Clinical trial NCT02677701
Conditions: Cystic Fibrosis
Sponsor: Seattle Children's Hospital
Start date: 2016-10-21; Completion date: 2020-02-13
Enrollment: 119 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
This is a study to examine the effect of combining chronic oral azithromycin with inhaled tobramycin in adolescent and adult subjects with cystic fibrosis who are chronically infected with P. aeruginosa.

Detailed description:
This study is a prospective, randomized, double-blinded, placebo-controlled trial of azithromycin 500mg taken orally thrice weekly vs. placebo in subjects with cystic fibrosis and chronic airway infection with P. aeruginosa who are utilizing chronic inhaled tobramycin therapy. It will include approximately 120 subjects able to complete a primary 6-week study phase. Subjects will be at least 12 years old with a baseline forced expiratory volume at one second (FEV1) between 25-100% predicted. Subjects will continue to use clinically prescribed inhaled tobramycin cycled on/off every 4 weeks. They will be provided over-encapsulated azithromycin 500mg tablets or placebo during the primary study phase. An optional extension phase will be offered to all subjects completing the primary 6-week study. This 8-week extension phase will include an initial 4 weeks without use of inhaled tobramycin or other inhaled antibiotics, followed by a 4-week period with inhaled tobramycin use. All subjects participating in the extension phase of the study will be provided azithromycin 500mg tablets to be taken thrice weekly for the entire 8-week period.

This study will investigate how use of chronic oral azithromycin affects some of the previously demonstrated benefits to health when using inhaled tobramycin. The primary measurements will focus on lung function. Additional measurements will focus on disease-related quality of life as reported by subjects in the trial. Exploratory outcomes, including measurements of safety, are also planned.

Arms: arm 1: azithromycin 500mg tablet over-encapsulated to match placebo in appearance, taken by mouth thrice weekly for 6 weeks arm 2: encapsulated placebo taken by mouth thrice weekly for 6 weeks
Interventions: intervention 1: azithromycin intervention 2: placebo (for azithromycin) intervention 3: inhaled tobramycin
Intervention descriptions: intervention 1: 500mg tablet over-encapsulated to match placebo intervention 2: None intervention 3: clinically prescribed inhaled tobramycin used by subjects participating in the study

Protocol documents:
Prot_000.pdf: 


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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 
Sponsor-Investigator 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:  TEACH-IP-15 
 
Protocol Title:  TEACH Trial: Testing the Effect of Adding CHronic Azithromycin to Inhaled 
Tobramycin. A randomized, placebo-controlled, double-blinded trial of azithromycin 500mg 
thrice weekly in combination with inhaled tobramycin 
 
Protocol Date: June 11, 2018 
 
 
 
 
Investigator Signature  
 
Date 
 
Print Name and Title 
Site # 
 
 
Site Name 
 
Address 
 
 
 
 
 
 
 


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TABLE OF CONTENTS 
 
1 
BACKGROUND ..........................................................................................................................................................15 
2 
STUDY RATIONALE ...................................................................................................................................................20 
2.1 RISK / BENEFIT ASSESSMENT ......................................................................................................................................21 
3 
STUDY OBJECTIVES...................................................................................................................................................21 
3.1 PRIMARY OBJECTIVE ..................................................................................................................................................21 
3.2 SECONDARY OBJECTIVES ............................................................................................................................................21 
4 
STUDY DESIGN ..........................................................................................................................................................22 
4.1 STUDY OVERVIEW .....................................................................................................................................................22 
5 
CRITERIA FOR EVALUATION ....................................................................................................................................23 
5.1 PRIMARY ENDPOINT ..................................................................................................................................................23 
5.2 SECONDARY ENDPOINTS.............................................................................................................................................23 
6 
SUBJECT SELECTION .................................................................................................................................................24 
6.1 STUDY POPULATION ..................................................................................................................................................24 
6.2 INCLUSION CRITERIA ..................................................................................................................................................24 
6.3 EXCLUSION CRITERIA .................................................................................................................................................25 
6.4 
STUDY SPECIFIC TOLERANCE FOR INCLUSION/EXCLUSION CRITERIA ..................................................................................26 
6.5 SCREEN FAIL CRITERIA ...............................................................................................................................................26 
7 
CONCURRENT MEDICATIONS..................................................................................................................................26 
7.1 ALLOWED MEDICATIONS AND TREATMENTS .................................................................................................................27 
7.2 CONDITIONALLY ALLOWED MEDICATIONS AND TREATMENTS ..........................................................................................27 
7.3 PROHIBITED MEDICATIONS AND TREATMENTS ..............................................................................................................28 
7.4 CHANGE IN MEDICATIONS OR THERAPIES .....................................................................................................................28 
8 
STUDY TREATMENTS................................................................................................................................................28 
8.1 RANDOMIZATION ......................................................................................................................................................28 
8.2 BLINDING .................................................................................................................................................................29 
8.3 UNBLINDING PROCEDURES .........................................................................................................................................29 
8.4 FORMULATION OF TEST AND CONTROL PRODUCTS ........................................................................................................29 
8.5 
SUPPLY OF STUDY DRUG TO THE SITE...........................................................................................................................30 
8.6 DOSE MODIFICATIONS ...............................................................................................................................................31 
8.7 STUDY DRUG ACCOUNTABILITY .........................................................................................................................31 
8.8 
MEASURES OF TREATMENT COMPLIANCE ..........................................................................................................31 
8.9 
STANDARD OF CARE TREATMENT WITH TISP ....................................................................................................32 
9 
STUDY PROCEDURES AND GUIDELINES .................................................................................................................32 
9.1 
CLINICAL ASSESSMENTS ......................................................................................................................................32 
9.2 
CLINICAL LABORATORY MEASUREMENTS..........................................................................................................35 
10 
EVALUATIONS BY VISIT............................................................................................................................................35 
10.1 
VISIT 1 – DAY -14............................................................................................................................................35 
10.2 
VISIT 2 - DAY 0 (VISIT WINDOW -2/+4 DAYS) ................................................................................................36 
10.3 
VISIT 3 – DAY 28 (VISIT WINDOW -2/+4 DAYS), WEEK 4 ..............................................................................36 
10.4 
VISIT 4 – DAY 56 (VISIT WINDOW +/- 4 DAYS), OPEN-LABEL WEEK 4 .................................................................37 


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10.5 
VISIT 5 - DAY 84 (VISIT WINDOW +/- 4 DAYS), OPEN-LABEL WEEK 8 ............................................................38 
10.6 
UNSCHEDULED* OR EARLY DISCONTINUATION OF STUDY DRUG OR STUDY PARTICIPATION VISIT..........38 
11 
ADVERSE EXPERIENCE REPORTING AND DOCUMENTATION...............................................................................39 
11.1 
ADVERSE EVENTS............................................................................................................................................39 
11.2 
SERIOUS ADVERSE EXPERIENCES (SAE) .......................................................................................................40 
11.3 
MEDICAL MONITORING...................................................................................................................................41 
12 
DISCONTINUATION AND REPLACEMENT OF SUBJECTS........................................................................................41 
12.1 
EARLY PERMANENT DISCONTINUATION OF STUDY TREATMENT .................................................................41 
12.2 
EARLY WITHDRAWAL OF SUBJECTS FROM THE STUDY.................................................................................41 
12.3 
REPLACEMENT OF SUBJECTS...........................................................................................................................42 
13 
PROTOCOL VIOLATIONS ..........................................................................................................................................42 
14 
DATA SAFETY MONITORING ...................................................................................................................................42 
15 
STATISTICAL METHODS AND CONSIDERATIONS...................................................................................................42 
15.1 
DATA SETS ANALYZED ...................................................................................................................................43 
15.2 
DEMOGRAPHIC AND BASELINE CHARACTERISTICS .......................................................................................43 
15.3 
ANALYSIS OF PRIMARY ENDPOINT .................................................................................................................43 
15.4 
ANALYSIS OF SECONDARY ENDPOINTS ..........................................................................................................43 
15.5 
INTERIM ANALYSIS..........................................................................................................................................44 
15.6 
SAMPLE SIZE....................................................................................................................................................45 
16 
DATA COLLECTION, RETENTION AND CLINICAL MONITORING ...........................................................................46 
16.1 
DATA COLLECTION INSTRUMENTS...........................................................................................................................46 
16.2 
DATA MANAGEMENT PROCEDURES........................................................................................................................47 
16.3 
DATA QUALITY CONTROL AND REPORTING ..............................................................................................................47 
16.4 
SECURITY AND ARCHIVAL OF DATA .........................................................................................................................47 
16.5 
AVAILABILITY AND RETENTION OF INVESTIGATIONAL RECORDS ...................................................................................48 
16.6 
MONITORING ......................................................................................................................................................48 
16.7 
SUBJECT CONFIDENTIALITY ....................................................................................................................................48 
17 
ADMINISTRATIVE, ETHICAL, REGULATORY CONSIDERATIONS............................................................................48 
17.1 
PROTOCOL AMENDMENTS.....................................................................................................................................49 
17.2 
INSTITUTIONAL REVIEW BOARDS ............................................................................................................................49 
17.3 
INFORMED CONSENT FORM...................................................................................................................................49 
17.4 
CONSENT FOR COLLECTION AND USE OF CFF REGISTRY ID NUMBER...........................................................................50 
17.5 
PUBLICATIONS .....................................................................................................................................................50 
17.6 
INVESTIGATOR RESPONSIBILITIES ............................................................................................................................50 
18 
REFERENCES ..............................................................................................................................................................52 
19 
APPENDIX 1 SCHEDULE OF EVENTS ........................................................................................................................54 
20 
APPENDIX 2 PROTOCOL DEFINED PULMONARY EXACERBATION DEFINITION..................................................56 
 


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LIST OF ABBREVIATIONS AND ACRONYMS 
AE 
adverse event 
BAL 
bronchoalveolar lavage 
CFR 
Code of Federal Regulations 
CF 
cystic fibrosis 
CFF 
Cystic Fibrosis Foundation 
CFFT 
Cystic Fibrosis Foundation Therapeutics 
CFRSD 
Cystic Fibrosis Respiratory Symptom Diary 
CFRSD-CRISS  
CFRSD-Chronic Respiratory Infection Symptom Score 
CFQ-R 
Cystic Fibrosis Questionnaire - Revised 
CFQ-R RSS 
CFQ-R Respiratory Symptom Scale 
CFTR 
cystic fibrosis transmembrane conductance regulator 
CRF 
case report form 
DSMB 
Data Safety Monitoring Board 
ECG 
electrocardiogram 
EDC 
Electronic data capture 
FDA 
Food and Drug Administration 
FEF25%-75% 
forced expiratory flow 
FEV1 
forced expiratory volume over one second 
FVC 
forced vital capacity 
GCP 
Good Clinical Practice 
HIPAA 
Health Insurance Portability and Accountability Act of 1996 
IRB 
Institutional Review Board 
IV 
intravenous 
LFT 
Liver function test 
mEq 
milliequivalent 
Pa 
Pseudomonas aeruginosa 
PFT 
pulmonary function test 
SAE 
serious adverse experience 
TDNCC 
Therapeutics Development Network Coordinating Center 
TISP 
Tobramycin inhalation solution or powder 


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PROTOCOL SYNOPSIS 
 
TITLE 
TEACH Trial: Testing the Effect of Adding CHronic Azithromycin to 
Inhaled Tobramycin. A randomized, placebo-controlled, double-
blinded trial of azithromycin 500mg thrice weekly in combination 
with inhaled tobramycin 
SPONSOR-
INVESTIGATOR 
Dave Nichols, MD (Seattle Children’s Hospital) 
 
FUNDING 
ORGANIZATION 
National Institutes of Health/National Heart, Lung, and Blood 
Institute 
Cystic Fibrosis Foundation Therapeutics, Inc. (CFFT) 
NUMBER OF SITES 
Approximately 40 
RATIONALE 
Patients with cystic fibrosis (CF) commonly acquire a chronic airway 
infection with Pseudomonas aeruginosa (Pa).  Both inhaled 
tobramycin and oral azithromycin have been proven beneficial in 
these patients and are currently used by the majority of eligible 
patients.  75% of US patients prescribed inhaled tobramycin are also 
prescribed chronic oral azithromycin. We believe that azithromycin 
may be inhibiting the anti-Pa effects and clinical benefits of inhaled 
tobramycin in clinically infected patients.  This study is designed to 
compare monotherapy with inhaled tobramycin versus combination 
therapy adding chronic oral azithromycin to inhaled tobramycin. 
STUDY DESIGN 
This is a prospective, randomized, placebo-controlled, double-blinded 
study of azithromycin in subjects with chronic Pa airway infection 
using inhaled tobramycin.  Subjects who have received two (2) or 
more cycles of inhaled tobramycin within the 24 weeks prior to 
enrollment will be recruited into the study.   This study will 
investigate whether azithromycin is associated with poorer clinical 
and microbiologic outcomes as compared to placebo during 
concurrent administration of inhaled tobramycin.   
Eligible subjects will be enrolled and randomized to either 
azithromycin or placebo at Visit 1, approximately 14 days prior to the 
start day of their next planned 28-day nebulized solution or dry 
powder tobramycin (TISP) cycle.   Both tobramycin inhalation 
solution (TIS) and tobramycin inhalation powder (TIP) will be 
allowed, based on clinical prescription.  Tobramycin solution should 
be nebulized with an approved nebulizer and air compressor. 
Subjects will be randomized in a 1:1 fashion to azithromycin (500 mg 
three times per week) or matched placebo.  Randomization will be 
stratified by FEV1 % predicted (25%-50%, >50%-75%, >75%), 
chronic oral azithromycin use for the past 30 days, inhaled tobramycin 
formulation (TIS, TIP), and site. Between Visit 1 (Day -14) and Visit 


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2 (Day 0), a two-week run-in period will be used to begin 
administration of either azithromycin or placebo.  Among those 
randomized to azithromycin, the 2-week run-in period will be used to 
initiate azithromycin and standardize uptake prior to the start of the 
next TISP cycle.  Among those randomized to placebo, the run-in 
period will be used as a standardized washout prior to the start of the 
next TISP cycle.  Subjects will begin TISP at Visit 2 in addition to 
their continued dosing of randomized study drug treatment 
(azithromycin or placebo). Subjects will continue both TISP and study 
drug dosing for 28 days (up until Visit 3), which corresponds with the 
end of a clinically prescribed 4-week cycle of TISP.   
Subjects completing the study through Visit 3 will be offered 
participation and consent to an 8-week open-label extension period 
during which azithromycin will be provided.  During the open-label 
period, subjects will be instructed to remain off of TISP for the first 4-
week period, followed by a 4-week period of TISP. 
DURATION OF 
SUBJECT 
PARTICIPATION 
AND DURATION OF 
STUDY 
Subjects will be enrolled in the randomized study for up to 42 days (6 
weeks). 
• Treatment V1-V2: azithromycin or placebo without TISP: 14 days 
(-2 days/+4 days) followed by: 
• Treatment V2-V3: azithromycin or placebo with TISP: 28 days (-2 
days/+4 days) 
Subjects participating in the optional open-label extension will be on 
study for up to 98 days (14 weeks). 
• Treatment V3-V4: azithromycin without TISP: 28 days (-/+4 
days) followed by: 
• Treatment V4-V5: azithromycin with TISP 28 days (-/+4 days) 
The total duration of the study is expected to be approximately 33.5 
months: 30 months for subject recruitment and 3.5 months for the 
final subject enrolled to complete the study. 
PRIMARY 
OBJECTIVE 
Determine if azithromycin impairs the previously-recognized clinical 
benefits of inhaled tobramycin by comparing changes in pulmonary 
function as measured by FEV1 between subjects randomized to 
azithromycin versus placebo.    


