Clinical trial NCT02781610
Conditions: Pulmonary Cystic Fibrosis
Keywords: Cystic fibrosis Pulmonary exacerbation Antibiotic Treatment duration Lung infection Cystic Fibrosis Foundation Cystic Fibrosis Foundation National Patient Registry
Sponsor: Chris Goss
Start date: 2016-06-01; Completion date: 2020-03-06
Enrollment: 982 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
Cystic fibrosis (CF), a life-shortening genetic disease, is marked by acute episodes during which symptoms of lung infection increase and lung function decreases. These pulmonary exacerbations are treated with varying antibiotics for varying time periods based on needs determined by individual patients, their families, and the health care providers. Cystic fibrosis pulmonary guidelines for the treatment of pulmonary exacerbation published by the Cystic Fibrosis Foundation (CFF) in 2009 provided recommendations for treatment and also identified key questions for which additional studies were needed.

A strong desire among clinicians to reduce treatment durations (and reduce cost, inconvenience, and potential toxicities) is in conflict with belief that patients not responding robustly to treatment might benefit from extending treatment.

This randomized, controlled, open-label study is designed to evaluate the efficacy and safety of differing durations of IV treatment, given in the hospital or at home for a pulmonary exacerbation in adult patients with CF.

Detailed description:
The study will assess the non-inferiority of 10 days versus 14 days treatment duration among patients who have an early robust improvement (ERR subjects) and the superiority of 21 days versus 14 days treatment duration among the subjects who do not meet the definition of ERR (non-ERR; NERR).

Subjects will undergo pulmonary function testing (spirometry) and complete a respiratory symptom score \[Chronic Respiratory Infection Symptom Score (CRISS)\] at initiation of IV treatment (Baseline/ Visit 1) and at Day 7-10 (Visit 2). At Visit 2, subjects will be allocated to groups ERR or NERR based on their initial clinical response as determined by the change in forced expiratory volume in 1 second (FEV1; percent of predicted) and CRISS from Baseline and then randomized to an IV treatment duration (nested within group).

ERR subjects \[≥8% predicted improvement in FEV1 from Visit 1 to Visit 2 and CRISS reduction of ≥11 points from Visit 1 to Visit 2\] will be randomized 1:1 to either 10 days or 14 days total IV antibiotic treatment duration. Remaining (NERR) subjects will be randomized 1:1 to receive either 14 or 21 days total IV antibiotic treatment duration. All subjects will be evaluated again at Visit 3, 14 days following scheduled completion of IV antibiotic treatment.

Arms: arm 1: ERR treatment duration - 10 Day Standard of care IV antibiotic(s) will be selected by the treating physician. Duration of treatment is the assigned intervention. arm 2: ERR treatment duration - 14 Day Standard of care IV antibiotic(s) will be selected by the treating physician. Duration of treatment is the assigned intervention. arm 3: NERR treatment duration - 14 Day Standard of care IV antibiotic(s) will be selected by the treating physician. Duration of treatment is the assigned intervention. arm 4: NERR treatment duration - 21 Day Standard of care IV antibiotic(s) will be selected by the treating physician. Duration of treatment is the assigned intervention.
Interventions: intervention 1: Standard of care IV antibiotic(s)
Intervention descriptions: intervention 1: IV antibiotics will be selected by the treating physician following standard of care. Duration of treatment is the assigned intervention.

Protocol documents:
Prot_001.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:  STOP2-IP-15 
 
Protocol Title:  Standardized Treatment of Pulmonary Exacerbations II (STOP2) 
 
Protocol Date:  November 2, 2018 
 
 
 
 
Investigator Signature 
 
Date 
 
 
 
Print Name and Title 
 
 
Site #: 
 
 
Site Name: 
 
 
Address: 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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TABLE OF CONTENTS 
1 
BACKGROUND.......................................................................................................................................... 13 
2 
STUDY RATIONALE ................................................................................................................................... 13 
2.1 
RISK / BENEFIT ASSESSMENT ................................................................................................................................ 14 
3 
STUDY OBJECTIVES ................................................................................................................................... 16 
3.1 
PRIMARY OBJECTIVE ........................................................................................................................................... 16 
3.2 
SECONDARY OBJECTIVES ...................................................................................................................................... 16 
3.3 
OTHER OBJECTIVES ............................................................................................................................................. 16 
4 
STUDY DESIGN ......................................................................................................................................... 16 
4.1 
STUDY OVERVIEW .............................................................................................................................................. 16 
5 
CRITERIA FOR EVALUATION ...................................................................................................................... 17 
5.1 
PRIMARY ENDPOINT ........................................................................................................................................... 17 
5.2 
SECONDARY ENDPOINTS ...................................................................................................................................... 17 
5.3 
EXPLORATORY ENDPOINTS ................................................................................................................................... 18 
6 
SUBJECT SELECTION ................................................................................................................................. 18 
6.1 
STUDY POPULATION ............................................................................................................................................ 18 
6.2 
INCLUSION CRITERIA ........................................................................................................................................... 18 
6.3 
EXCLUSION CRITERIA ........................................................................................................................................... 19 
6.4 
STUDY SPECIFIC TOLERANCE FOR INCLUSION/EXCLUSION CRITERIA .............................................................................. 19 
6.5 
SCREEN FAIL CRITERIA ......................................................................................................................................... 19 
7 
CONCURRENT MEDICATIONS ................................................................................................................... 20 
7.1 
ALLOWED MEDICATIONS AND TREATMENTS ............................................................................................................ 20 
7.2 
PROHIBITED MEDICATIONS AND TREATMENTS ......................................................................................................... 20 
8 
STUDY TREATMENTS ................................................................................................................................ 21 
8.1 
METHOD OF ASSIGNING SUBJECTS TO RESPONSE GROUP AND TREATMENT ARMS ................................................ 21 
8.2 
ANTIBIOTIC SELECTION ........................................................................................................................................ 21 
8.3 
TREATMENT LOCATION ........................................................................................................................................ 21 
8.4 
MEASURES OF TREATMENT COMPLIANCE ................................................................................................................ 22 
9 
STUDY PROCEDURES AND GUIDELINES ..................................................................................................... 22 
9.1 
CLINICAL ASSESSMENTS ....................................................................................................................................... 22 
9.2 
COLLECTION OF CLINICAL CARE LABORATORY RESULTS .............................................................................................. 24 
9.3 
RESEARCH LABORATORY MEASUREMENTS ............................................................................................................... 24 
10 
EVALUATIONS BY VISIT ............................................................................................................................. 25 
10.1 
VISIT 1 (DAY 1) ............................................................................................................................................. 25 
10.2 
VISIT 2 (DAY 7‐10 ±1 DAYS) ........................................................................................................................... 26 
10.3 
VISIT 3 (FOLLOW‐UP 2 WEEKS AFTER SCHEDULED COMPLETION OF IV TREATMENT /DAY 24 – 35 +/‐2 DAYS) ........ 26 
11 
ADVERSE EXPERIENCE REPORTING AND DOCUMENTATION ...................................................................... 27 
11.1 
ADVERSE EVENTS .......................................................................................................................................... 27 
11.2 
SERIOUS ADVERSE EXPERIENCES (SAE) .............................................................................................................. 28 
11.3 
MEDICAL MONITORING .................................................................................................................................. 29 
12 
DISCONTINUATION AND REPLACEMENT OF SUBJECTS .............................................................................. 29 


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12.1 
EARLY WITHDRAWAL OF SUBJECTS FROM THE STUDY ........................................................................................... 29 
12.2 
REPLACEMENT OF SUBJECTS ............................................................................................................................ 29 
13 
PROTOCOL VIOLATIONS ........................................................................................................................... 30 
14 
DATA SAFETY MONITORING ..................................................................................................................... 30 
15 
STATISTICAL METHODS AND CONSIDERATIONS ........................................................................................ 30 
15.1 
DATA SETS ANALYZED .................................................................................................................................... 30 
15.2 
DEMOGRAPHIC AND BASELINE CHARACTERISTICS ................................................................................................. 31 
15.3 
ANALYSIS OF PRIMARY ENDPOINT ..................................................................................................................... 31 
15.4 
ANALYSIS OF SECONDARY ENDPOINTS ................................................................................................................ 31 
15.5 
ANALYSIS OF EXPLORATORY ENDPOINTS ............................................................................................................. 32 
15.6 
INTERIM ANALYSIS ......................................................................................................................................... 33 
15.7 
SAMPLE SIZE ................................................................................................................................................. 33 
16 
DATA COLLECTION, RETENTION AND CLINICAL MONITORING ................................................................... 34 
16.1 
DATA COLLECTION INSTRUMENTS ..................................................................................................................... 34 
16.2 
DATA MANAGEMENT PROCEDURES .................................................................................................................. 34 
16.3 
DATA QUALITY CONTROL AND REPORTING ......................................................................................................... 35 
16.4 
SECURITY AND ARCHIVAL OF DATA .................................................................................................................... 35 
16.5 
AVAILABILITY AND RETENTION OF INVESTIGATIONAL RECORDS ................................................................................ 35 
16.6 
MONITORING ............................................................................................................................................... 36 
16.7 
SUBJECT CONFIDENTIALITY .............................................................................................................................. 36 
17 
ADMINISTRATIVE, ETHICAL, REGULATORY CONSIDERATIONS ................................................................... 36 
17.1 
PROTOCOL AMENDMENTS ............................................................................................................................... 36 
17.2 
INSTITUTIONAL REVIEW BOARDS ...................................................................................................................... 36 
17.3 
INFORMED CONSENT FORM ............................................................................................................................. 37 
17.4 
CONSENT FOR COLLECTION AND USE OF CFF REGISTRY ID NUMBER (US SITES ONLY) ................................................ 37 
17.5 
PUBLICATIONS .............................................................................................................................................. 38 
17.6 
INVESTIGATOR RESPONSIBILITIES ....................................................................................................................... 38 
18 
REFERENCES ............................................................................................................................................. 39 
19 
APPENDIX 1. SCHEDULE OF EVENTS .......................................................................................................... 41 
 
 
 


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LIST OF ABBREVIATIONS AND ACRONYMS 
AE 
adverse event 
ANOVA 
Analysis of variance 
CF 
cystic fibrosis 
CFF 
Cystic Fibrosis Foundation 
CFFNPR 
Cystic Fibrosis Foundation National Patient Registry 
CFFT 
Cystic Fibrosis Foundation Therapeutics 
CFR 
Code of Federal Regulations 
CFRSD 
Cystic Fibrosis Respiratory Symptoms Diary 
CRISS 
Chronic Respiratory Infection Symptom Score 
CFTR 
cystic fibrosis transmembrane conductance regulator 
CRF 
case report form 
CRP 
C-Reactive Protein 
DMC 
Data Monitoring Committee 
DSMB 
Data Safety Monitoring Board 
EDC 
electronic data capture 
ERR 
Early Robust Response 
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 
GLI 
Global Lung Initiative 
HIPAA 
Health Insurance Portability and Accountability Act of 1996 
ICH 
International Conference on Harmonisation 
IEC 
Independent Ethics Committee 
IRB 
Institutional Review Board 
IV 
intravenous 
MedDRA 
Medical Dictionary for Regulatory Activities 
NERR 
Non-Early Robust Response 
PEx 
pulmonary exacerbation  
PFT 
pulmonary function test 
SAE 
serious adverse experience 
TDNCC 
Therapeutics Development Network Coordinating Center 


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PROTOCOL SYNOPSIS 
TITLE 
Standardized Treatment of Pulmonary Exacerbations II (STOP2) 
SPONSOR-
INVESTIGATORS 
Patrick Flume, MD 
Medical University of South Carolina 
Christopher H. Goss, MD MSc 
University of Washington 
FUNDING 
ORGANIZATION 
Cystic Fibrosis Foundation Therapeutics, Inc (CFFT) 
NUMBER OF SITES 
Approximately 60 
RATIONALE 
In patients with cystic fibrosis (CF) who are experiencing a 
pulmonary exacerbation, a strong desire among clinicians to reduce 
treatment durations (and reduce cost, inconvenience, and potential 
toxicities) is in conflict with belief that patients not responding 
robustly to treatment might benefit from extending treatment.  An 
assessment taken after one week of treatment has been demonstrated 
to predict the overall response, especially for those with a robust 
improvement (Early Robust Response; ERR).  These patients are 
often treated with shorter courses of intravenous (IV) antibiotics in 
clinical practice and will likely experience no additional benefit from 
an extended IV treatment.  For those subjects who have a less robust 
early response to treatment, an extended treatment duration may be 
needed; however, the additional clinical benefit of such a prolonged 
course of IV antibiotic must outweigh potential risks of toxicity, 
treatment burden, and increased resource utilization. 
STUDY DESIGN 
This randomized, controlled, open-label study is designed to evaluate 
the efficacy and safety of differing durations of IV treatment, given in 
the hospital or at home for a pulmonary exacerbation in adult patients 
with CF.  The study will assess the non-inferiority of 10 days versus 
14 days treatment duration among ERR subjects and the superiority 
of 21 days versus 14 days treatment duration among the subjects who 
do not meet the definition of ERR (non-ERR; NERR) 
Subjects will undergo pulmonary function testing (spirometry) and 
complete a respiratory symptom score [Chronic Respiratory Infection 
Symptom Score (CRISS)] at initiation of IV treatment (Baseline/ 
Visit 1) and at Day 7-10 (Visit 2).  At Visit 2, subjects will be 
allocated to groups ERR or NERR based on their initial clinical 
response as determined by the change in forced expiratory volume in 
1 second (FEV1; percent of predicted) and CRISS from Baseline and 
then randomized to an IV treatment duration (nested within group).  
ERR subjects [≥8% predicted improvement in FEV1 from Baseline 
(Visit 1) to Visit 2 and CRISS reduction of ≥11 points from Baseline 
(Visit 1) to Visit 2] will be randomized 1:1 to either 10 days or 14 
days total IV antibiotic treatment duration. Remaining (NERR) 


