Multicenter Study of Patient-reported Gastrointestinal Symptoms in People With Cystic Fibrosis (GALAXY-OB-18)
Conditions: Cystic Fibrosis
Sponsor: Chris Goss



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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:  GALAXY-OB-18 
 
Protocol Title:  Multicenter study of patient-reported gastrointestinal symptoms  
in people with Cystic Fibrosis (GALAXY) 
 
Protocol Date:  19 NOV 2018 
 
 
 
 
Investigator Signature 
 
Date 
 
 
 
Print Name and Title 
 
 
Site #: 
 
 
Site Name: 
 
 
Address: 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

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TABLE OF CONTENTS 
1 
BACKGROUND ............................................................................................................................................ 12 
1.1 
OVERVIEW OF NON-CLINICAL STUDIES ................................................................................................................... 12 
1.2 
OVERVIEW OF CLINICAL STUDIES ........................................................................................................................... 13 
2 
STUDY RATIONALE ...................................................................................................................................... 15 
2.1 
RISK / BENEFIT ASSESSMENT ................................................................................................................................ 15 
3 
STUDY OBJECTIVES ..................................................................................................................................... 15 
3.1 
PRIMARY OBJECTIVE ........................................................................................................................................... 15 
3.2 
SECONDARY OBJECTIVES ...................................................................................................................................... 16 
4 
STUDY DESIGN ............................................................................................................................................ 16 
4.1 
STUDY OVERVIEW .............................................................................................................................................. 16 
5 
CRITERIA FOR EVALUATION ........................................................................................................................ 16 
5.1 
PRIMARY ENDPOINT ........................................................................................................................................... 16 
5.2 
SECONDARY ENDPOINTS ...................................................................................................................................... 16 
6 
SUBJECT SELECTION .................................................................................................................................... 17 
6.1 
STUDY POPULATION............................................................................................................................................ 17 
6.2 
INCLUSION CRITERIA ........................................................................................................................................... 17 
6.3 
EXCLUSION CRITERIA ........................................................................................................................................... 18 
6.4 
STUDY SPECIFIC TOLERANCE FOR INCLUSION/EXCLUSION CRITERIA .............................................................................. 18 
6.5 
SCREEN FAIL CRITERIA ......................................................................................................................................... 18 
7 
CONCURRENT MEDICATIONS ...................................................................................................................... 18 
7.1 
ALLOWED MEDICATIONS AND TREATMENTS ............................................................................................................ 18 
7.2 
PROHIBITED MEDICATIONS AND TREATMENTS ......................................................................................................... 19 
8 
STUDY TREATMENTS .................................................................................................................................. 19 
9 
STUDY PROCEDURES AND GUIDELINES ....................................................................................................... 19 
9.1 
CLINICAL ASSESSMENTS ....................................................................................................................................... 19 
10 
EVALUATIONS BY VISIT ............................................................................................................................... 20 
10.1 
ENROLLMENT VISIT (DAY 1) ............................................................................................................................ 20 
11 
ADVERSE EXPERIENCE REPORTING AND DOCUMENTATION ....................................................................... 21 
12 
DISCONTINUATION AND REPLACEMENT OF SUBJECTS ............................................................................... 21 
12.1 
EARLY WITHDRAWAL OF SUBJECTS FROM THE STUDY ........................................................................................... 21 
12.2 
REPLACEMENT OF SUBJECTS ............................................................................................................................ 21 
13 
PROTOCOL VIOLATIONS.............................................................................................................................. 21 
14 
DATA SAFETY MONITORING ....................................................................................................................... 21 
15 
STATISTICAL METHODS AND CONSIDERATIONS .......................................................................................... 22 
15.1 
GENERAL CONSIDERATIONS ............................................................................................................................. 22 
15.2 
DEMOGRAPHIC AND BASELINE CHARACTERISTICS ................................................................................................. 22 
15.3 
ANALYSIS OF PRIMARY ENDPOINT ..................................................................................................................... 22 
15.4 
ANALYSIS OF SECONDARY ENDPOINTS ................................................................................................................ 22 
15.5 
ANALYSIS OF MISSING DATA ............................................................................................................................ 23 