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SECONDARY 
OBJECTIVES 
The secondary objectives for the randomized period are to: 
• 
Compare changes in patient-reported quality of life between 
subjects randomized to azithromycin versus placebo  
The secondary exploratory objectives for the randomized period are 
to: 
• 
Compare the safety profile between subjects randomized to 
azithromycin versus placebo  
• 
Compare changes in additional spirometry measures, bacterial 
density, and weight between subjects randomized to azithromycin 
versus placebo  
• 
Compare rates of pulmonary exacerbations, hospitalizations, and 
acute antibiotic usage between subjects randomized to 
azithromycin versus placebo  
The objectives for those continuing in the open-label extension: 
• 
Among those randomized to azithromycin and remaining on 
azithromycin, obtain additional data to determine the long term 
effect of azithromycin on clinical outcomes   
• 
Among those randomized to placebo and switching to 
azithromycin, compare differences in clinical outcomes observed 
during the randomized and open-label periods 
NUMBER OF 
SUBJECTS 
Approximately 120 subjects randomized  
SUBJECT 
SELECTION 
CRITERIA:  
Inclusion Criteria 
Inclusion Criteria for Randomized Period: 
1. Male or female ≥ 12 years of age at Visit 1 
2. Documentation of a CF diagnosis as evidenced by one or more 
clinical features consistent with the CF phenotype and one or 
more of the following criteria: 
o Sweat chloride equal to or greater than 60 mEq/L by 
quantitative pilocarpine iontophoresis test (QPIT)  
o Two mutations in the CFTR gene believed to be disease 
causing in the opinion of the site investigator 
o Abnormal nasal potential difference (change in NPD in 
response to a low chloride solution and isoproterenol of less 
polarizing than -7 mV) 
3. Written informed consent (and assent when applicable) obtained 
from subject or subject’s legal representative 
4. Two or more respiratory cultures (sputum, OP swab, BAL sample) 
growing Pa collected within the 12 months prior to 
randomization, at least 1 month apart, with at least one collected 
in the 6 months prior to randomization.  
5. FEV1% predicted between 25-100% at Visit 1 
 


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6. Off TISP and other inhaled anti-pseudomonal antibiotics for at 
least two weeks at randomization 
7. Willingness to begin the next course of TISP at the scheduled 
Visit 2  
8. Use of at least 2 cycles of TISP within 24 weeks prior to Visit 1 
9. Ability to swallow capsules (similar in size to pancreatic enzyme 
capsules) 
10. Most recent LFTs less than 4x ULN.  Must be obtained within 12 
months prior to Visit 1   
11. Current azithromycin use at Visit 1 or prior chronic azithromycin 
use defined as four or more consecutive weeks. Subjects do not 
have to be using chronic oral azithromycin at Visit 1 
12. Stable clinical status with no significant change in medication or 
airway clearance routine for four weeks prior to Visit 1, as 
determined by site investigator 
 
Inclusion Criteria for Open-Label Period: 
1. Completion of the randomized, placebo-controlled period (up 
through Visit 3) 
2. Written informed consent (and assent when applicable) obtained 
from subject or subject’s legal representative  
3. Ability for subject to comply with the requirements of the study 
4. Willingness to begin the next course of TISP at the scheduled 
Visit 4 
5. Clinically stable at Visit 3 as assessed by the site investigator 
SUBJECT 
SELECTION 
CRITERIA:  
Exclusion Criteria 
Exclusion Criteria for Randomized Period: 
1. Weight < 40 kg at Visit 1 
2. For women of child-bearing potential:  
a. positive pregnancy test at Visit 1 or 
b. lactating or 
c. unwilling to practice a medically acceptable form of 
contraception (acceptable forms of contraception: 
abstinence, hormonal birth control, intrauterine device, or 
barrier method plus a spermicidal agent), unless surgically 
sterilized or postmenopausal during the study  
3. Inability to perform reproducible spirometry 
4. Inability or unwillingness to cycle off TISP for one 4-week period 
5. Respiratory culture with Burkholderia cepacia complex species 
within the 24 months prior to Visit 1 
6. Respiratory culture with nontuberculous mycobacteria (NTM) 
within 18 months prior to Visit 1 
7. Use of IV or oral anti-pseudomonal antibiotics within four weeks 
prior to Visit 1 (other than azithromycin) 
 


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8. Use of an investigational therapy within four weeks prior to    
Visit 1  
9. History of unresolved, abnormal neutropenia (ANC ≤ 1000 
cells/mm3) 
10. Current use of systemic corticosteroids equivalent to a daily dose 
more than 10 mg prednisone at Visit 1 
11. Current use of nelfinavir, warfarin, haloperidol, or methadone at 
Visit 1  
12. Initiation of approved CFTR modulators less than 30 days prior to 
Visit 1 
13. ECG abnormalities identified at Visit 1 that require prompt, 
further medical evaluation or QTc interval >480 msec for males 
and >486 msec for females at Visit 1 
14. Any other condition that, in the opinion of the site 
investigator/designee, would preclude informed consent or assent, 
make study participation unsafe, complicate interpretation of 
study outcome data, or otherwise interfere with achieving the 
study objectives 
 
Exclusion Criteria for Open-Label Period: 
1. Weight < 40 kg at Visit 3 
2. For women of child bearing potential: unwilling to practice a 
medically acceptable form of contraception (acceptable forms of 
contraception: abstinence, hormonal birth control, intrauterine 
device, or barrier method plus a spermicidal agent), unless 
surgically sterilized or postmenopausal during the study  
3. Identified respiratory culture positive for NTM or Burkholderia 
cepacia complex species during randomized study period 
4. Use of an investigational therapy at Visit 3 
5. Current use of systemic corticosteroids equivalent to a daily dose 
more than 10 mg prednisone  
6. Current use of nelfinavir, warfarin, haloperidol, or methadone  
7. Any other condition that, in the opinion of the site 
investigator/designee, would preclude informed consent or assent, 
make study participation unsafe, complicate interpretation of 
study outcome data, or otherwise interfere with achieving the 
study objectives 
TEST PRODUCT, 
DOSE, AND ROUTE 
OF 
ADMINISTRATION 
Over-encapsulated azithromycin tablets will be provided during the 
randomized period of the study.  Azithromycin will be dosed as one 
500 mg capsule three times per week.  
During the open-label extension period, azithromycin 500 mg tablets 
(without over-encapsulation) will be provided by the site pharmacy 
and dosed three times per week. 


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CONTROL 
PRODUCT, DOSE 
AND ROUTE OF 
ADMINISTRATION 
Placebo, matching the appearance of the azithromycin capsules and 
comprised of the same capsule material as the test product will be 
provided during the randomized period of the study. Placebo will be 
dosed as one capsule three times per week. 
STANDARD OF CARE 
TREATMENT: TISP 
In this study, TISP is given as standard of care, will be based on 
clinical prescription for 28 days on, followed by 28 days off, and will 
conform to manufacturer administration guidelines.   
CONCOMMITANT 
MEDICATIONS 
Allowed: For both the randomized and open-label periods, standard 
therapy for CF is allowed except for treatments noted in the 
conditionally allowed and prohibited medications sections below.  
Ongoing chronic treatment (>30 days prior to Visit 1) with inhaled 
dornase alpha, hypertonic saline, short and long acting 
bronchodilators, FDA-approved CFTR modulators, high dose 
ibuprofen, low-dose inhaled or systemic steroids and airway clearance 
is allowed.   
Conditionally Allowed: Acute treatment with drugs categorized as 
known to prolong QT interval is allowed according to the following:  
• 
For drugs commonly used to treat CF patients (e.g. 
ciprofloxacin, levofloxacin, moxifloxacin, fluconazole, propofol, 
sevoflurane, ondansetron), study drug (azithromycin or placebo) 
or open-label azithromycin does not need to be stopped.   
• 
For all other drugs categorized as known to prolong QT interval, 
acute use is allowed but study drug (azithromycin or placebo) or 
open-label azithromycin must be temporarily stopped during use 
of these medications.  After acute treatment is completed, 
subjects should restart study drug or open-label azithromycin on 
the next scheduled treatment day.  
• 
Chronic treatment (>30 days prior to Visit 1) with antidepressant 
medications citalopram and escitalopram is allowed without 
affecting study participation  if: 
o 
The subject has been using both chronic oral azithromycin 
AND citalopram (or escitalopram) consistently for greater 
than 30 days at Visit 1  
AND 
o 
The Visit 1 ECG demonstrates QTc within the normal limits 
as defined by the protocol 
Drugs known to prolong QT interval are described as follows: 
“Substantial evidence supports the conclusion that these drugs prolong 
the QT interval AND are clearly associated with a risk of torsades de 
pointes (TdP), even when taken as directed in official labeling”, and 


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are listed on the CredibleMeds® Website (Composite List of All QT 
Drugs under the category “Known Risk of TdP”).  
Acute use of macrolide antibiotics may be required for certain 
infections and is allowed but also requires temporarily stopping the 
study drug or open-label azithromycin. The study drug or open-label 
azithromycin should be restarted on the next scheduled day following 
completion of the prescribed macrolide antibiotic. 
Treatment for pulmonary exacerbations as required for acute care is 
allowed except for treatments noted in the prohibited medications 
section below.  Physicians are encouraged to prescribe acute antibiotic 
therapy and initiate or increase the dose of acute systemic 
corticosteroids (defined as less than 10 days) only in the presence of 
increased symptoms suggesting a pulmonary exacerbation. 
 
Prohibited: For both the randomized and open-label periods, the 
following medications are prohibited (for the randomized period, 
between Visit 1 through Visit 3; for the open-label period, between 
Visit 3 and Visit 5).   
o Investigational therapies  
o Chronic inhaled antibiotics other than cycled TISP (e.g., 
Cayston®, colistin). Chronic treatment is defined as inhaled 
antibiotics prescribed as a maintenance therapy and not used 
temporarily to treat a pulmonary exacerbation.  
o Increase in chronic systemic corticosteroid dose beyond 
prednisone equivalent of 10 mg per day, or initiation of 
chronic systemic (oral or intravenous) corticosteroids at any 
dose. Chronic use is defined as greater than 10 days 
continuous use.   
o New or increase in ibuprofen dose of greater than 800 mg total 
dose per 24 hours for more than 5 days 
o Nelfinavir, warfarin, haloperidol, or methadone 
PRIMARY ENPOINT 
Difference between the azithromycin and placebo treatment groups in 
the relative change in FEV1(liters) from randomization (Visit 1) to 
Visit 3. 
SECONDARY 
ENDPOINTS 
Randomized Period 
Secondary Endpoints: 
• Difference between the azithromycin and placebo treatment 
groups in the relative change in FEV1(liters) during administration 
of TISP from Visit 2 to Visit 3. 
• Difference between the azithromycin and placebo treatment 
groups in the change from Visit 1 to Visit 3 in the Cystic Fibrosis 
Respiratory Symptom Diary (CFRSD) - Chronic Respiratory 
Infection Symptom Score (CRISS©)  


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• Difference between the azithromycin and placebo treatment 
groups in the change from Visit 1 to Visit 3 in the scales derived 
from the CFQ-R  
 
Exploratory Secondary Endpoints: 
• Difference in adverse event rates and rates of abnormal QTc 
parameters from Visit 1 through Visit 3 between the azithromycin 
and placebo treatment groups  
• Difference in the proportion of subjects hospitalized from Visit 1 
through Visit 3 between the azithromycin and placebo treatment 
groups Difference in the proportion of subjects prescribed acute 
oral, inhaled and IV antibiotics from Visit 1 through Visit 3 
between the azithromycin and placebo treatment groups  
• Difference in the proportion of subjects experiencing a protocol-
defined pulmonary exacerbation requiring antibiotic therapy from 
Visit 1 through Visit 3 between the azithromycin and placebo 
treatment groups  
• Difference between the azithromycin and placebo treatment 
groups in the absolute change from Visit 1 to Visit 3 and Visit 2 to 
3 in FEV1 (liters and % predicted), absolute and relative change in 
FVC (liters and % predicted), and absolute and relative change in 
FEF25-75%  
• Difference between the azithromycin and placebo treatment 
groups in the change from Visit 1 to Visit 3 in weight  
• Difference in the change from Visit 1 to Visit 3 in sputum Pa 
bacterial density between the azithromycin and placebo treatment 
groups  
Open-Label Period 
• Among those randomized to azithromycin and remaining on 
azithromycin, longitudinal changes and/or rates in all clinical 
outcomes across  the randomized and open-label periods 
• Among those randomized to placebo and switching to 
azithromycin, differences in all clinical outcomes between the 
randomized and open-label periods 
PLANNED INTERIM 
ANALYSES  
An independent data monitoring board (DSMB) will review 
comprehensive interim reports when approximately 50% and 75% of 
patients have completed the randomized period of the study. Regular 
reporting frequency to the DSMB is detailed in the DSMB charter. A 
priori interim stopping rules for futility and efficacy/harm with 
respect to the primary endpoint are outlined in the DSMB charter. 
Serious adverse experiences (SAEs) will be monitored by the 
committee on an ongoing basis throughout the study. 


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STATISTICS 
Primary Analysis Plan 
All analyses will be performed using a modified intent-to-treat (m-
ITT) population, which is defined as all randomized subjects who 
received at least one dose of study drug.  All tests will be two-sided 
and evaluated at a 0.05 level of significance. 
 
The primary endpoint will be the difference between the azithromycin 
and placebo treatment groups in the relative change from Visit 1 to 
Visit 3 in FEV1 (liters).  The primary endpoint will be compared 
between treatment groups using linear regression adjusted for 
randomization strata. Least squares means and the treatment effect for 
the relative change will be presented as well as corresponding 95% 
confidence interval and p-values. The p-values will be evaluated 
against a two-sided 0.05 level of significance.  
Rationale for Number 
of Subjects 
The primary endpoint is the difference between the azithromycin and 
placebo treatment groups in the relative change from Visit 1 to Visit 3 
in FEV1 (liters).  Data from prior published studies of similar duration 
are available to estimate sample size and power for the study 
including a randomized, placebo-controlled trial of azithromycin in 
individuals with CF chronically infected with Pa and a randomized, 
placebo controlled trial of aztreonam lysine similarly among those 
with chronic Pa.  These studies suggest a standard deviation of the 
relative change in FEV1 ranging from 10 to 16.  Based on these prior 
studies, we anticipate the relative change in FEV1 from Visit 1 to Visit 
3 to be -2% in the azithromycin arm and +6.85% in the placebo arm 
for an overall treatment effect of 8.65%.   A sample size of 110 
provides 85% power to detect a treatment effect of 7.5% or greater 
assuming a standard deviation of 13.  110 subjects provides 93% 
power to detect a treatment effect similar to what was observed in the 
preliminary data (8.65%) assuming a standard deviation of 13.  It is 
noteworthy that the standard deviation from more recently completed 
studies CF studies have observed standard deviations in short term 
relative change in FEV (liters) ranging from 8-11, confirming our 
conservatism in the standard deviation estimate used for our sample 
size calculations.   Assuming a standard deviation of 11, a sample size 
of 110 provides 85% power to detect a treatment effect of 6.3% or 
greater in favor of the placebo group.   
It is anticipated from prior CF trials conducted through the TDNCC 
that the attrition rate will be less than 10%, and thus a sample size of 
120 will ensure at least 110 subjects will complete the trial.   


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1 
BACKGROUND 
Projected median survival of those with cystic fibrosis (CF) has dramatically improved in recent 
decades, largely as a result of new medications and therapies.  Pseudomonas aeruginosa (Pa) is 
the most common pathogen in the airways of people with CF. By early adolescence, half of all 
patients with CF are chronically infected with Pa1.  This prevalence increases to 70% or more by 
early adulthood, and persistent Pa airway infection is linked to more rapid loss of lung function 
and earlier mortality2,3.  Inhaled antibiotics achieve high airway concentrations while avoiding 
many safety concerns associated with prolonged systemic drug exposure4,5. Strategies to 
eradicate initial Pa airway infection or treat chronic infection have proven beneficial6-9.  
The aminoglycoside tobramycin was the first inhaled anti-pseudomonal antibiotic commercially 
developed for CF and remains the most prescribed inhaled antibiotic used in the US1.  Roughly 
two thirds of all US patients with CF and chronic Pa are prescribed inhaled tobramycin—
typically as 28 days of on-off cycles. Long-term use of oral azithromycin has also been shown to 
improve lung function and reduce exacerbations in CF patients with chronic Pa airway 
infection10,11.  While the mechanism of action is uncertain and potentially multifactorial, 
azithromycin has immunomodulatory effects and may function as an anti-inflammatory agent in 
CF12-15. Azithromycin is widely prescribed and is now the most common chronic antibiotic used 
in CF patients with persistent Pa1.  In queries of recent clinical trials and the US CF Foundation 
National Patient Registry, we find that ~70% of all patients with Pa and 75% of those prescribed 
inhaled tobramycin are now also prescribed oral azithromycin on a chronic basis. 
Potential interactions between concomitant medications and mechanisms for antibiotic resistance 
in CF are poorly understood.  These issues have been cited in current CF consensus treatment 
guidelines as two key unanswered questions in need of further study16. Based on recent pre-
clinical research demonstrating antagonism between azithromycin and tobramycin, but not the 
fluoroquinolone, ciprofloxacin17, we hypothesized that azithromycin may selectively inhibit 
tobramycin when targeting Pa airway infection in CF lung disease.  We have now observed a 
selective, antagonistic drug interaction between azithromycin and tobramycin in two in vitro 
models of biofilm growth with Pa, two animal models of biofilm-based Pa infection, and two 
non-overlapping CF clinical trials when retrospectively analyzing the impact of concomitant 
azithromycin use on clinical and microbiological outcome measures. 
In-vitro Data 
Initial studies were conducted with the laboratory strain of Pa PA0118. Using a flow cell biofilm 
culture method, we observe significant antibiotic effects, manifested as reduced biofilm biomass, 
with antibiotics individually (Figure 1a). However, when azithromycin was added, we observed 
neutral to increased effect with ciprofloxacin (Figure 1b) but antagonistic effects with 
tobramycin (Figure 1c).  
 


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Figure 1a 
 
 
        Figure 1b  
 
 
Figure 1c 
 
 
 
 
 
 
 
 
 
 
 
*P<0.01   ∞P<0.001 
 
Additional studies in the flow-cell biofilm model were conducted using 15 CF clinical isolates of 
Pa19. Twelve of the isolates grew sufficient biofilms to be tested in the antibiotic comparison 
studies. Of those 12, six showed antagonism when azithromycin was added to tobramycin. We 
then tested aztreonam in those six isolates and observed neutral effects in three isolates and 
additive effects in three isolates (Figure 2). The flow-cell system is devoid of any mammalian 
tissue. These data suggest that the suspected drug interaction occurs directly between the 
antibiotics in the context of bacterial infection rather than indirectly through altered host 
response. 
Figure 2 
 
 


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More recently, we have developed a biofilm aggregate model that incorporates lysed human 
neutrophils to enhance biofilm growth20. In this model, Pa develops non-surface attached 
biofilms suspended in nutrient poor media containing the lysed neutrophils, and may more 
closely resemble the bacterial communities that have been documented in airway secretions from 
people with CF. We have tested 30 CF clinical isolates in this model. Ten isolates were collected 
from a clinical trial, 10 were collected from patients at National Jewish Health, and 10 were 
obtained from the CF repository at Seattle, WA. 
In the biofilm aggregate model, we observe highly significant reduction in bacterial killing when 
azithromycin is added to tobramycin, with 2-3 log antagonism (100-1000 fold; Figure 3a). To 
date, we do not observe antagonism with other antibiotics commonly used for inhalation therapy 
in CF (Figure 3b; effect of azithromycin when added to anti-Pa antibiotics). 
 