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subjects will be randomized 1:1 to receive either 14 or 21 days total 
IV antibiotic treatment duration.  All subjects will be evaluated again 
at Visit 3, 14 days following scheduled completion of IV antibiotic 
treatment. 
DURATION OF 
SUBJECT 
PARTICIPATION 
AND DURATION OF 
STUDY  
Dependent on the treatment arm, subjects will be on study from 24 to 
35 days: 
 Treatment prior to randomization:  7 – 10 days 
 Treatment post-randomization: 
o ERR-10 subjects: 0 to 3 days = 10 days (±1 day) total IV 
treatment 
o ERR-14 subjects: 4 to 7 days = 14 days (±1 day) total IV 
treatment 
o NERR-14 subjects :  4 to 7 days = 14 days (±1 day) total IV 
treatment 
o NERR-21 subjects: 11 to 14 days = 21 days (±3 days) total IV 
treatment 
 Follow-up: 14 days after end of scheduled IV antibiotic treatment 
(±2 days) 
The total duration of the study is expected to be approximately 42 
months:  41 months for subject recruitment and 1 month for final 
subject follow-up. 
PRIMARY 
OBJECTIVE 
To evaluate the efficacy and safety of differing durations of 
IV antibiotic treatment for CF pulmonary exacerbations 
 
ERR Group: To determine if 10 days of IV antibiotic 
treatment (ERR-10) is as safe as and not clinically inferior (in 
terms of lung function response) to 14 days of IV antibiotic 
treatment (ERR-14) among subjects meeting the ERR 
threshold at Visit 2. 
 
NERR Group: To determine if 21 days of IV antibiotic 
treatment (NERR-21) is clinically superior (in terms of lung 
function response) and safe, compared to 14 days of IV 
antibiotic treatment (NERR-14) among subjects not meeting 
the ERR threshold at Visit 2.
SECONDARY 
OBJECTIVES 
The secondary objectives are to: 
 Evaluate efficacy of differing IV antibiotic treatment durations on 
other clinical outcomes such as weight, respiratory symptoms, 
and subsequent IV antibiotic treatments for pulmonary 
exacerbation. 
 Determine the feasibility, uptake and adherence to a standardized 
protocol of antibiotic selection. 
 


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Other objectives are to:  
 Provide a study platform for ancillary studies of PEx treatment in 
adults with CF, including investigations into respiratory 
microbiome, health economics, and systemic inflammation. 
 Establish a biorepository of CF serum and sputum samples 
before, during and after treatment for an adult PEx for use by the 
CF research community.  
NUMBER OF 
SUBJECTS 
Approximately 1330 screened to enroll a minimum of 310 completed 
ERR subjects and a minimum of 570 completed NERR subjects 
SUBJECT 
SELECTION 
CRITERIA:  
Inclusion Criteria 
Inclusion Criteria: 
1. Male or female ≥18 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: 
 Sweat chloride equal to or greater than 60 mEq/liter by 
quantitative pilocarpine iontophoresis test (QPIT)  
 Two well-characterized mutations in the cystic fibrosis 
transmembrane conductance regulator (CFTR) gene  
 Abnormal nasal potential difference (change in NPD in 
response to a low chloride solution and isoproteronol of less 
than -5 mV) 
3. Enrolled in the Cystic Fibrosis Foundation National Patient 
Registry (CFFNPR) prior to Visit 1 (US sites only) 
4. At the time of Visit 1, there is a plan to initiate IV antibiotics for a 
pulmonary exacerbation  
5. Performed spirometry at Visit 1 and Visit 2 and willing to 
perform spirometry at Visit 3 
6. Completed the CRISS questionnaire at Visit 1 and Visit 2 and 
willing to complete the CFRSD questionnaire at Visit 3 
7. Willing to adhere to a specific treatment duration determined by 
initial response to treatment and subsequent randomization 
8. Willing to return for  follow up Visit 3 
9. Written informed consent obtained from the subject or subject’s 
legal representative 
SUBJECT 
SELECTION 
CRITERIA:  
Exclusion Criteria 
Exclusion Criteria: 
1. Previous randomization in this study  
2. Treatment with IV antibiotics in the 6 weeks prior to Visit 1 
3. Admission  to the intensive care unit for current pulmonary 
exacerbation in the two weeks prior to Visit 2, unless admission 
was due to a desensitization protocol 
4. Pneumothorax in the two weeks prior to Visit 2 


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5. Primary diagnosis for current hospitalization is unrelated to 
worsening lower respiratory symptoms (e.g., pulmonary clean 
out, DIOS, sinusitis) 
6. Massive hemoptysis defined as > 250 cc in a 24 hour period or 
100 cc/day over 4 consecutive days occurring in the two weeks 
prior to Visit 2 
7. Current pulmonary exacerbation thought to be due to allergic 
bronchopulmonary aspergillosis (ABPA) 
8. At Visit 1, receiving ongoing treatment with a duration of more 
than 2 weeks with prednisone equivalent to >10mg/day 
9. History of  solid organ transplantation 
10. Receiving antimicrobial therapy to treat non-tuberculous 
mycobacterium (e.g., M. abscessus, M. avium complex) in the 
two weeks prior to Visit 2 
TEST PRODUCT, 
DOSE, AND ROUTE 
OF 
ADMINISTRATION 
Initial IV antibiotics will be selected by the treating physician using 
study-specific guidelines provided and taking into account prior 
sputum culture results, previous antibiotic intolerances, and known 
drug allergies.   
CONTROL 
PRODUCT, DOSE 
AND ROUTE OF 
ADMINISTRATION 
N/A 
CONCOMMITANT 
MEDICATIONS 
Allowed Medications and Treatments 
Chronic Therapies 
A stable therapeutic regimen between Baseline (Visit 1) and Visit 3 is 
the goal. Ongoing chronic treatment (>21 days prior to Visit 1) with 
Pulmozyme®, high dose ibuprofen, hypertonic saline, azithromycin, 
short and long bronchodilators, airway clearance, and FDA approved 
CFTR modulator therapy is allowed. Subjects that have been using 
any of these therapies chronically should be encouraged to continue 
them throughout the entire study period (through Visit 3). Any of 
these medications may be introduced between Visit 1 and Visit 3 if 
they are intended to remain as a chronic therapy.  Chronic 
medications can be stopped if the clinician has determined that the 
therapy is either ineffective or doing harm.   
Continuation of ongoing chronic treatment (>21 days prior to 
screening) with inhaled or oral antibiotics is allowed according to the 
schedule below: 
 If a subject is taking continuous inhaled or oral antibiotics, 
they may take them anytime between Visit 1 and 3. 
 If a subject is taking cycled inhaled antibiotics, they may 
maintain their current on/off cycle, but ideally will not start a 
new cycle during the 14 days prior to Visit 3.   


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Treatment of PEx 
Treatment with corticosteroids is allowed at the discretion of the 
treating clinician for the indication of the current PEx.  However, the 
decision to use corticosteroids should be made prior to randomization 
at Visit 2 as this will be included as a randomization stratum.   
Subjects should perform maximally effective airway clearance 
therapies during the course of treatment for the PEx.  These will be 
recommended by the treating clinician. 
Following Completion of Treatment of PEx 
Corticosteroids, if initiated during the treatment, should be weaned 
according to the clinician’s usual practice. 
Prohibited Medications and Treatments 
No antibiotics (oral or inhaled) should be taken following the 
scheduled completion of the IV treatment of PEx until after Visit 3 
except as noted in the Allowed Medications section.  
Investigational therapies are prohibited during the study. 
PRIMARY 
ENDPOINT 
Absolute change in percent predicted FEV1 from initiation of IV 
treatment (Baseline/Visit 1) to two weeks after scheduled completion 
of IV antibiotic treatment (Visit 3). 
SECONDARY 
ENDPOINTS 
Efficacy 
 Absolute change in CRISS from Visit 1 (Baseline) to Visit 3 
 Proportion of patients retreated for pulmonary exacerbation 
within 30 days following scheduled completion of IV antibiotics 
as collected in the CFFNPR 
 Time (days) to next pulmonary exacerbation following scheduled  
completion of IV antibiotics as collected in the CFFNPR 
 Relative change in FEV1 (liters) from Visit 1 (Baseline) to Visit 3 
 Absolute change in weight (kg) from Visit 1 (Baseline) to Visit 3 
Safety 
 Incidence of adverse events, including clinically significant 
abnormal lab values 
 Retreatment of pulmonary exacerbation prior to Visit 3 
Exploratory Endpoints 
 Baseline, treatment characteristics, and outcomes (via CFFNPR) 
of the un-randomized subjects by reason (e.g., ineligible, lost to 
follow-up)  
 Baseline, treatment characteristics, and outcomes (via CFFNPR) 
of the randomized but lost to follow-up subjects 
 Adherence to antibiotic selection protocol  
 Adherence to randomization scheme  


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 C-reactive protein at all visits and change from Visit 1 (Baseline) 
to Visit 2 and 3  
 Health related quality of life 
 Direct and indirect medical costs 
 Sputum microbiome 
PLANNED INTERIM 
ANALYSIS 
The Cystic Fibrosis Foundation Data Safety Monitoring Board 
(DSMB) will establish a Data Monitoring Committee (DMC) to 
review data relating to safety and efficacy, to conduct and review 
interim analyses, and to ensure the continued scientific validity and 
merit of the study. Serious adverse events will be monitored by the 
committee on an ongoing basis throughout the study. 
A pre-defined monitoring plan for feasibility, variance estimation, 
sample size adaptation, and study stopping rules will be formalized in 
conjunction with the DMC and will be in place prior to initiating the 
study. Feasibility will be closely monitored for the first 100 enrolled 
subjects to ensure adherence to antibiotic protocol, return for 
randomization, and adherence to randomized treatment duration.  
Each group (ERR and NERR) will have separate monitoring criteria 
and a decision to stop one may not be conditional on the other. 
STATISTICS 
Primary Analysis Plan 
The primary endpoint is absolute change in percent predicted FEV1 
from Visit 1 (Baseline) to two weeks after scheduled completion of 
IV antibiotics (Visit 3). The primary endpoint will be compared 
between treatment durations within ERR and NERR groups using 
Analysis of Variance (ANOVA) adjusted for dichotomous 
randomization strata: Visit 1 FEV1, number of IV-treated 
exacerbations in prior year, location of IV administration by Visit 2, 
and use of systemic corticosteroids by Visit 2.  
The treatment effect for each group (ERR and NERR) (estimated via 
adjusted ANOVA least squares means) will be presented along with 
corresponding 95% confidence intervals. Observed treatment effect 
and the 95% CI will provide primary inference and evidence of non-
inferiority, superiority, or lack thereof in both the ERR and NERR 
groups.   
ERR Group: The non-inferiority of ERR-10 versus ERR-14 will be 
tested against a 3.5% predicted non-inferiority margin with a two-
sided 0.05 level of significance. 
NERR Group: The superiority of NERR-21 versus NERR-14 will be 
tested with a two-sided 0.05 level of significance. 
Further details will be provided in the Statistical Analysis Plan (SAP).
 