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15.6 
INTERIM REVIEW ........................................................................................................................................... 23 
15.7 
SAMPLE SIZE ................................................................................................................................................. 23 
16 
DATA COLLECTION, RETENTION AND CLINICAL MONITORING .................................................................... 25 
16.1 
DATA COLLECTION INSTRUMENTS ..................................................................................................................... 25 
16.2 
DATA MANAGEMENT PROCEDURES .................................................................................................................. 26 
16.3 
DATA QUALITY CONTROL AND REPORTING ......................................................................................................... 26 
16.4 
SECURITY AND ARCHIVAL OF DATA .................................................................................................................... 26 
16.5 
AVAILABILITY AND RETENTION OF INVESTIGATIONAL RECORDS ................................................................................ 27 
16.6 
MONITORING ............................................................................................................................................... 27 
16.7 
SUBJECT CONFIDENTIALITY .............................................................................................................................. 27 
17 
ADMINISTRATIVE, ETHICAL, REGULATORY CONSIDERATIONS .................................................................... 27 
17.1 
PROTOCOL AMENDMENTS ............................................................................................................................... 27 
17.2 
INSTITUTIONAL REVIEW BOARDS AND INDEPENDENT ETHICS COMMITTEES ............................................................... 28 
17.3 
INFORMED CONSENT FORM ............................................................................................................................. 28 
17.4 
CONSENT FOR COLLECTION AND USE OF CFF REGISTRY ID NUMBER ....................................................................... 29 
17.5 
PUBLICATIONS .............................................................................................................................................. 29 
17.6 
INVESTIGATOR RESPONSIBILITIES....................................................................................................................... 29 
18 
REFERENCES ............................................................................................................................................... 30 
APPENDIX. SCHEDULE OF EVENTS ........................................................................................................................ 32 
 
 
 

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LIST OF ABBREVIATIONS AND ACRONYMS 
 
CFR 
Code of Federal Regulations 
CFTR 
cystic fibrosis transmembrane conductance regulator 
CF 
cystic fibrosis 
CFF 
Cystic Fibrosis Foundation 
CFFPR 
Cystic Fibrosis Foundation Patient Registry 
C.I. 
confidence interval 
CRF 
case report form 
CSBM 
complete bowel movements 
DIOS 
distal intestinal obstruction syndrome 
EDC 
Electronic data capture 
FDA 
Food and Drug Administration 
GCP 
Good Clinical Practice 
GI 
gastrointestinal 
HIPAA 
Health Insurance Portability and Accountability Act of 1996 
ICF 
informed consent form 
ICH 
International Conference on Harmonisation 
IRB 
Institutional Review Board 
NPD 
Nasal potential difference 
PAC-SYM 
Patient Assessment of Constipation-Symptoms 
PAGI-SYM 
Patient Assessment of Gastrointestinal-Symptoms 
PAC-QOL 
Patient Assessment of Constipation Quality of Life 
PAGI-QOL 
Patient Assessment of Gastrointestinal-Symptoms Quality of Life 
PEG 
polyethylene glycol 
PI 
Principal Investigator 
PRO 
patient reported outcome 
PROMIS 
FDA patient-reported outcomes measures 
PROs 
patient reported outcome surveys 
QOL 
Quality of Life 
SIBO 
small intestinal bacterial overgrowth 
TDNCC 
Therapeutics Development Network Coordinating Center 
 