      Figure 3a  
 
 
 
 
Figure 3b 
 
 
 
 
 
 
 
 
 
 
 
 
In-vivo Animal Model Data 
As part of a research project sponsored by the U.S. Department of Defense, we tested the ability 
of early azithromycin treatment, with or without subsequent additional antibiotics, to reduce Pa 
infection in cutaneous thermal injury (i.e., burn wound)17.   Pa grows as a biofilm in the presence 
of exuberant neutrophilic inflammation in both burn wound infections and CF lung disease21-23. 
Tobramycin alone effectively reduced Pa infection at the wound site and systemic spread to the 
lung (Figure 4a). As predicted, azithromycin had additive antibacterial effects when combined 
with subsequent ciprofloxacin treatment.  However, counter to our hypothesis, we found that the 
burden of Pa infection both at the wound site and systemically (lung) greatly increased when 
azithromycin treatment was followed by tobramycin (Figure 4b). Infection with combined 
azithromycin and tobramycin was no better than normal saline-treated control. 


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Figure 4a 
 
       Wound Site 
     Lung   
 
 
 
 
                
 
  
 
 
 
 
 
 
Figure 4b 
     Wound Site 
 
 
 
 
Lung 
 
 
 
 
 
 
 
 
 
We then conducted follow up studies using a fibrin-based plug model to retain a CF clinical 
strain of Pa within the airways of mice overexpressing the epithelial sodium channel (ENaC). 
The transgenic ENaC mice, despite normal CFTR, model airway dehydration and chronic 
neutrophilic bronchitis present in human CF patients. In this experiment, animals were treated 
with azithromycin and/or tobramycin together and at the same time for 48 hours prior to tissue 
specimen collection (Figure 4c). We observed that azithromycin reduced the ability of systemic 
tobramycin to kill Pa in the lung of these animals (unpublished).  
Figure 4c 
 
 
 
 
 
 
 


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Clinical Trials Data 
We have analyzed the concomitant use of azithromycin in two CF clinical trials testing inhaled 
antibiotic therapy in CF subjects with chronic Pa airway infection. One is the active comparator 
study of inhaled tobramycin and inhaled aztreonam published in 20127.  The other is the AIR-
CF2 study comparing twice daily vs. three times daily inhaled aztreonam lysine, following a 4-
week run-in period with inhaled tobramycin24. In both studies, we observe that subjects reporting 
concomitant use of chronic oral azithromycin have little improvement in clinical outcome 
measures while receiving inhaled tobramycin. Subjects without azithromycin use appear to 
respond similarly to inhaled tobramycin or inhaled aztreonam lysine. Azithromycin use does not 
appear to significantly alter the response to inhaled aztreonam lysine in these trials. This pattern 
of selective drug interaction between azithromycin and an inhaled aminoglycoside is consistent 
across multiple related outcome measures. In these studies, the mean age of subjects is 
approximately 25 years, mean FEV1 is approximately 55% predicted, and over 70% of enrolled 
subjects reported azithromycin as a concomitant medication. 
Active Comparator Trial 
Subjects randomized to inhaled tobramycin show a significant different change in FEV1% over 
one cycle (Figure 5a) and three cycles (Figure 5b) of inhaled antibiotics based on azithromycin 
use.  Change in FEV1% in subjects randomized to inhaled aztreonam lysine was not significantly 
affected by azithromycin use. Users of azithromycin failed to reach a clinically significant 
change in self-reported quality of life over four weeks of inhaled tobramycin based on the CFQ-
R respiratory symptom scale (Figure 5c) and experienced greater need for additional intravenous 
or inhaled antibiotic therapy (Figure 5d). Full analyses of azithromycin use in this study have 
been published19. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
Figure 5a 
Figure 5b 
Figure 5c 
Figure 5d 


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AIR-CF2 Clinical Trial 
During the 4-week run-in period with inhaled tobramycin, subjects with concomitant 
azithromycin use had lesser improvement in FEV1 (Figures 6a and 6b). Immediately after 
inhaled tobramycin use, subjects received inhaled aztreonam lysine. Users of azithromycin had 
significantly greater improvement in FEV1 with the non-aminoglycoside, aztreonam, than during 
the run-in period with tobramycin. Subjects without azithromycin use had approximately 4% 
relative increase in FEV1 (liters) during both the tobramycin and subsequent aztreonam lysine 
periods of this study. Self-reported quality of life, again based on the change in CFQR-RSS, was 
also similarly impacted by azithromycin use (Figure 6c).   
Figure 6a 
 
 
     Figure 6b  
 
 
 
 
 
 
 
 
 
 
 
2 
STUDY RATIONALE 
If our hypotheses are appropriately tested and proven correct, then current practice 
recommendations for tens of thousands of patients with CF worldwide may be altered.  Based on 
the CF registry data, we estimate there are >10,000 patients in the US currently prescribed 
azithromycin and inhaled tobramycin.  Over a lifetime, over 50% of patients will meet the 
clinical criteria to be prescribed these two medications as chronic therapy.  Additional concerns 
extend to the use of intravenous (IV) tobramycin, which is selected twice as often as any other 
anti-pseudomonal drug for CF pulmonary exacerbations25. Impact of azithromycin on IV 
aminoglycosides is beyond the scope of this project but demonstrate broader implications for our 
research.  There are sizable financial impacts related to the cost of these medications and 
outcomes related to decline in lung function (e.g., pulmonary exacerbations, quality of life, and 
survival).  
Taken together, the data summarized above provide strong evidence that a drug-drug interaction 
may be present in current CF care recommendations.  However, there is obvious risk for 
confounding by indication with azithromycin use when analyzing clinical data retrospectively.  
Reported baseline characteristics are similar between users and non-users of azithromycin in 
these data, but multiple recognized and unrecognized variables that may contribute to pulmonary 
decline are not accounted for.  Therefore, a prospective study to both control for such 
confounders and intentionally monitor drug use is needed. 
Our primary and secondary outcomes focus on relative change in FEV1 (liters) and self-reported, 
disease related quality of life. Additional information, such as comparison with alternative 
inhaled antibiotics or the effect on pulmonary exacerbations, is viewed as important but would 
Figure 6c 


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require a much larger study. The planned design will allow us to test the primary hypothesis of 
an adverse drug interaction between azithromycin and inhaled tobramycin. It may be that both 
agents, when used without the other, are beneficial but that the combination is disadvantageous. 
If our theory is proven through this study, then these data can be used to justify and design 
additional research to address other important and related questions. 
2.1 
Risk / Benefit Assessment 
No experimental or new medications are being introduced to subjects during this study.  
Removal of chronic azithromycin may decrease lung function or increase the rate of pulmonary 
exacerbation, based on prior studies of azithromycin in similar patients10,26.  Our preliminary 
data does not support this concern and suggest that removing azithromycin may be protective in 
the majority of subjects also using inhaled tobramycin.  This includes better clinical outcomes in 
lung function (FEV1), patient reported quality of life, and time to need additional antibiotics19.  
However, a withdrawal study of either medication has never been reported and our preliminary 
data on lung function may not fully predict the risk of pulmonary exacerbation.  Subjects 
experiencing a pulmonary exacerbation will be treated but will not be removed from the study. 
Identifying an undesirable drug-drug interaction pertinent to over 50% of US patients with CF 
has clear and important safety and efficacy implications.  Given that both of these medications 
benefit from strong support in US consensus guidelines, answering this question is a high 
priority. 
Recent reports raise concern about potential proarrhythmic cardiotoxicity with oral azithromycin 
treatment in non-CF populations27.  Patients with CF account for a significant portion of chronic 
azithromycin use in the US and cardiac arrhythmias have not been linked to this therapy.  
Similarly, the relative risk of cardiovascular death attributable to azithromycin was reported as 
<1 per 100,000 antibiotic courses in low risk patients27.  There are approximately 30,000 CF 
patients in the entire US, and a repeat study found no increased risk in younger, lower risk adult 
populations28. However, this study provides an opportunity to analyze electrocardiograms 
(ECGs), focusing on any effect on QTc interval, in a group of CF subjects both on and off of 
azithromycin.   
3 
STUDY OBJECTIVES 
3.1 
Primary Objective 
The primary objective of this study is to determine if azithromycin impairs the previously-
recognized clinical benefits of inhaled tobramycin by comparing changes in pulmonary function 
as measured by FEV1 between subjects randomized to azithromycin versus placebo. 
3.2 
Secondary Objectives 
The secondary objectives for the randomized period are to: 
o Compare changes in patient-reported quality of life between subjects randomized to 
azithromycin versus placebo  
The secondary exploratory objectives for the randomized period are to: 
o Compare the safety profile between subjects randomized to azithromycin versus placebo.  


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o Compare changes in additional spirometry measures, bacterial density, and weight 
between subjects randomized to azithromycin versus placebo  
o Compare rates of pulmonary exacerbations, hospitalizations, and acute antibiotic usage 
between subjects randomized to azithromycin versus placebo  
The objectives for those continuing in the open-label extension: 
o Among those randomized to azithromycin and remaining on azithromycin, obtain 
additional data to determine the long term effect of azithromycin on clinical outcomes   
o Among those randomized to placebo and switching to azithromycin, compare differences 
in clinical outcomes observed during the randomized and open-label periods 
4 
STUDY DESIGN 
4.1 
Study Overview 
This is a prospective, randomized, placebo-controlled, double-blinded study of azithromycin in 
subjects with chronic Pa airway infection using inhaled tobramycin.  Subjects who have received 
two (2) or more cycles of inhaled tobramycin within the 24 weeks prior to enrollment will be 
recruited into the study.  This study will investigate whether azithromycin is associated with 
poorer clinical and microbiologic outcomes as compared to placebo during concurrent 
administration of inhaled tobramycin.   
Approximately 120 eligible subjects will be enrolled and randomized to either azithromycin or 
placebo at Visit 1, approximately 14 days prior to the start day of their next planned 28-day 
nebulized solution or dry powder tobramycin (TISP) cycle.  Both tobramycin inhalation solution 
(TIS) and tobramycin inhalation powder (TIP) will be allowed, based on clinical prescription.  
Tobramycin solution should be nebulized with an approved nebulizer and air compressor. 
Subjects will be randomized in a 1:1 fashion to azithromycin (500 mg three times per week) or 
matched placebo.  Randomization will be stratified by FEV1 % predicted (25%-50%, >50%-75%, 
>75%), chronic oral azithromycin use for the past 30 days, inhaled tobramycin formulation (TIS 
or TIP), and site.  Between Visit 1 (Day -14) and Visit 2 (Day 0), a two-week run-in period will 
be used to begin administration of either azithromycin or placebo.   Among those randomized to 
azithromycin, the 2-week run-in period will be used to initiate azithromycin and standardize 
uptake prior to the start of the next TISP cycle.  Among those randomized to placebo, the run-in 
period will be used as a standardized washout prior to the start of the next TISP cycle.  Subjects 
will begin TISP at Visit 2 in addition to their continued dosing of randomized study drug 
treatment (azithromycin or placebo). Subjects will continue both TISP and study drug dosing for 
28 days (up until Visit 3), which corresponds with the end of a clinically prescribed 4-week cycle 
of TISP.   
Subjects completing the study through Visit 3 will be offered participation and consent to an 8-
week open-label extension period during which azithromycin will be provided.  During the open-
label period, subjects will be instructed to remain off of TISP for the first 4-week period, 
followed by a 4-week period of TISP.  
The total duration of the study is expected to be approximately 33.5 months: 30 months for 
subject recruitment and 3.5 months for the final subject enrolled to complete the study (Figure 
7). 


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Figure 7.  Study Schematic 
 
A follow up safety visit is not necessary for this study as it does not expose subjects to new or 
investigational products.  
5 
CRITERIA FOR EVALUATION 
5.1 
Primary Endpoint 
The primary endpoint in the study is the difference between the azithromycin and placebo 
treatment groups in the relative change in FEV1 (liters) from randomization (Visit 1) to Visit 3.   
5.2 
Secondary Endpoints 
Randomized Period 
Secondary Endpoints: 
• Difference between the azithromycin and placebo treatment groups in the relative change in 
FEV1(liters) during administration of TISP from Visit 2 to Visit 3. 
• Difference between the azithromycin and placebo treatment groups in the change from Visit 
1 to Visit 3 in the Cystic Fibrosis Respiratory Symptom Diary (CFRSD) - Chronic 
Respiratory Infection Symptom Score (CRISS©)  
• Difference between the azithromycin and placebo treatment groups in the change from Visit 
1 to Visit 3 in the scales derived from the CFQ-R  
 
Exploratory Secondary Endpoints: 
• Difference in adverse event rates and rates of abnormal QTc parameters from Visit 1 through 
Visit 3 between the azithromycin and placebo treatment groups  
• Difference in the proportion of subjects hospitalized from Visit 1 through Visit 3 between the 
azithromycin and placebo treatment groups Difference in the proportion of subjects 


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prescribed acute oral, inhaled and IV antibiotics from Visit 1 through Visit 3 between the 
azithromycin and placebo treatment groups  
• Difference in the proportion of subjects experiencing a protocol-defined pulmonary 
exacerbation requiring antibiotic therapy from Visit 1 through Visit 3 between the 
azithromycin and placebo treatment groups  
• Difference between the azithromycin and placebo treatment groups in the absolute change 
from Visit 1 to Visit 3 and Visit 2 to Visit 3 in FEV1 (liters and % predicted), absolute and 
relative change in FVC (liters and % predicted), and absolute and relative change in FEF25-
75%  
• Difference between the azithromycin and placebo treatment groups in the change from Visit 
1 to Visit 3 in weight  
• Difference in the change from Visit 1 to Visit 3 in sputum Pa bacterial density between the 
azithromycin and placebo treatment groups  
 
Open-Label Period 
• Among those randomized to azithromycin and remaining on azithromycin, longitudinal 
changes and/or rates in all clinical outcomes across  the randomized and open-label periods 
• Among those randomized to placebo and switching to azithromycin, differences in all 
clinical outcomes between the randomized and open-label periods 
6 
SUBJECT SELECTION 
6.1 
Study Population 
Subjects with a diagnosis of CF who meet all of the inclusion and none of the exclusion criteria 
will be eligible for enrollment in this study.   
6.2 
Inclusion Criteria 
Inclusion Criteria for Randomized Period: 
1. Male or female ≥ 12 years of age at Visit 1 
2. Documentation of a CF diagnosis as evidenced by one or more clinical features consistent 
with the CF phenotype and one or more of the following criteria: 
o Sweat chloride equal to or greater than 60 mEq/L by quantitative pilocarpine 
iontophoresis test (QPIT)  
o Two mutations in the CFTR gene believed to be disease causing in the opinion of the site 
investigator 
o Abnormal nasal potential difference (change in NPD in response to a low chloride 
solution and isoproterenol of less polarizing than -7 mV) 
3. Written informed consent (and assent when applicable) obtained from subject or subject’s 
legal representative 
4. Two or more respiratory cultures (sputum, OP swab, BAL sample) growing Pa collected 
within the 12 months prior to randomization, at least 1 month apart, with at least one 
collected in the 6 months prior to randomization  
5. FEV1% predicted between 25-100% at Visit 1 


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6. Off TISP and other inhaled anti-pseudomonal antibiotics for at least two weeks at 
randomization 
7. Willingness  to begin the next course of TISP at the scheduled Visit 2  
8. Use of at least 2 cycles of TISP within 24 weeks prior to Visit 1 
9. Ability to swallow capsules (similar in size to pancreatic enzyme capsules) 
10. Most recent LFTs less than 4x ULN.  Must be obtained within 12 months prior to Visit 1   
11. Current azithromycin use at Visit 1 or prior chronic azithromycin use defined as four or more 
consecutive weeks. Subjects do not have to be using chronic oral azithromycin at Visit 1 
12. Stable clinical status with no significant change in medication or airway clearance routine for 
four weeks prior to Visit 1, as determined by site investigator 
Inclusion Criteria for Open-Label Period: 
1. Completion of the randomized, placebo-controlled period (up through Visit 3) 
2. Written informed consent (and assent when applicable) obtained from subject or subject’s 
legal representative  
3. Ability for subject to comply with the requirements of the study 
4. Willingness to begin the next course of TISP at the scheduled Visit 4 
5. Clinically stable at Visit 3 as assessed by the site investigator 
6.3 
Exclusion Criteria 
Exclusion Criteria for Randomized Period: 
1. Weight < 40 kg at Visit 1 
2. For women of child-bearing potential:  
a. positive pregnancy test at Visit 1 or 
b. lactating or 
c. unwilling to practice a medically acceptable form of contraception (acceptable forms of 
contraception: abstinence, hormonal birth control, intrauterine device, or barrier method 
plus a spermicidal agent), unless surgically sterilized or postmenopausal during the study  
3. Inability to perform reproducible spirometry 
4. Inability or unwillingness to cycle off TISP for one 4-week period 
5. Respiratory culture with Burkholderia cepacia complex species within the 24 months prior to 
Visit 1 
6. Respiratory culture with nontuberculous mycobacteria (NTM) within 18 months prior to 
Visit 1 
7. Use of IV or oral anti-pseudomonal antibiotics within four weeks prior to Visit 1 (other than 
azithromycin) 
8. Use of an investigational therapy within four weeks prior to Visit 1  
9. History of unresolved, abnormal neutropenia (ANC ≤ 1000 cells/mm3) 
10. Current use of systemic corticosteroids equivalent to a daily dose more than 10 mg 
prednisone at Visit 1 


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11. Current use of nelfinavir, warfarin, haloperidol, or methadone at Visit 1  
12. Initiation of approved CFTR modulators less than 30 days prior to Visit 1 
13. ECG abnormalities identified at Visit 1 that require prompt, further medical evaluation or 
QTc interval >480 msec for males and >486 msec for females at Visit 1 
14. Any other condition that, in the opinion of the site investigator/designee, would preclude 
informed consent or assent, make study participation unsafe, complicate interpretation of 
study outcome data, or otherwise interfere with achieving the study objectives 
 
Exclusion Criteria for Open-Label Period: 
1. Weight < 40 kg at Visit 3 
2. For women of child bearing potential: unwilling to practice a medically acceptable form of 
contraception (acceptable forms of contraception: abstinence, hormonal birth control, 
intrauterine device, or barrier method plus a spermicidal agent), unless surgically sterilized or 
postmenopausal during the study  
3. Identified respiratory culture positive for NTM or Burkholderia cepacia complex species 
during randomized study period 
4. Use of an investigational therapy at Visit 3 
5. Current use of systemic corticosteroids equivalent to a daily dose more than 10 mg 
prednisone  
6. Current use of nelfinavir, warfarin, haloperidol, or methadone  
7. Any other condition that, in the opinion of the site investigator/designee, would preclude 
informed consent or assent, make study participation unsafe, complicate interpretation of 
study outcome data, or otherwise interfere with achieving the study objectives 
6.4 
Study Specific Tolerance for Inclusion/Exclusion Criteria 
Subjects who fail to meet one or more of the inclusion criteria or who meet any of the exclusion 
criteria will not be enrolled in this study. Waivers of any of the above study entry criteria will not 
be granted. 
6.5 
Screen Fail Criteria 
Any consented patient who is excluded from the study before randomization is considered a 
screen failure. All screen failures must be documented with the reason for the screen failure 
adequately stated. If a subject screen fails prior to randomization, they can be rescreened once if 
the site staff feels they meet eligibility criteria and following confirmation from the Sponsor-
Investigator or designee.  Rescreened subjects are required to complete all screening procedures 
(i.e., test results from previous screenings cannot be used).    
7 
CONCURRENT MEDICATIONS 
All subjects should be maintained on the same medications throughout the entire study period, as 
medically feasible, with no introduction of new chronic therapies. 


