Clinical trial NCT01594827
Conditions: Cystic Fibrosis
Keywords: Methicillin-resistant Staphylococcus aureus Vancomycin
Sponsor: Johns Hopkins University
Start date: 2012-10-01; Completion date: 2017-12-30
Enrollment: 29 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
The prevalence of methicillin resistant Staphylococcus aureus (MRSA) respiratory infection in Cystic Fibrosis (CF) has increased dramatically over the last decade. Evidence suggests that persistent infection with MRSA may result in an increased rate of decline in Forced Expiratory Volume (FEV)1 and shortened survival. Currently there are no conclusive studies demonstrating an effective aggressive treatment protocol for persistent MRSA respiratory infection in CF. Data demonstrating an effective and safe method of clearing persistent MRSA infection are needed.

The purpose of this study is to evaluate the safety and efficacy of a 28-day course of vancomycin for inhalation, 250 mg twice a day, (in combination with oral antibiotics) in eliminating MRSA from the respiratory tract of individuals with CF and persistent MRSA infection. Subjects will be assigned in a 1:1 ratio to either vancomycin for inhalation (250 mg twice a day) or taste matched placebo and will be followed for 3 additional months. In addition, both groups will receive oral rifampin, a second oral antibiotic (TMP-SMX or doxycycline, protocol determined), mupirocin intranasal cream and chlorhexidine body washes. Forty patients with persistent respiratory tract MRSA infection will be enrolled in this trial.

Detailed description:
Primary Objectives

The primary objectives of this trial are to:

1. Determine the efficacy of an aggressive treatment protocol in eradicating persistent MRSA infection in individuals with CF.
2. Determine the safety of an aggressive treatment protocol in eradicating persistent MRSA infection in individuals with CF.

Secondary Objectives

The secondary objectives of this trial are to:

1. Determine the efficacy of an aggressive treatment protocol in improving Forced Expiratory Volume (FEV)1, time to exacerbation, and quality of life in individuals with CF and persistent MRSA infection.
2. Determine if there is benefit to adding nebulized vancomycin to an aggressive oral antibiotic treatment protocol in eradicating persistent MRSA infection in individuals with CF.

Arms: arm 1: In the experimental arm CF participants are randomized to 28 days of inhaled sterile vancomycin (250 mg twice a day) as well as 28 days of oral/skin antibiotics targeted to aggressively treat MRSA infection: oral rifampin, a second oral antibiotic (TMP/SMX or doxycycline, protocol determined), mupirocin intranasal cream and chlorhexidine body washes. Patients will be followed for 3 months after completion of the treatment protocol. arm 2: In the active comparator arm CF participants are randomized to 28 days of inhaled sterile placebo (saline) and are treated with 28 days of oral/skin antibiotics targeted to aggressively treat MRSA infection: oral rifampin, a second oral antibiotic (TMP/SMX or doxycycline, protocol determined), mupirocin intranasal cream and chlorhexidine body washes. Patients will be followed for 3 months after completion of the treatment protocol.
Interventions: intervention 1: Inhaled Vancomycin intervention 2: Placebo (Sterile Water) intervention 3: Rifampin intervention 4: Trimethoprim/Sulfamethoxazole (TMP/SMX) intervention 5: Doxycycline intervention 6: Mupirocin Intranasal Creme intervention 7: 4% chlorhexidine gluconate liquid skin cleanser
Intervention descriptions: intervention 1: On Days 1-28, subjects will receive nebulized Vancomycin. This will be supplied as a 250 mg solution to be nebulized two times a day for 28 days in 5cc sterile water. Patients will use a Pari Sprint nebulizer and Pari Vios compressor as the delivery system. intervention 2: On Days 1-28, subjects will receive 5cc of a nebulized Placebo (Sterile water) twice a day. This is a taste (quinine 0.1mg/mL) matched nebulized placebo (sterile water). Patients will use a Pari Sprint nebulizer and Pari Vios compressor as the delivery system. intervention 3: Oral Rifampin by mouth for 28 days

1. \>45 kg: 600 mg by mouth daily
2. 35-45 kg : 450 mg by mouth daily
3. 25-34.9 kg: 300 mg by mouth daily intervention 4: Oral trimethoprim/sulfamethoxazole (DS-160/800)

1. \>45 kg: two DS tablets twice a day by mouth (320/1600)
2. 25-45 kg: one DS tablet twice a day by mouth (160/800) intervention 5: If sulfa intolerant or TMP/SMX Resistant, use instead oral doxycycline

1. \>45 kg: 100 mg by mouth twice a day
2. 35-45 kg : 75 mg by mouth twice a day iii. 25-34.9 kg: 50 mg by mouth twice a day intervention 6: Mupirocin 2% intranasal creme: half of single use tube applied into each nostril twice a day for 5 days. intervention 7: Hibiclens 15cc liquid skin cleanser packets (4% chlorhexidine gluconate): use three packets once weekly for four weeks in the shower from the neck to toes, with attention on the axilla, groin, and buttocks.

Protocol documents:
Prot_SAP_000.pdf: 
Title:  Persistent Methicillin Resistant Staphylococcus Aureus Eradication Protocol (PMEP) 
NCT01594827 
PI: Michael Boyle, MD 
Date: November 25, 2015 


PROTOCOL PMEP 3.8 
 
CONFIDENTIAL 
Version Date: 11-25-2015 Protocol V3.8  
Page 1 of 71 
 
Clinical Research Protocol 
 
TITLE: PERSISTENT MRSA ERADICATION PROTOCOL (PMEP) 
 
Protocol Number: 
 PMEP 3.8 
Version Date: 
 November 25, 2015 
Sponsor: 
Cystic Fibrosis Foundation 
6931 Arlington Road, 2nd floor 
Bethesda, MD 20814 
Principal Investigator: 
Name: Michael Boyle, MD 
1830 E. Monument Street, 5th floor 
Baltimore MD, 21205 
 
Telephone: 410-502-7042; Fax: 410-502-7048 
E-mail: mboyle@jhmi.edu 
Participating Centers: 
1. Johns Hopkins Hospital, 1800 Orleans Street , Baltimore, MD, 
21287 
2. University Hospitals/Case Medical Center,  11100 Euclid 
Avenue, Cleveland, Ohio 44106 
DSMB: 
The Cystic Fibrosis Foundation Therapeutics Data and Safety 
Monitoring Board 
Chairman: Dr. Wayne Morgan 
Telephone: (520) 626-6754;  Fax: (520) 626-9465 
Email: wmorgan@arc.arizona.edu  
Coordinating Center: 
CFFT Cystic Fibrosis Therapeutics Development Network 
Coordinating Center, Seattle, WA 98101  
Participating Laboratories 
Johns Hopkins Medical Laboratories, 1800 Orleans Street, Zayed B 
1065, Baltimore, MD 21287 
University Hospital Case Medical Center Laboratories, 11100 Euclid 
Avenue, Wearn Building, Room 611, Cleveland, OH 44106 
Seattle Children’s Hospital, Clinical Microbiology Lab, MS A-6901, 
4800 Sand Point Way NE, Seattle, WA 98105 
Case Western Reserve University, Dept. of Pediatrics, Bonfield 
Lab, 10900 Euclid Avenue, BRB 8th Floor, LC 4948, Room 822, 
Cleveland, Ohio 44106 
Approval: 
 
 
 
Michael Boyle, MD  
 
Date 


PROTOCOL PMEP 3.8 
 
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Page 2 of 71 
 
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 and providing the Cystic Fibrosis 
Foundation with complete and timely information, as outlined in the protocol.  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:  PMEP 3.8 
 
Protocol Title:  PERSISTENT MRSA ERADICATION PROTOCOL (PMEP) 
 
Protocol Date:    11/25/2015 
 
 
 
 
Investigator Signature  
 
Date 
 
Print Name and Title 
 
 
 
This confidential information is provided for the exclusive use of investigators of this trial 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, 
which is designated as "privileged" or "confidential". 


PROTOCOL PMEP 3.8 
 
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Page 3 of 71 
 
TABLE OF CONTENTS 
 
INVESTIGATOR’S STATEMENT………………………………………………….……………………………...2 
LIST OF ABBREVIATIONS……………………………………….…………………………………………...…..6 
STUDY SYNOPSIS…………………………………………...…..…………………..………………..………….….7 
1 
BACKGROUND ....................................................................................................................................... 14 
1.1 
OVERVIEW ..................................................................................................................................................... 14 
1.2 
PREVIOUS STUDIES OF TREATMENT OF MRSA IN CF .................................................................................... 14 
1.3 
PREVIOUS EXPERIENCE WITH NEBULIZED VANCOMYCIN .............................................................................. 15 
2 
STUDY RATIONALE .............................................................................................................................. 15 
2.1 
IMPORTANCE OF MRSA IN CYSTIC FIBROSIS ................................................................................................ 15 
2.2 
LACK OF CONCLUSIVE CLINICAL TRIALS OF MRSA THERAPY PROTOCOL IN CF.......................................... 16 
2.3 
RATIONALE FOR SPECIFIC DRUGS INCLUDED IN THE PROTOCOL ................................................................... 16 
3 
STUDY OBJECTIVES ............................................................................................................................. 16 
3.1 
PRIMARY OBJECTIVES ................................................................................................................................... 16 
3.2 
SECONDARY OBJECTIVES .............................................................................................................................. 17 
4 
STUDY DESIGN ....................................................................................................................................... 17 
4.1 
STUDY OVERVIEW ......................................................................................................................................... 17 
5 
CRITERIA FOR EVALUATION ............................................................................................................. 17 
5.1 
PRIMARY EFFICACY ENDPOINT ..................................................................................................................... 17 
5.2 
SECONDARY EFFICACY ENDPOINTS ............................................................................................................... 17 
5.3 
SAFETY EVALUATIONS .................................................................................................................................. 18 
5.4 
OTHER EVALUATIONS ................................................................................................................................... 18 
6 
SUBJECT SELECTION ........................................................................................................................... 18 
6.1 
STUDY POPULATION ...................................................................................................................................... 18 
6.2 
INCLUSION CRITERIA ..................................................................................................................................... 18 
6.3 
EXCLUSION CRITERIA .................................................................................................................................... 19 
7 
CONCURRENT MEDICATIONS ........................................................................................................... 19 
7.1 
ALLOWED ...................................................................................................................................................... 20 
7.2 
PROHIBITED ................................................................................................................................................... 20 
8 
STUDY TREATMENTS ........................................................................................................................... 20 
8.1 
METHOD OF ASSIGNING SUBJECTS TO TREATMENT GROUPS ......................................................................... 20 
8.2 
BLINDING ...................................................................................................................................................... 20 
8.3 
FORMULATION OF STUDY MEDICATION (VANCOMYCIN/PLACEBO) .............................................................. 20 
8.4 
SUPPLY OF STUDY MEDICATION AT THE SITE ................................................................................................ 22 
8.5 
STUDY MEDICATION ACCOUNTABILITY ........................................................................................................ 23 
8.6 
MEASURES OF TREATMENT COMPLIANCE ..................................................................................................... 23 
8.7 
OTHER PROTOCOL PRESCRIBED TREATMENTS: ............................................................................................. 23 
9 
STUDY PROCEDURES AND GUIDELINES ......................................................................................... 24 
9.1 
CLINICAL ASSESSMENTS ............................................................................................................................... 25 
9.2 
CLINICAL LABORATORY MEASUREMENTS .................................................................................................... 26 
9.3 
PHARMACOKINETIC MEASUREMENTS............................................................................................................ 26 
9.4 
RESEARCH LABORATORY MEASUREMENTS ................................................................................................... 27 
9.5 
GUIDELINES FOR TIMING OF USE OF CHRONIC ORAL AND INHALED ANTIBIOTICS ........................................ 27 
9.6 
GUIDELINES FOR TREATMENT OF CF EXACERBATIONS DURING THE STUDY ................................................ 28 
10 
EVALUATIONS BY VISIT ...................................................................................................................... 28 
10.1 
SCREENING VISIT (DAY -28) (±2 DAYS) .................................................................................................... 28 
10.2 
RUN-IN VISIT (DAY -14) (± 4 DAYS) ......................................................................................................... 29 
10.3 
VISIT 1 DAY 1 (START TREATMENT) ........................................................................................................ 29 


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10.4 
VISIT 2 REPEAT WITNESSED ADMINISTRATION OF STUDY DRUG ............................................................. 30 
10.5 
DAY 7-14  PHONE CALL OR EMAIL ........................................................................................................... 31 
10.6 
VISIT 3 DAY 14 (± 2 DAYS) (MID-POINT TREATMENT).............................................................................. 31 
10.7 
DAY 14-21 PHONE CALL OR EMAIL .......................................................................................................... 32 
10.8 
DAY 21-28 PHONE CALL OR EMAIL .......................................................................................................... 32 
10.9 
VISIT 4 DAY 29 (± 1 DAY) (END TREATMENT) .......................................................................................... 32 
10.10 
VISIT 5 DAY 58 (± 4 DAYS) - (1 MONTH POST-TREATMENT MONITORING VISIT) (PRIMARY OUTCOME) .. 33 
10.11 
VISIT 6 DAY 118 (± 7 DAYS) (3 MONTHS POST-TREATMENT MONITORING VISIT) .................................... 33 
10.12 
EARLY WITHDRAWAL VISIT (FOR ANY SUBJECT TERMINATING STUDY EARLY AND AFTER DAY 1) .......... 33 
11 
ADVERSE EVENTS REPORTING AND DOCUMENTATION ............................................................ 34 
11.1 
ADVERSE EVENTS ..................................................................................................................................... 34 
11.2 
SERIOUS ADVERSE EXPERIENCES (SAE) .................................................................................................. 36 
11.3 
KNOWN POTENTIAL RISKS OF STUDY DRUGS/PROCEDURES AND SPECIFIC AE GUIDANCE ...................... 37 
12 
DISCONTINUATION AND REPLACEMENT OF SUBJECTS ............................................................. 39 
12.1 
WITHDRAWAL OF SUBJECTS AND DROP-OUTS .......................................................................................... 39 
12.2 
TRIAL MODIFICATION RULES ................................................................................................................... 40 
13 
PROTOCOL VIOLATIONS .................................................................................................................... 40 
14 
DATA SAFETY MONITORING ............................................................................................................. 41 
15 
STATISTICAL METHODS AND CONSIDERATIONS ......................................................................... 41 
15.1 
DATA SETS ANALYZED ............................................................................................................................. 41 
15.2 
DEMOGRAPHIC AND BASELINE CHARACTERISTICS ................................................................................... 41 
15.3 
ANALYSIS OF PRIMARY ENDPOINT ........................................................................................................... 41 
15.4 
ANALYSIS OF SECONDARY ENDPOINTS ..................................................................................................... 41 
15.5 
INTERIM ANALYSIS ................................................................................................................................... 42 
15.6 
SAMPLE SIZE AND RANDOMIZATION ........................................................................................................ 42 
16 
DATA COLLECTION, RETENTION AND MONITORING ................................................................. 43 
16.1 
DATA COLLECTION INSTRUMENTS ........................................................................................................... 43 
16.2 
DATA MANAGEMENT PROCEDURES .......................................................................................................... 43 
16.3 
DATA QUALITY CONTROL AND REPORTING ............................................................................................. 43 
16.4 
ARCHIVING OF DATA ................................................................................................................................ 43 
16.5 
AVAILABILITY AND RETENTION OF INVESTIGATIONAL RECORDS ............................................................. 43 
16.6 
MONITORING ............................................................................................................................................ 44 
16.7 
SUBJECT CONFIDENTIALITY ...................................................................................................................... 44 
17 
ADMINISTRATIVE, ETHICAL, AND REGULATORY CONSIDERATIONS .................................... 44 
17.1 
PROTOCOL AMENDMENTS ........................................................................................................................ 44 
17.2 
INSTITUTIONAL REVIEW BOARDS AND INDEPENDENT ETHICS COMMITTEES ............................................ 44 
17.3 
INFORMED CONSENT FORM AND RECRUITMENT PLAN ............................................................................. 45 
17.4 
PARTICIPANT RISK / BENEFIT ASSESSMENT .............................................................................................. 45 
17.5 
PUBLICATIONS .......................................................................................................................................... 46 
17.6 
INVESTIGATOR RESPONSIBILITIES ............................................................................................................. 46 
 
18     APPENDICES…………………………………………………………………………………….....................56 
 
      18.1    APPENDIX 1- SCHEDULE OF STUDY VISITS………………………………………………….….….57 
 
18.2    APPENDIX 2- PREVIOUS PUBLISHED AND CLINICAL EXPERIENCE WITH NEBULIZED 
VANCOMYCIN……………………………………………………………………………………………..59 
 
18.3     APPENDIX 3 – PULMONAY EXACERBATION GUIDELINES………………………………………60 
 
18.4     APPENDIX 4- EXAMPLE VANCOMYCIN CERTIFICATE OF ANALYSES FOR 
MICROBIOLOGY/STERILITY…………………………………………………………………………….61 
 
18.5     APPENDIX 5- SUBJECT DIARY………………………………………………………………………...72 
 
 
19     REFERENCE LIST…........................................................................................................................................77