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PROTOCOL SYNOPSIS 
TITLE 
Multicenter study of patient-reported gastrointestinal symptoms  
in people with Cystic Fibrosis (GALAXY) 
SPONSOR-
INVESTIGATOR 
A. Jay Freeman, MD, MSc (Emory University/Children’s Healthcare 
of Atlanta) 
Baharak Moshiree, MD (University of North Carolina Charlotte, 
Atrium Health)  
Meghana Sathe, MD (University of Texas Southwestern/Children’s 
Health) 
FUNDING 
ORGANIZATION 
Cystic Fibrosis Foundation (CFF) 
NUMBER OF SITES 
Approximately 26 
RATIONALE 
There are currently no large, multicenter prospective clinical trials 
examining management of constipation or other gastrointestinal (GI) 
symptoms in people with cystic fibrosis (CF). Current 
recommendations in the CF literature are largely based on expert 
consensus and opinions. Yet, constipation and other GI symptoms are 
crucial factors in quality of life (QOL) and maintenance of optimal 
nutritional state in people with CF. This study will use GI-
symptomatology questionnaires to understand the multiple 
overlapping GI symptoms in people with CF. This would be followed 
by studies to improve GI outcomes through establishing evidence-
based algorithms, starting with constipation.  In the future, we would 
also like to evaluate the impact of CF modulators on common GI 
symptoms and evaluate how this might impact the development of 
symptom-specific algorithms. 
STUDY DESIGN 
This is a prospective, multicenter, observational study designed to 
collect gastrointestinal related data in patients with CF. 
Eligible subjects will be consented and enrolled in the study at the 
Enrollment Visit. At the visit, the subject or parent/guardian will 
complete the patient reported outcome surveys (PROs) using their 
mobile device (e.g., smartphone or tablet). The PROs will consist of 
four questionnaires: Patient Assessment of Constipation-Symptoms 
(PAC-SYM), Patient Assessment of Gastrointestinal-Symptoms 
(PAGI-SYM), Patient Assessment of Constipation Quality of Life 
(PAC-QOL) and the disease-specific questionnaire.  The disease-
specific questionnaire will include the Bristol Stool Scale and will 
collect information on presence of fecal incontinence, stool quality 
and stool frequency.  At the Enrollment Visit, weight and height will 
be collected in addition to medical history and concomitant 
medication information. The subject or parent/guardian will complete 
the PROs outside-the-clinic setting per the Schedule of Events using 
their mobile device.   

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DURATION OF 
SUBJECT 
PARTICIPATION 
AND DURATION OF 
STUDY  
Subjects will be on study for up to 29 days.   
The total duration of the study is expected to be approximately 13 
months: 12 months for subject recruitment and 1 month for the final 
subject enrolled to complete the study. 
PRIMARY 
OBJECTIVE 
Assess the feasibility of electronic PROs conducted outside-the-
clinic. 
SECONDARY 
OBJECTIVES 
 Estimate the prevalence and variability of GI symptoms occurring 
in pediatric and adult patients with CF 
 Describe current management of GI symptoms in patients with 
CF  
 Gather information to guide and inform on the design of future 
algorithm-based approaches to treating GI symptoms in people 
with CF  
NUMBER OF 
SUBJECTS 
Up to 400 
SUBJECT 
SELECTION 
CRITERIA:  
Inclusion Criteria 
1. All genders ≥ 2 years of age at time of consent 
2. Documentation of a Cystic Fibrosis (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 Patient Registry 
(subjects may enroll in the Registry at Enrollment Visit if not 
previously enrolled)  
4. Written informed consent (and assent when applicable) obtained 
from subject or subject's legal representative  
5. Willing to complete questionnaires on mobile device 
6. Able to use the Medidata Patient Cloud mobile application for 
completing the questionnaires 
SUBJECT 
SELECTION 
CRITERIA:  
Exclusion Criteria 
1. Presence of a condition or abnormality that, in the opinion of the 
Investigator, would complicate interpretation of study outcome 
data or interfere with achieving the study objectives  
2. Presence of a pulmonary exacerbation at the Enrollment Visit  
3. Hospitalization for distal intestinal obstruction syndrome (DIOS) 
within the 28 days prior to the Enrollment Visit  
4. Current gastrointestinal (GI) or abdominal/pelvic malignancy  
5. Abdominal or pelvic surgery within the 28 days prior to the 

