 years 
of age and older. 

Rational for lung function as primary endpoint 
We are using change in lung function parameters (FEV1, FEF25-75%  from spirometry, R5, R5-R20, AX, Fres from IOS) as a means of assessing 
response as this provides an objective means of demonstrating improvement in both large and small airways.  FEV1 is a well-established parameter in 
assessing lung function and overall asthma control while FEF25-75% is recognized for its ability to determine small airway obstruction. 14   IOS is an 
emerging pulmonary function test using sound waves reflected down the pulmonary airway and back designed to assess airway parameters in an effort 
independent fashion.  While the details of its full clinical use is beyond the scope of this article, there are several recent review articles that provide a 
detailed discussion of the utility of IOS.15,16 One key attribute of IOS is that data suggests it may be more sensitive in detecting changes in the small 
airways than traditional spirometry.17-20  Lung function is routinely used in practice as a means of assessing control and thus these findings will be readily 
applicable to the clinician. While the pivotal trials of Aerospan looked only at FEV1 changes ( a measure of large airway dysfunction), our study proposes 
to look into small airway function as well. 

Secondary endpoints 
Secondary endpoints include asthma symptom control as defined by the standardized asthma control test (ACT).  We will also examine the 
number of corticosteroid courses, ED visits, and admissions patients in each group has over the study period. 
2
STUDY RATIONALE 
Studies involving the efficacy of flunisolide have primarily been done on the older CFC formulation as discussed above.  In addition, none of 
these studies were targeted at asthma patients specifically with small airway disease.  Our goal is to provide greater clarity on the effect of 
HFA flunisolide at different doses in this unique patient population as HFA flunisolide has a smaller particle size than its CFC predecessor 
and thus improved deposition in the targeted areas. 
3
STUDY OBJECTIVES 

Primary Objective 
To assess the impact on lung function of two different doses of HFA flunisolide in asthma patients with small airway disease 


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4
STUDY DESIGN 

Study Overview 
This is a single center, open label, parallel group trial comparing the efficacy of two different strengths of HFA flunisolide on lung function in 
asthma patients with small airway disease. We will enroll approximately 50 pediatric patients (ages 6-18, see discussion on sample size 
below) with mild to moderate asthma based upon the National Heart, Lung, and Blood Institute asthma guidelines.21  These patients will be 
recruited from new patients presenting to a pediatric pulmonary clinic as well as from general pediatric clinics associated with the University 
of Louisville, School of Medicine. Patients will have been steroid-naïve for at least four weeks. Prior to enrollment, patients will have 
demonstrated small airway disease based on pre-bronchodilator FEF 25-75% of less than 65% predicted.22  Patients will be randomized to 
receive flunisolide at either 80mcg twice a day or 160mcg twice a day with every other consecutive patient receiving alternating therapy 
(Figure 1).  Prior to starting therapy, baseline IOS and spirometry pre and post bronchodilator (BD) will be obtained (Table 1).  Patients will 
be randomized as described above and will be followed up at six weeks.  At that point, repeat IOS and spirometry will be obtained again.  

Primary Efficacy Endpoint 
The average change in FEV1 and FEF25-75% measured by spirometry at baseline visit and again 6 weeks later as well the average change in 
R5, Area of Reactance (AX), and X5 between the two visits as measured by IOS. 

Secondary Efficacy Endpoints 
The number of protocol-defined asthma exacerbations requiring treatment with oral steroids between the two groups will be monitored.  We 
will also track frequency of albuterol use for acute symptoms, number of emergency room visits and hospital admissions for acute asthma 
exacerbations between the two groups. 

Safety Evaluations 
Rates of adverse events, withdrawal, adherence to treatment, and frequency of exacerbations; and resting respiratory rate and room air oxygen 
saturations over the 6 week treatment period, between patients in each treatment group. As we are using an FDA-approved drug for age-
appropriate population, and with approved dosages, we anticipate no major safety issues. 
5
SUBJECT SELECTION 

Study Population 
Subjects with a diagnosis of asthma who meet all of the inclusion and none of the exclusion criteria will be eligible for participation in this 
study. 