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List of Abbreviations 
AE 
adverse event 
ALT 
alanine aminotransferase 
AST 
aspartate aminotransferase 
BUN 
blood urea nitrogen 
CBC 
CFR 
CFF 
CFQ-R 
CFTR 
Complete Blood Count 
Code of Federal Regulations 
Cystic Fibrosis Foundation 
Cystic Fibrosis Quality of Life Questionnaire - Revised 
Cystic fibrosis transmembrane conductance regulator 
CF 
cystic fibrosis 
CRF 
case report form 
CRP 
C-reactive protein 
DMC 
Data Monitoring Committee 
DSMB 
Data Safety Monitoring Board 
FDA 
Food and Drug Administration 
FEV1 
FEV1% 
FVC 
Forced expiratory volume over one second 
Forced expiratory volume over one second percentage of predicted  
Forced vital capacity 
GCP 
Good Clinical Practice 
GERD 
GGT 
Gastroesophageal Reflux Disease 
gamma-glutamyl transferase 
HIPAA 
Health Insurance Portability and Accountability Act of 1996 
ICF 
informed consent form 
IEC 
IL-8 
Independent Ethics Committee 
Interleukin-8 
IRB 
Institutional Review Board 
LDH 
lactate dehydrogenase 
mEq 
MIC 
milliequivalent 
Minimal Inhibitory Concentration 
MRSA 
PI 
Methicillin-resistant Staphylococcus aureus 
Principal Investigator 
PK 
pharmacokinetic 
SAE 
serious adverse experience 
SGOT 
serum glutamic oxaloacetic transaminase 
SGPT 
serum glutamate pyruvate transaminase 
TDN-CC 
TMP/SMX 
VISA 
VRSA 
Therapeutics Development Network- Coordinating Center 
Trimethoprim / Sulfamethoxazole (Bactrim) 
Vancomycin-insensitive Staphylococcus aureus 
Vancomycin-resistant Staphylococcus aureus 


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PROTOCOL SYNOPSIS 
TITLE 
 Persistent MRSA Eradication Protocol (PMEP) 
SPONSOR 
Cystic Fibrosis Foundation 
NUMBER OF SITES 
2 (University Hospitals Case Medical Center and Johns Hopkins 
University) 
RATIONALE 
The prevalence of methicillin resistant Staphylococcus aureus 
(MRSA) respiratory infection in CF has increased dramatically 
over the last decade.  Epidemiologic evidence suggests that 
persistent infection with MRSA may result in an increased rate of 
decline in FEV1 and shortened survival.  Currently there are no 
conclusive studies demonstrating an effective aggressive 
treatment protocol for persistent MRSA respiratory infection in 
CF.  Data demonstrating an effective and safe method of clearing 
persistent MRSA infection are needed before potentially 
embarking on a national interventional trial. 
STUDY DESIGN 
This is a two-center (Case and Johns Hopkins), randomized and 
stratified on center and FEV1% predicted (FEV1% ≤ 60% and 
FEV1% > 60%) double-blind, comparator-controlled, parallel-
group study with 1:1 assignment to either vancomycin for 
inhalation (250 mg twice a day) or taste matched placebo for 28 
days in individuals with cystic fibrosis.  Patients will be followed 
for 3 additional months. In addition, both groups will receive oral 
rifampin, a second oral antibiotic (TMP-SMX or doxycycline, 
protocol determined), mupirocin intranasal cream and 
chlorhexidine body washes. 40 patients with persistent 
respiratory tract MRSA infection will be enrolled: 20 will be 
randomized to vancomycin for inhalation and 20 to a taste-
matched placebo.     
PRIMARY OBJECTIVE 
To evaluate the safety and efficacy of a 28-day course of 
vancomycin for inhalation, 250 mg twice a day, (in combination 
with oral antibiotics) in eliminating MRSA from the respiratory 
tract of individuals with CF and persistent MRSA infection. 


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SECONDARY 
OBJECTIVES 
To evaluate the efficacy of a 28-day course of vancomycin for 
inhalation (250 mg twice a day) in addition to oral antibiotics in 
individuals with CF and persistent MRSA infection on: 
 
FEV1% predicted 
 
CFQ-R (respiratory) 
 
Subsequent exacerbations (using standardized exacerbation 
scoring criteria-see appendix 3). 
 
MRSA colony forming units 
To evaluate the safety of a 28-day course of vancomycin for 
inhalation (250 mg twice a day) in addition to oral antibiotics, 
monitor for increasing incidence of gram negative pathogens, 
antimicrobial resistance to rifampin, 
trimethoprim/sulfamethoxazole (TMP/SMX), doxycycline, and 
vancomycin;  vancomycin sputum and serum levels. 
To evaluate the change in strains of MRSA (PFGE analysis), 
emergence of small colony variants of MRSA, and changes in 
sputum cell count and sputum cytokine profiles  
NUMBER OF SUBJECTS 
Forty (40) 
 
 


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SUBJECT SELECTION 
CRITERIA 
Inclusion Criteria: 
1. Male or female ≥ 12 years of age. 
2. Confirmed diagnosis of CF based on the following criteria: 
positive sweat chloride > 60 mEq/liter (by pilocarpine iontophoresis) 
and/or  
a genotype with two identifiable mutations consistent with CF or 
abnormal NPD, and  
one or more clinical features consistent with the CF phenotype. 
3. Written informed consent (and assent when applicable) 
obtained from subject or subject’s legal representative and 
ability for subject to comply with the requirements of the 
study. 
4. Two positive MRSA respiratory cultures in the last two years 
at least six months apart, plus a positive MRSA respiratory 
culture at Screening Visit and Run-in (Day -14) Visit.   
5. At least 50% of respiratory cultures from the time of the first 
MRSA culture (in the last two years) have been positive for 
MRSA. 
6. FEV1 >40% of predicted normal for age, gender, and height 
at Screening, for subjects 18 years of age and older. 
7. FEV1 >60% of predicted normal for age, gender, and height 
at Screening, for subjects 12-17 years old. 
8. Females of childbearing potential must agree to practice one 
highly effective method of birth control, including 
abstinence.  Note: highly effective methods of birth control 
are those, alone or in combination, that result in a failure rate 
less than 1% per year when used consistently and correctly. 
Female patients who utilize hormonal contraceptives as a 
birth control method must have used the same method for at 
least 3 months before study dosing.  If the patient is using a 
hormonal form of contraception and is receiving rifampin, 
patients will be required to also use barrier contraceptives as 
rifampin can affect the reliability of hormone 
therapy.  Barrier contraceptives such as male condom or 
diaphragm are acceptable if used in combination with 
spermicides. 
  Exclusion Criteria: 
1. An acute upper or lower respiratory infection, pulmonary 
exacerbation, or change in routine therapy (including 
antibiotics) for pulmonary disease within 42 days of the Day 
1 Visit (2 weeks prior to screening visit). 
2. Individuals on continuous inhaled antibiotics without 
interruption who are not willing to substitute vancomycin or 
placebo for their scheduled inhaled antibiotic during days 0-
28 of the study (every other month inhaled antibiotics are 
acceptable). 


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3. Use of oral or inhaled anti-MRSA drugs within two weeks of 
the Screening Visit. 
4. History of intolerance to inhaled vancomycin or inhaled 
albuterol. 
5. History of intolerance to both TMP/SMX and doxycycline.  
6. Resistance to both TMP/SMX and doxycycline at Screening. 
7. Resistance to vancomycin at Screening. 
8. Abnormal renal function, defined as creatinine clearance <50 
mL/min using the Cockcroft-Gault equation for adults or 
Schwartz equation in children, at Screening. 
9. Abnormal liver function, defined as ≥3x upper limit of 
normal (ULN), of serum aspartate transaminase (AST) or 
serum alanine transaminase (ALT), or known cirrhosis at the 
time of Screening. 
10. Serum hematology or chemistry screening results which in 
the judgment of the investigator would interfere with 
completion of the study. 
11. History of or listed for solid organ or hematological 
transplantation. 
12. History of sputum culture with non-tuberculous 
Mycobacteria in the last 6 months. 
13. History of sputum culture with Burkholderia Cepacia in the 
last year.  
14. Planned continuous use of soft contact lenses while taking 
rifampin and no access to glasses. 
15. Current use of oral corticosteroids in doses exceeding the 
equivalent of 10 mg prednisone a day or 20 mg prednisone 
every other day. 
16. Administration of any investigational drug or device within 
28 days of Screening or within 6 half-lives of the 
investigational drug (whichever is longer).  
17. Patients on inhaled antibiotics who have not been on the 
same regimen for the 4 months prior to screening 
18. Female patients of childbearing potential who are pregnant 
or lactating, or plan on becoming pregnant 
19. Any serious or active medical or psychiatric illness, which in 
the opinion of the investigator, would interfere with patient 
treatment, assessment, or adherence to the protocol. 
 
 
 


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TEST PRODUCT, DOSE 
AND MODE OF 
ADMINISTRATION 
Days 1-28: 
1) Nebulized Vancomycin  
a. 250 mg nebulized two times a day for 28 days in 5cc 
sterile water.  Patients will use a Pari Sprint nebulizer 
and Pari Vios compressor as the delivery system.  
2) Oral Rifampin  
a. >45 kg:  600 mg by mouth daily 
b. 35-45 kg : 450 mg by mouth daily 
c. 25-34.9 kg:   300 mg by mouth daily 
3) Protocol guided therapy  
a. Oral trimethoprim/sulfamethoxazole  (DS-160/800) 
i. >45 kg: two Double Strength (DS) tablets twice 
a day by mouth (320/1600)  
ii. 25-45 kg:  one DS tablet twice a day by mouth 
(160/800) 
b. If sulfa intolerant or TMP/SMX resistant, use instead 
oral doxycycline   
i. >45 kg:  100 mg by mouth twice a day 
ii. 35-45 kg : 75 mg by mouth twice a day 
iii. 25-34.9 kg:   50 mg by mouth twice a day 
4) Mupirocin 2% intranasal ointment: ½ of single use tube 
applied into each nostril twice a day x 5 days 
5) Hibiclens 15 cc liquid skin cleanser packets (4% chlorhexidine 
gluconate):  use three packets once weekly for four weeks in 
the shower from the neck to toes, with attention on the axilla, 
groin, and buttocks.  
6) Environmental:  While wearing gloves, wipe down high touch 
surfaces with Sani-Cloth Alcohol Free Germicidal wipes 
(provided) and wash all bed linens and towels in hot water 
weekly for the first three weeks. 
 
CONTROL PRODUCT, 
DOSE AND MODE OF 
ADMINISTRATION 
Days 1-28 
1) Nebulized Placebo  
a. Volume (5cc) and taste (quinine 0.1mg/mL) matched 
nebulized placebo (sterile water) for 28 days. 
2) Oral Rifampin  
a. >45 kg:  600 mg by mouth daily 
b. 35-45 kg : 450 mg by mouth daily 
c. 25-34.9 kg:   300 mg by mouth daily 
3) Protocol guided therapy  
a. Oral trimethoprim/sulfamethoxazole (DS-160/800) 
i. 
>45 kg: two DS tablets twice a day by mouth 
(320/1600)  
ii. 
25-45 kg:  one DS tablet twice a day by 
mouth (160/800) 


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b. If sulfa intolerant or TMP/SMX Resistant, use instead 
oral doxycycline   
i. >45 kg:  100 mg by mouth twice a day 
ii. 35-45 kg : 75 mg by mouth twice a day 
iii. 25-34.9 kg:   50 mg by mouth twice a day 
4) Mupirocin 2% intranasal ointment: half of single use tube 
applied into each nostril twice a day X 5 days. 
5) Hibiclens 15cc liquid skin cleanser packets (4% chlorhexidine 
gluconate): use three packets once weekly for four weeks in 
the shower from the neck to toes, with attention on the axilla, 
groin, and buttocks.  
6) Environmental:  While wearing gloves, wipe down high touch 
surfaces with Sani-Cloth Alcohol Free Germicidal wipes 
(provided) and wash all bed linens and towels in hot water 
weekly for the first three weeks. 
 
DURATION OF 
SUBJECT 
PARTICIPATION 
AND DURATION OF 
STUDY 
Subjects will be on study for up to 155 days 
Screening/Run In:  up to 30 days 
Treatment:  28 days  
Primary Endpoint: Day 58 
Follow-up:  3 months after completion of 28-day treatment 
period 
The total duration of the study is expected to be 48 months: 45 
months for subject recruitment and 3 months for final subject 
follow-up. 
 
CONCOMMITANT 
MEDICATIONS 
Allowed: All routine chronic CF medications except non-study 
anti-MRSA antibiotics (unless medically indicated). Inhaled anti-
pseudomonal antibiotics will be permitted except during the 28 
days study drug treatment period. 
Prohibited: Regular use of loop diuretics during days 1-28, 
inhaled antibiotics other than study drug on days 1-28,  IV 
antibiotics from day -42 to day 28 (unless medically indicated). 
EFFICACY 
EVALUATIONS 
Culture (quantitative and qualitative) and sensitivity; FEV1% 
predicted; CFQ-R (pulmonary); Exacerbations (standardized 
definition in appendix 3) 
PRIMARY ENDPOINT 
Percentage of patients MRSA free by induced sputum respiratory 
tract culture one month after completion of four-week eradication 
protocol (Day 58) in intervention arm vs. control arm 
SECONDARY 
ENDPOINTS 
 
Percentage of patients MRSA free by induced sputum 
respiratory tract culture at Visit 4 (Day 29) and Visit 6 (Day 
118) after completion of 28-day treatment period. 
 
Change in FEV1% predicted from baseline and screening to 
Visit 4 (Day 29), Visit 5 (Day 58), and Visit 6 (Day 118). 
 
Time to first pulmonary exacerbation (standard definition 
in appendix 3).   
 
Time to first anti-MRSA antibiotics (after treatment period) 


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 
Total number of pulmonary exacerbations at Visit 5 (Day 
58) and Visit 6 (Day 118).  
 
Change in patient reported CFQ-R (respiratory) from 
baseline at Visit 3 (Day 14), Visit 4 (Day 29), Visit 5 (day 
58), and Visit 6 (Day 118).  
 
Number of patients with newly developed MRSA resistance 
to vancomycin, TMP/SMX, doxycycline, and/or rifampin. 
OTHER EVALUATIONS 
 
Serum vancomycin peak level 60 minutes after completion 
of first dose of inhaled vancomycin on Visit 1 
 
Trough serum vancomycin level to be drawn prior to 
nebulization of vancomycin on Day 14 (two weeks into 
nebulized vancomycin). 
 
Sputum vancomycin level at Visit 1, 5 minutes after 
nebulizing vancomycin.  
 
Change in minimum inhibitory concentration (MIC) of 
vancomycin, rifampin, TMP/SMX, and tetracycline for 
MRSA.   
 
Strain analysis of MRSA for the epidemiologic study of 
Hospital Acquired (HA) and Community Acquired (CA) 
MRSA and the genetic relatedness of MRSA strains 
 
Skin (axillary) and nares nasal swabs for MRSA  
 
Emergence of small colony variants of MRSA 
 
Sensitivity analysis based on time infected with MRSA 
SAFETY EVALUATIONS Chemistry panel, AST, ALT, alkaline phosphatase, and CBC with 
differential, at Screening (Day -28), Visit 1 (Day 1), Visit 3 (Day 
14), Visit 4 (Day 29) and Visit 5 (Day 58) and Early Withdrawal. 
Incidence of adverse events. 
Continuous oxygen saturation checked throughout nebulized 
vancomycin dose at Visit 1 (Day 1), Visit 2 (Day 2-7), and Visit 3 
(Day 14). 
Spirometry checked immediately after and 15 minutes (+/-10 
mins.) after nebulized vancomycin dose is completed at Visit 
1(Day 1) and Visit 2 (Day 2-7). 
Serum vancomycin levels.  If a trough level at Day 14 is found to 
be greater than 8 micrograms/mL we will terminate inhaled 
study drug. 
Hand washing with chlorhexidine body wash at Run In Visit (-14 
days) to assess for skin sensitivity. 
SAFETY MONITORING 
Dr. Wayne Morgan, chair of the CFF DSMB, has agreed to chair a 
data monitoring committee composed of a biostatistician and 
another physician.  The DSMB will review the data after the first 
16 adults (≥ age 18) have been enrolled (8 in each group).  If there 
are no safety issues, then we will start enrolling individuals 12-17 
years of age as well.  The DSMB will perform an interim look after 
the first 8 pediatric patients have been dosed and/or six months 
following IRB approvals to enroll, whichever comes first.  The 
DSMB will receive monthly reports including enrollment for both 


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pediatric and adult groups, screen failures or study withdrawals, 
and FEV1 follow up data after administration of study drug. 
PRIMARY ANALYSIS 
PLAN 
(STATISTICS) 
Our primary analysis will compare the proportion of CF patients 
who have MRSA eradicated from their respiratory tract in the 
intervention group to the standard care group one month after 
completion of the treatment period (Visit 5 at day 58) using 
Pearson’s 2 test.  A secondary analysis will be performed 
comparing proportions of MRSA eradication at Visit 4 (day 29)  
and Visit 6 (day 118) after completion of 28-day treatment period 
Student’s t-test will be performed to compare the change in 
FEV1% predicted from baseline and screening between 
intervention and control groups at Visit 4 (Day 29), Visit 5 (Day 
58) and Visit 6 (Day 118).  We will also use the General Estimating 
Equations (GEE) framework to longitudinally analyze the change 
in lung function over 118 days.    
The respiratory domain of CFQ-R questionnaire will be expressed 
as mean ± standard deviation and statistical significance assessed 
between the groups using a 2-sample t-test from baseline (Visit 1) 
to Visit 3 (Day 14), Visit 4 (Day 29), Visit 5 (Day 58) and Visit 6 
(Day 118). 
A Kaplan-Meier plot will be used to graphically display estimates 
of the survivor function for the proportion of patients who do not 
have an exacerbation through day 118.   Hazard ratios and 95% CI 
due to treatment will be calculated using a Cox proportional 
hazards regression model.  Pre-specified potential variables that 
may be adjusted for include gender, season of enrollment, and 
center.    
RATIONALE FOR 
NUMBER OF SUBJECTS 
Enrollment of 40 participants (20 intervention, 20 control) will 
give us 92% power to detect a 55% absolute increase in percent 
of patients with MRSA not detected by induced sputum 
microbiology (75% in the intervention arm vs. 20% resolution in 
the control arm,  two tail alpha=0.05) 
 