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Enrollment Visit  
6. At the time of the Enrollment Visit, planned abdominal or pelvic 
surgery or bowel cleanout in the 28 days after the Enrollment 
Visit 
7. Initiation of new CFTR modulator therapy within the 4 weeks 
prior to the Enrollment Visit 
8. Intent to initiate new CFTR modulator therapy within 28 days of 
the Enrollment Visit 
TEST PRODUCT, 
DOSE, AND ROUTE 
OF 
ADMINISTRATION 
Not applicable 
CONTROL 
PRODUCT, DOSE 
AND ROUTE OF 
ADMINISTRATION 
Not applicable 
CONCOMMITANT 
MEDICATIONS 
Allowed: Standard therapy for CF is allowed. 
Prohibited: There are no prohibited medications.  
PRIMARY 
ENDPOINT 
Percentage of scheduled outside-the-clinic assessments with at least 
one of the four PROs fully completed. 
SECONDARY 
ENDPOINTS 
Assess the feasibility of electronic PRO surveys conducted 
outside-the-clinic setting: 
1. At each scheduled outside-the-clinic assessment, number (%) 
of subjects with at least one PRO fully completed 
2. For each PRO, number (%) of subjects with fully completed 
questionnaires at each scheduled outside-the-clinic assessment 
and overall 
3. Number (%) of completed PROs by subject, site, and other 
demographic and clinical features 
Estimate the prevalence and variability of GI symptoms: 
 Evaluate prevalence of protocol-defined constipation: 
4. Number (%) of enrolled subjects with any occurrence of 
constipation during 1 month of follow-up (the period 
prevalence) 
 Evaluate frequency and severity of each GI symptom at scheduled 
assessments and overall:  
5. Number (%) of subjects with presence of GI symptom 
6. Distribution of severity scores of GI symptom 
7. Mean severity score of GI symptom 
8. Distribution of stool frequency and type by Bristol Stool Scale  
9. Change in distribution of GI symptoms and stool 
frequency/type from enrollment visit overall and by whether 

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subjects were receiving treatment 
 Evaluate PRO scores overall and by sub-scale at scheduled 
assessments: 
10. Mean PRO score 
11. Within and across subject variability of PRO scores 
12. Mean PRO scores (also mean differences and 95% confidence 
interval) comparing subjects with constipation to those 
without constipation 
 Evaluate alternative CF specific definitions of constipation: 
13. Examine alternative definitions of constipation that are CF 
specific based on correlation with PRO questionnaires and 
maximizing the area under the receiver operating 
characteristic curve (ROC curve) for PAC-SYM scores 
14. Number (%) reporting constipation based on patient self-
assessment. Examine concordance of self-reported 
constipation against protocol/alternate definitions using 
Cohen’s kappa coefficient 
Describe current management of GI symptoms: 
 Evaluate treatment for GI symptoms and constipation at time of 
enrollment visit: 
15. Number (%) of all subjects receiving treatment 
16. Number (%) of all subjects initiating treatment  
17. Number (%) of all subjects receiving treatment by Medication 
class/type 
18. Among subjects with GI symptoms and constipation, number 
(%) receiving treatment 
 Evaluate symptom scores due to treatment: 
19.  Mean PRO scores (also mean differences and 95% 
confidence interval) comparing subjects receiving treatment 
for GI symptoms to those not receiving treatment 
20. Among subjects receiving treatment for constipation, mean 
absolute change in PRO scores over time overall and by 
medication type/class 
PLANNED INTERIM 
REVIEW 
When 100 subjects have enrolled, an interim review will be 
conducted by an External Advisory Committee to determine whether 
the study should continue or stop. The Advisory Committee decision 
to continue to enroll or stop will be made in consideration of several 
factors including but not limited to: overall rate of enrollment, 
adequate representation of sub-populations, missing PRO data, and 
prevalence of constipation as well as estimates of PRO variability.  
The two stage enrollment strategy will allow for enriching enrollment 
based on either under-enrolled sub-populations or on the observed 
variability of GI symptoms for demographics-related factors such as 