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Subject Eligibility Criteria 
5.2.1
Inclusion Criteria 
1. Diagnosis of asthma by pediatrician or asthma specialist  
2.  Informed consent by parent or legal guardian 
3.  6 years to 18 years of age at Screening Visit 
4.  Ability to comply with medication use, study visits and study procedures as judged by the site   investigator  
5.  FEF25-75% < 65% of predicted as a marker for small airway disease 
5.2.2
Exclusion Criteria 
1.  Acute wheezing at Screening visit or at Baseline visit 
2.  Acute intercurrent respiratory infection, defined as an increase in cough, wheezing, or respiratory rate with onset in 1 week preceding 
Screening visit or 3 weeks preceding Baseline visit 
3.  Oxygen saturation < 95% at Screening visit or at Baseline visit 
4.  Clinically significant upper airway obstruction as determined by the Site Investigator (e.g. severe laryngomalacia, markedly enlarged 
tonsils, significant snoring, diagnosed obstructive sleep apnea) 
5.  Severe gastroesophageal reflux, defined as persistent frequent emesis despite anti-reflux therapy 
6.  Physical findings that would compromise the safety of the subject or the quality of the study data as determined by site investigator 
7.  ICS use within 7 days of Baseline visit, systemic steroid use within 30 days of Baseline visit 
8.  CF, ILD, history of severe BPD or other underlying significant respiratory disease apart from asthma 
9.  Potential subjects who are pregnant may not enroll in the study  
6
CONCURRENT MEDICATIONS 
Subjects should be maintained on the same chronic medications throughout the entire study period, as medically feasible.  Each patient will 
be provided with an albuterol sulfate HFA inhaler as well as a spacer to be used with that device to be used for acute symptoms.  Patients will 
be directed to use this as opposed to other albuterol inhalers they might have during the duration of the study. 

Allowed 
All standard therapies are allowed except as in 6.2. 


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Prohibited 
Other ICS or combination ICS/LABA therapies at any time during the study period are prohibited. 
7
STUDY TREATMENTS 

Method of Assigning Subjects to Treatment Groups 
We will use a block randomization scheme to promote balance at the end of the study. Block randomization ensures that after each block of 
individuals are enrolled in the study (n individuals in total); an equal number of individuals will be assigned to each group (n/2 individuals in 
each group). We will use random block sizes of 8-12. Data about grouping will be kept by study coordinator in a secure, locked location in 
the clinic.  A password protected electronic database will also be created to store patient data in which will be kept on an encrypted, password 
protected computer. 

Test Formulation 
Subjects will be randomized equally to receive HFA Flunisolide 80mcg (AEROSPAN Inhalation Aerosol, MEDA Pharmaceuticals, Somerset, 
NJ) 1 inhalation BID or HFA Flunisolide 80mcg 2 inhalations BID.  All inhalations will be delivered using the built-in spacer device without 
any other attached devices, holding chambers, spacers, or masks.  Patients will be fully instructed on how to administer the medication 
exactly according to manufacturer’s specifications as discussed in the package insert.   
7.2.1 Packaging and Labeling 
As this is an open label study, patients will be given the device in standard packaging from MEDA Pharmaceuticals. 
7.2.2 Handling/Dispensing 
Study Test Drug will be distributed by MEDA Pharmaceuticals to the clinic site. Albuterol sulfate (PROAIR HFA, TEVA Respiratory, Inc, 
Sellersville, PA) will be dispensed to each patient at the time of enrollment. 
7.2.3 Dosage/Dosage Regimen 
Flunisolide HFA: Subjects will be instructed to administer Study Drug with one or two inhalations twice a day depending on the group per 
the manufacturer’s specifications as discussed in the package insert. 
Albuterol: In order to standardize each participant’s rescue therapy for acute symptoms, each enrollee will be provided with albuterol sulfate 
for breakthrough symptoms. 


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7.2.4 Administration Instructions 
Each study subject and family will be provided step-by-step instructions on how to properly administer their medication.  
7.2.5 Storage 
Study Drug and albuterol sulfate should be stored in the site pharmacy in a secure location at room temperature/humidity. 

Study Medication Accountability 
An accurate and current accounting of the dispensing and return of Study Drug for each subject will be maintained on an ongoing basis by a 
member of the study site staff.  The number of doses of Study Drug dispensed and returned by the subject will be recorded.  The study 
monitor will verify these documents throughout the course of the study. 