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7.1 
Allowed Medications and Treatments 
For both the randomized and open-label periods, standard therapy for CF is allowed except for 
treatments noted in the conditionally allowed and prohibited medications sections below.  
Ongoing chronic treatment (>30 days prior to Visit 1) with inhaled dornase alpha, hypertonic 
saline, short and long acting bronchodilators, FDA-approved CFTR modulators, high dose 
ibuprofen, low-dose inhaled or systemic steroids and airway clearance is allowed.   
7.2 
Conditionally Allowed Medications and Treatments 
Acute treatment with drugs categorized as known to prolong QT interval is allowed according to 
the following:  
• 
For drugs commonly used to treat CF patients (e.g. ciprofloxacin, levofloxacin, 
moxifloxacin, fluconazole, propofol, sevoflurane, ondansetron), study drug (azithromycin 
or placebo) or open-label azithromycin does not need to be stopped.   
• 
For all other drugs categorized as known to prolong QT interval, acute use is allowed but 
study drug (azithromycin or placebo) or open-label azithromycin must be temporarily 
stopped during use of these medications.  After acute treatment is completed, subjects 
should re-start study drug or open-label azithromycin on the next scheduled treatment day.  
• 
Ongoing chronic treatment (>30 days prior to Visit 1) with antidepressant medications 
citalopram and escitalopram is allowed without affecting study participation if: 
o 
The subject has been using both chronic oral azithromycin AND citalopram (or 
escitalopram) consistently for greater than 30 days at Visit 1  
AND 
o 
The Visit 1 ECG demonstrates QTc within the normal limits as defined by the protocol 
Drugs known to prolong QT interval are described as follows: “Substantial evidence supports the 
conclusion that these drugs prolong the QT interval AND are clearly associated with a risk of 
torsades de pointes (TdP), even when taken as directed in official labeling”, and listed on the 
CredibleMeds® Website (Composite List of All QT Drugs under the category “Known Risk of 
TdP”). 
Acute use of macrolide antibiotics may be required for certain infections and is allowed but also 
requires temporarily stopping the study drug or open-label azithromycin. The study drug or 
open-label azithromycin should be restarted on the next scheduled day following completion of 
the prescribed macrolide antibiotic. 
Treatment for pulmonary exacerbations as required for acute care is allowed except for 
treatments noted in the prohibited medications section below.  Physicians are encouraged to 
prescribe acute antibiotic therapy and initiate or increase the dose of acute systemic 
corticosteroids (defined as less than 10 days) only in the presence of increased symptoms 
suggesting a pulmonary exacerbation. 


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7.3 
Prohibited Medications and Treatments 
For both the randomized and open-label periods, the following medications are prohibited (for 
the randomized period, between Visit 1 through Visit 3; for the open-label period, between Visit 
3 and Visit 5).   
o Investigational therapies  
o Chronic inhaled antibiotics other than cycled TISP (e.g., Cayston®, colistin). Chronic 
treatment is defined as inhaled antibiotics prescribed as a maintenance therapy and not 
used temporarily to treat a pulmonary exacerbation.  
o Increase in chronic systemic corticosteroid dose beyond prednisone equivalent of 10 mg 
per day, or initiation of chronic systemic (oral or intravenous) corticosteroids at any dose. 
Chronic use is defined as greater than 10 days continuous use.   
o New or increase in ibuprofen dose of greater than 800 mg total dose per 24 hours for 
more than 5 days 
o Nelfinavir, warfarin, haloperidol, or methadone 
7.4 
Change in Medications or Therapies 
Subjects should receive all medication as clinically necessary, regardless of what impact this 
may have on the study. 
Maintaining a stable therapeutic regimen between Visit 1 and Visit 5 is desirable to minimize the 
risk of confounding. Unless otherwise medically indicated, subjects not using these therapies 
should not be started on them after Visit 1 or at any time during the trial and subjects that have 
been using them chronically should be strongly encouraged to continue them throughout the 
entire study period (through Visit 5).   
8 
STUDY TREATMENTS 
8.1 
Randomization 
At Visit 1, eligible subjects will be enrolled and randomized to study drug.  Study personnel at 
the investigative site will use the Medidata® Rave and Balance™ systems to randomize each 
subject.  An adaptive randomization (dynamic allocation based on minimization31) will be 
employed. Subjects will be randomly assigned in a 1:1 ratio to azithromycin (500 mg three times 
per week) or matched placebo. Randomization will be stratified by FEV1 % predicted (25%-50%, 
>50%-75%, >75%), chronic oral azithromycin use for the past 30 days, inhaled tobramycin 
formulation (TIS or TIP), and site. The dynamic allocation algorithm seeks to optimize 
randomization balance by minimizing a weighted average of the marginal imbalance32 of  
treatment allocation for each factor and for the study overall.  A random element is added to the 
otherwise deterministic minimization algorithm to reduce allocation predictability by using a 
biased coin33 to include a chance of allocation to a treatment arm other than the arm that 
optimizes balance.  After data collection at Visit 1, subjects will be randomized to one of the two 
treatment groups.  To randomize a new subject, study personnel at the investigative site will 
complete the electronic CRF in the Medidata Rave system required to provide the stratification 
information and the subject will then be assigned to a treatment group. 


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8.2 
Blinding 
Study treatment (azithromycin or placebo) will be assigned in a double-blinded fashion.  
Subjects and site research staff will not know the treatment assigned, with the exception of the 
dispensing site pharmacist or designee and designated TDNCC personnel.   
The following study procedures will be in place to ensure double-blind administration of study 
treatments:   
 Randomization assignments will be stored in a secure database and appropriately 
protected and backed up   
 Access to the randomization code will be strictly controlled and limited to designated 
TDNCC study personnel  
 Test and control treatments will be manufactured to be identical in appearance and  taste-
matched 
 Packaging and labeling of test and control treatments will be identical  
The study blind will be broken upon completion of the clinical study and after the study database 
has been locked and study results released. The site investigators will be provided with each 
subject’s treatment assignment following completion of data analysis. 
8.3 
Unblinding Procedures 
During the study, the blind may be broken for individual subjects in emergencies when 
knowledge of the subject’s treatment group is necessary for further patient management or when 
the event meets the FDA expedited reporting requirements as a suspected adverse reaction that is 
serious and unexpected (21 CFR 312.32(c)(1)(i)).  In those cases, knowledge of the treatment 
received is necessary for interpreting the event. Individual SAEs that are unexpected, deemed 
related to study drug, and confirmed by the Medical Monitor will be forwarded to the DSMB 
Chair within 7 business days. Additional information or data summaries may also be requested 
by the DSMB at this time.  
If the blind is broken and the subject is on study drug, a Safety Report will be sent to all 
participating investigators. Emergency unblinding procedures are provided in the Study Manual.   
Refer to protocol section 11.2.1 Serious Adverse Experience Reporting. 
8.4 
Formulation of Test and Control Products 
8.4.1 Formulation of Test Product 
Azithromycin 500 mg capsules will be provided.  Over-encapsulated azithromycin tablets 
capsules will be provided during the randomized period of the study.   
During the open-label extension period, commercially-available azithromycin 500 mg capsules 
(without over-encapsulation) will be used. 
8.4.2 Formulation of Control Product 
Placebo capsules using the same materials used for azithromycin over-encapsulation will be 
provided. The placebo will be appearance-matched.  


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8.4.3 Packaging and Labeling 
Capsules for the randomized period of the study will be provided in labeled bottles.  A six-week 
supply plus one extra (19) of capsules will be included in each bottle.  One bottle will be 
supplied at Visit 1. 
If the subject enrolls in the open-label period, commercially-available azithromycin will be 
provided by the site pharmacy. 
8.5 
Supply of Study Drug to the Site 
Study drug for the randomized period will be shipped to each site pharmacy. The initial study 
drug shipment will be shipped after site approval to enroll (i.e., all required regulatory 
documentation has been received by the TDNCC and a contract has been executed). Subsequent 
study drug shipments will be made as needed. 
For the open-label period, sites will obtain their own supplies of commercially-available 
azithromycin capsules.  
8.5.1 Dosage/Dosage Regimen 
Randomized study drug (azithromycin or placebo) and open-label azithromycin will be taken by 
mouth three times weekly during the following study periods: 
• Treatment V1-V2: azithromycin or placebo without TISP: 14 days  
• Treatment V2-V3: azithromycin or placebo with TISP: 28 days 
Subjects participating in the optional open-label extension: 
• Treatment V3-V4: azithromycin without TISP: 28 days  
• Treatment V4-V5: azithromycin with TISP 28 days 
8.5.2 Study Drug Preparation and Dispensing 
Appropriately trained site personnel will be responsible for dispensing study drug (includes the 
randomized period and open-label period).  Study drug shall be dispensed and labeled in 
accordance with federal and local state Board of Pharmacy regulations.  Capsules will be 
provided in labeled bottles from the study pharmacy with instructions to take one capsule three 
times weekly.  
If the subject enrolls in the open-label period, an 8-week supply plus one extra (25) of 
commercially-available azithromycin tablets will be dispensed at Visit 3.  
8.5.3 Administration Instructions  
Study drug (azithromycin or placebo and open-label azithromycin) should be taken by mouth 
with food and pancreatic enzymes (if clinically prescribed).   
It is recommended that the first dose be taken at the Visit 1 to ensure that the subject is able to 
swallow the capsule.  


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8.5.4 
Storage  
Study drug (azithromycin or placebo and open-label azithromycin) should be stored by the study 
site at controlled room temperature, 15 to 30 ºC (59 to 86 ºF) in a secure area under restricted 
access. If the temperature of study drug storage in the clinic/pharmacy exceeds or falls below this 
range, this should be reported to the Sponsor or designee.  
Subjects will be instructed to store study drug (azithromycin or placebo and open-label 
azithromycin) in original packaging at room temperature.   
8.6 
Dose Modifications 
8.6.1 Due to Toxicity 
If a study subject has moderate to severe toxicity (refer to Study Manual), the following schedule 
for dosage adjustment can be made at the discretion of the site investigator: 
• If a study subject receiving study drug three times weekly (TIW) experiences drug-
related toxicity, the dosing INTERVAL of the study drug will be extended to two times 
weekly (BIW; e.g., Monday and Thursday) 
• If a study subject does not tolerate receiving study drug BIW, the subject should be 
permanently discontinued from study drug due to intolerance. 
Dose can return to TIW at the discretion of the site investigator.  
8.6.2 Due to Treatment with Antibiotics – Temporary Discontinuation of Study Drug  
Study drug should be temporarily discontinued for subjects prescribed macrolide antibiotics. 
Study drug may be temporarily discontinued at the discretion of the treating clinician during 
acute treatment with other medications (e.g., additional antibiotics or drugs believed to increase 
QT prolongation).  
Regardless of study drug use, subjects should be encouraged to complete all study visits. 
8.6.3 Missed Doses 
Missed doses may be made up as long as they are not taken within 24 hours of the next 
scheduled dose. 
8.7 
Study Drug Accountability 
Study drug (azithromycin or placebo and open-label azithromycin) dispensed to subjects will be 
counted as noted in the Schedule of Events.  Study drug distribution will be recorded, including 
study drug identifier (randomized period), date, quantity, and subject ID. 
8.8 
Measures of Treatment Compliance 
Subject daily diaries recording study drug and TISP use will be reviewed and the number of 
doses taken will be recorded throughout the study.  Subjects will be asked to bring study drug 
bottles and the diary to each study visit and the number of study drug capsules remaining will be 
compared with the number ideally taken.  Subjects will be questioned at each visit about missed 
or extra doses of study drug, open-label azithromycin, and/or TISP.  Treatment compliance for 


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study drug will be based on the number of doses reported taken by the subject, with 
consideration of drug returns. 
8.9 
Standard of Care Treatment with TISP 
Subjects will not be allowed to change from inhaled tobramycin solution to inhaled tobramycin 
powder (i.e., TOBI® Podhaler) or vice versa while enrolled in the study.  Either tobramycin 
delivery mechanism will be allowed but subjects must be stable on one delivery mechanism, 
either solution or dry powder, for one or more on/off cycles (i.e., 8 weeks) prior to Visit 1.   
8.9.1 Administration Instructions 
If the subject is using inhaled tobramycin solution, inhaled tobramycin will be administered as 
per the manufacturer’s instructions (e.g., 300 mg in 4 or 5 mL solution, nebulized and inhaled 
twice daily using a device approved by the drug manufacturer). Tobramycin solution should be 
nebulized with an approved nebulizer and air compressor without mixing or diluting with other 
solutions, according to manufacturer instructions.   
If the subject is using inhaled tobramycin powder, the TOBI Podhaler will be administered as per 
the manufacturer’s instructions (e.g., 4 dry powder capsules inhaled twice daily using the 
supplied device).  
Ideally, tobramycin should be inhaled twice daily following airway clearance.  Airway clearance 
includes any inhaled bronchodilators, mucolytics (e.g., DNase, hypertonic saline), and 
mechanical clearance devices (e.g., Vest, acapella, hand percussion).  If airway clearance is not 
clinically recommended at least twice daily, then tobramycin should be inhaled following the 
single airway clearance session and again each day without airway clearance. 
Tobramycin should be stored refrigerated per manufacturer’s instructions.   
9 
STUDY PROCEDURES AND GUIDELINES 
The procedures described below will be performed at the visits noted in the Schedule of Events 
(Appendix 1) and in Section 10. 
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. 
9.1 
Clinical Assessments 
9.1.1 Concomitant Medications 
All concomitant medication and concurrent therapies will be documented as noted in the 
Schedule of Events.  Dose, route, unit, frequency of administration, indication for administration 
and dates of medication will be captured.   
9.1.2 Demographics and CFF Registry ID 
Demographic information (date of birth, sex, race) will be recorded at Visit1. CF Registry ID 
number will be recorded for participating CF subjects who provide optional consent. 


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9.1.3 Medical History  
Relevant medical history, including history of current disease, other pertinent respiratory history, 
and information regarding underlying diseases will be recorded.  Previous use of azithromycin 
and inhaled tobramycin will also be collected.  
9.1.4 CF Diagnosis 
Diagnosis date and sweat chloride test, CF genotype, and transepithelial nasal potential 
difference test result will be recorded as available.  
9.1.5 Physical Examination 
A complete or abbreviated physical examination will be performed by a licensed professional 
(MD, NP, RN, PA) as noted in the Schedule of Events.  The abbreviated exam includes 
respiratory, cardiovascular, and abdominal assessments.   
After the initial exam at Visit 1, new clinically significant, abnormal physical exam findings 
must be documented as AEs.  
9.1.6 Weight and Height   
Weight will be measured on the same scale and recorded as noted in the Schedule of Events. 
Adults and children may remain in clothes (without shoes). A standing height will be measured 
and recorded as noted in the Schedule of Events.   
Note that accurate height measurements will significantly improve the data quality, as this is 
incorporated into equations used to derive the FEV1% of predicted based on a reference 
population. 
9.1.7 Vital Signs 
Resting (minimum of 5 minutes) measurements of body temperature, blood pressure, pulse and 
respirations will be performed and recorded as noted in the Schedule of Events. 
9.1.8 Spirometry 
Spirometry will be performed at as noted in the Schedule of Events and in accordance with the 
current American Thoracic Society recommendations for the performance and interpretation of 
tests.  
Subjects should be encouraged to perform the same airway clearance routine and inhaled 
bronchodilators prior to each study visit.  Additional instructions for study personnel will be 
provided in the Study Manual.  
9.1.9 Respiratory Culture 
If the patient does not have sufficient culture history to assess eligibility, a respiratory culture 
may be collected prior to randomization. If the respiratory culture is positive, the remaining Visit 
1 procedures and randomization will be conducted at a subsequent visit.    