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1 
BACKGROUND 
1.1 
Overview 
Cystic fibrosis (CF) is the most common lethal autosomal recessive disorder in the Caucasian population1.  
With improvements in care, the average age of individuals living with CF continues to increase, and the median 
survival age is approximately 37 years2.  One consequence of improving survival is the emergence of 
pulmonary infections with new and resistant pathogens.  These infections are of importance because they may 
lead to respiratory failure, which continues to be the leading cause of mortality in individuals with CF.  
Methicillin-resistant Staphylococcus aureus (MRSA) is a particularly important emerging pathogen in CF.  The 
prevalence of infection with methicillin-resistant Staphylococcus aureus (MRSA) in the CF community has 
increased from 4% in 1999 to 23.7% in 20093.   
Recently, two very large CF observational studies utilizing the CF Foundation’s National Patient Registry 
database have demonstrated that infection with MRSA is associated with worse clinical outcomes4;5.  The first, 
published in 2008 by Dasenbrook et al. demonstrated that persistent respiratory infection with MRSA is 
associated with a more rapid decline in lung function as measured by FEV1.  The second, also published by 
Dasenbrook et al. in JAMA in 2010, demonstrated an association between persistent MRSA infection and 
increased mortality, even after adjustment for severity of lung disease.   
Given the striking increase in both prevalence of MRSA infection in CF and evidence of a detrimental effect of 
MRSA on CF clinical outcomes, there has been growing interest in treatment protocols designed to treat and/or 
eradicate MRSA CF respiratory infection. 
1.2 
Previous Studies of Treatment of MRSA in CF 
1.2.1 
Non-clinical Studies 
There have been few non-clinical investigations of MRSA infections in CF.  One study in mice demonstrated 
that CFTR-deficient mice were much more susceptible to chronic MRSA nasal infection than normal controls6.  
Another study in rats demonstrated that nebulized vancomycin achieved dramatically higher drug levels in the 
airway surface liquid layer than systemically administered vancomycin7.  In this same study, vancomycin was 
not detectable systemically in the rats after nebulization, suggesting that minimal amounts of vancomycin 
crossed the alveolar-capillary membrane when administered via the respiratory route. The authors concluded 
that nebulized vancomycin was likely to be associated with a very low risk of ototoxicity or nephrotoxicity in 
people because of the minimal observed systemic absorption.   
1.2.2 
Clinical Studies 
There have been several small clinical studies in CF assessing MRSA treatment regimens and their 
effectiveness in eradicating MRSA from the respiratory tract.   These studies have been limited however by 
small study populations, lack of control groups, single-center retrospective design, variable follow-up, and 
failure to distinguish incident vs. persistent MRSA infection8-11.  Doe and colleagues have reported the largest 
experience to date with a retrospective review of 37 patients at their Adult CF center in Manchester, UK 11.   
Although many different eradication regimens were used, most of the patients in their cohort (average age 25.6 
years, mean FEV1 2.2 L, and 75% with Pseudomonas aeruginosa) were treated with a combination of two oral 
antibiotics (rifampicin, fusidic acid, or trimethoprim) and nebulized vancomycin (200 mg four times a day for 
five days).  They reported that this resulted in eradication of MRSA in 81% of the participants at 6 months.  
There was no distinction made between those with incident MRSA and those with persistent MRSA infection in 
the study analysis, although they report that approximately 38% of those included had had multiple positive 
MRSA cultures.  There is one small study by Garske and coworkers which focused on treatment of CF adults 
with persistent MRSA8 (perhaps similar to our study population).  They enrolled seven CF adults with persistent 
MRSA (average FEV1 36% predicted, all with chronic PA, 6/7 with previous IV MRSA therapy); 5 of the 7 
patients (71%) were culture-negative six months after completing a six month treatment regimen of oral fusidic 
acid and rifampin8. Most other studies have focused on patients with incident MRSA infection rather than 
persistent infection.  Macfarlane and co-workers reported on 17 CF patients with incident MRSA treated with 


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oral and IV antibiotics. Utilizing a protocol which started with oral rifampicin and fusidic acid, they achieved a 
94% eradication rate at 12 months9.  A study by Solis and coworkers of 15 CF children treated with five-days of 
oral and nebulized vancomycin was associated with a 55% eradication rate 10.  
1.3 
Previous Experience with Nebulized Vancomycin 
There have been numerous reports of the clinical use of nebulized vancomycin in both CF and non-CF 
populations, all of which have demonstrated it to be well-tolerated and efficacious.  The doses reported in those 
aged >12 years of age have included 125 mg twice a day, 250 mg four times a day, and 500 mg twice a day12.   
In the largest study to date, 51 non-CF patients received 125 mg of nebulized vancomycin twice a day for an 
average of 14.7 days to eradicate respiratory MRSA13. Eradication success rate was 84.3%.  The authors 
reported that there were no adverse events associated with inhalation of vancomycin in the 51 participants.  
Also of importance, vancomycin was not detectable by serum levels two hours after inhalation of the 125 mg of 
vancomycin.  In a study by Doe and coworkers, nebulized vancomycin 200 mg four times a day for 5 days was 
administered to 18 CF patients11.  Three experienced chest tightness, but all episodes were graded as mild and 
none required discontinuation of the drug.  Maiz and colleagues also reported their experience with a 10 year-
old CF patient treated with nebulized vancomycin 250 mg two times a day for 17 continuous months without 
adverse events or antibiotic resistance14.  There was no increase in cough or wheezing during vancomycin 
administration. The patient had negative fecal cultures for VRE and despite repeatedly checking, there was no 
development of VISA.   The authors also reported that creatinine was normal throughout study and the patient 
did not develop ototoxicity.  Hayes and colleagues reported treating a post-transplant CF patient with refractory 
MRSA with inhaled vancomycin 250 mg twice a day for six months15.  The patient had undetectable serum 
vancomycin levels at 2 hours and despite taking numerous other nephrotoxic medications did not have a change 
in creatinine.   
Kahata and colleagues did report a single patient with chronic myelogenous leukemia in June 1994 who had an 
adverse reaction to inhaled vancomycin while preparing to receive an allegeneic bone marrow transplant16.  
Thirty minutes after inhaling vancomycin (dose unknown) the patient developed cough, fever, shortness of 
breath, eosinophilia, hypoxia, and elevated CRP.  The symptoms completely resolved with steroids. 
There have also been studies of achievable sputum levels after nebulization of vancomycin. In non-CF patients, 
mean sputum vancomycin levels after nebulizing 125mg were 262.5 g/g at 10 minutes and 50 g/g at 6 hours - 
both of which are still 25 times above a therapeutic MIC13.  In another report of a non-CF mechanically 
ventilated patient, sputum vancomycin levels were 2,352 g/mL 1 hour after nebulizing 120mg of 
vancomycin17.  The higher level in the latter study may be related to breath actuated nebulization (as opposed to 
continuous) and turning off the humidifier during nebulization.  There have not been any CF specific studies to 
date of achievable sputum levels after inhaled vancomycin.   
Finally, there is significant clinical experience with the use of nebulized vancomycin in CF, as the CF treatment 
community frequently uses nebulized vancomycin in clinical care.  Foundation Care, a compounding pharmacy 
which supplies CF healthcare providers nebulized vancomycin for clinical care, has documented treatment of 
over 95 CF patients with the dose described in the protocol without any treatment related serious adverse 
events. Please see Appendix 2 for a table summarizing known safety and efficacy of inhaled vancomycin 
reported in over 180 patients. 
2 
STUDY RATIONALE 
2.1 
Importance of MRSA in Cystic Fibrosis 
The prevalence of methicillin resistant Staphylococcus aureus (MRSA) respiratory infection in CF has 
increased dramatically over the last decade, with over 25% of CF patients now having pulmonary infection with 
MRSA3.  Epidemiologic evidence suggests that persistent infection with MRSA is an independent risk factor for 
an increased rate of decline in FEV1 and shortened survival4;5.   


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2.2 
Lack of Conclusive Clinical Trials of MRSA Therapy Protocol in CF 
Currently there are no conclusive studies demonstrating an effective aggressive treatment protocol for persistent 
MRSA respiratory infection in CF.  Pilot data demonstrating an effective and safe method of clearing MRSA 
infection are needed.  While there have been several small clinical studies in CF assessing MRSA treatment 
regimens, these studies have been limited by small study populations, single-center design, retrospective design, 
variable follow-up, and failure to distinguish incident vs. persistent MRSA infection. 
2.3 
Rationale for Specific Drugs included in the Protocol 
2.3.1 
Why inhaled vancomycin? 
1) Multiple reports in CF and outside of CF have suggested vancomycin to be an effective method of treating 
pulmonary MRSA infection. 
2) Multiple reports in CF and outside of CF have suggested inhaled vancomycin to be a safe and well tolerated 
method of treating pulmonary MRSA infection while minimizing systemic absorption. 
2.3.2 
Why oral rifampin? 
1) Rifampin has excellent mucosal penetration and has been shown to clear MRSA when added to vancomycin 
when vancomycin alone failed 18 
2)  Rifampin in combination with vancomycin has been shown to be bactericidal against biofilm producing 
MRSA19)  
3) Rifampin in combination with another antibiotic eradicated MRSA in previous CF studies8;11.    
2.3.3 
Why Mupirocin Nasal and 4% Chlorhexidine Gluconate Skin Treatment and Sani-Cloth Alcohol Free 
Germicidal Wipes? 
1) CF patients are known to have a significantly higher rate of staph aureus anterior nasal carriage compared to 
non-CF controls (66% vs. 32%)20.  
2) Mupirocin nasal treatment has been demonstrated in non-CF studies to successfully eradicate nasal 
colonization of MRSA in 93% of patients21. 
3) Stone and colleagues recently published a cross sectional study which demonstrated that S. aureus from the 
anterior nares may be transmitted between CF patients and household contacts22.  In their study, 15% of 
household contacts of MRSA positive CF patients cultured MRSA from their nares. Therefore we have 
elected to treat high touch home environment with chlorhexidine wipes and provide a handout with 
information on decreasing transmission within the home environment.  Sani-Cloth Alcohol Free Germicidal 
Wipes are documented to disinfect surfaces from MRSA and are fragrance free to avoid respiratory 
irritation. 
4) Recent review of regimens for the decolonization of MRSA concluded 4% chlorhexidine gluconate whole 
body washes in combination with mupirocin to be the regimen of choice23. 
 
3 
STUDY OBJECTIVES 
3.1 
Primary Objectives 
The primary objectives of this trial are to: 
1) 
Determine the efficacy of an aggressive treatment protocol in eradicating persistent MRSA 
infection in individuals with CF. 
2) 
Determine the safety of an aggressive treatment protocol in eradicating persistent MRSA 
infection in individuals with CF. 


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3.2 
Secondary Objectives 
The secondary objectives of this trial are to: 
1) 
Determine the efficacy of an aggressive treatment protocol in improving FEV1, time to 
exacerbation, and quality of life in individuals with CF and persistent MRSA infection. 
2) 
Determine if there is benefit to adding nebulized vancomycin to an aggressive oral antibiotic 
treatment protocol in eradicating persistent MRSA infection in individuals with CF.   
 
4 
STUDY DESIGN 
4.1 
Study Overview 
This is a two-center, double-blind, comparator-controlled, randomized, and stratified on center and FEV1%  
(FEV1% ≤ 60% and FEV1% > 60%) parallel-group study with 1:1 assignment to either vancomycin for 
inhalation (250mg twice a day) or taste matched placebo for 28-days in individuals with cystic fibrosis and 
chronic MRSA pulmonary infection.  In addition, both groups will receive oral rifampin, a second oral 
antibiotic (TMP-SMX or doxycycline, protocol determined), mupirocin intranasal ointment and chlorhexidine 
body washes. 40 patients with persistent respiratory tract MRSA infection will be enrolled: 20 will be 
randomized to vancomycin for inhalation and 20 to a taste-matched placebo.  
Screening data will be reviewed to determine subject eligibility.  Subjects who meet all inclusion criteria and 
none of the exclusion criteria will be entered into the study. 
Each subject will be administered study medication twice a day for 28 days. Subjects will be randomly assigned 
to the treatment or placebo. Evaluations will be taken at each of the 5 study visits. 
All subjects who receive at least one dose of study medication will be considered evaluable for safety and 
efficacy analyses.  Incidence of adverse events will be monitored beginning at the time of consent.  
Efficacy assessments will be based on culture results, changes in lung function and sputum MRSA density in 
sputum, CFQ-R scores, and exacerbations.   
Total duration of subject participation will be 146 ± 9 days.  Total duration of the study is expected to be 48 
months. 
5 
CRITERIA FOR EVALUATION 
5.1 
Primary Efficacy Endpoint 
Percentage of patients MRSA free by induced sputum respiratory tract culture 1 month (Visit 5, Day 58) after 
completion of four-week eradication protocol in intervention arm vs. control arm.  
5.2 
Secondary Efficacy Endpoints 
 
Percentage of patients MRSA free at Visit 4 (Day 29) and Visit 6 (Day 118).  
 
Change in FEV1 from baseline (Day 1) at Visit 4 (Day 29), Visit 5 (Day 58) and Visit 6 (Day 118). 
 
Change in FEV1 from Screening (Day -28) at Visit 4 (Day 29), Visit 5 (Day 58) and Visit 6 (Day 118). 
 
Time to first exacerbation (standard definition in appendix 3).   
 
Time to first anti-MRSA antibiotics (after treatment period) 
 
Total number of exacerbations at Visit 5 (Day 58) and Visit 6 (Day 118).  
 
Change in patient reported CFQ-R (respiratory) from baseline (Visit 1) to Visit 3 (Day 14), Visit 4 
(Day 29), Visit 5 (Day 58), and Visit 6 (Day 118). 
 
Number of patients with newly developed MRSA resistance to vancomycin, TMP/SMX, doxycycline, 
and/or rifampin at any point during follow-up. 


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5.3 
Safety Evaluations 
 
Chemistry panel, AST, ALT, alkaline phosphatase, and CBC with differential, at Screening (Day -28), 
Visit 1 (Day 1), Visit 3 (Day 14), Visit 4 (Day 29), Visit 5 (Day 58) and Early Withdraw Visit. 
 
Incidence of adverse events. 
 
Continuous oxygen saturation throughout nebulized vancomycin dose at Visit 1 (Day 1), Visit 2 
(Day 2-7) and Visit 3 (Day 14).  
 
Spirometry checked immediately after and 15 minutes (+/-10min) after nebulized vancomycin 
dose at Visit 1 (Day 1) and Visit 2 (Day 2-7). 
 
Hand washing with chlorhexidine body wash at Run In Visit (Day-14) to monitor for skin 
sensitivity. 
 
5.4 
Other Evaluations 
 
Serum vancomycin peak level 60 minutes after completion of first dose of inhaled vancomycin at Visit 1. 
 
Trough serum vancomycin level to be drawn prior to nebulization of vancomycin at Visit 3 (Day 14-two 
weeks into nebulized vancomycin). 
 
Sputum vancomycin level at Visit 1 (Day 1), 5±4 minutes after nebulizing vancomycin in patients. 
 
Change in minimum inhibitory concentration (MIC) of vancomycin, rifampin, TMP/SMX, and 
tetracycline for MRSA.  As per CDC guidelines. VISA if the MIC for vancomycin is 4-8µg/ml, and 
classified as VRSA if the vancomycin MIC is ≥16µg/ml.  We will also monitor for those MIC’s that are 
initially less than 2 µg/mL and convert to 2-4 µg/mL. 
6 
SUBJECT SELECTION 
6.1 
Study Population 
Subjects with a diagnosis of CF who meet the inclusion and exclusion criteria will be eligible for participation 
in this study.   
6.2 
Inclusion Criteria 
1. Male or female ≥ 12 years of age. 
2. Confirmed diagnosis of CF based on the following criteria: 
o 
positive sweat chloride > 60 mEq/liter (by pilocarpine iontophoresis) and/or  
o 
a genotype with two identifiable mutations consistent with CF or abnormal NPD, and  
o 
one or more clinical features consistent with the CF phenotype. 
3. Written informed consent (and assent when applicable) obtained from subject or subject’s legal 
representative and ability for subject to comply with the requirements of the study. 
4. Two positive MRSA respiratory cultures in the last two years at least six months apart, plus a positive 
MRSA respiratory culture at Screening Visit and Run-in (Day -14) Visit.   
5. At least 50% of respiratory cultures from the time of the first MRSA culture (in the last two years) 
have been positive for MRSA. 
6. FEV1 >40% of predicted normal for age, gender, and height at Screening, for subjects 18 years of age 
and older. 
7. FEV1 >60% of predicted normal for age, gender, and height at Screening, for subjects 12-17 years old. 
8. Females of childbearing potential must agree to practice one highly effective method of birth control, 
including abstinence.  Note: highly effective methods of birth control are those, alone or in 


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combination, that result in a failure rate less than 1% per year when used consistently and correctly. 
Female patients who utilize hormonal contraceptives as a birth control method must have used the 
same method for at least 3 months before study dosing. If the patient is using a hormonal form of 
contraception and is receiving rifampin, patients will be required to also use barrier contraceptives as 
rifampin can affect the reliability of hormone therapy.  Barrier contraceptives such as male condom or 
diaphragm are acceptable if used in combination with spermicides. 
 