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age-group (pediatric/adult), modulator use or pancreatic status. In 
addition to the interim review, the TDNCC will continuously monitor 
enrollment and provide the Advisory Committee quarterly reports of 
enrollment demographics. 
STATISTICS 
Primary Analysis Plan 
The analysis population consists of all eligible subjects who enroll 
into the study. Results will be based primarily on descriptive statistics 
of questionnaire results.  The primary endpoint is the percentage of 
scheduled outside-the-clinic assessments with at least one PRO fully 
completed out of the four questionnaires administered (the PAC-
SYM, PAGI-SYM, PAC-QOL and the disease-specific 
questionnaire). The denominator for the percentage is the expected 
number of outside-the-clinic assessments (# of enrolled subjects x 3 
outside-the-clinic assessments/subject).  Missing PRO data will be 
extensively summarized including a comparison of the 
representativeness of the enrolled subjects against the larger CF 
community.  
Constipation is defined as <3 bowel movements in the past week 
and/or Bristol Stool type 1 or 2. The secondary endpoint upon which 
the sample size is based is the number (%) of enrolled subjects with 
any occurrence of constipation during 1 month of follow-up. For all 
percentages, the 95% Confidence Interval (95% C.I.) will be 
calculated using the Wilson method. Summary statistics of stool 
frequency and type will be tabulated over time to evaluate overall 
disease fluctuation.   
Individual item responses will be summarized by the number and 
percentage having symptoms or receiving treatment. Questionnaire 
scores, overall as well as by subdomain, will be based on mean scores 
(and 95% C.I.s) with any group comparison made via the t-test. For 
subjects either receiving treatment or with constipation, mean 
absolute change in scores from the enrollment visit will be reported 
including the standard deviation and 95% C.I of the change.  For 
select endpoints, stratification by whether the site did or did not 
receive DIGEST Awards (CFF grant to a gastroenterologist to focus 
on the comprehensive GI care of patients with CF) will be 
considered. Additional stratification variables include: age, CF 
genotype, and pancreatic status.  
To evaluate change in PRO scores, a covariate adjusted repeated 
measures model of PRO scores will be fit in addition to select 
graphical figures showing PRO scores at scheduled assessments. No 
adjustment for multiplicity testing will be made. The details of all 
planned analyses will be outlined in the Statistical Analysis Plan 
(SAP). 
Rationale for Number 
of Subjects 
Sample size estimates for this study are based on two criteria: 
1. To assess feasibility and ensure representativeness of the 

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enrolled CF subjects  
2. To estimate prevalence of GI symptoms (specifically 
constipation) 
The sample size estimate for this study is based on a period 
prevalence of constipation (the proportion of subjects with occurrence 
of symptom over a 1 month interval of time) in the 20% - 30% range 
(25% average). Approximately 400 subjects will be needed to 
estimate a 25% prevalence of constipation with a 95% C.I. half-width 
of 4.5% (95% C.I. = 20.5%, 29.5%) and assuming a 12% missing 
data rate. With 400 subjects, this study will allow estimation of 
variability (between and within subject) in 160 pediatric subjects and 
240 adult subjects (alternatively 40 pediatric and 60 adults for 100 
subjects). 
 