Measures of Treatment Compliance 
Parents of subjects will be asked to bring all used and unused Study Drug containers to each study visit.  Albuterol use can be documented via 
changes in the counter.     
8
STUDY PROCEDURES AND GUIDELINES 
A Schedule of Events representing the required testing procedures to be performed for the duration of the study is diagrammed in Appendix 1. 
Prior to conducting any study-related activities, written informed consent and the Health Insurance Portability and Accountability Act 
(HIPAA) authorization must be signed and dated by the subject’s legal representative in accordance with site IRB requirements. 

Overview of Evaluations and Visits 
8.1.1 Screening Evaluation 
At the Screening visit, eligibility for the visit will be determined by the investigator based on inclusion and exclusion criteria. All eligible 
subjects will undergo spirometry to ensure that baseline values fit the inclusion criteria.   
8.1.2 Baseline Visit 
Eligible patients may proceed to the Baseline visit (Visit 2) no sooner than the next day but no later than 56 days following the Screening 
visit.  Specific procedures taken at this visit are listed below. If the 56 day window is exceeded, subjects must repeat the Screening visit prior 
to repeating the Baseline visit. Refer to section 12 for clarification regarding screen failure and re-screening. 


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8.1.3 Interim Visits 
Enrolled subjects will return at 6 weeks as detailed below. 

Clinical Assessments 
8.2.1 Demographics 
Demographic information (date of birth, gender, race, ethnicity) will be recorded at the Screening Visit. 
8.2.2 Medical History 
Relevant medical history, including history of current disease, other pertinent respiratory history, diagnosis through newborn screening, 
exposure to environmental tobacco smoke, and information regarding underlying diseases will be reviewed and recorded at the Screening 
Visit. 
8.2.3 Concomitant Medications and Pulmonary Exacerbations 
All concomitant medication and concurrent therapies will be documented at the Baseline visit.  Dose, route, unit frequency of administration, 
and indication for administration and dates of medication will be captured.  An interim history and chart review will be performed at each 
subsequent study visit, including interim hospitalizations for respiratory symptoms and interim courses of steroids (date, route, indication).  
8.2.4
Physical Examination 
A complete physical examination will be performed by a physician (either the investigator or a co-investigator) at the Screening visit.  An 
abbreviated physical examination will be performed by a physician (either the investigator of co-investigator) at Visits 2 and 3. Qualified staff 
(MD, NP, RN) may complete the abbreviated physical exam at all other visits.  New abnormal physical exam findings must be documented 
and will be followed by a physician or other qualified staff at the next scheduled visit. 
8.2.5 Height and Weight  
Weight and height will be recorded at each visit.   
8.2.6 Vital Signs 
Heart rate, respiratory rate, and blood pressure will be measured with the subject at rest at each study visit.  Body temperature will also be 
obtained. 


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8.2.7 Oximetry 
Oxygen saturation will be measured on room air with the subject at rest at each study visit. 
8.2.8 Adverse Events 
Occurrence of treatment emergent adverse events will be assessed throughout the study. Onset, duration, severity, outcome, treatment and 
relation to study treatment will be documented. 
9
EVALUATIONS BY VISIT 

Visit 1 (Screening) (Day -1 to -56) 
1.
Obtain written informed consent and HIPAA authorization 
2.
Assign the subject a unique subject identification number 
3.
Review medical history, including a history of asthma, diagnosis date, and prior treatments 
4.
Review concomitant medications 
5.
Record demographic data 
6.
Obtain Vital Signs (temperature, resting HR, respiratory rate, and blood pressure) 
7.
Measure oxygen saturation on room air (oximetry) 
8.
Perform spirometry (pre and post bronchodilator) 
9.
Perform physical examination (Investigator) 
10.
Review inclusion/exclusion criteria to determine eligibility for study drug (Investigator) 
11.
If patient is female and has had menarche, will perform urine pregnancy test in office to exclude pregnancy. 