6.3 
Exclusion Criteria 
1. An acute upper or lower respiratory infection, pulmonary exacerbation, or change in routine therapy 
(including antibiotics) for pulmonary disease within 42 days of the Day 1 Visit (2 weeks prior to 
Screening visit). 
2. Individuals on chronic continuous inhaled antibiotics without interruption who are not willing to 
substitute vancomycin or placebo for their scheduled inhaled antibiotic during days 0-28 of the study 
(every other month inhaled antibiotics are acceptable) 
3. Use of oral or inhaled anti-MRSA drugs within two weeks of the Screening Visit. 
4. History of intolerance to inhaled vancomycin or inhaled albuterol. 
5. History of intolerance to both TMP/SMX and doxycycline.  
6. Resistance to both TMP/SMX and doxycycline at Screening. 
7. Resistance to vancomycin at Screening. 
8. Abnormal renal function, defined as creatinine clearance <50 mL/min using the Cockcroft-Gault 
equation for adults or Schwartz equation in children, at Screening. 
9. Abnormal liver function, defined as ≥3x upper limit of normal (ULN), of serum aspartate transaminase 
(AST) or serum alanine transaminase (ALT), or known cirrhosis. at the time of Screening. 
10. Serum hematology or chemistry results which in the judgment of the investigator would interfere with 
completion of the study. 
11. History of or listed for solid organ or hematological transplantation 
12. History of sputum culture with non-tuberculous Mycobacteria in the last 6 months. 
13. History of sputum culture with Burkholderia Cepacia in the last year.   
14. Planned continuous use of soft contact lenses while taking rifampin and no access to glasses. 
15. Current use of oral corticosteroids in doses exceeding the equivalent of 10 mg prednisone a day or 20 
mg prednisone every other day 
16. Administration of any investigational drug or device within 28 days of screening or within 6 half-lives 
of the investigational drug (whichever is longer) 
17. Patients on inhaled antibiotics who have not been on the same regimen for the 4 months prior to 
screening. 
18. Female patients of childbearing potential who are pregnant or lactating, or plan on becoming pregnant 
19. Any serious or active medical or psychiatric illness, which in the opinion of the investigator, would 
interfere with patient treatment, assessment, or adherence to the protocol. 
7 
CONCURRENT MEDICATIONS 
All subjects should be maintained on a stable medical regimen throughout the entire study period, as medically 
feasible, with the exception that patients on continuous inhaled antibiotics will stop their non-study drug inhaled 


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antibiotic during the 28 day treatment period.  If subjects are on an alternating month inhaled antibiotic, study 
drug dosing will occur during an “off” cycle.  There should be no introduction of other new chronic therapies 
during the study period unless medically required. 
7.1 
Allowed 
All usual CF medications and treatments are allowed except anti-MRSA antibiotics beginning two weeks prior 
to the screening visit and throughout the study (unless medically indicated). 
7.2 
Prohibited 
Inhaled antibiotics other than study drug from Day 1 through Day 28 
Unless medically indicated, intravenous antibiotics from Day -42 through Day 28. 
Regular use of loop diuretics during days -14 through 28. 
8 
STUDY TREATMENTS 
8.1 
Method of Assigning Subjects to Treatment Groups 
Up to 40 eligible patients will be randomly assigned to vancomycin for inhalation or placebo treatment (Days 1-
28) in a 1:1 ratio using a SAS-based computer-generated randomization scheme developed by a biostatistician 
at Case.  The randomization will be performed in blocks of random sizes and stratified by FEV1% and center.  
The randomization will also be designed to assure an equal division between placebo and treatment among the 
first sixteen participants in preparation for the first DSMB safety review (after 16 participants are enrolled). The 
investigator or designee will complete a randomization worksheet (a Non-visit task at Day -4).   
8.2 
Blinding 
Due to the objectives of the study, the identity of test and control treatments will not be known to investigators, 
research staff, or patients.  The following study procedures will be in place to ensure double-blind 
administration of study treatments.   
Access to the randomization code will be strictly controlled.  Access to the randomization code will be limited 
to the randomization programmer, Manager of the Data Management Unit as a backup to the randomization 
programmer, and the drug packaging group. 
Packaging and labeling of test and control treatments will be identical.  
Since vancomycin levels in the serum and sputum will be measured, the results of these tests will not be 
available to the investigators.  
The study blind will be broken on completion of the clinical study and after all adverse events have been 
evaluated for relationship to study drug, coded, and reviewed by the DSMB.    
During the study, the blind may be broken only in emergencies when knowledge of the patient’s treatment 
group is necessary for further patient management. When possible, the Investigator should discuss the 
emergency with the DSMB prior to unbinding.   
8.3 
Formulation of Study Medication (Vancomycin/Placebo) 
Study Medication: Vancomycin hydrochloride is a tricyclic glycopeptide antibiotic obtained from 
Amycolatopsis orientalis.  It is an off-white lyophilized powder that is oxygen sensitive.  The manufacturer is 
Hospira, Inc. (Lake Forest, IL). 
Classification: Antibiotic 
Route of Administration: The compounded sterile preparation is intended for inhalation via a nebulizer device. 


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Method of preparation: The dispensing pharmacy will be Foundation Care (Earth City, MO).  Foundation Care 
is an FDA inspected facility and is also accredited by the Pharmacy Compounding Accreditation Board.  All 
preparations of vancomycin for inhalation are done in a sterile compounding room based on USP policies and 
procedures via aseptic technique.  Vancomycin will be reconstituted by adding 20 mL of sterile water to a 1g 
vial of sterile vancomycin powder.  Each batch of sterile vancomycin (1g/vial) will have a certificate of analysis 
assuring the identity, strength, quality, and purity of the drug substance [see Appendix 4 Figure 1 (Example 
Hospira certificate of analysis)] and be packaged in tamper proof, individual, single-dose (250 mg) plastic 
ampules.  [See Appendix 4 Figure 2 (Example of compounding formula record) and Appendix 4 Figure 3 
(Description of the manufacturing and packaging procedures)].  
The final product will undergo a series of analytical assays to determine the identity, strength, quality, and 
purity.  Before the vancomycin for inhalation can leave the facility, a series of checks and tests in accordance 
with Standard Operating Procedures after compounding is performed to ensure sterility and accuracy.  Each 
ampule is visually inspected for integrity, appropriate solution color, volume, particulates, cloudiness, and 
container leakage before leaving the clean room.  The product is double checked before dispensing.  A sample 
vial from each batch is sent to test for sterility, fungus, yeast, molds, and endotoxins.  A preliminary report is 
returned after 72 hours [see Appendix 4 Figure 4 (Example microbiology report) and Appendix 4 Figure 5 
(Example certificate of analysis)]. 
Stability and Storage: Stability testing has been previously performed.  The beyond use period has been set at 
60 days based upon prior testing of potency at 0, 30, 60, and 90 days after preparation.  Vancomycin for 
inhalation should be stored in a refrigerator at a temperature of 2-8°C.  Based on prior validation, the product is 
potent and stable for greater than 60 days when stored between 2-8°C.  
Study Placebo:  The placebo will be 5cc of sterile water and 0.5 mg of quinine for taste masking to maintain 
blind.  
Route of Administration: The compounded sterile preparation is intended for inhalation via a nebulizer device. 
Method of Preparation: The placebo will also be prepared by Foundation Care in sterile fashion as described 
above with identical analytical assays to determine quality and purity.  Each ampule is visually inspected for 
integrity, appropriate solution color, volume, particulates, cloudiness, and container leakage before leaving the 
clean room.  The product is double checked before dispensing.  A sample vial from each batch is sent to test for 
sterility, fungus, yeast, molds, and endotoxins.  A preliminary report is returned after 72 hours.   
The placebo formulation is based on previous recommendations by the FDA on inhaled placebo design to the 
investigators of the Cystic Fibrosis Foundation Inhaled Hypertonic Saline Trial. (N.Engl.J.Med. 354, 241-50, 
2006, personal communication with Donaldson).  We will be using less quinine for taste masking of the sterile 
water than was used in that trial. (0.1 mg of sterile quinine per ml of sterile water in this trial vs. 0.25 mg of 
sterile quinine per ml of sterile water in the Hypertonic Saline Trial.) Similar to that study, the quinine used will 
be sterile, USP grade, manufacturer DSM Minera.   
Storage: Identical to the vancomycin study drug, the placebo inhalation will be stored in a refrigerator at a 
temperature of 2-8°C during use.   
8.3.1 
Packaging and Labeling 
Study drug is supplied in cartons containing 60 single use ampules. Any excess study drug will be collected at 
Visit 4 (Day 29), stored by the investigative pharmacy, and destroyed at the end of the study or during an 
interim monitoring visit.  
Labeling: Each carton (kit) of study drug will be labeled with drug name (vancomycin/placebo), a lot number, 
an expiration date, the protocol name, directions for storage, and the words “For investigational use only”.   
8.3.2 
Handling/Dispensing 
Study drug should be stored securely under refrigeration both in the investigational pharmacy and at the 
patient’s home.  The investigator and/or the pharmacist have the authority to dispense drug, and each site’s 


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investigational pharmacy will oversee the dispensing and study drug/placebo supply.  Drug should be dispensed 
by the research pharmacy within 28 days of shipment from the central pharmacy. 
8.3.3 
Dosage/Dosage Regimen 
Nebulized Vancomycin: 250 mg nebulized two times a day for 28 days in 5cc sterile water.  The selection of 
this dose is based on previous experience in both studies in cystic fibrosis and clinical experience by Foundation 
Care (see appendix 2).  Patients will use a Pari LC Sprint Nebulizer cup and Pari Vios Compressor delivery 
system. Doses should be taken at least 4 hours apart. After the first 16 adult patients have been enrolled, the 
DSMB will review the safety data and if indicated will allow the inclusion of individuals with CF aged 12-17, 
as MRSA infection is a significant pathogen in this group.  Based on the studies by Solis10 and Generali12, and 
previous clinical experience by Foundation Care, the dosing for this group will also be 250 mg nebulized two 
times a day for 28 days in 5cc sterile water. This is consistent with current FDA Approved nebulized antibiotic 
use in Cystic Fibrosis patients with inhaled tobramycin (TOBI) and Aztreonam (CAYSTON), in which identical 
doses are used in adult and pediatric populations given the minimal systemic absorption. 
8.3.4 
Administration Instructions Nebulized Vancomycin/Placebo (Days 1-28) 
Patients who meet the inclusion criteria and are randomized at non-visit Day -4 will be dispensed a 28 day 
supply of Vancomycin 250mg twice a day or matched placebo on Visit 1 (Day 1).  Patients will be provided 
with two Pari LC Sprint nebulizer cups and a Pari Vios compressor which should be used to administer study or 
control medication.  In addition, patients will be provided with a Pari Expiratory Filter/Valve Set with 60 single 
use expiratory filter pads to be used with each drug administration. Patients will be provided with an albuterol 
HFA and instructed to take two puffs at home 5 to 30 minutes prior to study drug inhalation.  The treatment 
period is 28 days.  Witnessed study drug administration will occur in the clinic at Visit 1 (Day 1). Repeat 
witnessed administration will occur in the clinic at Visit 2 (Day 2-7) and Visit 3 (Day 14).  The witnessed dose 
will be placed into the opaque nebulizer cup by the subject to prevent the RC or physician from examining the 
characteristics of the study drug. Subsequent doses will be self-administered twice a day (morning and 
evening).  If a dose is missed, both doses should be taken as long as they are at least 4 hours apart. Order of 
inhaled medications/treatments when at home: 
1) Albuterol HFA (if patients already use albuterol nebulizers or levalbuterol, those medications can be 
substituted here) 
2) Hypertonic saline (if applicable) 
3) Dornase alfa (if applicable) 
4) Chest physiotherapy (VEST, flutter, acapella, or other airway clearance method, if applicable) 
5) Study or control medication 
6) Inhaled corticosteroids (if applicable) 
Patients will be instructed to refrain from using short acting bronchodilators 4 hours prior to appointment. All 
patients will receive a short acting bronchodilator prior to spirometry and study drug dosing at study Visit 1, 2 
and 3. On other visit days, participants will receive bronchodilator prior to spirometry and not have further 
bronchodilator prior to induced sputum unless it occurs more than 2 hours after previous bronchodilator use. 
Along with their nebulizers, patients will also be provided with nebulizer cleaning instructions. 
8.4 
Supply of Study Medication at the Site 
Once the results of the sputum culture from Run-In Visit 2 (Day -14) is confirmed positive, the participant will 
be randomized by the Foundation Care pharmacy utilizing a predesigned randomization sheet and the 
Foundation Care pharmacy will dispense study or control drug kits to the site Investigational Drug Service 
Pharmacy. Study medication will be sent overnight packed in dry ice labeled for investigational use only.     


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8.4.1 
Storage 
Study drug should be stored securely under refrigeration both in the investigational pharmacy and at the 
patient’s home.  The investigator and/or the pharmacist have the authority to dispense drug.  Drug should be 
dispensed within 28 days of shipment from the central pharmacy to IDS. 
8.5 
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 Investigational Drug Service Pharmacy at each site.  The 
number of study drug dispensed and returned by the subject will be recorded on the Investigational Drug 
Accountability Record.  The study monitor will verify these documents throughout the course of the study. 
8.6 
Measures of Treatment Compliance 
Subjects will be asked to keep a patient diary noting if study drug was taken as directed, refrigeration of the 
study drug,  any adverse events. They will be asked to bring their patient diary to each study visit along with all 
used and unused study drug containers. 
8.7 
Other Protocol Prescribed Treatments: 
8.7.1  Oral Rifampin (Lannett Company, Philadelphia PA) (Days 1-28).  Participants will be treated with 
oral rifampin on days 1-28 according to the following dosing guidelines: 
 
>45 kg:   
Rifampin 600 mg by mouth daily 
35-45 kg:  
Rifampin 450mg by mouth daily 
25-34.9 kg:    Rifampin 300mg by mouth daily 
 
Participants with known allergies, and/or intolerances to rifampin will forgo treatment with this antibiotic, at the 
discretion of the investigator.  Additionally, any participant whose current CF treatment regimen includes 
medication(s) that are known to produce adverse drug-drug interactions with rifampin will forgo treatment with 
rifampin.  Participants with evidence of MRSA resistance to rifampin at Screening will not be treated with this 
antibiotic. Rifampin will be dispensed as a combination of 300 mg and 150 mg capsules to create the protocol 
determined dose.  Rifampin may be stored at room temperature.  Rifampin is known to potentially cause 
gastroesophageal reflux symptoms (GERD).  For individuals experiencing this, an adverse event will be 
recorded and treatment will instituted by either increasing current GERD therapy or instituting treatment with a 
proton pump inhibitor.  The proton pump inhibitor will be ordered by the patient’s primary CF physician. 
Continued symptoms judged by the investigator or participant as more than mild despite treatment will result in 
discontinuation of the rifampin, although participants will be permitted to remain in the study. 
 
8.7.2  Protocol Determined Oral Antibiotic - TMP/SMX (Mutual Pharmaceutical Company, 
Philadelphia, PA) or Doxycycline (Keltman Pharmaceuticals, Flowood, MS) (Days 1-28) .  All 
participants will be treated with either TMP/SMX or doxycycline on days 1-28 according to the following 
protocol:  
 
Participants with MRSA susceptible by MIC testing to TMP/SMX and without history of sulfa allergy will 
be treated with trimethoprim/sulfamethoxazole (DS-160/800): 
>45 kg:   
Two DS tablets twice a day by mouth (320/1600) 
25-45 kg:    
One DS tablet twice a day by mouth (160/800) 
 
Participants with MRSA resistant by MIC testing to TMP/SMX and without history of doxycycline allergy 
will be treated with doxycycline: 
 


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>45 kg:   
100 mg by mouth twice a day 
35-45 kg:    
75 mg by mouth twice a day 
25-34.9 kg:  
50 mg by mouth twice a day 
 
Participants with evidence of only SCV MRSA at Screening will be treated with doxycycline, per the above 
dosing guidelines.  For participants with both SCV MRSA and normal colony MRSA at Screening, antibiotic 
choice will be based on the following: 
 
 
SCV MRSA + normal colony MRSA susceptible to TMP/SMX and doxycycline: treat with 
doxycycline 
 
SCV MRSA + normal colony MRSA resistant to TMP/SMX and susceptible to doxycycline: 
treat with doxycycline 
 
SCV MRSA + normal colony MRSA susceptible to TMP/SMX and resistant to doxycycline: 
treat with TMP/SMX 
 
8.7.3  Mupirocin 2% Intranasal Ointment (GlaxoSmithKline, Research Triangle Park, NC) (Days 1-5).  
All participants without known Mupirocin allergy will be treated with Mupirocin 2% intranasal ointment 
on days 1-5. Participants will use a total of 10 single use tubes of Mupirocin 2% intranasal tubes over 5 
days by administering one half of a tube into each nasal cavity and pinching their nose closed for one 
minute.  They will do this each morning and each evening for five days.  Mupirocin allergy will not be an 
exclusion criterion. 
 
8.7.4  Hibiclens (4% chlorhexidine gluconate) Liquid Skin Cleanser (Molnlycke Health Care, 
Norcross, GA) (once a week for weeks 1-4).  All participants without known chlorhexidine gluconate 
allergy will be provided with 12 packets of 4% chlorhexidine gluconate for use of three packets once 
weekly in the shower during days 1-28. Participants will scrub with Hibiclens on a washcloth from the 
neck to the toes, with attention to the axilla, groin, and buttocks.  Participants should not allow contact 
with skin above the neck.  Individuals with a chlorhexidine allergy will not do the Hibiclens scrubs but 
this will not be an exclusion criterion to participation in the trial. 
 
8.7.5  Wipe down of high touch household surfaces with Sani-Cloth Alcohol Free Germicidal wipes 
(PDI Incorporated, Orangeburg, NY) (once a week for weeks 1-4).  All participants will be provided 
with a packet of Sani-Cloth Alcohol Free wipes and a box of gloves to wipe down high touch surfaces in 
their home.  High touch surfaces include door handles, light switches, computer key boards, television 
sets/remote controls, telephones, kitchen and bathroom sink and counter areas, toilets/toilet seats. 
Performance of cleaning will be captured in the patient diary. 
 