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9.1.10 Subject Questionnaire: CFRSD-CRISS 
The subjects will be given a CF specific symptom diary called the CFRSD-CRISS as noted in the 
Schedule of Events. This diary includes 8 questions and takes less than 5 minutes to complete. 
The CFRSD-CRISS should be administered at the beginning of each visit. 
9.1.11 Subject Questionnaire: Cystic Fibrosis Questionnaire-Revised (CFQ-R) 
The CFQ-R is a patient reported quality of life instrument, regarding symptoms and mood over 
the preceding 2 weeks. The age appropriate version of the CFQ-R will be completed at the 
beginning of each visit as noted in the Schedule of Events by the subject. Completion should 
take less than 5 minutes.   
9.1.12 Subject Diary 
Subjects will be requested to complete a daily diary to document daily dose of study drug 
treatments and TISP treatments, and to record changes in concomitant medications and 
symptoms through the end of the study. The diary will be dispensed and reviewed as noted in the 
Schedule of Events. 
9.1.13 Electrocardiogram (ECG)  
Standard 12-lead ECG tracing will be obtained as noted in the Schedule of Events. ECG is only 
needed for an acute visit if the subject has a cardiovascular-related AE or will no longer be 
participating in the study. 
Testing will be conducted and reviewed at the site by trained personnel with experience 
interpreting electrocardiograms.  Any test results of clinical concern, should be reported to the 
Medical Monitor to determine follow up actions as described below.   
Testing will be performed using an ECG machine that automatically calculates the heart rate and 
measures PR, QRS, QT, and QTc intervals.  All tests will be measured in Lead II. 
Abnormal results at the time of follow-up testing are defined as a QTc >500 msec, or an increase 
in QTc of ≥60 msec.  It is recommended that testing be repeated after 10 minutes for any ECGs 
that meet the protocol definition for abnormal.  If test results are confirmed, subjects will be 
instructed to stop study drug or open-label azithromycin and the site investigator will continue to 
observe the subject for clinical signs of arrhythmia (specifically torsades de pointes).   
The ECG tracing will be collected for additional safety review.   
9.1.14 Signs and Symptoms Evaluation  
When a subject initiates a new IV, oral or inhaled antibiotic, the presence of specific signs and 
symptoms will be assessed and documented.  These data will be used to determine the incidence 
of a protocol defined pulmonary exacerbation based on the definition in Appendix 2.  
9.1.15 Adverse Events 
Information regarding occurrence of AEs will be captured throughout each subject’s study 
participation, starting after the first dose of study drug and ending once the subject has 


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terminated from the study. Duration (start and stop dates), grade, seriousness, outcome, treatment 
and relation to study participation will be recorded on the CRF. 
9.2 
Clinical Laboratory Measurements  
9.2.1 Pregnancy Test 
Urine or blood (approximately 2 cc) will be collected from females who are of childbearing 
potential for a pregnancy test as noted in the Schedule of Events and tested by the site according 
to site standard procedures.  
9.2.2 Sputum Collection for Microbiological and Host Response Analysis  
Expectorated sputum will be collected from subjects who are able to produce sputum as noted in 
the Schedule of Events.  The samples collected will be stored frozen at -70 to -80ºC at the site 
and batch shipped as instructed by the Therapeutics Development Network Coordinating Center 
(TDNCC).  Instructions for specimen collection, processing, storage and shipping of samples 
will be provided in the Study Laboratory Manual.  Processed aliquots will be banked for future 
analysis.   
10 EVALUATIONS BY VISIT 
Randomized Period 
10.1 Visit 1 – Day -14  
*A respiratory culture may be obtained prior to randomization to confirm eligibility criteria #4.  
If a respiratory culture is needed, the remaining Visit 1 procedures should be completed after 
confirming positive Pa culture results.  
1. 
Review the study with the subject (subject’s legal representative) and obtain written 
informed consent and HIPAA authorization and assent, if appropriate. 
2. 
Assign the subject a unique study number. 
3. 
If there is not a recent respiratory culture available, obtain culture to confirm eligibility:   
• Review culture results. 
• If Pa positive and meets criteria #4, schedule subsequent visit to complete 
remaining Visit 1 procedures. 
• If Pa negative, record as Screen Fail.   
4. 
Review and record previous use of azithromycin and inhaled tobramycin. 
5. 
Record demographics and CFF Registry ID, if consent obtained.   
6. 
Record medical history, including a history of CF diagnosis and date. 
7. 
Record concomitant medications. 
8. 
Administer PRO questionnaires (CFRSD-CRISS and CFQ-R).  
9. 
Perform a complete physical examination. 
10. 
Measure and record height and weight. 
11. 
Obtain and record vital signs. 


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12. 
Perform and record spirometry. 
13. 
Collect blood or urine for pregnancy test (if female of child-bearing potential). 
14. 
Obtain resting ECG. 
15. 
If able to expectorate sputum, collect expectorated sputum.    
16. 
Confirm subject eligibility. 
17. 
Randomize to study drug. 
18. 
Dispense study drug.   
19. 
Review study drug dose and schedule with subject. 
20. 
Provide subject diary and instructions for completion. 
21. 
Remind subject to NOT use inhaled tobramycin between this day and Visit 2.   
22. 
Instruct subject to bring study drug bottle, any remaining capsules, and diary to Visit 2. 
23. 
Schedule subject for Visit 2.   
10.2 Visit 2 - Day 0 (visit window -2/+4 days) 
1. 
Administer PRO questionnaires (CFRSD-CRISS and CFQ-R).  
2. 
Review subject diary.  
3. 
Perform pill count on returned study drug. 
4. 
Record any AEs.  
5. 
Record changes to concomitant medications.  If a new IV, oral or inhaled antibiotic was 
prescribed, ensure that a Signs and Symptoms form was completed.  
6. 
Perform an abbreviated physical examination. 
7. 
Measure and record height and weight. 
8. 
Obtain and record vital signs. 
9. 
Perform and record spirometry. 
10. If able to expectorate sputum, collect expectorated sputum.    
11. Provide subject diary.  
12. Review inhaled tobramycin schedule and remind subject to take TISP between Visits 2 and 
3. 
13. Instruct subject to bring study drug bottle, any remaining capsules, and diary to Visit 3. 
14. Schedule subject for Visit 3.  Visit 3 should coincide with completion of approximately 4 
weeks use of inhaled tobramycin combined with study drug. 
End of Randomized Period and Start of Open-Label Period 
10.3 Visit 3 – Day 28 (visit window -2/+4 days), Week 4 
1. 
Administer PRO questionnaires (CFRSD-CRISS and CFQ-R).  
2. 
Review subject diary.  
3. 
Perform pill count on returned study drug. 


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4. 
Record TISP use. 
5. 
Record any AEs. 
6. 
Record changes to concomitant medications. If a new IV, oral or inhaled antibiotic was 
prescribed, ensure that a Signs and Symptoms form was completed. 
7. 
Perform abbreviated physical examination. 
8. 
Measure and record height and weight. 
9. 
Obtain and record vital signs. 
10. 
Perform and record spirometry. 
11. 
Obtain resting ECG. 
12. If able to expectorate sputum, collect expectorated sputum. 
Visit 3: Additional procedures for subjects enrolling in the open-label extension 
13. 
Assess subject eligibility for open-label extension  
14. 
Review the open-label extension period of the study with the subject (subject’s legal 
representative) and obtain written informed consent and HIPAA authorization and assent, 
if appropriate. 
15. 
Dispense open-label azithromycin.   
16. 
Provide subject diary.   
17. 
Remind subject to NOT use inhaled tobramycin between this day and Visit 4.   
18. 
Instruct to bring the azithromycin bottle, any remaining tablets, and diary to Visit 4. 
19. 
Schedule subject for Visit 4. 
Open-Label Period 
10.4 Visit 4 – Day 56 (visit window +/- 4 days), Open-Label Week 4 
1. 
Administer PRO questionnaires (CFRSD-CRISS and CFQ-R).  
2. 
Review subject diary.  
3. 
Perform pill count on returned azithromycin. 
4. 
Record any AEs.  
5. 
Record changes to concomitant medications. If a new IV, oral or inhaled antibiotic was 
prescribed, ensure that a Signs and Symptoms form was completed. 
6. 
Perform abbreviated physical examination. 
7. 
Measure and record height and weight. 
8. 
Obtain and record vital signs. 
9. 
Perform and record spirometry.  
10. 
If able to expectorate sputum, collect expectorated sputum.  


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11. 
Provide subject diary.  
12. 
Instruct subject to bring the azithromycin bottle, any remaining tablets, and diary to    
Visit 5. 
13. 
Review inhaled tobramycin schedule and remind subject to take TISP between Visits 4 
and 5. 
14. 
Schedule subject for Visit 5. 
10.5 Visit 5 - Day 84 (visit window +/- 4 days), Open-Label Week 8 
1. 
Administer PRO questionnaires (CFRSD-CRISS and CFQ-R  
2. 
Review subject diary.  
3. 
Perform pill count on returned azithromycin. 
4. 
Record TISP use. 
5. 
Record any AEs.  
6. 
Record changes to concomitant medications. If a new IV, oral or inhaled antibiotic was 
prescribed, ensure that a Signs and Symptoms form was completed. 
7. 
Perform abbreviated physical examination. 
8. 
Measure and record height and weight. 
9. 
Obtain and record vital signs. 
10. 
Perform and record spirometry. 
11. 
Obtain resting ECG. 
12. 
If able to expectorate sputum, collect expectorated sputum.  
13. 
Instruct subject that study participation is complete and to use medications according to 
instructions from clinical care providers. 
10.6 Unscheduled* or Early Discontinuation of Study Drug or Study Participation Visit 
*An Unscheduled Visit may be conducted as a study visit when, in the opinion of the site 
investigator, safety follow up is required as a result of a possible study-related procedure or study 
drug-related event.   
1. 
Administer PRO questionnaires (CFRSD-CRISS and CFQ-R).  
2. 
Review subject diary.  
3. 
Perform pill count on returned study drug (if during randomized period) or azithromycin 
(if during open-label period). 
4. 
Record any AEs.  
5. 
Record changes to concomitant medications. If a new IV, oral or inhaled antibiotic was 
prescribed, ensure that a Signs and Symptoms form was completed. 
6. 
Perform complete physical examination. 


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7. 
Measure and record height and weight. 
8. 
Obtain and record vital signs. 
9. 
Perform and record spirometry. 
10. 
Obtain resting ECG, if appropriate (see footnote b in Table for Schedule of Events). 
11. 
If able to expectorate sputum, collect expectorated sputum. 
11 ADVERSE EXPERIENCE REPORTING AND DOCUMENTATION 
11.1 Adverse Events 
An 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 Prescribing or 
Product Information or of greater severity or frequency than expected based on the information 
in the Prescribing or Product Information. 
The site investigator will probe, via discussion with the subject, for the occurrence of AEs during 
each subject visit and record the information in the site’s source documents.  Adverse events will 
be recorded in the subject CRF.   
AE Severity 
The National Cancer Institute’s Common Terminology Criteria for Adverse Events (CTCAE) 
Version 4.0, as modified for CF, 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 Reference Binder.  If the experience is not covered in the modified criteria, the 
guidelines shown in Table 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 1.  AE Severity Grading 
Severity (Toxicity Grade) 
Description 
Mild (1) 
Mild; asymptomatic or mild symptoms; clinical or diagnostic 
observations only; intervention not indicated 
Moderate (2)  
Moderate; minimal, local or noninvasive intervention indicated; 
limiting age-appropriate Instrumental activities of daily living (e.g., 
preparing meals, using the telephone, managing money)  
Severe (3) 
 
Severe or medically significant but not immediately life-threatening; 
hospitalization or prolongation of hospitalization indicated; 
disabling; limiting self-care activities of daily living (e.g., bathing, 
dressing, feeding self, using toilet, taking medications) 
Life-threatening (4) 
Life-threatening consequences; urgent intervention indicated 
Death (5) 
Death related to AE 


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AE Relationship to Study Drug 
The relationship of an AE to the study drug (azithromycin or placebo for the randomized period, 
azithromycin for the open-label period) should be assessed using the following the guidelines in 
Table 2. 
Table 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. 
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 
Study sites will document all SAEs that occur (whether or not related to study drug) on an SAE 
Report Form.  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. 


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All SAE Report Forms will be reviewed by the site investigator and sent to the TDNCC within 
one business day of the site learning of the event.  Sites will send the SAE report by either: 
 Email (scanned copy) to: cfsaesfacsys@seattlechildrens.org 
 TDNCC SAE Fax: (206) 985-3278 
The site will notify the Medical Monitor of additional information or follow-up to an initial SAE 
Report as soon as relevant information is available.  The Medical Monitor may request additional 
information related to the SAE.  Follow-up information is reported on an SAE Report Form. 
In accordance with the standard operating procedures and policies of the local Institutional 
Review Board (IRB), the site investigator will report SAEs to the IRB.   
11.3 Medical Monitoring 
The TDNCC Medical Monitoring Group should be contacted directly at this number to report 
medical concerns or questions regarding safety. 
  (800) 341-0961 
The TDNCC Medical Monitoring Group will serve as the independent Medical Monitors for this 
study.  AEs and SAEs will be collected and organized by the TDNCC and provided to the 
TDNCC Medical Monitoring Group for review in a timely manner. The TDNCC Medical 
Monitoring Group will communicate with the independent DSMB at a predetermined schedule, 
and additionally as warranted. 
12 DISCONTINUATION AND REPLACEMENT OF SUBJECTS 
12.1 Early Permanent Discontinuation of Study Treatment  
A subject may be permanently discontinued from study treatment at any time if the subject, the 
investigator, or the Sponsor-Investigator feels that it is not in the subject’s best interest to 
continue.  The following is a list of possible reasons for early permanent discontinuation of study 
treatment:  
 Subject or subject’s legal representative decision 
 Adverse event, including pulmonary exacerbation  
 Protocol violation  
 Death 
If a subject is discontinued from treatment due to an AE, the subject will be followed and treated 
by the site investigator until the abnormal parameter or symptom has resolved or stabilized.   
All subjects who permanently discontinue study treatment early should come in for an early 
discontinuation of study treatment visit as soon as possible (see Appendix 1) and then should be 
encouraged to complete all remaining scheduled visits and procedures. 
Refer to Section 8.6.2 for temporary discontinuation of study drug.  
12.2 Early Withdrawal of Subjects from the Study 
All subjects are free to withdraw from participation at any time, for any reason, specified or 
unspecified, and without prejudice.  This may include subjects who withdraw from study 


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treatment early and who decline to continue to come in for remaining follow-up visits or it may 
include subjects who completed treatment and decline to come in for remaining follow up visits.   
Reasonable attempts will be made by the investigator to provide a reason for early subject 
withdrawals.  The reason for the subject’s early withdrawal from the study will be specified in 
the subject’s source documents.  Subjects who withdraw early from the study should be 
encouraged to come in for a final early study withdrawal visit (and the procedures to be followed 
would include those for an early discontinuation of study drug visit – see Appendix 1).   
12.3 Replacement of Subjects 
 Subjects who withdraw from the study will not be replaced.   
13 PROTOCOL VIOLATIONS 
A protocol violation occurs when the subject, investigator, or the Sponsor fails to adhere to 
significant protocol requirements affecting the inclusion, exclusion, subject safety and primary 
endpoint criteria.  Protocol violations for this study include, but are not limited to, the following: 
 Failure to meet eligibility criteria 
 Use of a prohibited concomitant medication. This includes the use of conditionally 
allowed medications without meeting the criteria to use these medications (e.g. 
Temporarily stopping study drug or open-label azithromycin). 
 Failure to obtain spirometry at Visits 1-3 
Failure to comply with Good Clinical Practice (GCP) guidelines will also result in a protocol 
violation. The Sponsor-Investigator will determine if a protocol violation should result in early 
discontinuation of study treatment for 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. This form will be signed by a Sponsor 
representative and the site investigator. A copy of the form will be filed in the site’s regulatory 
binder and in the Sponsor’s files. The site will report the violation to their IRB in accordance 
with their IRB reporting requirements. 
14 DATA SAFETY MONITORING 
A Data Safety Monitoring Board (DSMB) will review comprehensive interim enrollment, safety, 
and efficacy data reports when approximately 50% and 75% of patients have completed the 
randomized period of the study. Regular reporting frequency to the DSMB is detailed in the 
DSMB charter.   A priori interim stopping rules for futility and efficacy/harm with respect to the 
primary endpoint are outlined in the DSMB charter. SAEs will be monitored by the committee 
on an ongoing basis throughout the study.  Further details are included in the DSMB charter. 
15 STATISTICAL METHODS AND CONSIDERATIONS 
A detailed statistical analysis plan will be written that will describe all analyses that will be 
generated for this study. All analyses will be performed using SAS® (SAS Institute, Inc., Cary, 
NC, USA) or R (R Foundation for Statistical Computing, Vienna, Austria).  