Visit 2 (Baseline) (Day 0) 
Subjects who meet eligibility criteria at Visit 1 will be scheduled to return for Visit 2 no sooner than the next day but no later than 56 days 
following the Screening Visit.  The following procedures will be completed:  
1.
Obtain standardized asthma control score from parent/legal guardian  
2.
Review current health status/medical history 
3.
Review concomitant medications 
4.
Obtain vital signs (temperature, heart rate, respiratory rate and blood pressure) 


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5.
Measure oximetry 
6.
Measure height and weight 
7.
Perform abbreviated physical examination (Investigator) 
8.
Have patient perform IOS pre-bronchodilator 
9.
Have patient perform spirometry pre-bronchodilator 
10.
Have patient perform IOS post-bronchodilator 
11.
Have patient perform spirometry post-bronchodilator 
 
If the subject meets all eligibility: 
 
12.
Randomize to flunisolide HFA 80mcg 1 puff BID or flunisolide HFA 80mcg 2 puffs BID 
13.
Dispense Study Drug and albuterol sulfate with holding chamber.  
14.
Review instructions for Study Drug administration 
15.
Schedule subject for Visit 3 (Week 6 ± 1 week) 

Visit 3 (Week 6 ± 3 days) 
1.
Obtain standardized asthma control score from parent/legal guardian. 
2.
Review current health status/medical history and adverse events 
3.
Review concomitant medications. 
4.
Obtain vital signs (temperature, resting heart rate, respiratory rate and blood pressure) 
5.
Measure oximetry 
6.
Measure height and weight  
7.
Perform abbreviated physical examination 
8.
Have patient perform IOS pre-bronchodilator 
9.
Have patient perform spirometry pre-bronchodilator 
10.
Have patient perform IOS post-bronchodilator 
11.
Have patient perform spirometry post-bronchodilator 


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10 ADVERSE EXPERIENCE REPORTING AND DOCUMENTATION 
 Adverse Events 
An adverse event (AE) is any untoward medical occurrence in a clinical investigation of a patient administered a pharmaceutical product and 
that does not necessarily have a causal relationship with the treatment.  An AE is therefore any unfavorable and unintended sign, symptom or 
disease temporally associated with the administration of an investigational product, whether or not related to that investigational product.   
The Investigator will probe, via discussion with the subject, for the occurrence of AEs during each subject visit and record the information in 
the site’s source documents.  Adverse events will be recorded in the subject CRF.  Adverse events will be described by duration (start and 
stop dates and times), severity, outcome, treatment and relation to study medication, or if unrelated, the cause.  Again, as this is an FDA 
approved medication being used in approved ages with approved dosages, we do not anticipate significant AEs.  
AE Severity 
The National Cancer Institute’s Common Terminology Criteria for Adverse Events (CTCAE) Version 3.0, should be used to assess and grade 
AE severity, including laboratory abnormalities judged to be clinically significant. The modified criteria can be found in the study manual.  If 
the experience is not covered in the modified criteria, the guidelines shown in 2 below should be used to grade severity.  It should be pointed 
out that the term “severe” is a measure of intensity and that a severe AE is not necessarily serious. 
Table 2.  AE Severity Grading 
Severity (Toxicity Grade) 
Description 
Mild (1) 
Transient or mild discomfort; no limitation in activity; no 
medical intervention or therapy required. The subject may be 
aware of the sign or symptom but tolerates it reasonably well. 
Moderate (2) 
Mild to moderate limitation in activity, no or minimal medical 
intervention/therapy required. 
Severe (3) 
Marked limitation in activity, medical intervention/therapy 
required, hospitalizations possible. 
Life-threatening (4) 
The subject is at risk of death due to the adverse experience as it 
occurred. This does not refer to an experience that hypothetically 
might have caused death if it were more severe. 
 


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Table 3.  AE Relationship to Study Drug Administration 
Relationship 
to Study Drug 
Administration 
Comment 
Definitely 
Previously known toxicity of agent; or an event that follows a reasonable 
temporal sequence from administration of the Study Drug ; that follows a 
known or expected response pattern to the Study Drug administration; that is 
confirmed by stopping or reducing the dosage of the Study Drug ; and that is 
not explained by any other reasonable hypothesis. 
Probably 
An event that follows a reasonable temporal sequence from administration of 
the Study Drug; that follows a known or expected response pattern to the 
administration of the Study Drug; that is confirmed by stopping or reducing 
the dosage of the Study Drug; and that is unlikely to be explained by the 
known characteristics of the subject’s clinical state or by other interventions. 
Possibly 
An event that follows a reasonable temporal sequence from administration of 
the Study Drug; that follows a known or expected response pattern to 
administration of the Study Drug; but that could readily have been produced 
by a number of other factors. 
Unrelated 
An event that can be determined with certainty to have no relationship to 
administration of the Study Drug. 
 