Rationale for Number 
of Subjects 
ERR Group: 
A non-inferiority design to show that the change in FEV1 between 


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Visit 1 and Visit 3 in the ERR subjects who received 10 days of 
treatment (ERR-10) is no more than 3.5% predicted less than ERR 
subjects who received 14 days treatment (ERR-14) requires 310 
subjects (155 per arm) who complete the study.  STOP pilot data 
indicate a mean change (SD) in FEV1 between Baseline and Day 28 in 
patients with an early response to be 12.5 % predicted, 95% CI [9.5, 
15.6]. Assuming  two-sided alpha =0.05, standard deviation =9.0% 
predicted and the true difference between two groups is zero, the ERR 
study has 93% power to detect a 3.5 % non-inferiority margin which 
preserves 72% of the treatment effect or 63% of the lower bound of 
treatment effect observed in the STOP pilot.   
NERR Group: 
A superiority design to show that the change in FEV1 between Visit 1 
and Visit 3 in NERR subjects who received 21 days treatment 
(NERR-21) is at least 2.5% predicted greater than NERR subjects who 
received 14 days treatment (NERR-14) requires 570 subjects (285 per 
arm) who complete the study.  STOP pilot data indicate a mean 
change (SD) in FEV1 between Baseline and Day 28 in patients 
without an early response to be 4.0% predicted, 95% CI [1.9, 6.1].  
Assuming two-sided alpha =0.05 and standard deviation =9.0% 
predicted, the NERR study has 91% power to detect a 2.5% greater 
increase in FEV1 among those treated with 21 days compared to 14 
day IV antibiotic. Because this trial will enroll a slightly different 
patient population (including home IV, excluding patients who receive 
<7 days of IV antibiotics), a blinded, interim assessment of change in 
FEV1 % predicted and variance (pooled) will be performed and 
expected sample size may be adjusted for either the ERR or NERR 
groups. 
Based on STOP pilot data, we anticipate 1:2 allocation of subjects into 
the ERR and NERR groups. To meet the enrollment goal of a 
minimum of 310 completed ERR subjects and a minimum of 570 
completed NERR subjects), we will screen approximately 1330 
subjects. Of these, we expect approximately 1236 subjects will be 
enrolled and randomized (assuming a conservative 7% drop-out rate 
between Visit 1 and Visit 2) and a minimum of 310 completed ERR 
subjects and a minimum of 570 completed NERR subjects 
(assuming an approximate 4% drop-out rate between Visit 2 and Visit 
3). 
 


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1 
BACKGROUND 
Cystic fibrosis (CF), a life-shortening genetic disease, is marked by acute episodes during 
which symptoms of lung infection increase and lung function decreases, termed pulmonary 
exacerbations (PEx).  PEx are associated with reduced health-related quality of life1-3 
accelerated pulmonary function decline4 and decreased survival5-8, and are commonly treated 
with antibiotics and supportive respiratory care.  The incidence of PEx appears to be relatively 
constant over the life of a CF patient, but antibiotic treatments change as patient airway 
infections become more complex and lung disease advances.9  In adolescents and adults, the 
proportions of PEx that are treated with intravenous (IV) antibiotics steadily increases.9,10  
There has been no consensus as to how long to treat PEx with IV antibiotics and treatment 
durations can range from days to weeks.11 Cystic fibrosis consensus pulmonary guidelines for 
the treatment of PEx sponsored by the Cystic Fibrosis Foundation (CFF) in 200912 provided 
recommendations for PEx treatment and also identified key questions for which additional 
studies were needed, including whether there was an optimal duration of IV antibiotic 
treatment for CF pulmonary exacerbation. 
2 
STUDY RATIONALE 
Clinical trials provide the strongest evidence for medical decisions and are relied upon for evidence-
based treatment guidelines. Performing these trials can be expensive and burdensome; they typically 
require a specialized infrastructure that includes multiple sites with investigators and research 
coordinators, oversight providing intensive review of study protocols and study conduct, and 
development of rigorous data collection systems that require validation for accuracy. Because of the 
expense, many important questions may never be addressed.  This is especially true for comparison 
of therapies within the context of comparative effectiveness research (CER) studies.  These 
challenges are especially troublesome for those who treat patients with an orphan disease, such as 
CF.  Because there are fewer patients, studies require an even greater number of sites, often driving 
up the expense.  What are needed are innovative study designs that allow for greater flexibility, 
taking advantage of existing infrastructures to speed up the conduct of the trial and to reduce the 
overall cost.   
An acute drop in pulmonary function is highly associated with the diagnosis and treatment of PEx13 
and treatment with IV antibiotics has been shown to result in improved lung function in CF patients 
experiencing PEx.14  In 2011, 35.1% of patients of all ages followed in the Cystic Fibrosis 
Foundation National Patient Registry (CFFNPR, 9,516 patients) were treated at least once with IV 
antibiotics for PEx, with the median number of IV antibiotic treatment days per PEx varying greatly 
by CF care center, from 3 days to 24.2 days (CFF 2012).15  Unfortunately, it has been estimated that 
as many as a quarter of patients with PEx treated with IV antibiotics fail to return to even 90% of 
the lung function they had prior to exacerbation.16 
In 2011, the median duration of IV antibiotic treatment for PEx in the US was 13.5 days for children 
less than 18 years of age and 14.5 days for older patients.15  There have been no objective studies of 
the effect of antibiotic treatment duration on patient response.  For this reason, it is not known 
whether very short IV antibiotic treatment durations, apparently practiced in some US care 
centers,15 are associated with incomplete patient responses.  Similarly, if little additional benefit is 
realized beyond about 2 weeks of antibiotic treatment for PEx11 (as has been suggested by 
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approximately half of US CF patients15 may only serve to increase the risk of treatment-associated 
toxicity and burden without a corresponding improvement in health outcomes.  
Identification of an optimal IV antibiotic treatment duration, if one exists, has the potential to 
improve overall PEx treatment outcomes and at the same time reduce toxicity and treatment burden 
associated with overtreatment for PEx.    
Recently an observational pilot study of 220 CF subjects admitted to the hospital for treatment 
of a pulmonary exacerbation was conducted (STOP) to evaluate the variability of treatment 
durations and to identify the clinical outcome measures deemed most important to care-givers 
in determining treatment success. The design of the current STOP2 study has been informed by 
the first STOP study, the results of previous clinical trials and with input from both CF patients 
and clinicians obtained through surveys.  Specifically, the proposed primary efficacy measures 
(changes in respiratory symptoms and spirometry) are known to change within 2-4 weeks 
(previous clinical trials and the observational STOP trial); furthermore, the survey data 
indicated that these two measures were the most important in defining treatment success to 
caregivers (spirometry) and patients (symptom resolution).   In addition, these surveys indicated 
both a strong desire to reduce treatment duration (and reduce cost, inconvenience, and potential 
toxicities) and concern about whether subjects might be treated for too short of a period if they 
were not responding to treatment.  The STOP2 trial will evaluate three different treatment 
durations (10, 14, and 21 days), but will utilize an early assessment of response after 7 to 10 
days of treatment to determine whether to randomize a subject to a shorter or longer duration of 
treatment.  In the observational STOP study, an assessment performed after one week of 
treatment was shown to predict the overall response, especially for those with a robust 
improvement (Early Robust Response; ERR) (STOP unpublished data); these patients are often 
treated with shorter courses of IV antibiotics in clinical practice.  Subjects who are responding 
more slowly (Non-Early Robust Response; NERR) can be reassured they will not have early 
cessation of treatment, and that the treatment durations for subjects in the NERR groups are 
consistent with common practices.   
For practical reasons, this study must be open-label as to the treatment durations; however, 
aggregate results will be blinded and tightly controlled until the end of the trial.  Clinical care 
will be determined by the treating physician but will adhere to recommendations in the 
standardized protocol to assure patients are receiving optimal treatment and to reduce the 
variation in other treatment parameters. 
2.1 
Risk / Benefit Assessment 
Treatment-Associated Risks:  
This is an interventional study that will dictate the duration of IV antibiotics for the treatment of 
pulmonary exacerbation. There can be risks associated with the randomization as patients might 
be allocated to a duration of antibiotic therapy that may be too short or too long.  The potential 
risk of an insufficient duration of antibiotics is an early relapse of the exacerbation, although 
surveys of CF clinicians reveal that a majority consider any new treatment for an exacerbation, at 
any time after the previous treatment, to be a new event rather than a relapse.  The potential risks 
of an excess duration of antibiotics include unnecessary cost as well as the potential for injury 
attributed to the treatment, specifically drug toxicity (e.g., antibiotic-associated nephrotoxicity, 
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antibiotic use) or a complication related to the indwelling IV catheter (e.g., thrombus). Clinicians 
are keenly aware of these potential complications as part of standard therapy and monitor these 
risks routinely.  Generally, intravenous antibiotics used to treat acute pulmonary exacerbation in 
CF are all well tolerated, and CF patients have extensive experience receiving repeated courses 
of intravenous antibiotics for acute pulmonary exacerbation.     
It is noted that the duration of antibiotics will be 10, 14 or 21 days, which are consistent with 
current durations used to treat patients (CFFNPR data). Of note, 50% of patients will be 
randomized to 14 days of IV antibiotics, which is the most frequently used duration (CFFNPR 
data) and the most frequently reported duration by CF clinicians (survey data , not published).  In 
addition, the randomization is based upon the initial response to treatment such that the duration 
of antibiotics is even more likely to be consistent with current treatment practices [i.e., patients 
with a robust response will tend to get a shorter duration (10 vs 14 days) while those with a more 
sluggish response will tend to get a longer duration (14 vs. 21 days)]. This randomization 
allocation should mitigate the risks of inappropriately short or long durations as they will be tied 
to the initial patient response and are consistent with common practice among CF clinicians. 
There are other potential risks associated with antibiotic usage including adverse effects that are 
non-toxic (e.g., nausea, diarrhea) as well as selection of pathogens that are resistant to the 
therapy chosen (i.e., resistant bacteria, fungi).  It is noted that selection of resistant bacteria has 
been reported following standard of practice treatment of pulmonary exacerbations.17 The study 
Data Safety Monitoring Board (DSMB) will follow drug-related adverse events closely in the 
clinical trial.   
All other decisions regarding treatment of the pulmonary exacerbation (e.g., site of treatment, 
antibiotic selection, use of steroids) will be determined by the treating clinician.  There is a 
required assessment between days 7 and 10, which may not be consistent with the current site 
practice, but the tests performed are consistent with standard practice to assess response to 
therapy (i.e., spirometry, symptom assessment); any additional studies performed by the site 
clinicians are at their discretion. For these reasons, there is little additional treatment-associated 
risk to patients based upon their participation in this study.   
Risks of Study Procedures: All study procedures performed during the study are consistent with 
standard of clinical care and there are no perceived additional risks in regard to physical well-
being.  During the study, there will be additional blood draws.  The risk of collecting blood 
includes soreness, bruising, mild pain, mild bleeding or infection at the site. There is also risk of 
fainting or light-headedness. Topical application of a numbing agent to reduce the pain from the 
blood draws will be allowed. This may cause mild skin discoloration or swelling that resolves in 
1 to 2 hours. There is a small risk of wheezing, shortness of breath, and increased cough when 
performing spirometry.   
Risks to Confidentiality: As with any research study, there is a potential risk of breach of 
individual patient confidentiality. Study personnel at each site will enter data from source 
documents into a protocol-specific electronic Case Report Form (CRF).  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 subject identification (ID) number unique to this study. Only authorized 
individuals will be able to link the study ID to the subject’s name (site personnel at the individual 
sites, clinical site monitors, auditors).    