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15.1 Data Sets Analyzed 
All analyses will be performed using a modified intent-to-treat (m-ITT) population, which is 
defined as all randomized subjects who received at least one dose of study drug. Subjects who 
are discontinued from study drug temporarily or permanently are encouraged to complete all 
remaining study visits and will remain in the analyses population according to ITT.  The primary 
efficacy analyses will be repeated in the per-protocol population, which is defined as subjects 
having completed ≥80% of doses (azithromycin and or placebo) and who did not require the use 
of acute antibiotics or steroids. All tests will be two-sided and evaluated at a 0.05 level of 
significance. 
15.2 Demographic and Baseline Characteristics  
Baseline demographics and clinical characteristics recorded at Visit 1 will be summarized 
including (but not limited to) age, sex, CFTR genotype, race, height, weight, BMI, FEV1% 
predicted, Pa bacterial density, delivery method of chronic tobramycin (i.e., dry powdered or 
inhaled), and use of other chronic medications (e.g., CFTR modulators, inhaled dornase alfa and 
hypertonic saline).  
15.3 Analysis of Primary Endpoint 
The primary endpoint will be the difference between the azithromycin and placebo treatment 
groups in the relative change from Visit 1 to Visit 3 in FEV1 (liters).  The primary endpoint will 
be compared between treatment groups using linear regression adjusted for randomization strata. 
Least squares means and the treatment effect for the relative change will be presented as well as 
corresponding 95% confidence interval and p-values. The p-values will be evaluated against a 
two-sided 0.05 level of significance.  
Additional secondary analysis may be performed to adjust for potential baseline confounders 
including age, sex, and baseline FEV1.  Sensitivity analyses of the primary endpoint will be 
performed using the per-protocol population.  Additional sensitivity analyses will be performed 
to address missing data. Specifically, the least favorable treatment arm imputation method will 
be used which imputes that missing value with the mean change from the treatment arm with the 
worst change in the observed case analysis. Further details regarding the handling of missing 
data will be provided in the statistical analysis plan. 
15.4 Analysis of Secondary Endpoints 
Randomized Period  
Descriptive analyses and graphical displays will be used to summarize all secondary endpoints.  
Endpoints will be compared between the azithromycin and placebo treatment groups from Visit 
1 through Visit 3.  
All reported SAEs and AEs will be coded using MedDRA and grouped by body system.  The 
incidence of AEs (including emergent abnormal QTc parameters) between the azithromycin and 
placebo treatment groups will be tabulated by seriousness, severity, and relationship to study 
drug.  Rates of (S)AEs by System Organ Class (SOC) will also be summarized.  Poisson 
regression modeling will be used to derive rate ratios and corresponding 95% confidence and to 
compare groups using a using a two-sided 0.05 level test. Histograms showing the frequency of 
the number of (S)AEs in each treatment group will be included. 


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The proportion of subjects permanently or temporarily discontinuing study drug will also be 
tabulated by treatment group.  Drug discontinuation events will be categorized as:  (1) 
Permanently discontinued study drug, (2) Permanently discontinued study drug and withdrew 
from study, and (3) Temporarily discontinued study drug.  Reason for permanent drug 
discontinuation will be summarized.  Compliance measures will be computed separately for the 
TISP and azithromycin /placebo therapies.   
Continuous secondary endpoints including changes in sputum bacterial density, weight, patient-
reported quality of life (as measured by scales derived from the CFQ-R and CFRSD-CRISS), 
and pulmonary function (FEV1 % predicted, FVC, and FEF25%-75%) will be modeled similarly to 
the primary endpoint.  Predicted values for spirometry measures at each visit will be calculated 
using the Global Lung Initiative reference equations.30  Least squares means and the treatment 
effect for the change for each secondary endpoint from Visit 1 to Visit 3 will be presented as 
well as corresponding 95% confidence intervals and p-values. The relative change in 
FEV1(liters) during administration of TISP from Visit 2 to Visit 3 will be analyzed in a similar 
manner. 
Event rates  for hospitalization, pulmonary exacerbations, intravenous antibiotic usage, inhaled 
antibiotic usage, and oral antibiotic usage from Visit 1 through Visit 3 will be descriptively 
summarized and differences in the proportions of subjects with an event between the treatment 
groups will be estimated with accompanying 95% confidence intervals. Event rates will be 
compared between treatment groups using Poisson regression. 
Open-Label Period 
Selected endpoints obtained during the randomized period will continue to be collected during 
the open-label period of the study.  The change in lung function during the open-label period will 
be modeled among placebo subjects, and compared to both the change observed in this group 
during administration of TISP in the randomized trial and the change observed in the active 
group during administration of TISP in the randomized trial.  Moreover, among those 
randomized to azithromycin, differences in the lung function between the randomized and open-
label periods of TISP administration will be compared. Similarly, other endpoints measured in 
the open-label period will be used to estimate longer term changes in response to azithromycin in 
the group randomized to azithromycin.  Data from the placebo subjects who entered into the 
open-label period will be used to compare results with those observed during the randomized 
period of the trial.  Further details will be provided in the SAP that will be finalized prior to the 
first interim data analysis.   
15.5 Interim Analysis  
An independent data monitoring board (DSMB) will review comprehensive interim reports when 
approximately 50% and 75% of patients have completed the randomized period of the study. 
These interim reports will include an overview of enrollment, detailed summaries of SAEs, AEs, 
withdrawals, drug discontinuations, hospitalizations, protocol violations and other clinical safety 
endpoints. The primary endpoint and select secondary endpoints will be summarized as outlined 
in the statistical analysis plan. Should the DSMB consider stopping the trial based on the 
primary endpoint, they will be guided by a priori interim stopping rules for futility and 
efficacy/harm outlined in the DSMB charter. Regular reporting frequency to the DSMB is 


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detailed in the DSMB charter. SAEs will be monitored by the committee on an ongoing basis 
throughout the study. 
15.6 Sample Size  
The primary endpoint is the difference between the azithromycin and placebo treatment groups 
in the relative change from Visit 1 to Visit 3 in FEV1 (liters).   Data from prior published studies 
of similar duration are available to estimate sample size and power for the study including a 
randomized, placebo-controlled trial of azithromycin in individuals with CF chronically infected 
with Pa and a randomized, placebo controlled trial of aztreonam lysine similarly among those 
with chronic Pa.  These studies suggest a standard deviation of the relative change in FEV1 
ranging from 10 to 16.  Based on these prior studies, we anticipate the relative change in FEV1 
from Visit 1 to Visit 3 to be -2% in the azithromycin arm and +6.85% in the placebo arm for an 
overall treatment effect of 8.65%.   A sample size of 110 provides 85% power to detect a 
treatment effect of 7.5% or greater assuming a standard deviation of 13.  110 subjects provides 
93% power to detect a treatment effect similar to what was observed in the preliminary data 
(8.65%) assuming a standard deviation of 13.  It is noteworthy that the standard deviation from 
more recently completed studies CF studies have observed standard deviations in short term 
relative change in FEV (liters) ranging from 8-11, confirming our conservatism in the standard 
deviation estimate used for our sample size calculations.    Assuming a standard deviation of 11, 
a sample size of 110 provides 85% power to detect a treatment effect of 6.3% or greater in favor 
of the placebo group.  Figure 8 displays several scenarios for the statistical power we have to 
detect a range of differences in relative change in FEV1 (L).    
  
Figure 8.  Power to detect a range of differences in relative change in FEV1 (L) for total 
sample size of 110 (55 per group) assuming a two-sided 0.05 level t-test.  Curves (in ascending 
order) correspond to standard deviations of 15, 13, 11, 9, and 7. 


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4
6
8
10
12
0.3
0.4
0.5
0.6
0.7
0.8
0.9
1.0
Total Sample Size Equal to 110
Detectable Treatment Effect (Relative Change 
Power
Target Effect Size for the TEACH Trial
 
16 DATA COLLECTION, RETENTION AND CLINICAL MONITORING 
16.1 Data Collection Instruments 
The investigator will prepare and maintain adequate and accurate source documents designed to 
record all observations and other pertinent data for each subject who signs informed consent.  
Study personnel at each site will enter data from source documents corresponding to a subject’s 
visit into the protocol-specific electronic CRF when the information corresponding to that visit is 
available.  Subjects will not be identified by name in the study database or on any study 
documents to be collected by the Sponsor (or designee), but will be identified by a subject 
number and initials. 


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If a correction is required for a CRF, the time and date stamps track the person entering or 
updating CRF data and create an electronic audit trail.   
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.  At the completion of the study, a copy of the CRF data will be 
provided to the site to be retained at the Investigator’s site. 
16.2 Data Management Procedures 
TDNCC utilizes Medidata Solutions, Inc. (Medidata) Rave for their EDC studies. The Medidata 
Rave EDC system is designed to be US Code of Federal Regulations (CFR) 21 Part 11 compliant 
with a robust audit trail system and electronic signature capabilities.  Study personnel at each site 
will enter data from a subject’s visit onto electronic CRF screens via a web browser.  Study 
subjects will not be identified by name in the study database or on any data capture screens, but 
will be identified by initials and a unique subject identification number.  Only study personnel at 
the individual sites will be able to link the study ID to the subject’s name.  The Data 
Management group of the TDNCC will be responsible for data processing, in accordance with 
procedural documentation.  Database lock will occur once quality assurance procedures have 
been completed.  All procedures for the handling and analysis of data will be conducted using 
good computing practices 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, data validation checks will be applied on a 
regular basis. Queries are entered, tracked, and resolved through the EDC system directly.  The 
study database will be updated in accordance with the resolved queries. All changes to the study 
database will be documented in an audit trail.  
16.4 Security and Archival of Data 
The EDC system is hosted by Medidata; the data are stored at Medidata’s primary data center in 
Houston, Texas, with fail-safe data centers in New Jersey.  Data are regularly backed up by 
Medidata and stored with Iron Mountain. 
Medidata maintains 21 CFR Part 11-compliant electronic systems, with procedures in place to 
safeguard against unauthorized acquisition of data.  Any authorized communication with the 
Medidata servers at the Houston Data Center is conducted via SSL (128-bit) encryption.  Robust 
password procedures, consistent with 21 Part 11, are in place.  Robust physical security 
procedures are in place at the Houston Data Center to prevent unauthorized personnel physical 
access to the server rooms.  EDC account access is maintained and monitored by the Biostatistics 
and Clinical Data Management group of the TDNCC. 
Other databases will be stored on Seattle Children’s servers and are safeguarded against 
unauthorized access by established security procedures.  Network accounts are password 
protected and maintained and monitored by the Seattle Children’s Information Technology 
group.  Data is backed up regularly according to the Information Services group’s procedures.  
Note that there is an intention to make biospecimens and associated data available to 
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processed according to a rigorous standard operating procedure and stored at a central facility, 
with appropriate procedures to enable long term, stable storage. Researchers may apply, via a 
standardized process, for use of de-identified data and specimens for research purposes. 
Applications will undergo a scientific review process administered through CFFT. When 
applying for use of data or specimens, the applicant must agree to: (1) use the data and 
specimens only for research purposes and to not make any attempts to try to identify any 
individual subject; (2) secure the data and specimens using appropriate methods; and (3) destroy 
or return the data (and specimens) in accordance with the specimen/data use agreement after 
analyses are completed.  Before data or specimens will be released to an investigator, 
documentation of IRB exemption or approval from their institution must be provided to the 
CFFT.   
16.5 Availability and Retention of Investigational Records 
The investigator must make study data accessible to the monitor, other authorized representatives 
of the Sponsor (or designee), IRB, and Regulatory Agency (e.g., FDA) inspectors upon request.  
A file for each subject must be maintained that includes the signed informed consent, Health 
Insurance Portability and Accountability Act (HIPAA) authorization and assent form (if 
applicable) and copies of all source documentation related to that subject.  The investigator must 
ensure the reliability and availability of source documents from which the information on the 
CRF was derived. 
All study documents (e.g., patient files, signed informed consent forms, copies of CRFs, 
Essential Document and Study Reference Binders) must be kept secured for a period of two 
years following completion of the study.  There may be other circumstances for which the 
Sponsor is required to maintain study records and, therefore, the Sponsor should be contacted 
prior to removing study records for any reason. 
16.6 Monitoring 
By signing this protocol, the investigator grants permission to the Sponsor (or designee) and 
appropriate regulatory authorities to conduct on-site monitoring and/or auditing of all appropriate 
study documentation, if needed. Monitoring visits may be conducted by representatives of the 
Sponsor according to the U.S. CFR 21 Part 312 to ensure investigator compliance to 21 CFR 
Parts 50, 56 and 312 and to GCP.   
16.7 Subject Confidentiality 
In order to maintain subject confidentiality, only a subject number and subject initials will 
identify all study subjects on CRFs and other documentation submitted to the Sponsor. If specific 
consent is given, the subject’s CFF patient registry number will also be collected. Additional 
subject confidentiality issues (if applicable) are covered in the Clinical Study Agreement. 
17 ADMINISTRATIVE, ETHICAL, REGULATORY CONSIDERATIONS 
The study will be conducted according to the Declaration of Helsinki, Protection of Human 
Volunteers (21 CFR 50), Institutional Review Boards (21 CFR 56), and Obligations of Clinical 
Investigators (21 CFR 312). 


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To maintain confidentiality, all laboratory specimens, evaluation forms, reports and other records 
will be identified by a coded number and initials only.  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 Sponsor-Investigator and agreed to by the 
study Steering Committee.  Protocol amendments cannot be implemented without prior written 
IRB approval except as necessary to eliminate immediate safety hazards to patients.  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  
The protocol and consent form will be reviewed and approved by the IRB of each participating 
center prior to study initiation.  SAEs regardless of causality will be reported to the IRB in 
accordance with the standard operating procedures and policies of the IRB, and the investigator 
will keep the IRB informed as to the progress of the study.  The investigator will obtain 
assurance of IRB compliance with regulations. 
Any documents that the IRB may need to fulfill its responsibilities (such as protocol, protocol 
amendments, consent forms, information concerning patient recruitment, payment or 
compensation procedures, or other pertinent information) will be submitted to the IRB.  The 
IRBs written unconditional approval of the study protocol and the informed consent form will be 
in the possession of the investigator before the study is initiated.  The IRB’s unconditional 
approval statement will be transmitted by the investigator to the TDNCC prior to the shipment of 
study supplies to the site.  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 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.   
The IRB must be informed of revisions to other documents originally submitted for review; 
serious and/or unexpected adverse experiences occurring during the study in accordance with the 
standard operating procedures and policies of the IRB; new information that may affect 
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  
Informed consent will be obtained in accordance with the Declaration of Helsinki, 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), HIPAA, if applicable, and local regulations. 


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The investigator will prepare the informed consent form, assent and HIPAA authorization and 
provide the documents to the Sponsor or designee for approval prior to submission to the IRB.  
The consent form generated by the investigator must be acceptable to the Sponsor and be 
approved by the IRB.  The written consent document will embody the elements of informed 
consent as described in the US Code of Federal Regulations and will also comply with local 
regulations. The investigator will send an IRB-approved copy of the Informed Consent Form to 
the Sponsor (or designee) for the study file. 
A properly executed, written, informed consent will be obtained from each subject prior to 
entering the subject into the trial.  Information should be given in both oral and written form and 
subjects must be given ample opportunity to inquire about details of the study.  If appropriate 
and required by the local IRB, assent from the subject will also be obtained.  If a subject is 
unable to sign the informed consent form and the HIPAA authorization, a legal representative 
may sign for the subject.   A copy of the signed consent form (and assent) will be given to the 
subject and the original will be maintained with the subject’s records. 
During the course of the study, if modifications are made to the consent form that impact the 
subject, the subject will be re-consented as described above.  
17.4 Consent for Collection and Use of CFF Registry ID Number  
To facilitate possible future evaluation of retrospective and prospective information from all 
patients who screen for this study, consent will also be sought to collect the subject’s CFF 
Registry ID number at the screening visit.  The CFF Registry collects data on all CF patients who 
consented to participate in the CFF Registry and who are followed at CFF-accredited care 
centers.  The registry data includes information from clinical encounters, hospitalizations courses 
of antibiotics, and year-end surveys.  Data also include microbiology results, spirometry results, 
CF genotype and other information. If specific consent is given to collect this number, the 
subject’s CF Registry ID number will be recorded in the CRF. 
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 study Sponsor 
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 and only make changes after notifying 
the Sponsor (or designee), 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. 