8.7.6  Wash all linens and towels in hot water weekly for the first three weeks. All participants will 
be instructed for days 1-21 of the study to wash weekly in hot water all bedding linens and towels with 
which they will have contact. Performance of linen washing will be captured in the patient diary. 
9 
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 or subject’s legal 
representative.  If appropriate, assent must also be obtained prior to conducting any study-related activities. 


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9.1 
Clinical Assessments 
9.1.1 
Concomitant Medications 
All concomitant medication and concurrent therapies will be documented at Screening, the Run-in Visit, Visit 1, 
Phone Visits, Visit 2, Visit 3, Visit 4, Visit 5, and Visit 6 and at Early Withdrawal Visit when applicable.  Dose, 
route, unit, frequency of administration, and indication for administration and dates of medication will be 
captured. 
9.1.2 
Demographics  
Demographic information (date of birth, gender, race) will be recorded at Screening. 
9.1.3 
Medical History  
Relevant medical history, including history of current disease, other pertinent respiratory history, medications, 
and information regarding underlying diseases will be recorded at Screening and all subsequent visits.  In 
addition, at the screening visit we will determine history of previous treatment for MRSA, number of MRSA 
cultures, and length of MRSA positivity.    
9.1.4 
Physical Examination 
A complete physical examination will be performed by a physician (either the principle investigator or a 
physician subinvestigator) at Screening , Visit 4, Visit 6, and the Early Withdrawal Visit (if applicable).   The 
abbreviated physical exam may be completed by qualified staff (MD, NP, RN, PA) at all other visits.  An 
abbreviated physical exam will consist of an oropharyngeal, skin, lung, cardiac, and abdominal exam.  New 
abnormal physical exam findings will be documented and followed by a physician or other qualified staff.   
9.1.5 
Vital Signs and Height and Weight 
Body temperature, blood pressure, pulse and respirations will be performed after resting for five minutes at all 
visits. Height and weight will be recorded at all visits. 
9.1.6 
Oximetry 
Oximetry will be measured on room air with the subject at rest at all visits. During the observed nebulization of 
study drug Visits 1, 2 and 3, participant will undergo continuous oxygen saturation monitoring throughout the 
nebulization period and for 5 minutes afterward. 
9.1.7 
Spirometry 
Spirometry will be performed at all visits in accordance with the current American Thoracic Society 
recommendations for the performance and interpretation of tests.  Subjects will be given two inhalations of 
Albuterol HFA 10-30 minutes prior to initial spirometry.  For the repeat spirometry immediately after and 15 
minutes ( ± 10 mins) after  dosing of study drug at Visit 1 and Visit 2, a single value will be acceptable if FEV1 
percent predicted improves, is stable, or has a relative decrease less than 10% from consistent baseline prior to 
nebulization. 
9.1.8 
CFQ-R  
The CFQ-R (Cystic Fibrosis Quality of Life Questionnaire –Revised Assessment) is a validated CF-specific 
instrument that measures the health-related quality of life for patients with CF. Furthermore, the CFQ-R 
has been evaluated in clinical studies involving therapies for CF lung disease. The CFQ-R will be 
completed prior to any other interventions at Visits 1, 3, 4, 5 and 6 and Early Withdrawal Visit as 
applicable.  A minimum clinically important difference of 4 points will be considered clinically meaningful for 
the respiratory domain24.  


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9.1.9 
Other Clinical Procedures 
When required, sputum induction will be performed according to TDN SOP 530.02 or 535.01 (per nebulizer 
type)  and Processing TDN SOP 508.02.  
Subject Diary:  Participants will complete the subject diary daily beginning at the Run in Visit (day -14), 
continue throughout the drug administration period and up until 14 days after completion of drug administration 
(Day  42). For diary details see Appendix 5. 
Hibiclens hand wash: At the Day -14 Visit Participants will be provided one packet of Hibiclens hand cleanser 
and wash their hands with water and Hibiclens for 2 minutes.  Skin reaction will be observed for 15 minutes 
after washing; subsequent development of skin irritation will be noted as an adverse event. Skin irritation will 
be reassessed as part of the Visit 1 physical exam. Individuals with evidence of intolerance of the Hibiclens 
wash will not do the whole body washes, but this will not be a reason for exclusion from the trial. 
9.1.10 Adverse Events  
Information regarding occurrence of adverse events will be captured throughout the study starting at the time of 
consent and ending at the last study visit. Duration (start and stop dates and times), severity/grade, outcome, 
treatment and relation to study medication will be recorded on the case report form (CRF). Adverse events will 
be followed until resolution. 
9.2 
Clinical Laboratory Measurements 
9.2.1 
Hematology 
Blood will be obtained and sent to each site’s local clinical hematology lab for a complete blood count with 
differential (hemoglobin, hematocrit, red blood cell count, white blood cell count, white blood cell differential, 
and platelet count) at Screening, Visit 1, Visit 3, Visit 4, Visit 5 and Early Withdrawal Visit as applicable.  
9.2.2 
Blood Chemistry Profile and C-Reactive Protein 
Blood will be obtained and sent to each site’s local clinical chemistry lab for determination of serum sodium, 
potassium, chloride, bicarbonate, random glucose, BUN, creatinine, aspartate aminotransferase (AST/SGOT), 
alanine aminotransferase (ALT/SGPT), alkaline phosphatase, total bilirubin, direct bilirubin, gamma-glutamyl 
transferase (GGT), and albumin at Screening, Visit 1, Visit 3, Visit 4, Visit 5, and Early Withdrawal.  In 
addition a C-Reactive Protein (CRP) will be collected at Screening, Visit 1, Visit 3, Visit 4, Visit 5, and Early 
Withdrawal Visit as applicable. 
9.2.3 
Pregnancy Test 
A serum pregnancy test will be obtained from female subjects who are of childbearing potential at the 
Screening Visit.  A urine pregnancy test will be performed prior to nebulization of study drug at study Visits 1 
and 3. 
9.3 
Pharmacokinetic Measurements 
Blood for determination of serum concentrations of vancomycin will be collected 60 minutes ( ±10 mins) after 
the start of dosing at Visit 1 (Day 1) and a trough level prior to administration of nebulized vancomycin will be 
obtained on Visit 3.  Vancomycin serum concentrations will be determined at each site’s clinical chemistry lab 
using a standard ELISA method.  Investigators will be blinded to the results, however the laboratory will be 
instructed to contact the investigator and report any trough value in excess of 8 µg/ml. Results will be collected 
by the laboratory and forwarded to the DSMB for review.  


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9.4 
Research Laboratory Measurements 
9.4.1 
Cell Count and Differential 
9.4.2 
Sputum Cell Counts and Differential and Cytokine Measurements 
Sputum for determination of neuregulin-1, IL-8, IL-1B, and elastase will be collected at Run-in  (Day -14) and 
Visit 4 (Day 29).   Sputum for determination of cell count will be collected at Run-in  (Day -14), Visit 3 (Day 
14), Visit 4 (Day 29), and Visit 5 (Day 58).  Specimens will be collected in a sterile specimen cup.  The cup will 
be labeled, packed in ice and shipped overnight to the Core Laboratory of the Cystic Fibrosis Foundation at 
Rainbow Babies and Children’s Hospital for processing 
9.4.3 
Quantitative Bacteriology 
Sputum will be collected for culture and sensitivity at Screening, Run-in  (Day -14), Visit 3 (Day 14), Visit 4 
(Day 29), Visit 5 (Day 58), and Visit 6 (Day 118) and Early Withdrawal visit if necessary.  All sputum 
specimens should be collected in a sterile specimen cup, labeled with patient study number and initials, and sent 
to the study’s microbiology core laboratory in Seattle for culture including identification of MRSA small colony 
variants.  Specimens will be processed within 2 days of collection. Quantitative culture for MRSA colony 
forming units (CFU’s) will be performed on each microbiologic specimen at Screening, Run-in (Day -14), Visit 
3 (Day 14), Visit 4 (Day 29), Visit 5 (Day 58) and Visit 6 (Day 118).  CFU’s will be obtained at the Early 
Withdrawal Visit if the visit occurs between Visit 3 and Visit 5. Susceptibility testing for rifampin, vancomycin, 
tetracycline, and TMP/SMX will be performed on all MRSA isolated from samples collected.  MRSA 
comprehensive genetic strain analysis will be performed at Screening, Run-in (Day -14), Visit 3 (Day 14), Visit 
4 (Day 29), Visit 5 (Day 58), and Visit 6 (Day 118) and Early Withdrawal Visit if necessary. If induced sputum 
fails to produce sputum, a throat culture will be obtained and evaluated for the presence of MRSA. 
9.4.4 
Nasal and Axillary Cultures 
At the Run-in Visit (Day -14), Visit 4 (Day 29), and Visit 5 (Day 58) separate nasal and axillary cultures will be 
taken by rotating one culture swab in both nostrils and a separate culture swab in the left axilla. These will be 
assessed for the presence of MRSA in each site’s local microbiologic laboratory. 
9.4.5 
Rectal Culture (Optional) 
At the Run-in Visit (Day -14) and at Visit 4 (Day 29) an optional rectal culture will be obtained in individuals 
age 18 or older who agree to participate by having the patient rotate one culture swab in the anal opening. These 
will be assessed for the presence of MRSA and Vancomycin resistant enterococcus in each site’s local 
microbiologic laboratory. 
9.4.6 
Sputum Vancomycin Measurements 
Spontaneous expectorated sputum will be collected for vancomycin peak measurements at Visit 1 (Day 1).  
After completion of nebulization of study drug, patient will immediately gargle three times with 30 mL normal 
saline solution to avoid contamination of specimens by drug deposited in the oropharynx.  All sputum 
specimens should be collected in a sterile specimen cup and labeled with patient study number and initials.  
Specimens from Case will be placed stored in a -80°C freezer in the research center and then walked over to the 
Case Western Reserve University Research Pharmacology Lab.  Specimens from Hopkins will be stored in a -
80°C freezer until shipped overnight on ice to the Case Western Reserve University Research Pharmacology 
Lab.   
9.5 
Guidelines for Timing of Use of Chronic Oral and Inhaled Antibiotics 
Patients on alternating month chronic inhaled antibiotics (same regimen for at least 4 months) (i.e. TOBI, 
Cayston, Colistin) will be invited to the Screening Visit during the beginning of their “on” month.  All patients 
will go through the 28 day screening period while on their chronic inhaled antibiotic therapy. Study drug dosing 
will occur during an “off” cycle.  For those patients on chronic (same regimen for at least 4 months) continuous 


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inhaled antibiotics, they would have to be willing to hold their inhaled antibiotics during the study period.  To 
minimize differences between groups, patients would be required to screen during their TOBI month.  If a 
patient is not on TOBI, but is on two other inhaled antibiotics, then they would have to screen while on colistin.  
If a patient is not on either TOBI or colistin, then patients would have to screen on Cayston.     
Individuals may not have been on any oral anti-MRSA antibiotics in the two weeks prior to the Screening Visit.  
These include any of the oral antibiotics in the protocol (rifampin, TMP/SMX, doxycycline) and clindamycin, 
minocycline, tetracycline, ciprofloxacin, moxifloxacin, or any other antibiotic with known anti-MRSA effect.  
After the 28-day treatment protocol ends, participants may not be started on oral anti-MRSA antibiotics unless 
indicated by symptoms and MRSA has been documented to be present in their sputum by culture. 
9.6 
Guidelines for Treatment of CF Exacerbations During the Study  
Participants that experience a pulmonary exacerbation during the 28 day study drug treatment period will be 
assessed by another clinical caregiver on the CF team besides the study PI.  If in the assessment of that 
caregiver the participant is in need of addition of other antibiotics for best clinical care, the participant will be 
discontinued from the study and treated.  They will be replaced in the study, but their data will be utilized in the 
calculation of the exacerbation outcomes if they received more than 14 days of nebulized study drug. 
 Participants that experience a pulmonary exacerbation which occur after completion of the 28 day study drug 
period will also be assessed by another clinical caregiver on the CF team besides the study PI.  If in the 
assessment of that caregiver the participant is in need of addition of other antibiotics for best clinical care, the 
participant will be treated with IV or oral antibiotics determined by their most recent available respiratory 
culture.  They will remain in the study and their data will be utilized in the calculation of eradication and 
exacerbation outcomes. 
10 EVALUATIONS BY VISIT 
10.1 Screening Visit (Day -28) (±2 days) 
1. 
Before any study procedures are performed, review the study with the subject and/or subject’s 
legal representative and obtain written informed consent and HIPAA authorization and assent, if 
appropriate. 
2. 
Assign the subject a unique screening number. 
3. 
Record demographics data. 
4. 
Record medical history, including a history of CF, diagnosis date, and prior CF treatments including 
treatment for MRSA. Record the dates of all previous MRSA cultures for the previous three years 
and date of first positive MRSA culture ever (if available). 
5. 
Review inclusion and exclusion criteria to assure patient eligible to participate 
6. 
Record concomitant medications with particular attention to potential drugs which may interact 
with rifampin, doxycycline or TMP/SMX. 
7. 
Perform and record vital signs, height and weight. 
8. 
Perform and record oximetry. 
9. 
Perform a complete physical examination. 
10. 
Patient takes two inhalations of albuterol HFA 10-30 minutes prior to spirometry. 
11. 
Perform and record spirometry (make sure meets inclusion criteria before performing blood tests). 
12. 
Collect blood for clinical laboratory tests (chemistry, hematology, LFT’s, CRP, pregnancy test, if 
applicable). 
13. 
Induce and collect sputum into one cup for bacterial culture, antibiotic sensitivity, MRSA colony 
forming units, and small colony variants of MRSA, and comprehensive genetic strain analysis.  
14. 
Schedule subject for Run-in Visit in 14 days (± 4 days). 


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10.2 Run-In Visit (Day -14) (± 4 days) 
1. 
Record follow-up medical history. 
2. 
Record any adverse event 
3. 
Concomitant medications review. 
4. 
Perform and record vital signs, height and weight. 
5. 
Perform and record oximetry  
6. 
Perform abbreviated physical examination. 
7. 
Patient takes two inhalations of albuterol HFA 10-30 minutes prior to spirometry. 
8. 
Perform and record spirometry. 
9. 
Obtain axillary and nasal swab for MRSA (to be submitted to local microbiology lab). 
10. 
Obtain optional rectal swab for presence of Vancomycin Resistant Enterococcus. 
11. 
Induce and collect sputum into one cup for bacterial culture, antibiotic sensitivity, MRSA colony 
forming units, and small colony variants of MRSA, and comprehensive genetic strain analysis and 
one cup for cell count and cytokine measurements. 
12. 
Test hand washing with Hibiclens cleaner for two minutes and review skin response fifteen minutes 
later. 
13. 
Initiate subject diary 
14. 
Schedule subject for Visit 1 in 14 days (± 4 days). 
 
 
10.2b Non-visit task at Day -4 (±3 days):  Review Culture Results from Run-in Visit, confirm presence 
of MRSA, perform randomization. 
10.3 Visit 1 Day 1 (Start Treatment) 
1. 
Perform CFQ-R. 
2. 
Record follow-up medical history. 
3. 
Record any adverse events 
4. 
Concomitant medications review. 
5. 
Review subject diary  
6. 
Perform abbreviated physical examination. 
7. 
Perform and record vital signs including height and weight. 
8. 
Perform and record oximetry. 
9. 
Perform urine pregnancy test if applicable.  If positive, patient is withdrawn from the study. 
10. Patient takes two inhalations of albuterol HFA 10-30 minutes prior to spirometry 
11. Perform and record spirometry. 
12. Initiate continuous oxygen saturation monitoring to be continued throughout study drug 
nebulization and for five minutes afterward. 


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13. Nebulize first dose of study drug utilizing expiratory neb cup with expiratory filter in place until 
sputtering or 15 minutes, whichever comes first.  
14. After completion of nebulization, have participant immediately gargle three times with 30 mL 
normal saline solution for 10 s and expectorate the solution to avoid contamination of subsequent 
specimens by drug deposited in the oropharynx. 
15. Immediately after gargling, perform and record spirometry (single value acceptable if within FEV1 
percent predicted improves, is stable, or has a relative decrease less than 10% from baseline). 
16. Immediately after performing spirometry, obtain expectorated sputum vancomycin level and record 
time of collection.  Goal is to collect sputum within 5 minutes (± 4 minutes) after nebulization of 
study drug.  If patient unable to expectorate sputum, then no sputum collected for this 
measurement.  
17. Perform and record spirometry 15 ± 10 minutes after completion of study drug (single value 
acceptable if FEV1 percent predicted improves, is stable, or has a relative decrease less than 10% 
from baseline). Patient to be observed at least one hour post completion of nebulization. 
18. Collect blood to obtain serum vancomycin level 60 (± 10) minutes after completion of nebulized 
study drug and collect blood for clinical laboratory tests (chemistry, hematology, LFT’s, CRP).  
19.    Record serial number of compressor on source document. 
20. Dispense PARI Vios compressor and LC Sprint neb cups (2) and Expiratory Filter and nebulizer 
cleaning instructions. 
21. Dispense nebulized study drug and provide teaching on nebulization of study drug  
22. Dispense protocol determined antibiotics, nasal mupirocin, and Hibiclens. 
23. Provide teaching about protocol determined antibiotics. 
24. Have participant take protocol determined oral antibiotics; provide snack as needed. 
25. Provide teaching about nasal mupirocin. 
26. Have participant use nasal mupirocin.  
27. Provide teaching about Hibiclens wash. 
28. Provide Sani-Cloth Alcohol Free Germicidal wipes, gloves and teaching about wiping high touch 
surfaces and washing towels and bed linens. 
29. Schedule subject for Visit 2 in 2-7 days. 
 