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Potential Benefits:  As this is a randomized allocation to a treatment duration, there is no 
anticipation that patients will realize additional benefit beyond that associated with routine 
management of their pulmonary exacerbations.  The anticipated overall benefit is definition of 
optimal treatment durations and standardized practice in the future. 
3 
STUDY OBJECTIVES 
3.1 
Primary Objective 
The primary objective of this study is to evaluate the efficacy and safety of differing 
durations of IV antibiotic treatment for CF pulmonary exacerbations. Objectives for these 
two groups are as follows: 
ERR Group: To determine if 10 days of IV antibiotic treatment (ERR-10) is as safe as 
and not clinically inferior (in terms of lung function) to 14 days of IV antibiotic treatment 
(ERR-14) among subjects meeting the ERR threshold at Visit 2. 
NERR Group: To determine if 21 days of IV antibiotic treatment (NERR-21) is clinically 
superior (in terms of lung function) and safe, compared to 14 days of IV antibiotic treatment 
(NERR-14) among subjects not meeting the ERR threshold at Visit 2.  
3.2 
Secondary Objectives 
The secondary objectives are to: 
 Evaluate efficacy of differing IV antibiotic treatment durations on other clinical outcomes 
such as weight, respiratory symptoms, and subsequent IV antibiotic treatments for pulmonary 
exacerbation. 
 Determine the feasibility, uptake and adherence to a standardized protocol of antibiotic 
selection. 
3.3 
Other Objectives 
 Provide a study platform for ancillary studies of PEx treatment in adults with CF, including 
investigations into respiratory microbiome, health economics, and systemic inflammation. 
 Establish a biorepository of CF serum and sputum samples before, during and after treatment 
for an adult PEx for use by the CF research community.  
4 
STUDY DESIGN 
4.1 
Study Overview 
This randomized, controlled, open-label study is designed to evaluate the efficacy and safety of 
differing durations of IV treatment, given in the hospital or at home for a pulmonary 
exacerbation in adult patients with CF (Figure 1).  Approximately 1330 subjects will be screened 
in an effort to enroll a minimum of 310 completed ERR subjects and a minimum of 570 
completed NERR subjects. 
The study will assess the non-inferiority of 10 days versus 14 days treatment duration among 
ERR subjects and the superiority of 21 days versus 14 days treatment duration among NERR 
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The duration of participation for each subject is dependent on the response group (ERR versus 
NERR) and randomization within group.   Subjects will be on study anywhere from 24 to 35 
days. Subjects will undergo pulmonary function testing (spirometry) and complete a respiratory 
symptom score (CRISS) at initiation of IV treatment (Baseline/Visit 1) and at Day 7-10 (Visit 2).  
At Visit 2, subjects will be allocated to groups ERR or NERR based on their initial clinical 
response as determined by the change in FEV1 (percent of predicted) and CRISS from Baseline 
and then randomized to an IV treatment duration (nested within group).  ERR subjects [those 
who have experienced ≥8% predicted improvement in FEV1 from Baseline (Visit 1) to Visit 2 
and CRISS reduction of ≥11 points from Baseline (Visit 1) to Visit 2] will be randomized 1:1 to 
either 10 days or 14 days total IV antibiotic treatment (ERR-10 and ERR-14 arms). NERR 
subjects (who have not experienced changes from Visit 1 that qualify them for the ERR group) 
will be randomized 1:1 to receive either 14 or 21 days total IV antibiotic treatment (NERR-14 
and NERR-21 arms).  All subjects will be evaluated again at Visit 3, 14 days following 
scheduled completion of IV antibiotic treatment (Figure 1). 
Total duration of the study is expected to be approximately 42 months:  41 months for subject 
recruitment and 1 month for final subject follow-up.  
Figure 1. STOP2 Study Schematic 
 
 
5 
CRITERIA FOR EVALUATION 
5.1 
Primary Endpoint 
The primary endpoint in the study is a comparison in the absolute changes in percent predicted 
FEV1 from initiation of IV antibiotic treatment at Visit 1 to two weeks after scheduled 
completion of IV antibiotic treatment (Visit 3).   
5.2 
Secondary Endpoints 
Efficacy 
 Absolute change in CRISS from Visit 1 (Baseline) to Visit 3 
 Proportion of patients retreated for pulmonary exacerbation within 30 days following 
scheduled completion of IV antibiotics as collected in the CFFNPR 


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 Time (days) to next pulmonary exacerbation following scheduled completion of IV 
antibiotics as collected in the CFFNPR 
 Relative change in FEV1 (liters) from Visit 1 (Baseline) to Visit 3 
 Absolute change in weight (kg) from Visit 1 (Baseline) to Visit 3 
Safety 
 Incidence of adverse events, including clinically significant abnormal lab values 
 Retreatment of pulmonary exacerbation prior to Visit 3 
5.3 
Exploratory Endpoints 
 Baseline, treatment characteristics, and outcomes (via CFFNPR) of the un-randomized 
subjects by reason (e.g., in-eligible, lost to follow-up)  
 Baseline, treatment characteristics, and outcomes (via CFFNPR) of the randomized but lost 
to follow-up subjects 
 Adherence to antibiotic selection protocol  
 Adherence to randomization scheme  
 C-reactive protein at all visits and change from Visit 1 (Baseline) to Visit 2 and 3  
 Health related quality of life 
 Direct and indirect medical costs 
 Sputum microbiome 
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 participation in this study.   
6.2 
Inclusion Criteria 
1. Male or female ≥18 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: 
a. Sweat chloride equal to or greater than 60 mEq/liter by quantitative pilocarpine 
iontophoresis test (QPIT)  
b. Two well-characterized mutations in the cystic fibrosis transmembrane conductance 
regulator (CFTR) gene  
c. Abnormal nasal potential difference (change in NPD in response to a low chloride 
solution and isoproteronol of less than -5 mV) 
3. Enrolled in the Cystic Fibrosis Foundation National Patient Registry (CFFNPR) prior to Visit 
1 (US sites only) 
4. At the time of Visit 1, there is a plan to initiate intravenous (IV) antibiotics for a pulmonary 
exacerbation  


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5. Performed spirometry at Visit 1 and Visit 2 and willing to perform spirometry at Visit 3 
6. Completed the CRISS questionnaire at Visit 1 and Visit 2 and willing to complete the 
CFRSD questionnaire at Visit 3 
7. Willing to adhere to a specific treatment duration determined by initial response to treatment 
and subsequent randomization 
8. Willing to return for  follow up Visit 3  
9. Written informed consent obtained from the subject or subject’s legal representative 
6.3 
Exclusion Criteria 
1. Previous randomization in this study  
2. Treatment with IV antibiotics in the 6 weeks prior to Visit 1 
3. Admission  to the intensive care unit for current pulmonary exacerbation in the two weeks 
prior to Visit 2, unless admission was due to a desensitization protocol 
4. Pneumothorax in the two weeks prior to Visit 2 
5. Primary diagnosis for current hospitalization is unrelated to worsening lower respiratory 
symptoms (e.g., pulmonary clean out, DIOS, sinusitis) 
6. Massive hemoptysis defined as > 250 cc in a 24 hour period or 100 cc/day over 4 consecutive 
days occurring in the two weeks prior to Visit 2 
7. Current pulmonary exacerbation thought to be due to allergic bronchopulmonary 
aspergillosis (ABPA) 
8. At Visit 1, receiving ongoing treatment with a duration of more than 2 weeks with 
prednisone equivalent to >10mg/day 
9. History of solid organ transplantation 
10. Receiving antimicrobial therapy to treat non-tuberculous mycobacterium (e.g., M. abscessus, 
M. avium complex) in the two weeks prior to Visit 2 
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. Screen failures can be re-screened for this study at a subsequent pulmonary 
exacerbation. 


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7 
CONCURRENT MEDICATIONS 
7.1 
Allowed Medications and Treatments 
7.1.1 Chronic Therapies 
A stable therapeutic regimen between Baseline (Visit 1) and Visit 3 is the goal. Ongoing chronic 
treatment (>21 days prior to Visit 1) with Pulmozyme®, high dose ibuprofen, hypertonic saline, 
azithromycin, short and long bronchodilators, airway clearance, and FDA- approved CFTR 
modulator therapy is allowed. Subjects that have been using any of these therapies chronically 
should be encouraged to continue them throughout the entire study period (through Visit 3). Any 
of these medications may be introduced between Visit 1 and Visit 3 if they are intended to 
remain as a chronic therapy.  Chronic medications can be stopped if the clinician has determined 
that the therapy is either ineffective or doing harm.   
Continuation of ongoing chronic treatment (>21 days prior to screening) with inhaled or oral 
antibiotics is allowed according to the schedule below: 
 If a subject is taking continuous inhaled or oral antibiotics, they may take them anytime 
between Visit 1 and 3. 
 If a subject is taking cycled inhaled antibiotics, they may maintain their current on/off cycle, 
but ideally will not start a new cycle during the 14 days prior to Visit 3.   
7.1.2 Treatment of PEx 
Refer to Section 8.2 Antibiotic Selection for the study recommendations for antibiotic use.   
Treatment with corticosteroids is allowed at the discretion of the treating clinician for the 
indication of the current PEx.  However, the decision to use corticosteroids should be made prior 
to randomization at Visit 2 as this will be included as a randomization stratum.   
Subjects should perform maximally effective airway clearance therapies during the course of 
treatment for the PEx.  These will be recommended by the treating clinician. 
7.1.3 Following Completion of Treatment of PEx 
Corticosteroids, if initiated during the treatment, should be weaned according to the clinician’s 
usual practice. 
7.2 
Prohibited Medications and Treatments 
No antibiotics (oral or inhaled) should be taken following the scheduled completion of the IV 
treatment of PEx until after Visit 3 except as noted in Section 7.1.1 (above).   
Investigational therapies are prohibited during the study.  The combination modulator 
ivacaftor/tezacaftor or a triple combination therapy is not considered an investigational therapy 
and those subjects who are on an open label extension or an Expanded Access Program will be 
considered eligible for STOP2 as long as it is part of a stable regimen (i.e., >30 days of 
treatment). 


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8 
STUDY TREATMENTS 
8.1 
Method of Assigning Subjects to Response Group and Treatment Arms 
All eligible subjects will undergo pulmonary function testing (spirometry) and complete a 
respiratory symptom score (CRISS) at Baseline (Visit 1) and at Day 7-10 (Visit 2).  At Visit 2, 
subjects will be allocated to either the ERR or NERR group based upon their initial clinical 
response as determined by the change from Baseline in FEV1 (percent of predicted as determined 
by GLI equations) 18,19 and CRISS and then randomized to a treatment arm (duration nested 
within response group). The spirometry and CRISS measures must be present and entered into 
EDC for both Baseline (Visit 1) and Visit 2 for randomization to occur. 
ERR subjects [≥8% predicted improvement in FEV1 from Baseline (Visit 1) to Visit 2 and 
CRISS reduction of ≥11 points from Baseline (Visit 1) to Visit 2] will be randomized 1:1 to 
either 10 days (ERR-10) or 14 days (ERR-14) total IV antibiotic treatment duration while 
remaining subjects not meeting the ERR threshold will be randomized 1:1 to receive either 14 
(NERR-14) or 21 (NERR-21) days total IV antibiotic treatment duration. A minimum of 310 
subjects (155 per duration arm) will be allocated to the ERR group and a minimum of 570 subjects 
(285 per duration arm) to the NERR group. Randomization will occur by a predetermined scheme. 
Within each response group, subjects will be stratified by Visit 1 FEV1 (FEV1 < 50% of 
predicted versus ≥50% predicted), number of IV-treated exacerbations in prior year (0-1 versus 
2+ in prior year), location of IV treatment by Visit 2 (exclusively home versus any hospital 
nights), and use of systemic corticosteroids by Visit 2. 
Randomization will occur centrally using a web based randomization system linked to the 
electronic data capture (EDC) system.  Only authorized site personnel are given access to the 
EDC system. Authorized site personnel will enter subject eligibility information as well as any 
information needed for randomization stratification. The system will provide the appropriate 
authorized site personnel with a randomization assignment for that subject that matches a 
specific treatment duration. 
8.2 
Antibiotic Selection 
Initial IV antibiotics will be selected using study-specific guidelines provided and taking into 
account prior sputum culture results, previous antibiotic intolerances, and known drug allergies.  
Antibiotics may be changed at Visit 2 if presumed to be an insufficient response, sooner if there 
is a rapid decline, new intolerance or drug allergy.  Such changes should still adhere to the 
study-specific guidelines and may represent newly identified pathogens in sputum cultures.  If 
an antibiotic change is made due to insufficient response, the decision to change should be made 
prior to randomization at Visit 2.   
Once the subject has completed the assigned IV antibiotic duration, no additional oral, inhaled, 
or IV antibiotics should be administered, except as specified in Section 7.1 above.   
8.3 
Treatment Location 
The location of treatment (i.e., home vs. hospital) is at the discretion of the treating clinician.  
The patient may be treated entirely at home, entirely in the hospital, or any portion of treatment 
in the hospital with completion at home.   


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8.4 
Measures of Treatment Compliance 
Treatment compliance will be based on adherence to the study-specific antibiotic regimen and to 
the assigned duration of treatment.  The site will record antibiotic use in the Concomitant 
Medications CRF and the IV Antibiotic Treatment CRF. 
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 (if applicable) 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, 
dates of medication, and administration in the hospital or at home will be recorded on the CRF. 
9.1.2 Demographics and CFF Registry ID 
Demographic information (date of birth, sex, race) will be recorded.  CF Registry number will be 
recorded (US sites only).  
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. Supplemental medical history 
will be collected from the CFFNPR, if applicable.  
9.1.4 CF Diagnosis 
Diagnosis date and CF diagnosis criteria will be recorded. 
9.1.5 Physical Examination 
A complete or abbreviated physical examination will be performed by a licensed professional 
(e.g., MD, NP, RN, PA) as noted in the Schedule of Events.  The abbreviated exam includes 
respiratory, cardiovascular, and abdominal assessments.   
After randomization, new clinically significant abnormal physical exam findings must be 
evaluated to determine if they should be documented as adverse events (AEs).  
9.1.6 Weight and Height   
Weight will be measured on the same scale if possible and recorded as noted in the Schedule of 
Events. Subjects may remain in clothes (without shoes). A standing height will be measured and 
recorded as noted in the Schedule of Events. 