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4. Report to the Sponsor or designee 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 with the Sponsor (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 and the Sponsor (or designee) 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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18 REFERENCES 
 
1. 
2013 Annual Data Report; Cystic Fibrosis Foundation Patient Registry. 2014. 
2. 
Courtney JM, Bradley J, McCaughan J, et al. Predictors of mortality in adults with cystic fibrosis. Pediatr Pulmonol. 
2007;42(6):525-532. 
3. 
Lopes AJ, Mafort TT, de Sa Ferreira A, Santos de Castro MC, Cassia de Firmida M, de Andrade Marques E. Is the type 
of chronic pulmonary infection a determinant of lung function outcomes in adult patients with cystic fibrosis? Monaldi 
archives for chest disease 2012;77(3-4):122-128. 
4. 
Ruddy J, Emerson J, Moss R, et al. Sputum tobramycin concentrations in cystic fibrosis patients with repeated 
administration of inhaled tobramycin. Journal of aerosol medicine and pulmonary drug delivery. 2013;26(2):69-75. 
5. 
Lenoir G, Antypkin YG, Miano A, et al. Efficacy, safety, and local pharmacokinetics of highly concentrated nebulized 
tobramycin in patients with cystic fibrosis colonized with Pseudomonas aeruginosa. Paediatric drugs. 2007;9 Suppl 
1:11-20. 
6. 
Vandyke RD, McPhail GL, Huang B, et al. Inhaled tobramycin effectively reduces FEV1 decline in cystic fibrosis. An 
instrumental variables analysis. Annals of the American Thoracic Society. 2013;10(3):205-212. 
7. 
Assael BM, Pressler T, Bilton D, et al. Inhaled aztreonam lysine vs. inhaled tobramycin in cystic fibrosis: A 
comparative efficacy trial. J Cyst Fibros. 2012. 
8. 
Ramsey BW PM, Quan JM, Otto KL, Montgomery AB, Williams-Warren J, Vasiljev-KM, Borowitz D, Bowman CM, 
Marshall BC, Marshall S, Smith AL. Intermittent administration of inhaled tobramycin in patients with cystic fibrosis. 
Cystic Fibrosis Inhaled Tobramycin Study Group. N Engl J Med. 1999;340:23-30. 
9. 
Mayer-Hamblett N, Rosenfeld M, Treggiari MM, et al. Standard care versus protocol based therapy for new onset 
Pseudomonas aeruginosa in cystic fibrosis. Pediatr Pulmonol. 2013. 
10. 
Saiman L, Marshall BC, Mayer-Hamblett N, et al. Azithromycin in patients with cystic fibrosis chronically infected 
with Pseudomonas aeruginosa: a randomized controlled trial. JAMA. 2003;290:1749-1756. 
11. 
Equi A, Balfour-Lynn IM, Bush A, Rosenthal M. Long term azithromycin in children with cystic fibrosis: a 
randomised, placebo-controlled crossover trial. Lancet. 2002;360(9338):978-984. 
12. 
Ratjen F, Saiman L, Mayer-Hamblett N, et al. Effect of azithromycin on systemic markers of inflammation in patients 
with cystic fibrosis uninfected with Pseudomonas aeruginosa. Chest. 2012;142(5):1259-1266. 
13. 
Verleden GM, Vanaudenaerde BM, Dupont LJ, VanRaemdonck DE. Azithromycin reduces airway neutrophilia and 
interleukin-8 in patients with bronchiolitis obliterans syndrome. Am J Respir Crit Care Med. 2006;174:566-570. 
14. 
Ribeiro CM, Hurd H, Wu Y, et al. Azithromycin treatment alters gene expression in inflammatory, lipid metabolism, 
and cell cycle pathways in well-differentiated human airway epithelia. PLoS ONE. 2009;4(6):e5806. 
15. 
Cigana C, Nicolis E, Pasetto M, Assael BM, Melotti P. Anti-inflammatory effects of azithromycin in cystic fibrosis 
airway epithelial cells. Biochem Biophys Res Commun. 2006;350:977-982. 
16. 
Mogayzel PJ, Jr., Naureckas ET, Robinson KA, et al. Cystic fibrosis pulmonary guidelines. Chronic medications for 
maintenance of lung health. Am J Respir Crit Care Med. 2013;187(7):680-689. 
17. 
Nichols DP, Caceres S, Caverly L, et al. Effects of azithromycin in Pseudomonas aeruginosa burn wound infection. The 
Journal of surgical research. 2013. 
18. 
Nichols DP, Caceres S, Caverly L, et al. Effects of azithromycin in Pseudomonas aeruginosa burn wound infection. The 
Journal of surgical research. 2013;183(2):767-776. 
19. 
Nick JA, Moskowitz SM, Chmiel JF, et al. Azithromycin May Antagonize Inhaled Tobramycin when Targeting 
Pseudomonas aeruginosa in Cystic Fibrosis. Annals of the American Thoracic Society. 2014. 
20. 
Caceres SM, Malcolm KC, Taylor-Cousar JL, et al. Enhanced in vitro formation and antibiotic resistance of 
nonattached Pseudomonas aeruginosa aggregates through incorporation of neutrophil products. Antimicrob Agents 
Chemother. 2014;58(11):6851-6860. 
21. 
Armour AD, Shankowsky HA, Swanson T, Lee J, Tredget EE. The impact of nosocomially-acquired resistant 
Pseudomonas in a burn unit. J Trauma. 2007;63:164-171. 
22. 
Dales L, Ferris W, Vandemheen K, Aaron SD. Combination antibiotic susceptibility of biofilm-grown Burkholderia 
cepacia and Pseudomonas aeruginosa isolates from patients with pulmonary exacerbations of cytic fibrosis. Eur J Clin 
Microbiol Infect Dis. 2009;28(10):1275-1279. 
23. 
Aaron SD, Ferris W, Ramotar K, Vandemheen K, Chan F, Saginur R. Single and combination antibiotic susceptibilities 
of planktonic, adherent, and biofilm-grown Pseudomonas aeruginosa isolates cultured from sputa of adults with cystic 
fibrosis. J Clin Microbiol. 2002;40:4172-4179. 


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24. 
McCoy KS, Quittner AL, Oermann CM, Gibson RL, Retsch-Bogart GZ, Montgomery AB. Inhaled aztreonam lysine 
for chronic airway Pseudomonas aeruginosa in cystic fibrosis. Am J Respir Crit Care Med. 2008;178(9):921-928. 
25. 
Wagener JS, Rasouliyan L, Vandevanter DR, et al. Oral, inhaled, and intravenous antibiotic choice for treating 
pulmonary exacerbations in cystic fibrosis. Pediatr Pulmonol. 2012. 
26. 
Saiman L, Anstead M, Mayer-Hamblett N, et al. Effect of azithromycin on pulmonary function in patients with cystic 
fibrosis uninfected with Pseudomonas aeruginosa: a randomized controlled trial. JAMA. 2010;303:1707-1715. 
27. 
Ray WA, Murray KT, Hall K, Arbogast PG, Stein CM. Azithromycin and the risk of cardiovascular death. N Engl J 
Med. 2012;366(20):1881-1890. 
28. 
Svanstrom H, Pasternak B, Hviid A. Use of azithromycin and death from cardiovascular causes. N Engl J Med. 
2013;368(18):1704-1712. 
29. 
Rabin HR, Butler SM, Wohl ME, et al. Pulmonary exacerbations in cystic fibrosis. Pediatric Pulmonology. 
2004;37(5):400-406. 
30. 
Wang X, Dockery DW, Wypij D, Fay ME, Ferris BG, Jr. Pulmonary function between 6 and 18 years of age. Pediatr 
Pulmonol. 1993;15(2):75-88. 
31. 
Pocock SJ, Simon R. Sequential treatment assignment with balancing for prognostic factors in the controlled clinical 
trial. Biometrics. 1975;31(1):103-115. 
32. 
Han B, Enas NH, McEntegart D. Randomization by minimization for unbalanced treatment allocation. Stat. Med. 
2009;28(27):3329-3346. 
33. 
Brown S, Thorpe H, Hawkins K, Brown J. Minimization-reducing predictability for multi-centre trials whilst retaining 
balance within centre. Stat. Med. 2005;24(24):3715-3727. 
 


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19 APPENDIX 1 SCHEDULE OF EVENTS 
 
RANDOMIZED, PLACEBO-
CONTROLLED, DOUBLE BLIND 
OVERLAP 
OPEN-LABEL, FOLLOW-ON 
UNSCHEDULED/  
EARLY TERM  
VISIT f 
 
VISIT 1* 
Day -14  
 
VISIT 2 
(Day 0) 
 (-2 to +4 days) 
VISIT 3 
Day 28 
(-2 to +4 days) 
VISIT 4EXT 
Day 56 
(± 4 days) 
VISIT 5EXT  
Day 84 
(±4 days) 
Informed Consent 
X 
 
Xe 
 
 
 
Respiratory Culture (as needed) 
 Xh 
 
 
 
 
 
Demographics and Medical History 
X 
 
 
 
 
 
Complete CFQ-R and CFRSD-CRISS 
X 
X 
X 
X 
X 
X 
Complete Physical Exam 
X 
 
 
 
 
X 
Abbreviated Physical Exam 
 
X 
X 
X 
X 
 
Height 
X 
X 
X 
X 
X 
X 
Weight 
X 
X 
X 
X 
X 
X 
Vital Signs 
X 
X 
X 
X 
X 
X 
Spirometry 
X 
X 
X 
X 
X 
X 
Pregnancy Test at site (Urine or Serum) a 
X 
 
 
 
 
 
ECG Testing 
X 
 
X 
 
X 
X b 
Collect sputum for analysis and banking c 
X 
X 
X 
X 
X 
X 
Randomize to azithromycin or placebo 
X 
 
 
 
 
 
Dispense azithromycin/placebo dose and 
review dose schedule 
X 
 
           
 
 
 
Dispense open-label azithromycin and review 
dose schedule 
 
 
Xe 
 
 
 
Provide Subject Diary 
X 
X 
Xe 
X 
 
 


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RANDOMIZED, PLACEBO-
CONTROLLED, DOUBLE BLIND 
OVERLAP 
OPEN-LABEL, FOLLOW-ON 
UNSCHEDULED/  
EARLY TERM  
VISIT f 
 
VISIT 1* 
Day -14  
 
VISIT 2 
(Day 0) 
 (-2 to +4 days) 
VISIT 3 
Day 28 
(-2 to +4 days) 
VISIT 4EXT 
Day 56 
(± 4 days) 
VISIT 5EXT  
Day 84 
(±4 days) 
Instruct to hold use of inhaled tobramycin for 
off-cycle until the next study visit 
X 
 
Xe 
 
 
 
Concomitant Medication Review 
X 
X 
X 
X 
X 
X 
Adverse Events 
 
X 
X 
X 
X 
X 
Review Subject Diary and pill count 
 
X 
X 
X 
X 
X 
Record TISP use  
 
 
X 
 
X 
X 
Review inhaled tobramycin schedule 
 
X 
 
X 
 
 
Assess eligibility for Open-label 
 
 
Xe 
 
 
 
Signs and Symptoms Assessment g 
Start 
 
Stop 
Starte 
 
Stop 
 
 
* If the patient does not have sufficient culture history to assess eligibility, a respiratory culture may be collected prior to randomization.  If the respiratory 
culture is positive, the remaining Visit 1 procedures and randomization will be conducted at a subsequent visit.   
      a     Only females of child-bearing potential 
b 
ECG is only required at an Unscheduled visit (if the subject has a cardiovascular related adverse event) or at an Early Termination Visit (when the subject 
permanently discontinues study drug or will no longer be participating in the study) 
c 
Expectorated sputum will be collected from subjects who are able to produce sputum  
e 
Perform only if rolling over into Open-Label 
     f      Early termination includes early permanent discontinuation of study drug or early study withdrawal. An Unscheduled Visit may be conducted as a study visit when, 
in the opinion of the site investigator, safety follow up is required as a result of a possible study-related procedure or study drug-related event.   
g 
Assessment only when a new antibiotic is prescribed during the study 
h     If there is not a recent respiratory culture available, obtain culture to confirm eligibility.   


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20 APPENDIX 2 PROTOCOL DEFINED PULMONARY EXACERBATION 
DEFINITION 
 
The presence of a pulmonary exacerbation is established by the following: 
(1) 
One of the major criteria alone  
             or  
(2) 
Two of the minor signs/symptoms and fulfillment of symptom duration   
 
Major Criteria: (One finding alone establishes the presence of a pulmonary exacerbation) 
(1) Absolute decrease in FEV1 %predicted of ≥10%  
(2) Oxygen saturation <90% on room air or absolute decrease of ≥ 5%  
(3) New lobar infiltrate(s) or atelectasi(e)s on chest radiograph 
(4) Hemoptysis (more than streaks on more than one occasion in past week) 
 
Minor Signs/Symptoms: (Two minor signs/symptoms are required in the absence of major 
criteria. If at least 2 minor signs/symptoms are present, at least one needs to be 3 or more 
days in duration to meet the pulmonary exacerbation definition) 
(1) Increased work of breathing or respiratory rate 
(2) New or increased adventitial sounds on lung exam 
(3) Weight loss ≥5% of body weight or decrease across 1 major percentile in weight 
percentile for age in past 6 months 
(4) Increased cough 
(5) Decreased exercise tolerance or level of activity 
(6) Increased chest congestion or change in sputum 
 
 
 
 
 
 
 
  

SAP_001.pdf: 
Statistical Analysis Plan 
TEACH-IP-15–CONFIDENTIAL 
1 
  
TEACH-IP-15 
 
FINAL REPORT  
 
 
 
 
PROTOCOL NUMBER:  
 
TEACH-IP-15 
 
 
 
 
PROTOCOL TITLE: 
Testing the Effect of Adding CHronic 
Azithromycin to inhaled Tobramycin. A 
randomized, placebo-controlled, double-blinded 
trial of azithromycin 500mg thrice weekly in 
combination with inhaled tobramycin 
 
PRINCIPAL 
INVESTIGATOR:  
Dave Nichols, MD 
 
Seattle Children’s Hospital 
 
 
 
 
 
FUNDING AGENCIES:   
National Institutes of Health/National Heart, 
Lung, and Blood Institute (NHLBI) 
 
Cystic Fibrosis Foundation Therapeutics, Inc. 
(CFFT) 
 
 
PREPARED BY: 
CF Therapeutics Development Network 
Coordinating Center:  
 
Nicole Hamblett, PhD 
Sonya Heltshe, PhD 
 
 
 
 
 
Valeria Beckett, MS 
 
 
 
 
 
Arthur Baines, MS 
 
 
RELEASE DATE:  
 
 
February 1, 2017 
 
  
 
 


Statistical Analysis Plan 
TEACH-IP-15–CONFIDENTIAL 
2 
PREFACE 
 
 
The Statistical Analysis Plan (SAP) as outlined in this document will be finalized prior to the 
completion of the first comprehensive DSMB interim report.  Any modifications to the SAP after 
finalization will be documented.  The SAP contains all modifications and updates to the planned 
analyses that were outlined in the original study protocol.  This plan details all a priori specified 
analyses that will be performed upon study completion and database lock, with detailed 
specifications for all tables, figures, and statistical models.   


Statistical Analysis Plan 
TEACH-IP-15–CONFIDENTIAL 
3 
Signature Page 
 
 
 
 
Analysis plan approved by: 
 
 
 
 
______________________________________________      ____________ 
Dave Nichols, MD  
 
 
 
 
       
 
Date 
Principal Investigator 
 
 
 
 
______________________________________________      ____________ 
Nicole Mayer Hamblett, PhD 
 
 
 
 
 
Date 
DCC Principal Investigator 
 
 
 
 
______________________________________________      ____________ 
Sonya Heltshe, PhD 
 
 
 
 
 
 
Date 
Senior Biostatistician 
 
 
 
 
 
 
 
  
 


Statistical Analysis Plan 
TEACH-IP-15–CONFIDENTIAL 
4 
1.     Overview 
 
1.1 
Study Rationale and Design 
 
Patients with cystic fibrosis (CF) commonly acquire a chronic airway infection with Pseudomonas 
aeruginosa (P.a.). Both inhaled tobramycin and oral azithromycin have been proven beneficial in 
these patients and are currently used by the majority of eligible patients. Seventy five percent of 
US patients prescribed inhaled tobramycin are also prescribed chronic oral azithromycin. We 
believe that azithromycin is inhibiting the anti-P.a. effects and clinical benefits of inhaled 
tobramycin. This study will investigate whether azithromycin is associated with poorer clinical and 
microbiologic outcomes as compared to placebo during concurrent administration of inhaled 
tobramycin.   
 
This is a prospective, randomized, placebo-controlled, double-blinded study of azithromycin in 
subjects with chronic Pa airway infection using inhaled tobramycin.  Subjects who have received 
two (2) or more cycles of inhaled tobramycin within the 24 weeks prior to enrollment will be 
recruited into the study.   Approximately 120 eligible subjects (allowing for 10 withdrawn) will be 
enrolled and randomized to either azithromycin or placebo at Visit 1 (Day -14), approximately 14 
days prior to the start day of their next planned 28-day nebulized solution or dry powder 
tobramycin (TISP) cycle. Subjects will be randomized in a 1:1 fashion to azithromycin (500 mg 
three times per week) or matched placebo.   
 
Between Visit 1 (Day -14) and Visit 2 (Day 0), a two-week run-in period will be used to begin 
administration of either azithromycin or placebo.    Among those randomized to azithromycin, the 
2-week run-in period will be used to initiate azithromycin and standardize uptake prior to the start 
of the next TISP cycle.  Among those randomized to placebo, the run-in period will be used as a 
standardized washout prior to the start of the next TISP cycle.    Subjects will begin TISP at Visit 
2 in addition to their continued dosing of randomized study drug treatment (azithromycin or 
placebo). Subjects will continue both TISP and study drug dosing for 28 days (up until Visit 3), 
which corresponds with the end of a clinically prescribed 4-week cycle of TISP. Subjects 
completing the study through Visit 3 (Day 28) will be offered participation and consent to an 8-
week open-label extension period during which azithromycin will be provided.  During the open-
label period, subjects will be instructed to remain off of TISP for the first 4-week period, followed 
by a 4-week period of TISP. Total duration of subject participation will be up to 6 weeks for those 
enrolled in the randomized study and up to 98 days for subjects participating in the optional open-
label extension.  Subjects who meet all inclusion criteria and none of the exclusion criteria will be 
eligible for the study.  
 
The primary objective of this study is to determine if azithromycin impairs the previously-
recognized clinical benefits of inhaled tobramycin by comparing changes in pulmonary function as 
measured by FEV1 between subjects randomized to azithromycin versus placebo.  
 