10.4 Visit 2 Day 2-7 (Repeat Witnessed Administration of Study Drug) 
1. 
Record follow-up medical history. 
2. 
Record any adverse events 
3. 
Concomitant medications review. 
4. 
Review subject diary  
5. 
Perform and record vital signs including height and weight. 
6. 
Perform abbreviated physical examination. 
7. 
Perform and record oximetry. 
8. 
Patient takes two inhalations of albuterol HFA 10-30 minutes prior to spirometry 


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9. 
Perform and record spirometry. 
10. Initiate continuous oxygen saturation monitoring to be continued throughout study drug 
nebulization and for five minutes afterward. 
11. Nebulize first dose of study drug until sputtering or 15 minutes, whichever comes first.  
12. Within five minutes of completion of nebulization, perform and record spirometry (single value 
acceptable if FEV1 percent predicted improves, is stable, or has a relative decrease less than 10% 
from baseline). 
13. Perform and record spirometry 15 ± 10 minutes after completion of study drug (single value 
acceptable if FEV1 percent predicted improves, is stable, or has a relative decrease less than 10% 
from baseline). 
14. Observe participant for at least one hour after administration of study drug. 
15. Schedule phone call to occur on Day 7-14 
16. Schedule subject for Visit 3 at day 14 (± 2 days)  
 
10.5 Day 7-14  Phone Call or Email 
1. 
Record any adverse events 
2. 
Subject Diary Review  
3. 
Concomitant Medication Review 
 
10.6 Visit 3 Day 14 (± 2 days) (Mid-point Treatment) 
1. 
Perform CFQ-R. 
2. 
Record follow-up medical history 
3. 
Record any adverse events. 
4. 
Record changes to concomitant medications. 
5. 
Collect all used study medication and containers; return all unused study medication and containers 
to subject for continued self-administration. 
6. 
Review subject diary for adverse events and dosing adherence. 
7. 
Perform and record vital signs, height and weight. 
8. 
Perform and record oximetry. 
9. 
Perform abbreviated physical examination. 
10. Perform urine pregnancy test if applicable.  If positive, patient is withdrawn from the study.  
11. 
Patient takes two inhalations of albuterol HFA 10-30 minutes prior to spirometry. 
12. 
Perform and record spirometry. 
13. Induce and collect sputum in one cup for bacterial culture, antibiotic sensitivity, MRSA colony 
forming units, small colony variants of MRSA and MRSA comprehensive genetic strain analysis, and 
another cup for cell count  
14. Collect blood sample for clinical laboratory tests and serum vancomycin level and record time of 
collection:  serum vancomycin level, chemistry, LFTs, hematology, and CRP. 


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15. Administer nebulized study drug until sputtering or 15 minutes, whichever comes first. 
16. Have participant take protocol determined oral antibiotics (if they haven’t already taken today); 
provide snack as needed.  
17. Schedule phone call visit 2 and 3 to occur on Day 14-21 and Day 21-28 
18. Schedule subject for Visit 4 on Day 29 (± 1 day)  
 
10.7 Day 14-21 Phone Call or Email 
1. 
Record any adverse events. 
2. 
Subject Diary Review 
3. 
Concomitant Medication Review 
10.8 Day 21-28 Phone Call or Email 
1. 
Record any adverse events. 
2. 
Subject Diary Review 
3. 
Concomitant Medication Review 
 
10.9 Visit 4 Day 29 (± 1 day) (End treatment) 
1. 
Perform CFQ-R. 
2. 
Record follow-up medical history 
3. 
Record any adverse events. 
4. 
Record changes to concomitant medications. 
5. 
Review subject diary for adverse events and dosing adherence.  Provide subject with dairies to be 
continued for 14 days after end of treatment (through Day 42.) 
6. 
Perform complete physical examination including height and weight. 
7. 
Perform and record vital signs. 
8. 
Perform and record oximetry. 
9. 
Patient takes two inhalations of albuterol HFA 10-30 minutes prior to spirometry. 
10. Perform and record spirometry. 
11. Collect blood sample for clinical laboratory tests:  Chemistry, LFTs, Hematology, and CRP. 
12. Obtain axillary and nasal swab for MRSA. 
13. Obtain optional rectal swab for presence of Vancomycin Resistant Enterococcus. 
14. Induce and collect sputum in one cup for bacterial culture, antibiotic sensitivity, MRSA colony 
forming units, small colony variants of MRSA,  MRSA comprehensive genetic strain analysis and 
another cup for sputum cell count and cytokine measurements, 
15. Collect all used and unused study medication and containers and Subject Diary. 
16.     Schedule subject for Visit 5 on Day 58 (± 4 days) 
 


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10.10 Visit 5 Day 58 (± 4 days) - (1 Month Post-treatment Monitoring Visit) (Primary Outcome) 
1. 
Perform CFQ-R. 
2. 
Record follow-up medical history 
3. 
Record any adverse events. 
4. 
Record changes to concomitant medications. 
5. 
Review subject diary through Day 42 for adverse events. 
6. 
Perform and record vital signs, height and weight. 
7. 
Perform and record oximetry. 
8. 
Perform abbreviated physical examination. 
9. 
Collect blood sample for clinical laboratory tests:  Chemistry, LFTs, Hematology, and CRP. 
10. 
Patient takes two inhalations of albuterol HFA 10-30 minutes prior to spirometry. 
11. 
Perform and record spirometry. 
12. 
Obtain axillary and nasal swab for MRSA. 
13. Induce and collect sputum for bacterial culture, antibiotic sensitivity, MRSA colony forming units, 
small colony variants of MRSA, MRSA comprehensive genetic strain analysis and another cup for 
sputum cell count. 
14. Schedule subject for Visit 6 in 60 days (± 7 days) 
10.11 Visit 6 Day 118 (± 7 days) (3 Months Post-treatment Monitoring Visit) 
1. 
Perform CFQ-R. 
2. 
Record follow-up medical history. 
3. 
Record any adverse events. 
4. 
Record changes to concomitant medications. 
5. 
Perform complete physical examination. 
6. 
Perform and record vital signs including height and weight. 
7. 
Perform and record oximetry. 
8. 
Patient takes two inhalations of albuterol HFA 10-30 minutes prior to spirometry. 
9. 
Perform and record spirometry. 
10. Induce and collect sputum for bacterial culture, antibiotic sensitivity, small colony variants of MRSA, 
and MRSA comprehensive genetic strain analysis.  
10.12 Early Withdrawal Visit (for any subject terminating study early and after Day 1) 
1. 
Perform CFQ-R. 
2. 
Record follow-up medical history. 
3. 
Record any adverse events. 
4. 
Record changes to concomitant medications. 
5. 
Collect all used and unused study medication and containers and Subject Diary (if applicable). 
6. 
Review subject diary for adverse events and dosing adherence. 


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7. 
Perform complete physical examination. 
8. 
Perform and record vital signs including height and weight. 
9. 
Perform and record oximetry. 
10. 
Collect blood sample for clinical laboratory tests:  Chemistry, LFTs, Hematology, vancomycin level, 
and CRP if the visit occurs in treatment period between Visits 1 and 4. 
11. 
Patient takes two inhalations of albuterol HFA 10-30 minutes prior to spirometry. 
12. 
Perform and record spirometry. 
13. If the early withdrawal visit occurs between Visit 3 and Visit 5, induce and collect sputum for 
bacterial culture, antibiotic sensitivity, MRSA colony forming units, small colony variants of MRSA, 
and MRSA comprehensive genetic strain analysis. 
14. Collect all used and unused study medication and containers and Subject Diary. 
 
11 ADVERSE EVENTS REPORTING AND DOCUMENTATION 
11.1 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 (including an abnormal laboratory finding), symptom or disease 
temporally associated with the administration of an investigational product, whether or not related to that 
investigational product.  An unexpected AE is one of a type not identified in nature, severity, or frequency in 
the current Investigator’s Brochure or of greater severity or frequency than expected based on the information in 
the Investigator’s Brochure. 
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 patient CRF 
beginning after the consent form is signed and at each visit until the last study visit.  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. AEs will be followed until resolution.  
AE Severity 
The National Cancer Institute’s Common Terminology Criteria for Adverse Events (CTCAE) Version 3.0, as 
modified for cystic fibrosis, 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 Table 11-1 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 11-1.  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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AE Relationship to Study Drug 
The relationship of an AE to the study drug should be assessed using the following the guidelines in Table 11- 
2. 
Table 11- 2.  AE Relationship to Study Drug 
Relationship 
to Drug 
Comment 
Definitely 
Previously known toxicity of agent; or an event that follows a reasonable 
temporal sequence from administration of the drug; that follows a known or 
expected response pattern to the suspected drug; that is confirmed by stopping 
or reducing the dosage of the drug; and that is not explained by any other 
reasonable hypothesis. 
Probably 
An event that follows a reasonable temporal sequence from administration of 
the drug; that follows a known or expected response pattern to the suspected 
drug; that is confirmed by stopping or reducing the dosage of the 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 drug; that follows a known or expected response pattern to that suspected 
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 the 
study drug. 
 
The investigator will classify the study drug action taken with regard to the adverse event in the appropriate 
section of the eCRF.  The action taken should be classified according to the categories shown in Table 11-3.   
Table 11-3 
Classifications for Study Drug Action Taken with Regard to an Adverse Event 
Drug Interrupted 
Study drug administration stopped in response to an adverse event.   
Drug Withdrawn 
Study drug administration permanently discontinued in response to an adverse 
event. 
Dose Not Changed 
Study drug dose not changed in response to the adverse event. 
Dose Reduced 
Study drug dose reduced in response to an adverse event. 
Not Applicable 
Action taken regarding study drug administration does not apply.   
“Not applicable” should be used in circumstances such as when the 
investigational treatment had been completed before the adverse event began 
and no opportunity to decide whether to continue, interrupt, or withdraw 
treatment is possible. 
 
Adverse Event Outcome 
An adverse event should be followed until resolution.  The investigator will describe the outcome of the adverse 
event in the appropriate section of the CRF.  The outcome should be classified according to the categories 
shown in Table 11-4. 


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Table 11-3 
Classifications for Outcome of an Adverse Event 
Recovered/Resolved 
Resolution of an adverse event with no residual signs or symptoms. 
Recovered/ Resolved 
With Sequelae 
Resolution of an adverse event with residual signs or symptoms. 
Not Recovered/ Not 
Resolved 
Either incomplete improvement or no improvement of an adverse event, such 
that it remains ongoing. 
Fatal 
Outcome of an adverse event is death. “Fatal” should be used when death is at 
least possibly related to the adverse event. 
Unknown 
Outcome of an adverse event is not known, e.g., a subject lost to follow-up. 
11.2 Serious Adverse Experiences (SAE) 
An SAE is defined as any AE occurring at any dose that results in any of the following outcomes: 
 
death 
 
a life-threatening adverse experience 
 
inpatient hospitalization or prolongation of existing hospitalization 
 
a persistent or significant disability/incapacity 
 
a congenital anomaly/birth defect  
Other important medical events may also be considered an SAE when, based on appropriate medical judgment, 
they jeopardize the subject or require intervention to prevent one of the outcomes listed.  
11.2.1 Serious Adverse Experience Reporting 
All serious adverse events (SAEs), as defined below will be reviewed by the site investigator, recorded on 
an SAE Reporting form and followed through to resolution by a study physician. The collection period for 
all SAEs will begin after informed consent is obtained and end after procedures for the final study visit 
have been completed. All SAEs will be reported by telephone, email or fax within 24 hours (one working 
day) of awareness of the event to the following:  
Cystic Fibrosis Foundation TDN DMC Chairman: Dr. Wayne Morgan, phone: (520) 626-6754 fax: (520) 
626-9465, or email: wmorgan@arc.arizona.edu 
Also, in accordance with the standard operating procedures and policies of the local Institutional Review 
Board (IRB)/Independent Ethics Committee (IEC), the site investigator will report SAEs to the local 
IRB/IEC.   
At Johns Hopkins this will be:  
Johns Hopkins Medical Institutional Review Board, Reed Hall B-130; 1620 McElderry Street, Baltimore, 
Maryland 21205-1911. Phone: 410-955-3008, Fax: 410-955-4367 or 443-287-5353, or email: 
jhmirb@jhmi.edu  
At Case University this will be: 
University Hospitals Case Medical Center Institutional Review Board 
Lakeside Hospital Rm. 1400 
11100 Euclid Avenue 
Cleveland, Ohio  44106 
Phone: (216) 844-1529  
FAX: (216) 844-1547 
http://www.uhhospitals.org/Research/InstitutionalReviewBoard/tabid/1294/Default.aspx 
 


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A written SAE report must follow as soon as possible, which includes a full description of the event and 
any sequelae.  The site will notify the TDN DMC of additional information or follow-up to an initial SAE 
Report as soon as relevant information is available.  
A serious adverse event is any event that: 
• 
is fatal 
• 
is life-threatening (life-threatening is defined as the subject was at immediate risk of death from 
the AE as it occurred) 
• 
is significantly or permanently disabling 
• 
requires hospitalization, or prolongs hospitalization 
• 
is a congenital anomaly or birth defect 
Important medical events that may not result in death, be life-threatening, or require hospitalization may be 
considered serious adverse drug experiences when, based upon appropriate medical judgment, they may 
jeopardize the subject and may require medical or surgical intervention to prevent one of the outcomes listed in 
this definition.  Examples of such medical events include bronchospasm requiring intensive treatment in an 
emergency room or at home, blood dyscrasias or convulsions that do not result in hospitalization, or the 
development of drug dependency or drug abuse. All SAEs will be followed until resolution including in any 
participants removed from the study due to toxicity. 
11.2.2 Reporting SAEs to the FDA 
The PI will use the following determinations to report SAEs to the FDA: 
Does the reported adverse event meet one of the FDA's or the protocol’s definitions for serious? 
Is the event unexpected? 
Is the event related to study drug? 
If the answer to all 3 questions is yes, the event will be reported to the FDA in addition to all other relevant 
regulatory authorities as discussed in Section 11.2.1 of this protocol.  The SAE form will be submitted to the 
FDA within 10 working days of the initial report. 
11.3 Known Potential Risks of Study Drugs/Procedures and Specific AE Guidance 
11.3.1 Inhaled Albuterol  
Inhaled albuterol will be taken prior to inhalation of study drug/placebo.  Albuterol may cause tremor, 
nervousness, and tachycardia.  All of the individuals in the trial will have been exposed to albuterol in the past 
as part of their clinical care so will be aware of potential albuterol effects 
11.3.2 Nebulized Vancomycin 
The main risk of nebulized vancomycin is bronchospasm, although the incidence across several series of reports 
is less than 5% (Appendix 2). To minimize the risk of bronchospasm, participants will be pretreated with two 
puffs of inhaled albuterol HFA inhaler 10-60 minutes prior to administration of nebulized vancomycin. Patient 
will then do spirometry and have continuous pulse oximetry tested, followed by administration of nebulized 
vancomycin or placebo. Immediately after nebulizing the study drug, and again 15 (+/-10) minutes after 
completing the nebulization, participant will repeat spirometry. Previous studies of nebulized colistin, a 
commonly used and generally well-tolerated CF medication have suggested that inhalation is associated with an 
average drop in FEV1 of 13±8% in patients without an asthma history and 17±8% in patients with a history of 
asthma25. The guidelines for spirometry after nebulized vancomycin are therefore: 
1) FEV1 percent predicted improves, is stable, or has a relative decrease less than 10% from baseline: patient 
considered tolerating nebulization and protocol proceeds. 


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2)  FEV1 percent predicted has a relative decrease of 10-20% from baseline:  All participants are monitored 
with appropriate follow-up treatment including PFTs until FEV1 has returned to within 10% of baseline. If a 
participant is symptomatic (chest tightness or dyspnea), the participant is treated immediately with two puffs 
of inhaled albuterol HFA inhaler. If a participant remains asymptomatic but has not returned to within 10% 
of baseline within 10 minutes of spirometry initiation, the participant is treated with two puffs of inhaled 
albuterol HFA inhaler. If patient does not note dyspnea and returns to within 10% of baseline within one 
hour of inhalation, patient may participate in the study.  If FEV does not return to 10% of baseline after an 
hour, the participant is withdrawn from the study regardless of symptoms.   
3) FEV1 percent predicted has a relative decrease of 20% or more from baseline: Participant is treated 
immediately with two puffs of inhaled albuterol HFA inhaler and continually monitored with appropriate 
follow-up treatment until FEV1 has returned to within 10% of baseline. Patient is withdrawn from the study. 
A second potential risk is the development of vancomycin resistant strains of MRSA.  Given that patients 
will also be treated in the protocol with other antibiotics to which their MRSA is known to be sensitive, 
this concern is minimized.  This emergence of resistant MRSA has not been reported in any inhaled 
vancomycin studies to date.  Finally, there is the potential emergence of gram negative pathogens as 
observed with the prophylaxis of MSSA in previous treatment trials. However, because most patients 
with MRSA are also co-infected with P. aeruginosa (70-80%) emergence of P. aeruginosa will not be a 
concern for a large number of patients.  Other potential risks of nebulized vancomycin include bad taste 
and idiosyncratic allergic reaction.  
11.3.3 Nebulized Placebo  
The main risk of inhaling the nebulized placebo is experiencing a mildly bitter taste.  There is little known risk 
for inhalation of sterile water.  The quinine dose used is less than half that used in placebo in previous well 
tolerated nebulized drug trials. 
11.3.4 Oral Trimethoprim/Sulfamethoxazole (TMP/SMX) 
The main risk of taking TMP/SMX is an allergic reaction in those sensitive to sulfa products, usually 
manifested as a generalized rash.  Most if not all of the participants will have received TMP/SMX in the past or 
be aware if they have a sulfa allergy.  In those with known sulfa allergy, doxycycline will be substituted.  
Another potential reaction is nausea, although participants will be encouraged to avoid taking their oral 
medications on an empty stomach to minimize this risk. 
11.3.5 Oral Doxycycline 
Only individuals with known sulfa allergies will receive doxycycline.  Oral doxycycline is generally well 
tolerated, with the main risks being nausea and rash. 
11.3.6 Oral Rifampin 
All individuals except those with a known allergy and/or intolerance, those individuals whose current CF 
treatment regimen includes medication(s) that are known to produce adverse drug-drug interactions with 
rifampin, or those individuals with evidence of rifampin resistance at Screening will receive oral rifampin.   The 
most commonly observed potential side effect of rifampin is gastroesophageal reflux symptoms (GERD).  For 
individuals experiencing this, an adverse event will be recorded and treatment will instituted by either 
increasing current GERD therapy or instituting treatment with a proton pump inhibitor.  The proton pump 
inhibitor will be ordered by the patient’s primary CF physician. Continued symptoms judged by the investigator 
or participant as more than mild despite treatment will result in discontinuation of the rifampin, although 
participants will be permitted to remain in the study.  One other potential risk of oral rifampin includes elevated 
liver function tests.  Patients will undergo laboratory monitoring at 2 and 4 weeks into their course. 