 
 

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1 
BACKGROUND 
Cystic Fibrosis (CF) is an autosomal recessive disease caused by mutations in the CF 
transmembrane regulator (CFTR) gene. CFTR encodes a chloride channel that regulates fluidity 
within the ducts of the body including the lung, stomach, intestine, liver, pancreas, sweat glands, 
and reproductive organs.  In the lung, mutations in CFTR result in thick secretions that impair 
movement of cilia and clearance of infection.  In the gastrointestinal (GI) tract, mutations 
similarly affect fluidity of secretions, as well as pH. Recent studies have shown that CFTR is 
also located in the neurons that innervate the GI tract(1).  Together these mechanisms contribute 
to suboptimal fluidity, inflammation and dysmotility resulting in a number of gastrointestinal 
manifestations of CF.   
GI symptoms are highly prevalent in people with CF, adding to the burden of a complex 
multisystem disease. Tabori et al. showed a frequency of abdominal complaints ranging from 20-
80% in persons with CF(2).  Questionnaires directed at abdominal complaints have been used in 
pediatric and adult CF clinics and demonstrate a high frequency of abdominal complaints, many 
of them severe (Bozic and Freedman, unpublished data) (3, 4). Concerns expressed by people 
with CF include poor weight gain, pancreatic insufficiency, poor appetite, abdominal pain, 
constipation, nausea/bloating and reflux.  These symptoms frequently overlap, with many 
individual patients experiencing more than one, and they greatly impact the day-to-day quality of 
life (QOL) of persons with CF.   
In addition, the impact of CFTR modulators on GI symptoms is not yet well understood.  This is 
due to the variance in location and functional consequence of CFTR within the GI tract, 
including the pancreas, cholangiocytes, and intestinal epithelium.  
The aim of the current project is to describe the burden of GI symptoms and their relationship to 
morbidity in people with CF utilizing existing patient-reported outcome (PRO) measures.  Based 
on these results, we will focus on a series of studies to improve GI outcomes through 
establishing evidence-based algorithms. In the future, we would also like to evaluate the impact 
of CF modulators on common GI symptoms and evaluate how this might impact the 
development of symptom-specific algorithms.  
1.1 
Overview of Non-Clinical Studies 
Exploration of GI disease in animal models of CF has focused on impaired bicarbonate and 
chloride secretion related to CFTR dysfunction in order to help explain the clinical 
manifestations of the disease. In these models the GI tract demonstrates physiological sequelae 
of impaired CFTR function similar to that seen in the lungs. This includes, but is not limited to, 
altered fluid pH(1, 3), thickened mucus secretions(2, 4), increased inflammation(5), impaired 
motility(5, 6) and dysbiosis(7, 8). 
CFTR is present throughout the GI tract from the esophagus to the rectum(9).  As the biologic 
and physiological processes of the intestine and its associated GI organs change, so do the 
manifestations of impaired CFTR activity.  However, CF animal models have demonstrated that 
these manifestations do not exist in isolation, with CF therapies often having benefits to the GI 
tract beyond their primary target, the lung.  As an example, successful treatment of dysbiosis 
and/or small intestinal bacterial overgrowth (SIBO) in mouse models results not only in 
quantitative and qualitative changes in bacterial flora, but also decreased mucus accumulation, 
decreased inflammation and improved intestinal transit times(10). 