The secondary objectives for the randomized period are to: 
 
Compare changes in patient-reported quality of life between subjects randomized to 
azithromycin versus placebo  
 
The secondary exploratory objectives for the randomized period are to: 
 
Compare the safety profile between subjects randomized to azithromycin versus placebo  
 
Compare changes in additional spirometry measures, bacterial density, and weight between 
subjects randomized to azithromycin versus placebo 
 
Compare rates of pulmonary exacerbations, hospitalizations, and acute antibiotic usage 
between subjects randomized to azithromycin versus placebo  
 
The objectives for those continuing in the open-label extension: 


Statistical Analysis Plan 
TEACH-IP-15–CONFIDENTIAL 
5 
 
Among those randomized to azithromycin and remaining on azithromycin, obtain additional 
data to determine the long term effect of azithromycin on clinical outcomes   
 
Among those randomized to placebo and switching to azithromycin, compare differences in 
clinical outcomes observed during the randomized and open label periods 
 
1.2 
Interim Data Safety Monitoring Board Reviews 
 
Safety monitoring and study conduct will be assessed by a DSMB with members appointed by 
the NHLBI. The DSMB is responsible for safeguarding the interests of study participants, 
assessing the safety and efficacy of study procedures and for monitoring overall study conduct. 
Serious adverse events (SAEs) will be monitored on an ongoing basis. In addition to SAE 
monitoring, quarterly summary reports tabulating SAEs by treatment group will be provided to the 
DSMB. A comprehensive interim report will be provided to the DSMB when approximately 50% of 
patients have completed the randomized portion of the trial. The report will include an overview of 
enrollment by site, detailed summaries of all SAEs, AEs, withdrawals, drug discontinuations, 
hospitalizations, protocol violations and other clinical safety endpoints. Table shells detailing the 
results to be presented in the semi-annual reports are included in Appendix A (randomized 
period) and Appendix B (open-label period), whereas Appendix C will include listings of protocol 
violations and SAE narratives. 
 
1.3 
Statistical Monitoring Guidelines and Stopping Rules 
 
While there are no pre-determined stopping rules for safety, the DSMB may decide to stop the 
study either temporarily or permanently if there are significant concerns regarding subject safety. 
There is however pre-specified stopping rule for efficacy/harm and futility with respect to the 
primary endpoint.  
 
Should the DSMB consider stopping the trial based on the primary endpoint, they will be guided 
by a formal stopping rule to be assessed when approximately 50% of patients have completed 
the randomized portion of the trial. The primary endpoint is the difference between the 
azithromycin and placebo treatment groups in the relative change in FEV1 (liters) from 
randomization at Visit 1 (Day -14) to Visit 3 (Day 28). We hypothesize that azithromycin is 
associated with poorer clinical outcomes (inferiority) as compared to placebo during concurrent 
administration of inhaled tobramycin and thus there will be a smaller improvement or a worsening 
in FEV1 in the azithromycin treatment group as compared to placebo treatment from Visit 1 (Day -
14) to Visit 3 (Day 28). Assuming a sample size of 110 subjects, two-sided type 1 error of 0.05, 
and a standard deviation for the relative change of 13%, the study has approximately 85% power 
to detect a difference (relative change in FEV1 in the azithromycin treatment group minus the 
relative change in FEV1 in the placebo treatment group) of less than or equal to -7.5% (e.g. 
azithromycin is clinically inferior to placebo).   
 
For the purposes of calculating formal boundaries for stopping under the null and alternative 
hypotheses (no difference, and clinical inferiority of azithromycin, respectively), we will use the 
hypothesized treatment effect of -7.5%. Assuming a conservative O’Brien-Fleming boundary1, the 
two-sided stopping rule would suggest that the trial be stopped early in favor of the alternative 
hypothesis (azithromycin inferiority) if the observed treatment effect is less than -9.8% at the 
interim review (n=55). Should there be evidence in the opposite direction where azithromycin is 
clinically superior to placebo, the trial will be stopped at the interim analysis when observed 
treatment effect is 9.8% or greater. The trial could stop under the null hypothesis if the observed 
treatment effect is greater than 0.05% but less than 9.8% and the DSMB has simultaneous safety 
or accrual concerns. If the trial was to continue to completion, the null hypothesis will be rejected 
in favor of the alternative if the observed treatment effect is less than or equal to -4.9% at the end 
of the trial. 
 


Statistical Analysis Plan 
TEACH-IP-15–CONFIDENTIAL 
6 
The probability of stopping at the interim analysis if the true treatment effect is 0.0% is 0.016 (or 
less than 2%). Similarly, if the treatment effect is ±3.75% or ± 7.5% the probability of stopping is 
0.05 and 0.26, respectively. 
 
The actual stopping boundaries will be computed at the time of the comprehensive interim report 
to the DSMB.  Thus, the actual stopping boundaries may differ from those provided above 
depending on the number of subjects evaluable for the primary endpoint.  R RCTdesign software 
will be used to calculate the formal stopping boundary and adjust for this interim analysis in the 
final analysis. 
 
 
2 
Report Generation 
 
2.1 
Data Flow 
 
An electronic data capture system, Medidata Rave, will be utilized for collection of study data. 
The Investigator will prepare and maintain adequate and accurate source documents designed to 
record all observations and other pertinent data for each subject who signs informed consent.  
 
Study personnel at each site will enter data from source documents corresponding to a subject’s 
visit or assessment into the protocol-specific electronic Case Report Form (eCRF). Subjects will 
not be identified by name in the study database or on any study documents to be collected by the 
Sponsor (or designee), but will be identified by a site number, subject number and initials. If a 
correction is required for an eCRF, the time and date stamp will track the person entering or 
updating eCRF data and creates an electronic audit trail.  
 
The data will be entered into a validated database. The DCC will be responsible for data 
processing, in accordance with procedural documentation. All procedures for the handling and 
analysis of data will be conducted using good computing practices for the handling and analysis 
of data for clinical trials.  
 
Once data have been entered into the study database, a system of computerized data validation 
checks will be implemented and applied to the database on a regular basis. Queries are entered, 
tracked, and resolved through the EDC system directly. The study database will be updated in 
accordance with the resolved queries. All changes to the study database will be documented in 
an audit trail.  
 
2.2 
Screening Spirometry 
 
The study sites were permitted to use their spirometers with their proprietary reference equations 
to determine study eligibility per FEV1 (% predicted) inclusion criteria. Because database 
randomization was built using the FEV1 (liters) as an input to GLI equations to calculate percent 
of predicted FEV1 for stratification, minor discrepancies in resulting % predicted values would 
potentially prevent some patients from participating in the study. 
 
With this in mind, the lower limit of inclusion criteria (25-50% predicted) was lowered to 20% 
predicted (as determined by GLI equations) in the database. Because this change was limited to 
database randomization mechanism and did not affect study inclusion criterion, no protocol 
amendment was issued. The sites were asked to document all FEV1 % predicted calculation 
discrepancies in the investigator log. 
 
2.3 
Report Generation 
 
The final statistical report will describe and justify any deviations from the original statistical plan 
described herein.  Analyses will be performed using SAS 9.4 software or most current version of 


Statistical Analysis Plan 
TEACH-IP-15–CONFIDENTIAL 
7 
R. All programs used to produce this report will be documented, tested, and archived and all 
tables, figures and listings will be validated before considered final. 
 
2.4 
Data Sets Analyzed 
 
All analyses will be performed using a modified intent-to-treat (m-ITT) population, which is defined 
as all randomized participants who received at least one dose of study drug. Participants who are 
discontinued from study drug temporarily or permanently are encouraged to complete all 
remaining study visits and will remain in the analyses population according to ITT. The primary 
efficacy analyses will be repeated in the per-protocol population, which is defined as participants 
having completed ≥80% of doses (azithromycin and or placebo) and who did not require the use 
of acute antibiotics or steroids. 
 
2.5 
Definitions 
 
Baseline – Baseline refers to Visit 1 (Day -14) when participants were randomized. 
 
Study drug – During the randomized period, the study drug refers to the drug the participant was 
randomized to (either azithromycin or placebo). During the open-label period, the study drug 
refers to open-label azithromycin.  
 
Treatment group – During the randomized period, the treatment group refers to participants 
randomized to either azithromycin or placebo. During the open-label period, the treatment group 
refers to participants either remaining on azithromycin or switching from placebo to azithromycin. 
 
References 
 
1. Emerson, SS and Fleming, TR.  Symmetric group sequential test designs.  Biometrics. 
45:905-923, 1989.   
 
 
 
 
 
 


Statistical Analysis Plan 
TEACH-IP-15–CONFIDENTIAL 
8 
Appendix A.  Overview of Planned Analyses 
 
A.1   Summary of Enrollment and Study Visit Completion 
The cumulative enrollment of participants randomized into the study is graphically summarized. 
The number of participants screened, eligible, randomized, treated, withdrawn, and completing 
the study during the randomized period is summarized by both treatment group and site.  
Reasons for screen failure are summarized. Screen failures are participants that signed informed 
consent but did not meet eligibility criteria or chose not to participate in the study. The number of 
participants who withdrew early from the study is tabulated by treatment group and reason for 
withdrawal is summarized. Participant disposition figure detailing enrollment, treatment allocation, 
follow-up, and analyses populations is provided. 
 
A.2   Demographics and Baseline Characteristics 
Baseline demographics and clinical characteristics are descriptively summarized by treatment 
group and overall. Summarized characteristics include age, sex, CFTR genotype, race, height, 
weight, BMI, FEV1 (liters and % predicted), delivery method of chronic tobramycin (i.e., dry 
powdered or inhaled), current use of chronic azithromycin, and use of other chronic medications. 
Fisher Exact tests are used to test at a two-sided 0.05 level of significance for differences in 
categorical variables across treatment arms. A two-sided t-test assuming unequal variance is 
used to test the difference between treatment arms for all continuous variables at a two-sided 
0.05 level of significance.  
 
A.3   Summary of Protocol Adherence Measures 
 
The number of participants expected to have completed each visit and the number of participants 
who have missed a visit during the randomized period are summarized by treatment group. The 
follow-up time in the randomized period is summarized overall and by treatment group and also 
as the average time for each participant. 
 
The proportion of participants who discontinued the study drug or experienced a dose 
modification during the randomized period is shown by treatment group. Reasons for drug 
discontinuation or other change to study drug regimen are also summarized.  
 
Study drug compliance (azithromycin or placebo) is summarized in terms of the protocol defined 
treatment regimen during the randomized period. Compliance percentage is calculated for each 
participant as the number of doses reported taken divided by the number of doses expected 
(three 500 mg capsules per week over the six-week period, i.e. 18 doses), multiplied by 100.  
Also summarized is the compliance with TIS/TIP, calculated in a similar manner and assuming 
that the expected number of doses is 84 (inhaled twice daily over the six-week period). The 
average drug compliance is summarized in each treatment group. Also shown is the number and 
percentage of participants with ≥ 80% compliance. 
 
The number of participants included in the per-protocol population is provided by treatment group 
are reasons for exclusions are listed. Per-protocol population is defined as all randomized 


Statistical Analysis Plan 
TEACH-IP-15–CONFIDENTIAL 
9 
participants having completed ≥80% of doses of study drug (azithromycin or placebo) and who 
did not require the use of acute antibiotics or steroids. 
 
 
A.4   Summary of Adverse Events 
The safety population is used in all summaries of adverse events (AEs) and serious adverse 
events (SAEs). Note that all tables summarizing AEs also include SAEs (which are a subset of 
the AEs) unless otherwise specified. 
 
According to our regulatory reporting criteria, a pulmonary exacerbation requiring a hospitalization 
results in an SAE (regardless of its expectedness). For the TDN trials, sites are asked to record 
the symptoms or physical findings associated with the pulmonary exacerbation as individual 
adverse events and to designate the seriousness of each of these events. Thus a single 
pulmonary exacerbation can be reported as several SAEs.    
 
The incidence of AEs (including emergent abnormal QTc parameters) between the azithromycin 
and placebo treatment groups is tabulated by seriousness, severity, and relationship to study 
drug. The proportion of participants with at least one (S)AE, the average number of (S)AEs per 
patient, and the rate of (S)AEs per day of follow-up are reported. Poisson regression modeling is 
used to derive rate ratios and corresponding 95% confidence and to compare groups using a 
using a two-sided 0.05 level test. The difference in the proportion of participants experiencing at 
least one (S)AE between treatment groups is also reported, with  corresponding 95% confidence 
intervals  calculated using the Newcombe-Wilson method and p-values derived  from a Fisher’s 
exact test. Histograms showing the frequency of the number of (S)AEs in each treatment group 
are included. 
 
All reported SAEs and AEs are coded using MedDRA and grouped by body system. Detailed 
summary tables of individual (S)AEs grouped by SOC are included to show the number and 
percent of participants experiencing each (S)AE by treatment group. The number and rate of 
events for each (S)AE is also reported by treatment group. Poisson regression is used to derive 
rate ratios and corresponding 95% confidence intervals comparing treatment arms for each SOC. 
Treatment groups are compared by the proportion of participants experiencing (S)AEs by System 
Organ Class (SOC) as well as the difference in proportions with corresponding 95% confidence 
intervals to compare treatment arms.  
 
All SAE narratives are included in a listing appended to this report.  
 
 
A.5   Summary of Spirometry Results 
 
The primary endpoint is the difference between the azithromycin and placebo treatment groups in 
the relative change from Visit 1 to Visit 3 in FEV1 (liters). The primary efficacy analysis is 
conducted on the m-ITT population and repeated on per-protocol population. Predicted values for 
spirometry measures at each visit are calculated using the Global Lung Initiative reference 
equations. 
 
A linear regression model adjusted for randomization strata is used to compare the primary 
endpoint between treatment groups. Least squares means and the treatment effect are presented 


Statistical Analysis Plan 
TEACH-IP-15–CONFIDENTIAL 
10
along with corresponding 95% confidence intervals and p-values. The primary analysis is 
adjusted for the group sequential monitoring.  
 
The primary endpoint is also summarized descriptively as a plot of average values in each 
treatment group at each post-randomization visit accompanied by 95% confidence intervals 
(using t-distribution approximation).  
 
Additional secondary analysis may be performed to adjust for potential baseline confounders 
including age, sex, use of CFTR modulators, and baseline FEV1. To address missing data, the 
least favorable treatment arm imputation method is used to impute that missing value with the 
mean change from the treatment arm with the worst change in the observed case analysis. In 
further sensitivity analyses, the primary endpoint is summarized for a select number of baseline 
covariates including age, sex, baseline FEV1, chronic azithromycin use, and inhaled tobramycin 
formulation. 
 
The exploratory spirometry endpoints, i.e. absolute change from Visit 1 to Visit 3 in FEV1 (liters 
and % predicted), absolute and relative change in FVC (liters and % predicted), and absolute and 
relative change in FEF25-75% are summarized descriptively as plots of mean values and 
corresponding 95% confidence intervals over time.  
 
Additionally, changes in spirometry measures from Visit 1 to Visit 3 and Visit 2 to Visit 3 are 
modeled using linear regression adjusted for randomization strata. The estimates of least squares 
means, differences in the least squares means between the treatment groups, and corresponding 
95% confidence intervals and p-values are presented.  
 
All of the spirometry measures are summarized at each study visit during the randomized period 
and as a change from Visit 1 and Visit 2. The differences between treatment groups are 
presented with accompanying 95% confidence intervals and p-values calculated using two-
sample t-tests. 
 
Post-hoc comparisons of participants responding and not responding to monotherapy are 
summarized. Several ‘responder’ definitions are considered, e.g. XX% or greater relative increase 
in FEV1 % predicted from Visit 1 to Visit 3, XX% or greater relative increase in FEV1 % predicted 
from Visit 2 to Visit 3, 11 or greater point decline in CFRSD-CRISS from Visit 1 to Visit 3, and a 
XX point increase in CFQ-R respiratory symptom scale. 
 
 
A.6   Pulmonary Exacerbations, Hospitalizations and Antibiotic Usage 
 
The number of pulmonary exacerbations and hospitalizations is descriptively summarized. 
Proportions of participants initiating intravenous, inhaled, and oral antibiotics during randomized 
period are also presented. The differences in the proportions of participants experiencing at least 
one event between treatment groups are estimated with accompanying 95% confidence intervals 
calculated using the Newcombe-Wilson method and p-values derived from a Fisher’s exact test. 
 
 
A.7   Summary of Weight 
 
Mean changes in weight (kg) from Visit 1 to each post-randomization visit for both treatment 
groups during the randomized period are summarized descriptively in a figure. 95% confidence 
intervals (using t-distribution approximation) are included at each time point. The number of 
participants at each time point is included in a legend below the figure.   


Statistical Analysis Plan 
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11
 
A linear regression model adjusted for randomization strata is used to compare changes in weight 
(kg) between treatment groups. Least squares means and the treatment effect are presented 
along with corresponding 95% confidence intervals and p-values.  
 
The weight (kg) is also summarized at each study visit during the randomized period and as a 
change from Visit 1 and Visit 2. The differences between treatment groups are presented with 
accompanying 95% confidence intervals and p-values calculated using two-sample t-tests. 
 
 
A.8   Summary of Patient-Reported Quality of Life Measures 
 
Mean changes in CFRSD-CRISS and CFQ-R Respiratory Symptom Scale (RSS) from Visit 1 to 
each post-randomization visit for both treatment groups during the randomized period are 
summarized descriptively in figures. 95% confidence intervals (using t-distribution approximation) 
are included at each time point. The number of participants at each time point is included in a 
legend below the figures.   
 
Linear regression models adjusted for randomization strata are used to compare changes in 
CFRSD-CRISS and CFQ-R RSS between treatment groups. Least squares means and the 
treatment effect are presented along with corresponding 95% confidence intervals and p-values.  
 
CFRSD-CRISS and CFQ-R RSS are also summarized at each study visit during the randomized 
period and as a change from Visit 1 and Visit 2. The differences between treatment groups are 
presented with accompanying 95% confidence intervals and p-values calculated using two-
sample t-tests