Table 4.  AE Relationship to Pulmonary Function Testing (Spirometry/IOS) 
Relationship 
to PFTs 
Comment 
Definitely 
Previously known event that follows a reasonable temporal sequence from 
spirometry/IOS; that follows a known or expected response pattern to 
spirometry/IOS; that is confirmed by stopping spirometry/IOS; and that is not 
explained by any other reasonable hypothesis. 


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Probably 
An event that follows a reasonable temporal sequence from the 
spirometry/IOS; that follows a known or expected response pattern to the 
spirometry/IOS; that is confirmed by stopping spirometry/IOS; and that is 
unlikely to be explained by the known characteristics of the subject’s clinical 
state or by other interventions. 
Possibly 
An event that follows a reasonable temporal sequence from the 
spirometry/IOS; that follows a known or expected response pattern to the 
spirometry/IOS; but that could readily have been produced by a number of 
other factors. 
Unrelated 
An event that can be determined with certainty to have no relationship to the 
spirometry/IOS. 
 
 Serious Adverse Experiences (SAE) 
An SAE is defined as any untoward medical occurrence that at any dose: 
•Results in death 
•Is considered life threatening (i.e., in the view of the investigator the adverse experience places the subject at immediate risk of death 
from the reaction, as it occurred; it does not include a reaction that, had it occurred in a more severe form, might have caused 
death) 
•Requires hospital admission or prolongation of an existing hospitalization 
•Results in persistent or significant disability/incapacity (i.e., a substantial disruption of a person’s ability to conduct normal life 
functions) 
•Is a congenital anomaly/birth defect 
•Is an important medical event (i.e., when based upon appropriate medical judgment, the adverse experience may jeopardize the 
subject and may require medical or surgical intervention to prevent one of the above listed outcomes) 
10.2.1 Serious Adverse Experience Reporting 
All SAEs that occur after informed consent is obtained until the end of subject’s participation in the study (whether Test Drug related or not) 
will be documented in an SAE Report.  All SAEs will be reviewed by the investigator. 


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If only a partial SAE report is available, preliminary information will be documented on an SAE Report form, reviewed by the investigator, 
and reported to the PI within one business day of learning of the event.  When additional relevant information is available, this information 
will be submitted promptly on a new SAE Report form. 
Reporting of SAEs to the Independent Review Board (IRB) will be performed by the investigator in accordance with the standard operating 
procedures and policies of the IRB.   
 Medical Monitoring 
The on-call medical monitor should be contacted directly at the following number to report medical concerns or questions regarding safety:   
• Medical Monitor’s Pager:   (502) 478-0074 
11 SCREEN FAILURES AND RE-SCREENING OF SUBJECTS 
Subjects who fail to meet eligibility criteria at either the Screening visit or at the Baseline visit will be classified as screen failures and will not 
be randomized.  Subjects who fail eligibility at the Baseline visit may repeat a Baseline visit, following resolution of failed eligibility criteria 
as applicable, within the 56 day window following the Screening visit. If the 56 day window is exceeded, the subject will be classified as a 
screen failure, but can be re-consented and re-screened at a later date. 
12 SUSPENSION OF STUDY DRUG, WITHDRAWALS, EARLY TERMINATION PROCEDURES, AND SUBJECT 
REPLACEMENT 
 Discontinuation of Study Drug, Subject Withdrawals, Early Termination Procedures  
A subject may permanently discontinue study drug at any time if the subject, the site investigator, or the Sponsor feels that it is not in the 
subject’s best interest to continue.  If a subject discontinues treatment due to an adverse event, the subject will be followed and treated by the 
Investigator until the abnormal parameter or symptom has resolved or stabilized.  If study drug is permanently discontinued, the participant 
should be encouraged to remain in the study and to complete all study visits and procedures,  

The following is a list of possible reasons for discontinuation of study drug or withdrawal. Note that in the case of the second two reasons, the 
participant should be encouraged to complete the remaining study visits rather than withdraw: 
♦ subject withdrawal of consent  
♦ subject is not compliant with study procedures 
♦ adverse event 
♦ study drug intolerance  