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11.3.7 Nasal Mupirocin Ointment 
Nasal mupirocin is generally well tolerated, with no serious reactions reported related to short term use.  
Occasional participants may report localized burning at the site of nasal application. 
11.3.8 Hibiclens Liquid Skin Cleanser 
One of the identified potential side effects of Hibiclens Liquid Skin Cleaner with chlorhexidine is skin 
sensitivity, although the absolute risk is low and Hibiclens is currently routinely used in healthcare settings.  
Participants will undergo an observed test hand washing to assess for skin reaction prior to dispensing for home 
use.  Participants that demonstrate significant rash or skin sensitivity to the Hibiclens Liquid Skin Cleanser will 
be allowed to participate in the protocol but will not do the skin washes with Hibiclens described in the protocol 
and will not be included in the data analysis of axillary culture results. 
11.3.9 Sani-Cloth Alcohol Free Germicidal wipes 
Sani-Cloth Alcohol Free Germicidal wipes were selected specifically because of the absence of odor. The main 
risk is skin irritation, so participants will be provided non-latex gloves for use and instructions on avoiding skin 
or eye contact.   
11.3.10 Laboratory Work 
Blood sampling can be associated with discomfort, fainting or lightheadedness and/or bruising. There is 
no known adverse event associated with the collection of urine specimens. 
11.3.11 Sputum Induction Procedure and Spirometry 
The risks associated with the sputum induction (SI) procedure consist of cough, wheeze, chest-tightness, and 
decrease in pulmonary function test values.  These are generally mild in nature and self-limited, however, all 
subjects will be pre-treated with 2-3 puffs of albuterol prior to the SI procedure to minimize these risks. 
Subjects will fast one hour prior to the procedure. Pulmonary function is monitored frequently throughout the 
12-minute procedure and the procedure is terminated if the peak flow decreases more than 20% from baseline. 
Spirometry testing rarely causes discomfort however, some people get a sense of dizziness and/or headache 
when performing these tests.  
12 DISCONTINUATION AND REPLACEMENT OF SUBJECTS 
12.1 Withdrawal of Subjects and Drop-outs  
A subject may be discontinued from the study or study treatment at any time if the subject, the investigator, or 
the DSMB feels that it is not in the subject’s best interest to continue.  The following is a list of possible reasons 
for study or treatment discontinuation:  
Subject withdrawal of consent 
Subject is not compliant with study procedures 
Adverse event 
Lost to follow-up 
At the discretion of the investigator, if deemed appropriate, for any reason 
At the discretion of the DMC, if deemed appropriate, for any reason 
If a subject is withdrawn from the study due to an adverse event any time after first dose of study drug, the 
subject will be followed and treated by the Investigator until the abnormal parameter or symptom has resolved 
or stabilized.  Subjects will be encouraged to complete the early withdrawal visit.  


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All subjects are free to withdraw from participation at any time, for any reason, specified or unspecified, and 
without prejudice. If a subject decides to withdraw after first dose of study drug on Day 1, the subject will be 
asked to return to the clinic to complete an Early Withdrawal Visit. 
Reasonable attempts will be made by the investigator to provide a reason for subject withdrawals.  The reason 
for the subject’s withdrawal from the study will be specified in the subject’s source documents.  Subjects who 
withdraw from the study prior to day 58 (primary endpoint) will be replaced.  Subjects who withdraw after day 
58 will not be replaced. Refer to Section 10 for early termination procedures. 
12.2 Trial Modification Rules 
Given the early phase of the study and the small study sample size, establishing formal trial modification or 
stopping rules based on predefined statistical analyses is not possible. Determinations of safety require medical 
judgments of the DMC that cannot be prospectively defined in detail. The reasons for stopping, interrupting, 
modifying the trial, or changing the DMC safety monitoring plan could include but are not limited to: 
 
• A pattern of SAEs that may possibly be drug related because they are consistent with the known 
effects of the drug; a clear temporal association with the use of the drug; improvement upon withdrawal of the 
drug; and/or lack of alternative explanations (e.g., concurrent disease or other drugs or chemicals). 
 
• The occurrence of drug-related Grade 3 or Grade 4 adverse events or laboratory abnormalities in ≥ 
33% of patients in a treatment arm. 
 
• Unexpected increases in the incidence or severity of disease-related symptoms (e.g., cough, dyspnea, 
and/or decline in lung function (> 20% decline over the study treatment period of 1 month) that appears to be 
drug-related because there are not likely alternative explanations for these events 
 
Specific SAEs which would result in termination of the study include: 
1) 
A single respiratory event at any time that is judged by the DMC as life-threatening and probably related 
to study drug. 
2) 
Greater than 20% absolute decline in FEV1 during the study drug treatment month in more than 33% of 
individuals and determined by the DMC to be probably related to study drug, any time after enrollment of the 
first 16 participants.  
3) 
Bronchospasm with initial nebulization of study drug resulting in withdrawal from the study as 
described in protocol section 11.3.2 in more than 33% of individuals, any time after enrollment of the first 16 
participants. 
4) 
Trough serum vancomycin levels in excess of 8 ug/ml in more than 33% of individuals, any time after 
enrollment of the first 16 participants  
5) 
Chemistry or hematologic abnormalities graded as level 3 or more in more than 33% of individuals and 
judged by the DMC as probably related to study drug, any time after enrollment of the first 16 participants 
13 PROTOCOL VIOLATIONS 
Protocol Violations for this study include, but are not limited to, the following: failure to meet 
inclusion/exclusion criteria, investigator non-compliance with study drug regimen, use of a prohibited 
concomitant medication, etc. 
Failure to comply with Good Clinical Practice (GCP) guidelines will also result in a protocol violation. The 
DSMB will determine if a protocol violation will result in withdrawal of a subject. 
When a protocol violation occurs, it will be discussed with the investigator and a Protocol Violation Form 
detailing the violation will be generated by the investigator or monitor. This form will be signed by the 
Investigator. A copy of the form will be filed in the site’s regulatory binder and submitted to Hospital IRB. 


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14 DATA SAFETY MONITORING 
The Cystic Fibrosis Foundation Data Safety Monitoring Board (DSMB) will establish a Data Monitoring 
Committee (DMC) to review data relating to safety and efficacy, to conduct and review interim analyses, and to 
ensure the continued scientific validity and merit of the study, according to the Cystic Fibrosis Foundation Data 
Safety Monitoring Board Operations Manual and a DMC Charter to be established for this protocol. After 16 
adult participants have been enrolled, the DMC will conduct a review for the purpose of monitoring study 
conduct and assessing patient safety. A follow up review will occur after the first 8 pediatric participants have 
been dosed and/or six months following IRB approvals to enroll pediatric patients, whichever comes first. 
Further details regarding the timing and content of the interim reviews is included in the statistical section 
below. 
All participant withdrawals due to respiratory adverse events will be reported to the DSMB chair within 48 
hours of the study team being aware of the event. 
The DSMB will receive monthly reports to include: 
Enrollment for both groups: 12-17 years and 18-years and up  
Screen failures or study withdrawals  
All FEV1 follow-up data after administration of study drug 
15 STATISTICAL METHODS AND CONSIDERATIONS 
Prior to the analysis of the final study 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.   
15.1 Data Sets Analyzed 
All eligible patients who are randomized into the study and receive at least one dose of the study drug (the 
Safety Population) will be included in the safety analyses. 
15.2 Demographic and Baseline Characteristics 
The following demographic variables at screening will be summarized by treatment arm:  race, gender, age, 
height and weight.   
15.3 Analysis of Primary Endpoint 
Our hypothesis for our primary outcome states that the treatment arm will result in significantly greater 
eradication of persistent MRSA from the respiratory tract of CF adolescents and adults compared to the 
placebo arm on day 58. Our primary analysis will include comparing the proportion of CF patients in the 
treatment arm who have a negative MRSA culture at Visit 5 to the proportion of patients in the placebo 
arm who have a negative MRSA culture at Visit 5. Secondary analyses will include the above comparisons, 
but at Visits 4 and 6. χ2 or Fishers exact test will be used to determine statistical significance. A secondary 
analysis will also be performed comparing proportions of MRSA positive cultures among the three 
cultures obtained at Visits 3, 4, and 5 during the study. Generalized estimating equations (GEE), using a 
logit link, will be used to model this longitudinal data. The GEE model will be used to test for main effects 
of treatment arm, time, and treatment x time interaction.  Furthermore, sensitivity analyses will be 
performed to evaluate the robustness of the primary outcome to missing culture data (missing data 
should be minimal) using 1) imputation with last observation carried forward and multivariate 
imputation  by chained equations 2) treating all missing cultures as negative, and 3) treating all missing 
cultures as positive.   
15.4 Analysis of Secondary Endpoints 
Our hypothesis for these secondary outcomes states that the treatment arm will improve clinical 
measures (lung function, QOL, and exacerbations) compared to placebo. Statistical significance for 


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differences in lung function (FEV1%) at Visit 4 will be assessed between the two treatments using a 2-
sample t-test. We will use linear mixed models to longitudinally analyze and compare the change in lung 
function over 208 days in the two arms.  CF respiratory scores will be expressed as mean  standard 
deviation and statistical significance assessed between the two arms at Visit 4 using a 2-sample t-test. A 
Kaplan-Meier plot will be used to graphically display estimates of the survivor function for the 
proportion of patients who do not have an exacerbation through day 118.  Hazard ratios and 95% CI due 
to treatment will be calculated using a Cox proportional hazards regression model26. Pre-specified 
potential variables that may be adjusted for include gender, season of enrollment, and center.  
 
Hypothesis (H1c): Our third hypothesis is that the treatment will have similar effects in regards to the 
development of antimicrobial resistance and adverse events compared to placebo. Previous MSSA 
treatment studies have resulted in increased gram negative pathogens; therefore, we will monitor for this 
development. Rates of occurrence of development of microbial resistance, gram negative pathogens will 
be summarized separately by treatment arm.  Between-group comparisons will be made using a chi-
square test or Fishers exact test.  
Safety and tolerability data will be summarized by treatment group.   
Adverse event rates will be coded by body system and MedDra classification term. Adverse events will be 
tabulated by treatment group and will include the number of patients for whom the event occurred, the 
rate of occurrence, and the severity and relationship to study drug.  Fisher’s exact test will be used to 
compare the various treatment groups with respect to incidence of the more commonly occurring AEs. 
15.5 Interim Analysis 
No interim analyses are planned. A safety analysis will be planned after the first 16 adults are enrolled.  If the 
DSMB agrees based on initial safety data, enrollment eligibility will then be expanded to include those aged 12-
17 as well. A follow-up safety analysis will be performed by the DSMB after the first 8 pediatric participants 
have been dosed and/or six months following IRB approvals to enroll pediatric patients, whichever comes first. 
15.6 Sample Size and Randomization 
This study is powered on the primary outcome: the percentage of patients that are induced sputum negative for 
MRSA at Visit 5 (day 58). We are planning a study with 20 experimental and 20 control patients. There are no 
treatment studies published in CF patients with persistent MRSA to guide the assumptions for the primary 
outcome for the two arms. In fact, the results from this study will be used to power future multi-center trials. 
Based on our experience, treatment with oral antibiotics in those with persistent MRSA results in an 
approximate eradication rate of 15-25%. An experimental arm eradication rate of 75% would be considered 
significant, though some may even consider a lower percentage significant as well. Based on these assumptions, 
we have greater than 80% power if the MRSA eradication rate in the experimental arm is at least 65%, 
assuming a 20% eradication rate in the placebo arm (multiple assumptions about the eradication rate and their 
associated power are shown in Table 1). Ultimately, the eradication rate that is deemed clinically significant 
will be measured against the potential negatives of an intense treatment protocol including side effects and 
increased treatment burden. 
 
 
 
 
 
Table 1: Power Estimates for Three Different Assumptions of Percent 
Eradicated in High Intensity Treatment Arm  
Percent eradicated  
(Experimental Arm) 
80%  
75% 
65%  
Power 
0.98 
0.95 
0.84 
N = 40 Persistent MRSA patients (20 in each arm);  
two tailed α = 0.05; Control arm eradication rate: 20% 


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Randomization will be performed by a biostatistician at Case in cooperation with each centers investigational 
drug service, with 1:1 randomization to placebo and study drug.  The randomization will be designed to assure 
an equal division between placebo and treatment among the first sixteen participants in preparation for the first 
DSMB safety review (after 16 participants are enrolled). 
16 DATA COLLECTION, RETENTION AND MONITORING 
16.1 Data Collection Instruments 
Source documents will be created for this protocol and an electronic data base will be created which will serve 
as the case report forms (CRFs) for the research staff. Secondarily, information derived from the source 
documents/CRFs and required for the DMC  reports will be entered into a spreadsheet for the purpose of data 
analysis. The spreadsheet may include, but is not limited to: demographic information, adverse events including 
seriousness, severity, relatedness to study drug or procedures, medical history, laboratory results and 
concomitant medications. Study personnel may enter data from source documents onto case report forms and 
the DMC spreadsheet.  The spreadsheet will be secured and password protected. Study participants will not be 
identified by name in the study spreadsheet or on any source documents/CRFs but will be identified by a site 
number, subject number and initials. All clinical information requested in this protocol will be entered on the 
CRFs.  If a correction is made on a CRF, the study staff member will line through the incorrect data, write in the 
correct data and initial and date the change. 
The Investigator is responsible for all information collected on subjects enrolled in this study.  All data collected 
during the course of this study must be reviewed and verified for completeness and accuracy by the 
Investigator.  A copy of the CRF will remain at the Investigator’s site at the completion of the study. 
16.2 Data Management Procedures 
All procedures for the handling and analysis of data will be conducted using good computing practices meeting 
FDA guidelines for the handling and analysis of data for clinical trials. 
16.3 Data Quality Control and Reporting 
After data have been entered into the study database, a system of computerized data validation checks will be 
implemented and applied to the database.  Query reports (Data Clarification Requests) pertaining to data 
omissions and discrepancies will be forwarded to the Investigators and study monitors for resolution.  The study 
database will be updated in accordance with the resolved query reports.  All changes to the study database will 
be documented. 
16.4 Archiving of Data 
At all times, appropriate backup copies of the database and related software files will be maintained and the 
information will be appropriately protected from illegitimate access.  Databases are backed up by the database 
administrator in conjunction with any updates or changes to the database.  Backup copies will be maintained at 
an off-site safe storage location.  When the structure of the database is changed, a permanent archive of the 
database will be made to protect against loss of data in the changeover.  When each backup is made, the media 
will be checked for usability and the integrity of the database will be verified. 
At critical junctures of the protocol (e.g., production of interim reports and final reports), a permanent archive 
of the database will be made.  Archived versions of the database will be saved for at least three years after the 
end of the study.   
16.5 Availability and Retention of Investigational Records 
The Investigator must make study data accessible to the monitor, other authorized representatives of the DSMB 
(or designee), IRB/IEC, and Regulatory Agency (e.g., FDA) inspectors upon request.  A file for each subject 
must be maintained that includes the signed Informed Consent, HIPAA Authorization and Assent Form and 


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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 (patient files, signed informed consent forms, copies of CRFs, Study File Notebook, etc.) 
must be kept secured for a period of 2 years following completion of the trial.  
16.6 Monitoring 
Each site will hire an independent monitor who will monitor the study in accordance with current GCPs.  On 
site – checking of the eCRFs for completeness and clarity, cross-checking with source documents, and 
clarification of administrative matters will be performed.  By signing this protocol, the Investigator grants 
permission to the monitor (or designee), and appropriate regulatory authorities to conduct on-site monitoring 
and/or auditing of all appropriate study documentation. 
16.7 Subject Confidentiality 
In order to maintain subject confidentiality, only a site number, subject number and subject initials will identify 
all study subjects on CRFs and other documentation submitted to the DSMB.  
17 ADMINISTRATIVE, ETHICAL, AND 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 laboratory specimens, evaluation forms, reports and other records will be 
identified by a coded number and initials and no patient names.  All study records will be kept in a locked file 
cabinet and code sheets linking a patient’s name to a patient identification number will be stored separately in 
another locked file cabinet.  Clinical information will not be released without written permission of the subject, 
except as necessary for monitoring by the FDA.  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 Protocol Amendments 
Any amendment to the protocol will be written by the principal investigator or his designee.  A protocol 
amendment intended to eliminate an apparent immediate hazard to patients may be implemented immediately, 
provided the IRBs are notified within five working days. 
17.2 Institutional Review Boards and Independent Ethics Committees 
The protocol and consent form will be reviewed and approved by the IRB/IEC of each participating center prior 
to study initiation.  Serious adverse events regardless of causality will be reported to the IRB/IEC in accordance 
with the standard operating procedures and policies of the IRB/IEC, and the Investigator will keep the IRB/IEC 
informed as to the progress of the study.  The Investigator will obtain a list of IRB/IEC members or other 
assurance of compliance with regulations. 
Any documents that the IRB/IEC may need to fulfill its responsibilities (such as protocol, protocol amendments, 
Investigator’s Brochure, consent forms, information concerning patient recruitment, payment or compensation 
procedures, or other pertinent information) will be submitted to the IRB/IEC.  The IRB/IECs 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. This approval must refer to the study by exact protocol title and 
number and should identify the documents reviewed and the date of review. 
Protocol and/or informed consent modifications or changes may not be initiated without prior written IRB/IEC 
approval except when necessary to eliminate immediate hazards to the patients 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.   