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CF animal models have been effective in describing the multiple GI manifestations of CF and 
providing an initial understanding of the complex interactions among symptoms.  However, due 
to differences of severity among CFTR-related phenotypes between species, animal models have 
a limited role in therapeutic investigations necessitating an increased focus on clinical studies. 
1.2 
Overview of Clinical Studies 
There are currently no large, multicenter prospective clinical trials examining management of 
many of the GI symptoms in people with CF. Current recommendations in the CF literature still 
are largely based on expert consensus and opinions. However, generalized GI symptoms seen 
often in CF include nausea, abdominal pain, abdominal distension, constipation or diarrhea, 
decreased appetite and weight loss and these symptoms are crucial factors that impact patient’s 
quality of life as well as the maintenance of an optimal nutritional state in people with CF(1, 3). 
The majority of studies of GI comorbidities seen in CF have been investigated in small single 
center studies, often retrospective. For example, although constipation is common in people with 
CF, and a source of significant abdominal pain, available studies have focused on the less 
common distal intestinal obstruction syndrome (DIOS).  Studies focused on the lifetime 
prevalence of constipation are scarce, but some report that constipation is common in pediatrics 
with a prevalence ranging between 26-47% and 42% in adults(2, 4). The main obstacle in 
formulating formal treatment recommendations for the GI symptoms in CF has been the overlap 
of many GI symptoms simultaneously in the same patient with CF and the lack of a focused 
symptom-based questionnaire that correctly identifies constipation and other GI disorders 
specifically in patients with CF(1, 3-5). The pathophysiology of many of these GI symptoms in 
CF is unique and perhaps different than what is seen in the general population with multifactorial 
causes which include both an increased viscosity of intestinal mucus with subsequent prolonged 
transit times in the stomach (gastroparesis), small intestinal bacterial overgrowth (SIBO), or 
colon (colonic dysmotility or fecal incontinence due to severe constipation) (5, 6). In this study, 
we will focus on more common GI conditions that impact the lives of a large number of people 
with CF. 
Recently a systematic review of abdominal complaints in adult and pediatric people with CF was 
undertaken, called the JenAbdomen-CF Score 1.0, which is a comprehensive 17 item survey(7). 
This survey is based on the patient-reported outcomes measures (PROMIS) set forth by the Food 
and Drug Administration (FDA) in 2009 to better identify GI symptoms in the general 
population in order to guide future treatments(8). The JenAbdomen study included a total of 131 
patients with CF of all ages and found the most common GI symptoms to be loss of appetite 
(99%), dysgeusia (91%), followed by abdominal pain (80%), flatulence (78%), and distension 
(63%). Constipation was noted by 32% of adults and 30% of children and juveniles combined 
using a frequently used stool consistency scale called the Bristol Stool Scale(9). Unfortunately, 
other important measures of constipation such as quantification of the frequency of spontaneous 
bowel movements (SBM), complete bowel movements (CSBM), or others in regards to an 
obstructive defecation seen often in CF such as fecal incontinence or rectal prolapse were not 
included(10). Moreover, the JenAbdomen questionnaire and PROMIS do not identify the 
severity of GI symptoms which may be important endpoints in CF.  
Other specific questionnaires focused on GI symptoms in people with CF have been developed 
and studied by several investigators. These include the GI Symptom Tracker (Abbot 
Pharmaceuticals) which is focused predominantly on symptoms associated with pancreatic 

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insufficiency and inadequate pancreatic enzyme therapy. The GI CF screening questionnaire was 
used as a screening questionnaire for pulmonologists and other providers involved in the care of 
a CF individual to determine the need for referral of patients to gastroenterologists (Bozic, 
Freedman, Schwarzenberg, personal communication). These questionnaires are not suitable for 
determining prevalence of GI symptoms in CF, nor for capturing the detail necessary to develop 
treatment algorithms. 
Several validated questionnaires exist for capturing the overlap of GI symptoms in the general 
population and for categorizing them into specific groups based on most likely GI diagnoses. 
The validated questionnaires most cited and often used by the National Institutes of Health (NIH) 
and accepted by the FDA for purposes of clinical drug trials are the ROME IV 
questionnaires(11), Patient Assessment of Gastrointestinal Symptoms (PAGI-SYM)(12), Patient-
Assessment of Constipation Symptoms (PAC-SYM)(13) and Patient- Assessment of 
Constipation Quality of Life (PAC-QOL)(14).  
ROME IV is used as a diagnostic tool for what was previously termed “Functional Bowel 
Diseases”; however, it does not stratify patients based on symptom intensity and was purely 
formed for diagnostic purposes. It is a long and laborious set of questionnaires and although also 
validated in children more than 4 years of age, its limitations include the inability to analyze 
symptom severity. In contrast, the PAC-SYM is a 12-item questionnaire that evaluates many 
different GI symptoms including nausea, vomiting, upper or lower abdominal pain, constipation 
and other questions related to stool habits(13). A higher score corresponds with worse 
symptoms; with a range from 1 to 4 points. In the general adult population, a decrease in score of 
about 1 point indicates moderate improvement and a decrease of about 0.5 points indicating 
minimal improvement. Another validated scale system is the Bristol Stool Scale discussed 
above(9, 15) which is primarily based on a pictorial identification of stool consistency and 
validated both in the pediatric and adult population. A lower score on the Bristol Stool Scale 
(Type 1 and 2) corresponds with harder stool, whereas a higher score suggests diarrhea (Type 6, 
7) with total range of scores ranging from 1 to 7.   
The PAGI-SYM is a 20-item questionnaire with six subscales: heartburn/regurgitation, 
fullness/early satiety, nausea/vomiting, bloating, upper abdominal pain, and lower abdominal 
pain and has good internal consistency and reliability (α=0.79-0.91) (12). This questionnaire 
correlates well with the PAGI-QOL scores (p value < 0.0001) and was developed in fact in 
conjunction with a disease-specific QOL instrument, the PAGI-QOL, making it a robust 
internationally utilized instrument. The PAGI-SYM is a helpful questionnaire for assessing 
symptom severity with good construct validity in subjects with reflux, dyspepsia, abdominal pain 
and gastroparesis - all symptoms and disorders which people with CF could have. The initial 
purpose of this questionnaire was its application in clinical trials and for assessment of 
effectiveness of new medical treatments.  
In addition to the PAGI-QOL, other important quality of life measures also exist for constipation 
and would be important to capture in the CF population. The PAC-QOL has 28 questions also 
rated on a 5 point Likert scale from 0 to 4 which range from not at all (0) to all of the time (4) 
(14). These questions are focused more on the intensity of bloating and constipation, as well as 
covering 4 subscales including worries and concerns (11 items), physical discomfort (4 items), 
Psychosocial discomfort (8 items) and satisfaction of treatment (5 items).   