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 Replacement of Subjects 
Subjects who withdraw from the study will not be replaced.   
13 PROTOCOL VIOLATIONS 
A protocol violation occurs when the investigator fails to adhere to significant protocol requirements affecting the inclusion, exclusion, 
subject safety and primary endpoint criteria. Protocol violations for this study include, but are not limited to, the following: failure to meet 
inclusion/exclusion criteria, or incorrectly following protocols laid out in this document. The Principal Investigator will determine if a 
protocol violation will result in subject withdrawal. 
When a protocol violation occurs, it will be discussed with the investigator and a Protocol Violation Form detailing the violation will be 
generated. This form will be signed by the Investigator. A copy of the form will be filed in the site’s regulatory binder. 
14 DATA SAFETY MONITORING 
As this is an FDA approved drug being used in approved populations at approved doses, the elements listed under “safety evaluations” as 
above will be tracked by the PIs but no formal data safety review board will be in place. 
15 STATISTICAL METHODS AND CONSIDERATIONS 
Prior to the analysis of the data, a detailed Statistical Analysis Plan (SAP) will be written describing all analyses that will be performed.  The 
SAP will contain any modifications to the analysis plan described below. 
 Analysis of Physiologic Effects (Lung Function) 
The primary goal of the current study is to determine the effects of  Aerospan on lung function in children with small airway obstruction. 
Participants recruited into this randomized parallel group study will be randomly assigned to either receive (1) 80 mcg of Aerospan twice a 
day or (2) 160 mcg of Aerospan twice a day, during the six-week study period. Outcomes will be measured at baseline and at six-week 
follow-up as described above.  
First we will start with straightforward tests for differences among the two groups to test if our randomization scheme was successful. 
Analysis of Variance (ANOVA) techniques will be used to test for difference among continuous variables, while Kruskal-Wallis, Fischer’s 
Exact Tests and Wilcoxon methods will be used to test for differences among categorical variables.  
The primary endpoint will be changes in outcomes, over time, from baseline to six-week follow-up. The change in scores from baseline to 
six-week follow-up will initially be compared using paired t-tests and Chi-squared tests for trend. Repeated measurements will be analyzed 
using generalized linear mixed-effects regression modeling (GLMM) techniques. For continuous outcomes (e.g., FEV1, FEF 25-75%, Fres, 
X5, AX, R5-R20.) the identity link function and normal distribution will be used. For count data (e.g., use of Beta-agonists, episodes of 