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The IRB/IEC must be informed of revisions to other documents originally submitted for review; serious and/or 
unexpected adverse events occurring during the study in accordance with the standard operating procedures and 
policies of the IRB; new information that may affect adversely the safety of the patients of the conduct of the 
study; an annual update and/or request for re-approval; and when the study has been completed. 
17.3 Informed Consent Form and Recruitment Plan 
Participants will be recruited from amongst the adult and pediatric CF patients at each of the two participating 
centers.  The investigators and sub-investigators on this protocol will have access to these patients because they 
are the primary caregivers for the patients.  Potential participants will be approached in CF clinic by one of the 
investigators, clinical nurses or research nurses. This will take place in the privacy of the exam room either 
while they are waiting to be seen by their physician or after they have been seen. Potential subjects will be 
provided information verbally about the study and if interested, they will be provided with contact information 
for the study team and a consent form to take home and review. 
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. 
An IRB-approved copy of the Informed Consent Form will be kept in the Regulatory Binder. 
The Informed Consent Form will document the study-specific information the Investigator provides to the 
subject and the subject's agreement to participate, including information about the Health Insurance Portability 
& Accountability Act (HIPAA) that protects the subject’s individually identifiable health information (protected 
health information) and authorization (or agreement) in order for researchers to be able to use or disclose the 
subject’s protected health information for research purposes.  Among other things, the Investigator will fully 
explain in layman's terms the nature of the study, along with the aims, methods, anticipated benefits, potential 
risks and discomforts, and any monetary compensation participation may entail.  The Informed Consent Form 
must be signed and dated before any study procedures are performed.  The original and any amended signed 
and dated Informed Consent Form(s) must be retained in the subject's file at the study site; and a copy must be 
given to the subject. 
17.4 Participant Risk / Benefit Assessment 
Overall the Risk / Benefit Balance in this study is heavily in favor of potential benefit.  MRSA is the most 
rapidly increasing infectious pathogen seen in individuals with CF, with 25% of patients now 
demonstrating pulmonary infection with MRSA3. The current therapeutic strategies for eliminating MRSA 
infection have been ineffective and little clinical trial data is available to guide therapy.  Small clinical 
studies suggest that the addition of nebulized to vancomycin to current regimens improves clinical 
outcomes11;12;14;15.  
 
The risks involved with this protocol mainly involve those related to nebulized vancomycin.  The other 
drugs utilized in the treatment regimen and the study procedures are all routinely used in clinical 
practice and clinical research.  The main potential risk from nebulized vancomycin is bronchospasm.  
While nebulized vancomycin is commonly used clinically and has been well tolerated, there have been 
reports of mild bronchospasm.  Review of studies and experience to date suggest the incidence to be <5% 
(Appendix 2)12. To minimize the risk of bronchospasm, patients will nebulize or inhale albuterol prior to 
their inhaled vancomycin dose.  At Visit 1, participants will be monitored closely while nebulizing 
vancomycin/placebo for the first time, including pre and post nebulization spirometry to assure 
tolerance of study drug prior to having study drug dispensed for home use. This witnessed study drug 
nebulization is repeated within 2-7 days (Visit 2) to provide additional participant monitoring. Other 
potential risks of use of nebulized vancomycin include development of vancomycin resistant MRSA 
(unlikely given the short term use) and idiosyncratic allergic reaction. These are discussed in more detail 
in section 11.3.2.  Most importantly however, current evidence suggests that the potential for side effects 


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from the change in route of administration of vancomycin to nebulization is actually significantly less 
than the risks seen with administration of intravenous vancomycin (which requires close serum 
monitoring and is known to be associated with renal toxicity and ototoxicity). 
 
The identified risks of nebulized vancomycin are also well balanced by the potential benefits of MRSA 
eradication, which include both immediate improved lung function and long term improvement in 
survival4;5.  Persistent MRSA infection has also been identified as a risk factor for persistent lung function 
decline after CF pulmonary exacerbations and this risk for failure to recover with exacerbation would be 
eliminated27.    
17.5 Publications  
The preparation and submittal for publication of manuscripts containing the study results shall be in accordance 
with a process determined by mutual written agreement among the Principal Investigator and participating 
institutions.  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.  
17.6 Investigator Responsibilities 
By signing the Agreement of Investigator form, the Investigator agrees to: 
1. Conduct the study in accordance with the protocol, except when to protect the safety, rights or 
welfare of subjects. 
2. Personally conduct or supervise the study (or investigation). 
3. Ensure that the requirements relating to obtaining informed consent and IRB review and approval 
meet federal guidelines, as stated in § 21 CFR, parts 50 and 56. 
4. Report to the IRB any AEs that occur in the course of the study, in accordance with §21 CFR 
312.64. 
5. Ensure that all associates, colleagues and employees assisting in the conduct of the study are 
informed about their obligations in meeting the above commitments. 
6. Maintain adequate and accurate records in accordance with §21 CFR 312.62 and to make those 
records available for inspection by the IRB and DSMB (or designee). 
7. Ensure that an IRB that complies with the requirements of §21 CFR part 56 will be responsible for 
initial and continuing review and approval of the clinical study. 
8. Promptly report to the IRB all changes in the research activity and all unanticipated problems 
involving risks to subjects or others (to include amendments and IND safety reports). 
9. Seek IRB approval before any changes are made in the research study, except when necessary to 
eliminate hazards to the patients/subjects. 
10. Comply with all other requirements regarding the obligations of clinical investigators and all other 
pertinent requirements listed in § 21 CFR part 312. 
 
 
 
 
 
 
 
 
 


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APPENDIX 1 – SCHEDULE OF STUDY VISITS 
 
SCREENING 
VISIT  
(Day-28) 
(± 2 days) 
RUN-IN 
VISIT  
(Day -
14)  
(± 4 
days) 
VISIT 1 
(START 
TREATMENT) 
(Day 1) 
 
VISIT 2 
(REPEAT 
ADMIN) 
(Day 2-7) 
PHONE 
VISIT 1 
(Day 
7-14) 
VISIT 3  
(MID-POINT 
TREATMENT)  
(Day 14)  
(± 2 days) 
PHONE 
VISITS 
2 & 3 
(Day 14-
21) 
(Day 21-
28) 
VISIT 4  
(END 
TREATMENT) 
(Day 29)  
(±1 day)  
VISIT 5   
1 MONTH 
MONITORING 
(Day 58)  
(± 4 days) 
VISIT 6  
3 MONTH 
MONITORING 
(Day 118)  
(± 7 days) 
EARLY 
WITHDRAW  
VISIT 
Informed Consent 
X 
 
 
 
 
 
 
 
 
 
 
Randomization 
 
Xn 
 
 
 
 
 
 
 
 
 
Medical History (a) 
Xa 
X 
X 
X 
 
X 
 
X 
X 
X 
X 
Demographics 
X 
 
 
 
 
 
 
 
 
 
 
Complete Physical Exam  
X 
 
 
 
 
 
 
X 
 
X 
X 
Abbreviated Physical Exam 
 
X 
X 
X 
 
X 
 
 
X 
 
 
Height, Weight  
X 
X 
X 
X 
 
X 
 
X 
X 
X 
X 
Vital Signs, Oximetry (b) 
X 
X 
Xb 
Xb 
 
Xb 
 
X 
X 
X 
X 
CFQ-R (c)  
 
 
X 
 
 
X 
 
X 
X 
X 
X 
Administer albuterol (d) 
X 
X 
X 
X 
 
X 
 
X 
X 
X 
X 
Spirometry (e) 
X 
X 
Xe 
Xe 
 
X 
 
X 
X 
X 
X 
Sputum Induction Procedure 
(f) 
X 
X 
 
 
 
X 
 
X 
X 
X 
 Xo 
Sputum Culture and 
Sensitivity  
 
X 
X 
 
 
 
X 
 
X 
X 
X 
 Xo 
Sputum MRSA Colony 
Forming Units (g) 
X 
X 
 
 
 
X 
 
X 
X 
X 
Xo 
Small Colony Variants of 
MRSA (g) 
X 
X 
 
 
 
X 
 
X 
X 
X 
 Xo 
MRSA: Comprehensive 
Genetic Strain Analysis (g) 
X 
X 
 
 
 
X 
 
X 
X 
X 
 Xo 
Sputum Cell Count (h) 
 
X 
 
 
 
X 
 
X 
X 
 
 
Sputum Cytokine 
Measurements (h) 
 
X 
 
 
 
 
 
X 
 
 
 
Nasal, Axillary, Rectal Swabs 
for Culture (i) 
 
Xi 
 
 
 
 
 
Xi 
Xi 
 
 
Administration of Study Drug 
 
 
Xb 
Xb 
 
Xb 
 
 
 
 
 
Expectorated Sputum 
Vancomycin Level (j) 
 
 
X 
 
 
 
 
 
 
 
 
Serum Vancomycin Levels (k) 
 
 
Xk 
 
 
Xk 
 
 
 
 
Xq 


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SCREENING 
VISIT 
(Day-28) 
(± 2 days) 
RUN-IN 
VISIT 
(Day -14) 
(± 4 days) 
VISIT 1 
(START 
TREATMENT) 
(Day 1) 
VISIT 2 
(REPEAT 
ADMIN) 
(Day 2-7) 
PHONE 
VISIT 1 
(Day 7- 
14) 
VISIT 3 (MID-
POINT 
TREATMENT) 
(Day 14) 
(± 2 days) 
PHONE 
VISITS 
2 & 3 (Day 
14-21) (Day 
21-28) 
VISIT 4 
(END 
TREATMENT) 
(Day 29) 
(±1 day) 
VISIT 5 
1 MONTH 
MONITORING 
(Day 58) 
(± 4 days) 
VISIT 6 
3 MONTH 
MONITORING 
(Day 118) 
(± 7 days) 
EARLY 
WITHDRAW 
VISIT 
Chemistry/LFTs/Hematology/C 
RP 
X 
X 
X 
X 
X 
Xp 
Pregnancy Test (Urine or 
Serum) (l) 
Xl 
Xl 
Xl 
Initiate Subject Diary 
X 
Subject Diary Review 
X 
X 
X 
X 
X 
X 
X 
Xp 
Concomitant Medication 
Review 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Adverse Experiences Review 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Hibiclens Test Hand Washing 
(m) 
X 
Provide Snack 
X 
X 
Administration of  protocol 
determined oral antibiotics, 
nasal mupirocin and Hibiclens 
X 
Xr 
Dispense supply of study drug, 
nebulizer,  protocol determined 
oral antibiotics, mupirocin and 
Hibiclens and provide teaching 
X 
 
Collect used and unused study 
drug and containers 
 
X 
Xp 
 
 
 
 
 
 
 
 
 
 
 
a) History of previous treatment for MRSA, number of MRSA cultures, and length of MRSA positivity 
at screening visit 
b) Continuous pulse oximetry is performed during nebulization of study drug and for 5 minutes afterward 
at Visit 1, Visit 2 and Visit 3. Observe for 1 hour post nebulized study drug at Visit 1 and Visit 2.  
c) On days CFQ-R is performed, it is done before any other interventions 
d) Two puffs of Albuterol 10-30 minutes prior to spirometry.  *Participants will not have further 
Albuterol prior to induced sputum unless it occurs more than 2 hours after previous Albuterol. 
e) Single spirometry value also obtained immediately after study drug nebulization and again 15 minutes 
(±10) after study drug nebulization at Visit 1 and Visit 2. 
f) Follow TDN Sputum Induction protocol 530.02 or 535.01 (per Nebulizer type); throat swab if 
inadequate sputum produced 
g) Only if culture grows MRSA 
 
 
h) Follow TDN Sputum Processing Protocol 508.02  
i) Rectal swabs optional and only age >18; no rectal swab at Visit 5 
 
 
   j) Spontaneous expectorated sputum collected 5±4 minutes after nebulizing study drug. Gargle with    
30cc of saline for ten seconds x3 prior to collection. 
k) Peak drawn 60 ±10 minutes after end of nebulization at Visit 1; trough drawn with other blood 
tests prior to nebulization at Visit 3. 
l) 
Serum pregnancy test done at screening, urine at other time points. 
m) Wash with water and one packet of Hibiclens hand cleanser for 2 minutes. Skin reaction will 
be observed for 15 minutes after washing 
n) Randomization will be a non-visit task on Day -4 (±3 days) once culture results from Run-in  
confirm presence of MRSA 
o) Sputum induction  done if Early Withdrawal Visit occurs between Visit 3 and 
Visit 5.  
p) If applicable, only if Early Withdrawal occurs between Visit 1 and Visit 4 
q) If applicable, only if Early Withdrawal Visit occurs before Visit 3 
r) Only oral antibiotic at Visit 3 if  subject hasn’t already taken that day. 


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APPENDIX 2 – Previous Published and Clinical Experience with Nebulized Vancomycin 
 
First 
Author 
Year 
CF Status 
# Patients 
Dose 
Frequency 
Treatment 
Length 
Side Effects 
 
 
Shirai 
1995 
No 
51 
125mg 
4x DAY 
7-120 days 
Vancomycin not detectable in serum 2 hours 
after inhalation. No side effects were reported 
in any of the 51 patients. 
Doe 
2010 
Yes 
18 courses 
200mg 
4x DAY 
5 days 
3 patients with chest tightness 
Solis 
2003 
Yes 
12 (18 courses) 
4mg/kg/dose 
4x DAY 
5 days 
None reported 
Weathers 
1990 
No 
1 
40mg 
3x DAY 
6 days 
None Reported in 3 y/o child on chronic vent 
 
Gradon 
1992 
No 
1 
120mg 
4x DAY 
4 days 
Serum vancomycin level 30min after 
administration was 2.2mcg/mL 
 
 
 
Kahata 
1997 
No 
1 
Not reported 
Not reported 
Not reported 
Cough, fever, shortness of breath, eosinophilia, 
hypoxia, and elevated CRP 30 minutes after 
inhalation in bone marrow transplant candidate. 
Resolved with steroids. 
 
 
 
Maiz 
1998 
Yes 
1 
250mg 
2x DAY 
17 months 
No VRE (checked twice). No VISA (checked 5 
times). Creatinine normal throughout study. No 
otoxicity. No increase in cough or wheezing 
during vancomycin administration. 
 
 
Miller 
2003 
No 
1 
120mg 
3x day 
1 day 
Patient with ventilator associated pneumonia. 
Sputum level of 2,352 mcg/mL. No side effects 
reported. 
 
Hayes 
2010 
Yes (post-Tx) 
1 
250mg 
2x DAY 
6 months 
Undetectable serum vancomycin levels at 2 
hours (checked twice). No change in creatinine 
Clinical 
Location 
Year 
CF Status 
# Patients 
Dose 
Frequency 
Treatment 
Length 
Side Effects 
Foundation 
Care* 
2004- 
2010 
Yes 
42 
250mg 
2x DAY 
varying 
None reported 
Foundation 
Care* 
2004- 
2010 
Yes 
22 
125mg 
2x DAY 
varying 
None reported 
 
Case 
2005- 
2010 
Yes 
22 
125-500mg 
2x DAY 
up to 24 months 
No VRE, VRSA, or chest tightness 
 
Akron 
2010 
Yes 
9 
125mg 
2x DAY 
1 bronchospasm resolved with albuterol 
pretreatment. 


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18.3  APPENDIX 3 – Pulmonary Exacerbation Guidelines 
 
18.3.1  Definition of a pulmonary exacerbation 
 
For this study, pulmonary exacerbation is defined as a change in antibiotic therapy 
(IV, inhaled, or oral) for any 4 or more of the following signs/symptoms: 
 
• change in sputum 
• new or increased hemoptysis 
• increased cough 
• increased dyspnea 
• malaise, fatigue, or lethargy 
• temperature above 38°C (equivalent to approximately 100.4°F) 
• anorexia or weight loss 
• sinus pain or tenderness 
• change in sinus discharge 
• change in physical examination of the chest 
• decrease in pulmonary function by 10% 
• radiographic changes indicative of pulmonary infection 
 
18.3.2  Data Collected on each Exacerbation 
 
The following information will be determined for protocol-defined pulmonary 
exacerbations: 
• Number of pulmonary exacerbations 
• Number of days with pulmonary exacerbations 
• Time-to-first pulmonary exacerbation 
• Number of pulmonary exacerbations requiring hospitalizations 
• Number of days hospitalized for pulmonary exacerbations 
• Time-to-first hospitalization for pulmonary exacerbation 
• Number of pulmonary exacerbations requiring IV antibiotic therapy 
• Number of days on IV antibiotic therapy for pulmonary exacerbations 
• Time-to-first IV antibiotic therapy for pulmonary exacerbations 
 
 
 
 
 
 
 
 
 
 


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19.  REFERENCE LIST 
Reference List 
 
 
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3.  Cystic Fibrosis Foundation, Patient Registry 2009 Annual Report.  2010. Bethesda, 
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