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9.1.7 Spirometry 
Spirometry will be performed as noted in the Schedule of Events and in accordance with the 
current American Thoracic Society recommendations for the performance and interpretation of 
tests.  At Visit 1, repeat spirometry does not need to be performed if spirometry test results are 
available within the three days prior to Visit 1.  If spirometry was performed more than 3 days 
prior to Visit 1, spirometry is required to be performed at Visit 1.  If spirometry cannot be 
performed at Visit 1, it can be performed the next day.  
Subjects who routinely use bronchodilators should use them consistently throughout the 
enrollment period. Standard guidelines are noted below as a reference: 
 Subjects who routinely use short acting inhaled bronchodilators should use them 15 minutes 
to 2 hours prior to pulmonary function tests (PFTs) during study visits. 
 Subjects who routinely use long acting bronchodilator agents should use them 15 minutes to 
6 hours prior to PFTs during study visits. 
Spirometry (FEV1) will be centrally standardized to the Global Lung Initiative (GLI) percent 
predicted equations for response group allocation and analysis. 
9.1.8 Subject Questionnaire: CFRSD© 
Subjects will complete a CF-specific symptom diary called the CFRSD as noted in the Schedule 
of Events. This diary includes 16 questions and takes less than 5 minutes to complete. The 
CFRSD should be administered at the beginning of the visit. 
9.1.9 Subject Questionnaire: CRISS©   
Subjects will complete a CF-specific symptom diary called the CRISS as noted in the Schedule 
of Events. This diary includes 8 questions and takes less than 5 minutes to complete. The CRISS 
should be administered at the beginning of the visit. 
9.1.10  Subject Questionnaire: EQ-5D-5L 
Subjects will complete the EQ-5D-5L health questionnaire as noted in the Schedule of Events.  
The EQ-5D-5L is a standardized generic measure of health status developed by the EuroQol 
Group and used in clinical and pharmacoeconomic evaluations.  It is a self-completed 
questionnaire with five (5) descriptive questions in the areas of mobility, self-care, usual 
activities, pain/discomfort and anxiety/depression and a visual analogue scale (EQ-VAS) that 
records the subject’s self-rated health on a 20 cm vertical scale.  
9.1.11  Adverse Events 
Information regarding occurrence of AEs will be captured throughout each subject’s study 
participation, starting at randomization and ending once the subject has terminated from the 
study. Duration (start and end dates), grade, seriousness, outcome, treatment, and relation to 
study treatment arm will be recorded on the CRF. 
9.1.12  Signs and Symptoms Evaluation 
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9.1.13  Collection of Health Care Resource Use 
Health care resource use will be documented throughout the trial as noted in the Schedule of 
Events. Inpatient hospitalization days, outpatient medical visits (primary care and specialists), 
and emergency department visits will be collected. Indirect costs including travel time to 
medical visits, caregiver time, and IV antibiotic treatment time at home will be collected as 
noted in the Schedule of Events. Job classification information for subjects and for their 
informal caregivers will also be collected as noted in the Schedule of Events.  
9.1.14  CFFNPR Data Entry (US Sites Only) 
For the hospitalization or home IV antibiotic treatment for the pulmonary exacerbation that 
triggers enrollment into this study, an episode must be completed in the CFFNPR.   
9.2 
Collection of Clinical Care Laboratory Results 
9.2.1 Respiratory Cultures for CF Pathogens 
Results from respiratory culture(s) used to determine care for the initial pulmonary exacerbation 
and any respiratory cultures performed as part of clinical care during the study will be recorded 
on the CRF. 
9.2.2 Clinical Chemistry  
Results for BUN and creatinine used to determine care for the initial pulmonary exacerbation and 
any BUN and creatinine tests performed as part of clinical care during the study will be recorded 
on the CRF. 
Results for serum glucose performed as part of clinical care for the initial pulmonary 
exacerbation and during the study will be recorded on the CRF (if more than one is performed on 
a given day, only one test per day will be recorded).  
9.3 
Research Laboratory Measurements  
9.3.1 Blood Collection for C-Reactive Protein (CRP) Testing 
Blood will be obtained as noted in the Schedule of Events and sent to each site’s clinical 
chemistry lab for determination of CRP.  
9.3.2 Sputum for Microbiome 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.  
Subjects that are enrolled at study sites located in Canada will be excluded from the collection of 
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9.3.3 Specimens for Long-Term Biorepository Storage 
Approximately 7.5 mL of blood for serum aliquots will be collected for the CFFT biorepository 
as noted in the Schedule of Events.  The samples collected will be stored frozen at -70 to -80ºC 
at the site and batch shipped to the CFFT biorepository for long-term biorepository storage. 
Instructions for specimen collection, processing, storage and shipping of samples will be 
provided in the Study Laboratory Manual.  
Any expectorated sputum remaining after microbiome analysis may be sent to the CFFT 
biorepository for long-term biorepository storage.  
Subjects that are enrolled at study sites located in Canada will be excluded from the collection of 
serum specimens for long-term biorepository storage. 
10 EVALUATIONS BY VISIT 
Note: Day 1 is defined as the day IV antibiotics are initiated.  Visit 1 procedures may occur up to 
three days prior to initiation of IV antibiotics (Day 1) or up to one calendar day after IV 
antibiotics are initiated. 
10.1 Visit 1 
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 screening number. 
3. Record demographics data and, for US sites, CFF Registry ID.  
4. Record medical history, including a history of CF, diagnosis date, prior CF treatments and 
number of exacerbations in the previous year.  
5. Record concomitant medications including current and planned systemic steroid use.  
6. Confirm that the subject will begin treatment for the PEx following recommendations in the 
treatment protocol. 
7. If a respiratory specimen for CF pathogens has been collected for clinical care, obtain results 
and record.  
8. If Chemistry tests for BUN, creatinine and serum glucose have been collected for clinical 
care, obtain results and record. 
9. Provide CRISS Self-Report to subject for completion. 
10. Provide EQ-5D-5L to subject for completion. 
11. Collect subject health care resource use information.  
12. Perform a complete physical examination by a physician or designee. 
13. Measure and record height and weight. 
14. Perform and record spirometry if not performed within the past 3 days. 
15. If able to expectorate sputum, collect expectorated sputum for microbiome. 
16. Collect blood and test for CRP at site.  


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17. Collect blood and freeze serum for banking. 
18. Complete Signs and Symptoms Assessment. 
19. Schedule subject for Visit 2 to occur on Day 7 - 10 of IV antibiotics. 
10.2 Visit 2 (Day 7-10 ±1 days) 
1. Provide CRISS Self-Report to subject for completion. 
2. Provide EQ-5D-5L to subject for completion. 
3. Measure and record weight. 
4. Perform and record spirometry. 
5. Collect subject health care resource use information. 
6. Record any respiratory microbiology results since Visit 1. 
7. If Chemistry tests for BUN, creatinine and serum glucose have been collected for clinical 
care, obtain results and record. 
8. Record changes to concomitant medications.   
9. Perform abbreviated physical examination. 
10. Re-confirm eligibility. 
11. Enter required data into EDC for randomization (refer to CRF Completion Guidelines, 
includes CRISS and spirometry). 
12. Randomize subject to treatment duration.  
13. If able to expectorate, collect expectorated sputum for microbiome. 
14. Collect blood and test for CRP at site. 
15. Collect blood and freeze serum for banking.  
16. Record any adverse events. 
17. Schedule subject for Visit 3 dependent on treatment arm and to occur 2 weeks after 
scheduled completion of IV treatment. 
10.3 Visit 3 (Follow-up 2 weeks after scheduled completion of IV treatment /Day 24 – 35 
+/-2 days) 
1. Provide CFRSD Self-Report to subject for completion. 
2. Provide EQ-5D-5L to subject for completion. 
3. Collect subject health care resource use information. 
4. Record any respiratory microbiology results since Visit 1. 
5. If Chemistry tests for BUN, creatinine and serum glucose have been collected for clinical 
care, obtain results and record. 
6. Record any adverse events.  


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7. Record changes to concomitant medications. 
8. Perform abbreviated physical examination. 
9. Measure and record weight. 
10. Perform and record spirometry. 
11. If able to expectorate, collect expectorated sputum for microbiome. 
12. Collect blood and test for CRP at site. 
13. Collect blood and freeze serum for banking. 
11 ADVERSE EXPERIENCE REPORTING AND DOCUMENTATION 
11.1 Adverse Events 
An adverse event (AE) is any untoward medical occurrence in a subject that is participating in 
this clinical investigation that is related to study participation (treatment arm assignment), study 
procedures, or any other significant AE as determined by the investigator.   
AEs are defined as new or worsening of signs or symptoms, including clinically significant 
abnormal clinical laboratory values, that occur after randomization (Visit 2) until Visit 3.  
An unexpected AE is one of a type not identified in nature, severity, or frequency or of greater 
severity or frequency than expected.  
The Investigator will probe, via discussion with the subject, for the occurrence of AEs and record 
the information in the site’s source documents.  AEs 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 cystic fibrosis, should be used to assess and grade AE severity, 
including laboratory abnormalities judged to be clinically significant. The modified criteria can 
be found in the Study 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) 


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Life-threatening (4) 
Life-threatening consequences; urgent intervention indicated 
Death (5) 
Death related to AE 
 
AE Relationship to Treatment Arm Assignment 
The relationship of an AE to the treatment arm assignment should be assessed using the 
following the guidelines in Table 2. 
Table 2.  AE Relationship to Treatment Arm Assignment 
Relationship 
to Treatment  
Comment 
Definitely 
An event that follows a reasonable temporal sequence from the clinical trial 
treatment arm assignment; that follows a known or expected response pattern 
to treatment arm assignment; and that is not explained by any other reasonable 
hypothesis. 
Probably 
An event that follows a reasonable temporal sequence from the clinical trial 
treatment arm assignment; that follows a known or expected response pattern 
to treatment arm assignment; and that is not explained by any other reasonable 
hypothesis; and that is unlikely to be explained by the known characteristics of 
the subject’s clinical state or by other interventions. 
Possibly 
An event that follows a reasonable temporal sequence from the clinical trial 
treatment arm assignment; that follows a known or expected response pattern 
to treatment arm assignment; 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 
treatment arm assignment. 
11.2 Serious Adverse Experiences (SAE) 
An SAE is defined as any AE occurring that results in any of the following outcomes: 
 death 
 a life-threatening adverse experience 
 inpatient hospitalization (excluding the initial enrollment hospitalization) or hospitalizations 
that occur after the initial enrollment and start of IV antibiotic treatment at home will be 
reported  
 prolongation of existing hospitalization beyond the planned duration as indicated by 
randomization 
 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 
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11.2.1  Serious Adverse Experience Reporting 
Study sites will document all SAEs that occur (whether or not related to treatment arm 
assignment) 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. 
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 TDNCC of additional information or follow-up to an initial SAE Report 
as soon as relevant information is available.  The TDNCC 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/Independent Ethics Committee (IRB/IEC), the site investigator will report SAEs 
to the IRB/IEC.   
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  
12 DISCONTINUATION AND REPLACEMENT OF SUBJECTS 
12.1 Early Withdrawal of Subjects from the Study 
Early withdrawal of subjects may occur any time after the subject is randomized.  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 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 fail to adhere to treatment duration assignment are encouraged to complete all 
remaining study visits. Subjects should not be withdrawn for failure to adhere to treatment 
duration assignment. 
12.2 Replacement of Subjects 
Subjects who withdraw from the study will not be replaced.   


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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 inclusion/exclusion criteria 
 Use of a prohibited concomitant medication 
 Failure to adhere to treatment duration assignment (within the pre-specified margins of 
acceptable durations) 
 Failure to perform spirometry at each study visit 
Failure to comply with Good Clinical Practice (GCP) guidelines will also result in a protocol 
violation.  
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 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/IEC in 
accordance with their IRB/IEC reporting requirements. 
14 DATA SAFETY MONITORING  
The Cystic Fibrosis Foundation DSMB will establish a Data Monitoring Committee (DMC) to 
review data relating to safety and efficacy, to conduct and review interim analyses, and to ensure 
the continued scientific validity and merit of the study, according to the Cystic Fibrosis 
Foundation DSMB Operations Manual and a DMC Charter created for this protocol.  Details 
regarding the timing and content of the interim reviews are included in Section 15.6, Interim 
Analysis below, the DMC Charter developed in conjunction with the DMC, and the Statistical 
Analysis Plan. 
SAEs will be monitored by the committee on an ongoing basis throughout the study. 
15 STATISTICAL METHODS AND CONSIDERATIONS 
A detailed Statistical Analysis Plan (SAP) 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). The SAP will 
contain any modifications to the analysis plan described below.   
15.1 Data Sets Analyzed 
The primary NERR analyses will be performed using an intent-to-treat (ITT) population, which 
is defined as all subjects randomized at Visit 2. The analysis for NERR will be repeated in the 
per-protocol (PP) population, which is defined as subjects in the ITT population who have no 
protocol violations as defined in Section 13. The primary ERR analyses will be performed using 
PP population; the analysis will be repeated in the ITT population. 
Subjects who fail to adhere to treatment duration assignment are encouraged to complete all 
remaining study visits and will remain in the analyses population according to ITT. 