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coughing, episodes of wheezing, etc.) the log link function and the Poisson distribution will be used. If we dichotomize outcomes (e.g., a 
Beta-agonist was used, coughing occurred, etc.) the logit link function and Bernoulli distribution will be used. Statistical analyses will be 
performed using SAS® Version 9.3 (SAS Institute Inc., Cary, NC). 
 Sample Size 
Based on our preliminary studies, we anticipate that 10% of all potential participants will not be eligible and/or willing to participant; and that 
10% of the eligible/willing participants will be lost to follow-up. Therefore, we will recruit a total of n=50 individuals for the current study. 
This is a feasible sample size for the research team to recruit and enroll in the current study. Power calculations were based on the anticipated 
total sample size (n=40) that will be available for complete analysis.  
We will develop separate mixed-effects general linear models for each of the continuous outcomes. From the anticipated sample size (n=40) 
the study has 86% power to detect a 10% main effect of each treatment for each outcome, our anticipated effect size given preliminary 
studies. When using count data the study has 94% power to detect a 10% decrease in the rate of outcomes (coughing, wheezing, etc.), our 
anticipated change in the rate. Using the dichotomized version of some outcomes, this study has 80% power to detect on odds ratio of 1.32 
with a two sided α=0.05 (n=40). Therefore, we have more than sufficient numbers of participants in each comparison group.   
16 DATA COLLECTION, RETENTION AND MONITORING 
 Data collection 
Data that will be collected during the study include: enrollment and randomization information, spirometry/IOS data, other subject data 
collected during the study visit, and asthma controls scores.  This data will be kept in a secure, locked filing cabinet in the pediatric 
pulmonary clinic office.   
An electronic database of data will be created using Microsoft Excel.  This database will be encrypted, password protected, and stored 
exclusively on a password protected computer in the pediatric pulmonary clinic.   
 Availability and Retention of Investigational Records 
The Investigator must make study data accessible to the IRB upon request.  A file for each subject must be maintained that includes the 
signed Informed Consent, HIPAA Authorization and copies of all source documentation related to that subject.  The Investigator must ensure 
the reliability and availability of source documents from which the information on the CRF was derived.  All study documents (subject files, 
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17 ADMINISTRATIVE, ETHICAL, REGULATORY CONSIDERATIONS 
The study will be conducted according to the Declaration of Helsinki, Protection of Human Volunteers (21 CFR 50), Institutional Review 
Boards (21 CFR 56), and Obligations of Clinical Investigators (21 CFR 312). 
To maintain confidentiality, all lung function data, evaluation forms, reports and other records will be identified by a coded number and 
initials only.  All study records will be kept in a locked file cabinet and code sheets linking a subject’s name to a subject identification number 
will be stored separately in another locked file cabinet.  Clinical information will not be released without written permission of the subject.  
The Investigator must also comply with all applicable privacy regulations (e.g., Health Insurance Portability and Accountability Act of 1996, 
EU Data Protection Directive 95/46/EC). 
17.1.1 Protocol Amendments 
Any amendment to the protocol will be written by the Study Principal Investigators. 
A protocol amendment intended to eliminate an apparent immediate hazard to subjects may be implemented immediately, provided the IRBs 
are notified within five working days. 
17.1.2 Institutional Review Boards and Independent Ethics Committees 
The protocol and consent form will be reviewed and approved by the IRB.  Serious adverse experiences regardless of causality will be 
reported to the IRB in accordance with the standard operating procedures and policies of the IRB, and the Investigator will keep the IRB 
informed as to the progress of the study.  The Investigator will obtain a list of IRB members or other assurance of compliance with 
regulations. 
Any documents that the IRB may need to fulfill its responsibilities (such as protocol, protocol amendments, Investigator’s Brochure, consent 
forms, information concerning subject recruitment, payment or compensation procedures, or other pertinent information) will be submitted to 
the IRB.  The IRBs written unconditional approval of the study protocol and the informed consent form will be in the possession of the 
Investigator before the study is initiated.   
Protocol and/or informed consent modifications or changes may not be initiated without prior written IRB approval except when necessary to 
eliminate immediate hazards to the subjects or when the change(s) involves only logistical or administrative aspects of the study.  Such 
modifications will be submitted to the IRB/IEC and written verification that the modification was submitted and subsequently approved 
should be obtained.   
The IRB must be informed of revisions to other documents originally submitted for review; serious and/or unexpected adverse experiences 
occurring during the study in accordance with the standard operating procedures and policies of the IRB; new information that may affect 


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adversely the safety of the subjects of the conduct of the study; an annual update and/or request for re-approval; and when the study has been 
completed. 
17.1.3 Informed Consent Form  
Informed consent will be obtained in accordance with the Declaration of Helsinki, ICH GCP, US Code of Federal Regulations for Protection 
of Human Subjects (21 CFR 50.25[a,b], CFR 50.27, and CFR Part 56, Subpart A), the Health Insurance Portability and Accountability Act 
(HIPAA, if applicable), and local regulations. 
The Investigator will prepare the informed consent form and HIPAA authorization and provide the documents to the IRB.  The consent form 
generated by the Investigator must be approved by the IRB/IEC.  The written consent document will embody the elements of informed 
consent as described in the International Conference on Harmonization and will also comply with local regulations.  
A properly executed, written, informed consent and HIPA authorization will be obtained from the legal guardian of each subject prior to 
entering the subject into the trial.  Information should be given in both oral and written form and subjects’ legal representatives must be given 
ample opportunity to inquire about details of the study.  A copy of the signed consent form will be given to the legal representative of the 
subject and the original will be maintained with the subject’s records. 
17.1.4 Publications  
The publication or presentation of any study results shall comply with all applicable privacy laws, including, but not limited to, the Health 
Insurance Portability and Accountability Act of 1996.  
 
 