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Handling of missing data will be outlined in the SAP, including sensitivity analyses. 
15.2 Demographic and Baseline Characteristics 
Treatment duration arms (ERR-10, ERR-14, NERR-14, NERR-21) within ERR and NERR 
groups will be described and compared with respect to Baseline demographic and clinical 
characteristics including age, sex, CFTR genotype, race, height, weight, and all randomization 
strata.  For all analyses, Baseline clinical characteristics will be defined as measurements 
obtained at Visit 1. 
15.3 Analysis of Primary Endpoint 
The primary endpoint is absolute change in percent predicted FEV1 from Visit 1 (Baseline) to 
two weeks after scheduled completion of IV antibiotics (Visit 3). The primary endpoint will be 
compared between treatment durations within ERR and NERR groups using Analysis of 
Variance (ANOVA) adjusted for dichotomous randomization strata: Visit 1 FEV1 , number of 
IV-treated exacerbations in prior year, location of IV administration by Visit 2, and use of 
systemic corticosteroids by Visit 2.  
The treatment effect for each group (ERR and NERR) (estimated via adjusted ANOVA least 
squares means) will be presented along with corresponding 95% confidence intervals. Observed 
treatment effect and the 95% CI will provide primary inference and evidence of non-inferiority, 
superiority, or lack thereof in both the ERR and NERR groups.    
ERR Group: The non-inferiority of ERR-10 versus ERR-14 will be tested against a 3.5 % 
predicted non-inferiority margin with a two-sided 0.05 level of significance. 
NERR Group: The superiority of NERR-21 versus NERR-14 will be tested with a two-sided 0.05 
level of significance. 
Further details will be provided in the SAP, which will be finalized before the clinical data lock 
for the study. 
15.4 Analysis of Secondary Endpoints 
Descriptive analyses and graphical displays will be used to summarize all secondary endpoints, 
including changes from baseline in continuous endpoints and rates over the follow-up period for 
event based endpoints.  The ITT and PP populations will be used for all secondary analyses. 
All reported SAEs and AEs will be coded using MedDRA and grouped by body system.  (S)AEs 
will be tabulated by treatment durations within ERR and NERR groups using standard coding 
terms sorted by body system.  The incidence of AEs (including emergent abnormal lab values 
collected for clinical care) in each treatment duration arm will be tabulated by seriousness, 
severity, and relationship to arm.  If an AE is reported more than once during the study period for 
a given subject, the greatest severity and the worst-case relationship will be presented in tables.  
The number of (S)AEs will be summarized by treatment duration arms within ERR and NERR 
groups as follows: (i) The proportion of subjects with at least one (S)AE, (ii) The average 
number of (S)AEs per patient, and (iii) The rate of (S)AEs per patient month of follow-up.  
Histograms showing the frequency of the number of (S)AEs in each treatment duration arm will 
be included.  Rates of (S)AEs by System Organ Class (SOC) will be presented by treatment 
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intervals for each SOC.  The rate ratios will be compared using a two-sided 0.05 level test for 
Poisson count data. 
Descriptive summaries of antibiotics received by patients will be presented by treatment duration 
arm within ERR and NERR groups. Proportion of patients retreated with IV antibiotics (as 
collected in the CFFNPR) for pulmonary exacerbation within 30 days following scheduled 
completion of IV antibiotic treatment will be summarized by treatment duration arm within ERR 
and NERR groups and differences in the proportion of subjects will be estimated and tested 
using a two-sided test of proportions. Time (days) to next exacerbation following scheduled 
completion of IV antibiotics will be presented using Kaplan-Meier survival estimation and 
compared between treatment durations within ERR and NERR groups using a Cox proportional 
hazards model with a test of the treatment effect at a two-sided significance level of 0.05. The 
hazard ratio and its 95% confidence interval will be presented. An additional secondary analysis 
may stratify by or adjust for the randomization strata. 
Absolute change in CRISS, relative change in FEV1 (liters), and absolute change in weight (kg) 
from Baseline (Visit 1) to two weeks after scheduled completion of IV antibiotics (Visit 3) will 
be summarized. Mean differences between treatment duration arms within ERR and NERR 
groups at each visit and corresponding 95% CIs will be presented. Changes from Baseline (Visit 
1) to Visit 3 will be assessed using a two-sample, two-sided t-test and additional secondary 
analysis may adjust for the randomization strata. 
15.5 Analysis of Exploratory Endpoints 
The proportion of subjects discontinuing study before versus after randomization and before the 
end of assigned treatment duration will be tabulated by reason for discontinuation and by 
treatment duration arm, if randomized.  Reason for discontinuations will be summarized. The 
screen failure reasons will be also summarized for all screening attempts. Characteristics of the 
un-randomized subjects by reason (e.g., lost to follow-up, missing FEV1 or CRISS at Visit 2, 
patient withdrawal) will be summarized using descriptive characteristics.  Similarly, the 
randomized but lost to follow-up subjects (no Visit 3) will be described.  Comparison of these 
two groups with the randomized completed subjects will be performed for baseline 
characteristics, treatments and outcomes utilizing both the study data and the CFFNPR.  
There will be descriptive summaries of adherence to antibiotic selection protocol and adherence 
to randomization scheme by response group (ERR and NERR), and treatment duration arm 
(ERR-10, ERR-14, NERR-14, and NERR-21). 
Descriptive comparisons of the two cohorts treated for 14 days (ERR-14 and NERR-14) will be 
performed to characterize associations between early assessments of clinical response (at Visit 2) 
and after completion of treatment for a PEx (Visit 3). 
Clinical lab CRP at each of the study visits and change in CRP from Baseline (Visit 1) will be 
summarized by response group (ERR and NERR) and by treatment duration arm (ERR-10, ERR-
14, NERR-14, and NERR-21). Associations with CRP and change in CRP with clinical 
outcomes will be examined. 
For all randomization arms (ERR-10, ERR-14, NERR-14, and NERR-21), quality of life and 
medical cost metrics will be collected for a comprehensive health economic analysis by Larry 
Kessler  ScD, Professor and Chair, Dept. of Health Services, School of Public Health, University 
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Pharmacoeconomics and Outcomes Research Good Research Practices for Cost-Effectiveness 
Analysis Alongside Clinical Trials Task Force. 
For all treatment duration  arms (ERR-10, ERR-14, NERR-14, and NERR-21), the expectorated 
sputum will undergo analysis to describe and compare the respiratory microbiome by John 
Lipuma, MD, Professor of Pediatrics and Director of Pediatric Infectious Diseases,  University of 
Michigan, Ann Arbor. 
15.6 Interim Analysis 
A pre-defined monitoring plan for feasibility, variance estimation, sample size adaptation, and 
study stopping rules will be formalized in conjunction with the DMC and will be in place prior to 
initiating the study. Feasibility will be closely monitored for the first 100 enrolled patients to 
ensure adherence to protocol, return for randomization, and adherence to randomized treatment 
duration arm.  
Each treatment group (ERR and NERR) will have separate monitoring criteria and a decision to 
stop one may not be conditional on the other. 
15.7 Sample Size  
ERR Group: 
A non-inferiority design to show that the change in FEV1 between Visit 1 and Visit 3 in the ERR 
subjects who received 10 days of treatment (ERR-10) is no more than 3.5 % predicted less than 
ERR subjects who received 14 days treatment (ERR-14) requires 310 subjects (155 per arm) who 
complete the study.  STOP pilot data indicate a mean change (SD) in FEV1 between baseline and 
Day 28 in patients with an early response to be 12.5 % predicted, 95% CI [9.5, 15.6]. Assuming  
two-sided alpha =0.05, standard deviation =9.0% predicted and the true difference between two 
groups is zero, the ERR study has 93% power to detect a 3.5 % non-inferiority margin which 
preserves 72% of the treatment effect or 63% of the lower bound of treatment effect observed in 
the STOP pilot.   
NERR Group: 
A superiority design to show that the change in FEV1 between Visit 1 and Visit 3 in NERR 
subjects who received 21 days treatment (NERR-21) is at least 2.5 % predicted greater than NERR 
subjects who received 14 days treatment (NERR-14) requires 570 subjects (285 per arm) who 
complete the study.  STOP pilot data indicate a mean change (SD) in FEV1 between baseline and 
Day 28 in patients without an early response to be 4.0 % predicted, 95% CI [1.9, 6.1].  Assuming 
two-sided alpha =0.05 and standard deviation =9.0% predicted, the NERR study has 91% power to 
detect a 2.5% or greater increase in FEV1 among those treated with 21 days compared to 14 day 
IV antibiotic. A 2.5% improvement was chosen to represent a minimal clinically important 
difference in lung function to justify the additional burden and potential toxicity of 21 days of 
treatment versus 14.  It is important to note that statistical significance can be shown at the end 
of the superiority NERR study with a smaller treatment effect than 2.5%. 
Observed treatment effect (mean difference in absolute FEV1 change) and the 95% CI will 
provide primary inference and evidence of non-inferiority, superiority, or lack thereof in both 
the ERR and NERR groups. Motivated to ensure conclusive results, this study was designed to 
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NERR 95% CI half-width=1.5% when both SD=9%).  
Because this trial will enroll a slightly different patient population (including home IV, excluding 
patients who receive <7 days of IV antibiotics), a blinded, interim assessment of change in FEV1 
% predicted and variance (pooled) will be performed and expected sample size may be adjusted 
for either the ERR or NERR groups.  
Based on STOP pilot data, we anticipate 1:2 allocation of subjects into the ERR and NERR 
groups. To meet the enrollment goal of a minimum of 310 completed ERR subjects and a 
minimum of 570 completed NERR subjects, we will screen  approximately 1330 subjects. Of 
these, we expect approximately 1236 subjects will be enrolled and randomized (assuming a 
conservative 7% drop-out rate between Visit 1 and Visit 2) and a minimum of 310 completed 
ERR subjects and a minimum of 570 completed NERR subjects (assuming an approximate 4% 
drop-out rate between Visit 2 and Visit 3).  
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 site number, 
subject number and, for US sites only, initials. 
If a correction is required for a CRF, the time and date stamp tracks the person entering or 
updating CRF data and creates 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.  A CD containing the CRF data will be provided to the site to 
be retained with the essential documents at the Investigator’s site at the completion of the study.  
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 
Biostatistics and Clinical 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 
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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. 
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 
investigators for future exploration. The biospecimens will be collected under IRB/IEC approval, 
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) securing 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/IEC 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/IEC, and Regulatory Agency (e.g., FDA) 
inspectors upon request.  A file for each subject must be maintained that includes the signed 
Informed Consent, HIPAA Authorization and Assent Form and 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, 
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after database lock and accessible for 5 years following database lock.  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.  
16.7 Subject Confidentiality 
In order to maintain subject confidentiality, only a site number, subject number, subject initials 
(US sites only) and subject’s CFF patient registry number (US sites only) will identify all study 
subjects on CRFs and other documentation submitted to the Sponsor.   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). 
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). 
17.1 Protocol Amendments 
Any amendment to the protocol will be written by the Sponsor.  Protocol amendments cannot be 
implemented without prior written IRB/IEC 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/IECs are notified within 
five working days. 
17.2 Institutional Review Boards  
The protocol and consent form will be reviewed and approved by the IRB/IEC of each 
participating center prior to study initiation.  SAEs regardless of causality will be reported to the 
IRB/IEC in accordance with the standard operating procedures and policies of the IRB/IEC, and 
the Investigator will keep the IRB/IEC informed as to the progress of the study.  The Investigator 
will obtain assurance of IRB/IEC compliance with regulations. 
Any documents that the IRB/IEC 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/IEC.  The 
IRB/IEC’s 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/IEC’s 
unconditional approval statement will be transmitted by the Investigator to the Sponsor or 


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designee 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/IEC approval except when necessary to eliminate immediate hazards to the patients 
or when the change(s) involves only logistical or administrative aspects of the study.  Such 
modifications will be submitted to the IRB/IEC and written verification that the modification 
was submitted and subsequently approved should be obtained.   
The IRB/IEC 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/IEC; 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, ICH GCP, US 
Code of Federal Regulations for Protection of Human Subjects (21 CFR 50.25[a,b], CFR 50.27, 
and CFR Part 56, Subpart A), the Health Insurance Portability and Accountability Act (HIPAA, 
if applicable), and local regulations. 
The Investigator will prepare the informed consent form, assent (if applicable) and HIPAA 
authorization (if applicable) and provide the documents to the Sponsor or designee for approval 
prior to submission to the IRB/IEC.  The consent form generated by the Investigator must be 
acceptable to the Sponsor and be approved by the IRB/IEC.  The written consent document will 
embody the elements of informed consent as described in the International Conference on 
Harmonisation 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/IEC, 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 of 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 (US Sites Only) 
To facilitate future evaluation of retrospective and prospective information from all patients who 
screen for this study, the subject’s CFF Registry ID number will be collected.  The CFFNPR 
collects data on all CF patients who consented to participate in the CFFNPR 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 such as survival.  


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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/IEC review and 
approval meet federal guidelines, as stated in § 21 CFR, parts 50 and 56. 
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/IEC 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/IEC and the Sponsor (or designee) all changes in the research 
activity and all unanticipated problems involving risks to subjects or others (to include 
amendments). 
9. Seek IRB/IEC 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. 
Bradley J, McAlister O, Elborn S. Pulmonary function, inflammation, exercise capacity and 
quality of life in cystic fibrosis. Eur Respir J 2001; 17(4): 712-5. 
2. 
Britto MT, Kotagal UR, Hornung RW, Atherton HD, Tsevat J, Wilmott RW. Impact of 
recent pulmonary exacerbations on quality of life in patients with cystic fibrosis. Chest 
2002; 121(1): 64-72. 
3. 
Orenstein DM, Pattishall EN, Nixon PA, Ross EA, Kaplan RM. Quality of well-being 
before and after antibiotic treatment of pulmonary exacerbation in patients with cystic 
fibrosis. Chest 1990; 98(5): 1081-4. 
4. 
Konstan MW, Morgan WJ, Butler SM, et al. Risk factors for rate of decline in forced 
expiratory volume in one second in children and adolescents with cystic fibrosis. J Pediatr 
2007; 151(2): 134-9, 9 e1. 
5. 
Ellaffi M, Vinsonneau C, Coste J, et al. One-year outcome after severe pulmonary 
exacerbation in adults with cystic fibrosis. Am J Respir Crit Care Med 2005; 171(2): 158-
64. 
6. 
Emerson J, Rosenfeld M, McNamara S, Ramsey B, Gibson RL. Pseudomonas aeruginosa 
and other predictors of mortality and morbidity in young children with cystic fibrosis. 
Pediatr Pulmonol 2002; 34(2): 91-100. 
7. 
Liou TG, Adler FR, Fitzsimmons SC, Cahill BC, Hibbs JR, Marshall BC. Predictive 5-year 
survivorship model of cystic fibrosis. Am J Epidemiol 2001; 153(4): 345-52. 
8. 
Mayer-Hamblett N, Rosenfeld M, Emerson J, Goss CH, Aitken ML. Developing cystic 
fibrosis lung transplant referral criteria using predictors of 2-year mortality. Am J Respir 
Crit Care Med 2002; 166(12 Pt 1): 1550-5. 
9. 
Wagener JS, Rasouliyan L, VanDevanter DR, et al. Oral, inhaled, and intravenous antibiotic 
choice for treating pulmonary exacerbations in cystic fibrosis. Pediatr Pulmonol 2013; 
48(7): 666-73. 
10. VanDevanter DR, Yegin A, Morgan WJ, Millar SJ, Pasta DJ, Konstan MW. Design and 
powering of cystic fibrosis clinical trials using pulmonary exacerbation as an efficacy 
endpoint. Journal of cystic fibrosis : official journal of the European Cystic Fibrosis Society 
2011; 10(6): 453-9. 
11. VanDevanter DR, O'Riordan MA, Blumer JL, Konstan MW. Assessing time to pulmonary 
function benefit following antibiotic treatment of acute cystic fibrosis exacerbations. Respir 
Res 2010; 11: 137. 
12. Flume PA, Mogayzel PJ, Jr., Robinson KA, et al. Cystic fibrosis pulmonary guidelines: 
treatment of pulmonary exacerbations. Am J Respir Crit Care Med 2009; 180(9): 802-8. 
13. Rabin HR, Butler SM, Wohl ME, et al. Pulmonary exacerbations in cystic fibrosis. Pediatr 
Pulmonol 2004; 37(5): 400-6. 
14. Regelmann WE, Elliott GR, Warwick WJ, Clawson CC. Reduction of sputum Pseudomonas 
aeruginosa density by antibiotics improves lung function in cystic fibrosis more than do 
bronchodilators and chest physiotherapy alone. Am Rev Respir Dis 1990; 141(4 Pt 1): 914-
21. 
15. Cystic Fibrosis Foundation Patient Registry 2011 Annual Data Report to the Center 
Directors. 2012. 
16. Sanders DB, Bittner RC, Rosenfeld M, Hoffman LR, Redding GJ, Goss CH. Failure to 
recover to baseline pulmonary function after cystic fibrosis pulmonary exacerbation. Am J 
Respir Crit Care Med 2010; 182(5): 627-32. 


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17. Smith AL, Doershuk C, Goldmann D, et al. Comparison of a beta-lactam alone versus beta-
lactam and an aminoglycoside for pulmonary exacerbation in cystic fibrosis. J Pediatr 1999; 
134(4): 413-21. 
18. Quanjer PH, Stanojevic S, Cole TJ, et al. Multi-ethnic reference values for spirometry for 
the 3-95-yr age range: the global lung function 2012 equations. Eur Respir J 2012; 40(6): 
1324-43. 
19. Stanojevic S, Wade A, Stocks J, et al. Reference ranges for spirometry across all ages: a 
new approach. Am J Respir Crit Care Med 2008; 177(3): 253-60. 
 


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19 APPENDIX 1. SCHEDULE OF EVENTS 
 
Visit 1 
Visit 2 
Visit 3 1 
Event/Assessment 
Day 1 4 
Between Day 7 
- 10 of IV 
Antibiotics 
(±1 days) 
Between Day 24 - 35 
2 wks after scheduled 
completion of IV 
treatment  
(+/-2 days) 
Informed Consent 
X 
 
 
Medical History, Demographics, CF 
Diagnosis, CF Registry ID 
X 
 
 
Collect subject health care resource use 
X 2 
X 3 
X 3 
Concomitant Medication Review  
X 
X 
X 
Collect results of clinical care respiratory 
cultures for microbiology 
X 
 
 
Collect results of clinical care BUN, 
creatinine and serum glucose 
X 
 
 
Subject Questionnaire: CRISS  
X 
X 
 
Subject Questionnaire: CFRSD 
 
 
X 
Subject Questionnaire: EQ-5D-5L 
X 
X 
X 
Complete Physical Exam 
X 
 
 
Abbreviated Physical Exam 
 
X 
X 
Height  
X 
 
 
Weight 
X 
X 
X 
Spirometry 
X 
X 
X 
Collect sputum for microbiome  
X 
X 
X 
Collect blood and test for  CRP at site   
X 
X 
X 
Collect blood and freeze serum for banking  
X 
X 
X 
Complete Signs and Symptoms Assessment 
X 
 
 
Allocation to group and Randomization to IV 
treatment duration  
 
X 
 
Adverse Event Review 
 
X 
X 
1 Visit day will vary, dependent on group and duration arm 
2 Subject and care-giver job classifications  
3  Subject-reported travel time to visits, IV treatment times, caregiver care times, additional clinic visits. At Visit 3, only Health Care Resource 
Use information that was not previously collected or has changed since data was collected at Visit 2 will be collected.   
4  Day 1 is defined as the day that IV antibiotics are initiated. Visit 1 may occur up to three days prior to the initiation of IV antibiotics or up to 1 
calendar day after IV antibiotics are initiated. 

SAP_000.pdf: 
STOP-2 
FINAL REPORT 
PROTOCOL NUMBER: 
STOP2-IP-15 
PROTOCOL TITLE: 
Standardized Treatment of Pulmonary 
Exacerbations II (STOP 2) 
PRINCIPAL 
INVESTIGATORS: 
Patrick Flume, MD 
Medical University of South Carolina 
Christopher H. Goss, MD MSc 
University of Washington 
FUNDING AGENCIES:  
Cystic Fibrosis Foundation 
Therapeutics, Inc (CFFT) 
PREPARED BY: 
CF Therapeutics Development Network 
Coordinating Center:  
Sonya Heltshe, PhD 
Valeria Beckett, MS 
Michelle Skalland, MS 
Shelly Ma, MS 
RELEASE DATE: 
February 14, 2017 
February 14, 2017 
STOP2-IP-15 Final Report SAP 
 1 




 
  
1.     Overview 
 
1.1 
Study Rationale and Design 
 
In patients with cystic fibrosis (CF) who are experiencing a pulmonary exacerbation, a strong 
desire among clinicians to reduce treatment durations (and reduce cost, inconvenience, and 
potential toxicities) is in conflict with belief that patients not responding robustly to treatment might 
benefit from extending treatment.  An assessment taken after one week of treatment has been 
demonstrated to predict the overall response, especially for those with an early robust 
improvement (Early Robust Response; ERR).  These patients are often treated with shorter 
courses of intravenous (IV) antibiotics in clinical practice and will likely experience no additional 
benefit from an extended IV treatment (although this has never been objectively studied).  
Patients who have a less robust early response to treatment often receive extended treatments in 
a belief that better overall responses are attained. Although the additional clinical benefit of 
prolonged courses of IV antibiotics should outweigh potential risks of toxicity, treatment burden, 
and increased resource utilization, these relationships have also never been objectively tested. 
 
This randomized, controlled, open-label study is designed to evaluate the efficacy and safety of 
differing durations of IV treatment, given in the hospital or at home. for a pulmonary exacerbation 
in adult patients with CF.  The study will assess the non-inferiority of 10 days versus 14 days of 
treatment among ERR subjects and the superiority of 21 days versus 14 days treatment duration 
among the subjects who do not meet the ERR definition(non-ERR; NERR) 
Subjects will undergo pulmonary function testing (spirometry) and complete a respiratory 
symptom score [Chronic Respiratory Infection Symptom Score (CRISS)] at initiation of IV 
treatment (Baseline/ Visit 1) and at Day 7-10 (Visit 2).  At Visit 2, subjects will be allocated to 
groups ERR or NERR based on their initial clinical response as determined by their change in 
forced expiratory volume in 1 second (FEV1; percent of predicted) and CRISS from Baseline and 
then subsequently randomized to an IV treatment duration (nested within group).  
 
ERR subjects [≥8% predicted improvement in FEV1 from Baseline (Visit 1) to Visit 2 and CRISS 
reduction of ≥11 points from Baseline (Visit 1) to Visit 2] will be randomized 1:1 to either 10 days 
or 14 days total IV antibiotic treatment duration. Remaining (NERR) subjects will be randomized 
1:1 to receive either 14 or 21 days total IV antibiotic treatment duration.  All subjects will be 
evaluated again at Visit 3, 14 days following scheduled completion of IV antibiotic treatment. 
Dependent on the treatment arm, subjects will be on study from 24 to 35 days.  
 
The primary objective of this study is to evaluate the efficacy and safety of differing 
durations of IV antibiotic treatment for CF pulmonary exacerbations.  
 
ERR Group: To determine if 10 days of IV antibiotic treatment (ERR-10) is as safe as and 
not clinically inferior (in terms of lung function response) to 14 days of IV antibiotic 
treatment (ERR-14) among subjects meeting the ERR threshold at Visit 2. 
 
NERR Group: To determine if 21 days of IV antibiotic treatment (NERR-21) is clinically superior 
(in terms of lung function response) and safe, compared to 14 days of IV antibiotic treatment 
(NERR-14) among subjects not meeting the EER threshold at Visit 2. 
 
The secondary objectives are to: 
 
• 
Evaluate efficacy of differing IV antibiotic treatment durations on other clinical outcomes 
such as weight, respiratory symptoms, and subsequent IV antibiotic treatments for 
pulmonary exacerbation. 
February 14, 2017 
STOP2-IP-15 Final Report SAP 
 3 


 
• 
Determine the feasibility, uptake and adherence to a standardized protocol of antibiotic 
selection. 
Other objectives are to:  
• 
Provide a study platform for ancillary studies of PEx treatment in adults with CF, including 
investigations into respiratory microbiome, health economics, and systemic inflammation. 
• 
Establish a biorepository of CF serum and sputum samples before, during and after 
treatment for an adult PEx for use by the CF research community. Interim DSMB 
Reviews 
 
1.2 
Data Monitoring Committee Reviews 
 
Oversight for this trial will be performed by the Cystic Fibrosis Foundation (CFF) Data Safety 
Monitoring Board (DSMB; Chair, Wayne Morgan, MD).   A Data Monitoring Committee (DMC) has 
been selected by the Associate Chair Dr. Richard Simon to specifically monitor this trial according 
to the DMC Charter.  The DMC consists of at least two physicians experienced in treating 
patients with CF and a biostatistician.  The DMC is responsible for safeguarding the interests of 
study participants, assessing the safety and efficacy of study procedures, and for monitoring the 
overall conduct of the study.   
 