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REFERENCES 
 
1. 
Shafazand S, Colice G. Flunisolide HFA for the treatment of asthma: an old friend reformulated. Expert opinion on pharmacotherapy. 
2004;5(5):1163-1173. 
2. 
Corren J, Tashkin DP. Evaluation of efficacy and safety of flunisolide hydrofluoroalkane for the treatment of asthma. Clinical 
therapeutics. 2003;25(3):776-798. 
3. 
Hauber HP, Gotfried M, Newman K, et al. Effect of HFA-flunisolide on peripheral lung inflammation in asthma. The Journal of 
allergy and clinical immunology. 2003;112(1):58-63. 
4. 
Gillman SA, Anolik R, Schenkel E, Newman K. One-year trial on safety and normal linear growth with flunisolide HFA in children 
with asthma. Clinical pediatrics. 2002;41(5):333-340. 
5. 
Sumino K, Cabana MD. Medication adherence in asthma patients. Current opinion in pulmonary medicine. 2013;19(1):49-53. 
6. 
Morton RW, Everard ML, Elphick HE. Adherence in childhood asthma: the elephant in the room. Archives of disease in childhood. 
2014;99(10):949-953. 
7. 
Price D, Bosnic-Anticevich S, Briggs A, et al. Inhaler competence in asthma: Common errors, barriers to use and recommended 
solutions. Respiratory medicine. 2012. 
8. 
Sleath B, Ayala GX, Gillette C, et al. Provider demonstration and assessment of child device technique during pediatric asthma visits. 
Pediatrics. 2011;127(4):642-648. 
9. 
Corjulo MT. Mastering the metered-dose inhaler: an essential step toward improving asthma control in school. NASN Sch Nurse. 
2011;26(5):285-290. 
10. 
Hagmolen of ten Have W, van de Berg NJ, Bindels PJ, van Aalderen WM, van der Palen J. Assessment of inhalation technique in 
children in general practice: increased risk of incorrect performance with new device. The Journal of asthma : official journal of the 
Association for the Care of Asthma. 2008;45(1):67-71. 
11. 
Amirav I, Newhouse MT. Treatment failures in children with asthma due to inappropriate use of Turbuhaler. The Journal of 
pediatrics. 2002;140(4):483. 
12. 
Melani AS. Flunisolide for the treatment of asthma. Expert review of clinical pharmacology. 2014;7(3):251-258. 
13. 
Gulliver T, Morton R, Eid N. Inhaled corticosteroids in children with asthma: pharmacologic determinants of safety and efficacy and 
other clinical considerations. Paediatric drugs. 2007;9(3):185-194. 
14. 
Ciprandi G, Capasso M, Leonardi S, et al. Impaired FEF25-75 values may predict bronchial reversibility in allergic children with 
rhinitis or asthma. Journal of biological regulators and homeostatic agents. 2012;26(1 Suppl):S19-25. 
15. 
Bickel S, Popler J, Lesnick B, Eid N. Impulse oscillometry: interpretation and practical applications. Chest. 2014;146(3):841-847. 


IRB Number 14.1024 
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Version #: 2.0 
Version Date:  6/15/2015 
Page 36 of 36 
 
 
16. 
Komarow HD, Myles IA, Uzzaman A, Metcalfe DD. Impulse oscillometry in the evaluation of diseases of the airways in children. 
Annals of allergy, asthma & immunology : official publication of the American College of Allergy, Asthma, & Immunology. 
2011;106(3):191-199. 
17. 
Komarow HD, Skinner J, Young M, et al. A study of the use of impulse oscillometry in the evaluation of children with asthma: 
analysis of lung parameters, order effect, and utility compared with spirometry. Pediatric pulmonology. 2012;47(1):18-26. 
18. 
Oppenheimer BW, Goldring RM, Herberg ME, et al. Distal airway function in symptomatic subjects with normal spirometry 
following World Trade Center dust exposure. Chest. 2007;132(4):1275-1282. 
19. 
Pisi R, Tzani P, Aiello M, et al. Small airway dysfunction by impulse oscillometry in asthmatic patients with normal forced expiratory 
volume in the 1st second values. Allergy and asthma proceedings : the official journal of regional and state allergy societies. 
2013;34(1):e14-20. 
20. 
Shi Y, Aledia AS, Tatavoosian AV, Vijayalakshmi S, Galant SP, George SC. Relating small airways to asthma control by using 
impulse oscillometry in children. The Journal of allergy and clinical immunology. 2012;129(3):671-678. 
21. 
National Asthma E, Prevention P. Expert Panel Report 3 (EPR-3): Guidelines for the Diagnosis and Management of Asthma-
Summary Report 2007. The Journal of allergy and clinical immunology. 2007;120(5 Suppl):S94-138. 
22. 
Ciprandi G, Capasso M, Tosca M, et al. A forced expiratory flow at 25-75% value <65% of predicted should be considered abnormal: 
a real-world, cross-sectional study. Allergy and asthma proceedings : the official journal of regional and state allergy societies. 
2012;33(1):e5-8.