The Table below outlines reporting schedule, content, and participation throughout the study. 
 
 
Abbreviated summary reports tabulating SAEs by treatment duration arm will be reported to the 
DSMB on semi-annual basis starting after the first patient is randomized. There will be one initial 
interim report at approximately 10% of enrollment, followed by a second identical report at 20% of 
enrollment, if deemed necessary.  The initial interim report will focus on feasibility, adherence to 
protocol, return for randomization, and adherence to randomized treatment duration arm. An 
unblinded, open review by treatment duration arm with the DMC and the Sponsor-Investigators of 
Sections 1-3 and Appendix A of this document will take place. The safety data summarized by 
treatment duration group will be presented in the closed section of the DMC meeting (Sections 4-
5), as outlined in the table above. 
 
Comprehensive interim reports including efficacy endpoints and formal statistical monitoring will 
be generated after approximately 50% and 75% of subjects have been randomized.  The 
contents of these reports are outlined in the table above and will be comprised of both an open 
(pooled enrollment) and a closed report (feasibility, safety, and efficacy by treatment duration 
arm).  
 
1.3 
Report Generation 
 
Content of Reporting  
Semi-
Annual    
(no meeting) 
Initial 10% 
Enrollment 
(teleconference) 
Initial 20% 
Enrollment      
(as needed)  
(teleconference) 
Comprehensive 
50% 
Enrollment 
(teleconference) 
Comprehensive 
75% 
Enrollment 
(teleconference) 
Enrollment/Feasibility (Pooled) 
-- 
-- 
-- 
O 
O 
Enrollment/Feasibility (by Duration Arm) 
C 
O 
O 
C 
C 
Abbreviated Safety Summaries (by Duration Arm) 
C 
C 
C 
C 
C 
Comprehensive Efficacy Interim (by Duration Arm) 
-- 
-- 
-- 
C 
C 
O - OPEN report for DMC, Study Biostatisticians, Study manager, and Sponsor-Investigators 
C - CLOSED report for DMC and Study Biostatisticians only 
February 14, 2017 
STOP2-IP-15 Final Report SAP 
 4 


 
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 
R. No adjustments for multiple comparisons will be made. Any analyses requiring CFFNPR data 
will be performed after the study close-out. The timing of these analyses will depend on 
availability of the Registry data containing relevant study participant information. Any tables or 
figures requiring such data are noted with an asterisk in the table and figure shells that follow. 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. 
 
1.4 
Definition of the Analysis Populations 
 
Enrollment and screening summaries will be generated using all screened participants. All 
compliance and safety analyses will be performed using an intent-to-treat (ITT) population, 
defined as all subjects randomized at Visit 2. The ITT population will also be used to generate all 
NERR primary efficacy analyses. The primary ERR analyses will be performed using per-protocol 
population (PP), defined as subjects in the ITT population who have no protocol violations. 
 
2. 
Results 
 
2.1 
Enrollment and Screen Failures 
The cumulative enrollment of participants randomized into the study is graphically summarized. 
The number of participants screened, eligible, randomized, withdrawn, and completing the study 
is summarized by treatment duration arm and site within ERR and NERR groups.   
The un-randomized participants are categorized as screen failures, those discontinuing the study 
before randomization, or eligible but not randomized. Reasons for screen failures, study 
discontinuations, and decision to not randomize are given. The screen failure reasons are 
summarized for all screening attempts. 
Participants who are deemed eligible at Visit 1 but are not assessed at Visit 2 are further 
summarized by age group, admission FEV1, and IV antibiotic location (home vs hospital). 
Participant disposition figure detailing enrollment, treatment allocation, follow-up, and analyses 
populations is provided. 
 
2.2 
Withdrawals, Treatment Duration Compliance, and Prohibited Antibiotic Utilization 
The number of participants who withdrew early from the study is tabulated by treatment duration 
arm within ERR and NERR groups. The reason for withdrawal is also listed. Withdrawals are 
further summarized by age group, admission FEV1, and IV antibiotic location (home vs hospital). 
Treatment duration adherence is summarized descriptively by treatment duration arm within ERR 
and NERR groups. Also included are descriptive summaries of prohibited antibiotic use and 
unplanned use of corticosteroids. 
 
2.2 
Demographics and Baseline Characteristics 
 
Treatment duration arms within ERR and NERR groups are described and compared with respect 
to Baseline demographic and clinical characteristics including age, sex, CFTR genotype, race, 
height, weight, and all randomization strata.  For all analyses, Baseline clinical characteristics are 
defined as measurements obtained at Visit 1. 
 
2.3 
Adverse Events 
 
February 14, 2017 
STOP2-IP-15 Final Report SAP 
 5 


 
All reported SAEs and AEs are coded using MedDRA and grouped by body system.  (S)AEs are 
tabulated by treatment durations within ERR and NERR groups using standard coding terms 
sorted by body system.  The incidence of AEs (including emergent abnormal lab values collected 
for clinical care) in each treatment duration arm is tabulated by seriousness, severity, and 
relationship to arm.  If an AE is reported more than once during the study period for a given 
subject, the greatest severity and the worst-case relationship is presented in tables.  The number 
of (S)AEs is summarized by treatment duration arms within ERR and NERR groups as follows: (i) 
The proportion of subjects with at least one (S)AE, (ii) The average number of (S)AEs per patient, 
and (iii) The rate of (S)AEs per patient week of follow-up.  Histograms showing the frequency of 
the number of (S)AEs in each treatment duration arm are included.  Rates of (S)AEs by System 
Organ Class (SOC) are presented by treatment duration arm.  Poisson regression modeling is 
used to derive rate ratios and 95% confidence intervals for each SOC.  The rate ratios is 
compared using a two-sided 0.05 level test for Poisson count data. 
 
2.4 
Other Safety Measures 
Summaries of proportions of participants experiencing any elevated and clinically significant BUN 
or creatinine findings between Visit 1 and Visit 3 are provided. 
Also summarized are proportions of participants retreated with IV antibiotics. Retreatment is 
defined as any additional IV antibiotics administered 3 or more days after the stop date of the 
initial IV antibiotic treatment for pulmonary exacerbation and prior to Visit 3 (e.g. rescue treatment 
or treatment of the new pulmonary exacerbation). 
 
2.5 
Summary of Primary Efficacy Endpoint 
 
The primary endpoint is the absolute change in percent predicted FEV1 from Visit 1 (Baseline) to 
two weeks after scheduled completion of IV antibiotics (Visit 3). The primary endpoint is 
compared between treatment durations within ERR and NERR groups using Analysis of Variance 
(ANOVA) adjusted for dichotomous randomization strata: Visit 1 FEV1 , number of IV-treated 
exacerbations in prior year, location of IV administration by Visit 2, and use of systemic 
corticosteroids by Visit 2. The treatment effect for each group (ERR and NERR) (estimated via 
adjusted ANOVA least squares means) is presented along with corresponding 95% confidence 
intervals. Observed treatment effect and the 95% CI provide primary inference and evidence of 
non-inferiority, superiority, or lack thereof in both the ERR and NERR groups.    
ERR Group (PP population): The non-inferiority of ERR-10 versus ERR-14 is tested against a 3.5 
% predicted non-inferiority margin with a one-sided 0.025 level of significance.  
NERR Group (ITT population): The superiority of NERR-21 versus NERR-14 is tested with a two-
sided 0.05 level of significance. 
The primary analysis for ERR is repeated in the ITT population, and the primary analysis for 
NERR is repeated in the PP population. 
 
2.6 
Summary of Antibiotics and Other Medications 
 
Descriptive summaries of antibiotics received by participants are presented by treatment duration 
arm within ERR and NERR groups. Also summarized is the use of steroids or airway clearance 
any time during the study. Proportion of patients retreated with IV antibiotics (as collected in the 
CFFNPR) for pulmonary exacerbation within 30 days following scheduled completion of IV 
antibiotic treatment is summarized by treatment duration arm within ERR and NERR groups and 
differences in the proportion of subjects are estimated and tested using a two-sided test of 
proportions. 
 
2.7 
Time to Next Pulmonary Exacerbation 
February 14, 2017 
STOP2-IP-15 Final Report SAP 
 6 


 
 
Time (days) to next exacerbation following scheduled completion of IV antibiotics is presented 
using Kaplan-Meier survival estimation and compared between treatment durations within ERR 
and NERR groups using a Cox proportional hazards model with a test of the treatment effect at a 
two-sided significance level of 0.05. The hazard ratio and its 95% confidence interval are 
presented. Additionally, results from a model adjusted for randomization strata are shown. Also 
performed are exploratory analyses testing proportion of time spent receiving home IVs and the 
timing of corticosteroid initiation. 
 
2.8 
Summary of CRISS 
 
Absolute change in CRISS from Baseline (Visit 1) to two weeks after scheduled completion of IV 
antibiotics (Visit 3) is summarized. Mean differences between treatment duration arms within 
ERR and NERR groups at each visit and corresponding 95% CIs are presented. Changes from 
Baseline (Visit 1) to Visit 3 are assessed using a two-sample, two-sided t-test. Additionally, an 
ANOVA model adjusted for randomization strata is used to compare the change in CRISS 
between treatment duration arms within ERR and NERR groups. Also summarized is the 
proportion of participants who experienced a clinically meaningful reduction in CRISS of 11 or 
more units. 
 
2.9 
Summary of Spirometry Results 
 
Absolute and relative changes in spirometry measures from Baseline (Visit 1) to each post-
baseline visit are summarized. Mean differences between treatment duration arms within ERR 
and NERR groups at each visit and corresponding 95% CIs are presented. Changes from 
Baseline (Visit 1) to Visit 3 are assessed using a two-sample, two-sided t-test. Additionally, an 
ANOVA model adjusted for randomization strata is used to compare the relative change in FEV1 
(L) between treatment duration arms within ERR and NERR groups. 
 
2.10 
Summary of Anthropometric Measures 
 
Absolute changes in weight (kg) and BMI from Baseline (Visit 1) to each post-baseline visit are 
summarized. Mean differences between treatment duration arms within ERR and NERR groups 
at each visit and corresponding 95% CIs are presented. Changes from Baseline (Visit 1) to Visit 3 
are assessed using a two-sample, two-sided t-test. Additionally, an ANOVA model adjusted for 
randomization strata is used to compare the change in weight (kg) between treatment duration 
arms within ERR and NERR groups. 
 
2.11 
Summary of CRP Results 
 
Clinical lab CRP at each of the study visits and change in CRP from Baseline (Visit 1) are 
summarized by response group (ERR and NERR) and by treatment duration arm. Associations 
between Baseline (Visit 1) CRP and change in CRP with clinical outcomes (e.g. baseline values 
and changes in spirometry, weight, and CRISS) are summarized. Further, clinical baseline 
characteristics and outcomes are summarized by CRP response. 
 
2.12 
Randomized Completers, Randomized Lost to Follow-up, and Un-Randomized 
Participants 
 
Baseline characteristics of the un-randomized subjects are summarized descriptively.  Similarly, 
the randomized but lost to follow-up subjects (no Visit 3) are described.  Comparisons of these 
two groups with the randomized completed subjects are performed for baseline characteristics, 
treatments and outcomes utilizing both the study data and the CFFNPR.  
 
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2.13 
ERR-14 and NERR-14 Participants 
 
Descriptive comparisons of the two cohorts treated for 14 days (ERR-14 and NERR-14) are 
performed to characterize associations between early assessments of clinical response (at Visit 
2) and after completion of treatment for a PEx (Visit 3). Comparisons of these two groups are 
performed for baseline characteristics, treatments and outcomes utilizing both the study data and 
the CFFNPR.  
 
2.14 
Study Impact on PEx Treatment Duration 
 
Summarized are distributions of pulmonary exacerbation treatment durations (as collected in the 
CFFNPR) observed at the STOP2 study centers during the conduct of this study and after the 
study completion (Month, Year through Month, Year). Also shown are distributions of pulmonary 
treatment durations observed at a select non-STOP2 CF centers during the same time frames. 
 
2.15 
Appendix A 
 
Listing 1 shows protocol violations and exceptions and Listing 2 provides SAE narratives from the 
clinical tracking spreadsheet.  
 
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