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While this project collects data needed to develop protocols for several key GI symptoms in 
people with CF, we have chosen constipation as the first symptom we will be addressing in our 
CF patient population. Clear definitions of chronic constipation in CF do not exist but are needed 
in establishing a diagnosis and subsequent treatment plans in the acute and chronic settings. The 
most commonly accepted definition of constipation has been based on ROME IV criteria 
defining constipation as less than 3 bowel movements a week. The FDA uses this definition in 
combination with endpoints such as the number of CSBM and Bristol Stool Scale Type 1 and 2 
as defining constipation(16). The FDA’s PROMIS also defined chronic constipation as decreased 
stool frequency as measured by the number of CSBM a week to assess treatment response and 
for the purposes of clinical trials(8). Abdominal pain and discomfort were excluded in the 
definition of constipation although these are common in our patients with CF(16). The European 
Society for Pediatric Gastroenterology, Hepatology and Nutrition (ESPGHAN) has proposed a 
definition of constipation in CF which considers: 1) abdominal pain and/or distention, 2) reduced 
frequency or increased consistency of stool in the last few weeks or months, and 3) Symptoms 1 
and 2 are relieved by laxatives(17). However, this definition was primarily proposed to 
differentiate constipation from DIOS. It remains to be seen whether any of these definitions 
adequately describe the experience of constipation in a patient with CF that is relevant for 
clinically and/or research utility.  
Most of the current recommendations for treatment of constipation in CF are based on expert 
practices and guidelines rather than formal clinical trials. Given the lack of clinical data, 
Freeman et al.(18) has come up with an algorithm for treatment of constipation in CF which is 
based primarily on expert opinion and which has not been formally tested yet in the clinical 
setting. Our proposal would use GI-symptomatology questionnaires to understand the multiple 
overlapping GI symptoms in people with CF. This would be followed by interventions directed 
at the most high-frequency symptoms.  
2 
STUDY RATIONALE 
There are currently no large, multicenter prospective clinical trials examining management of 
constipation or other GI symptoms in people with CF. Current recommendations in the CF 
literature are largely based on expert consensus and opinions. Yet, constipation and other GI 
symptoms are crucial factors in QOL and maintenance of optimal nutritional state in people with 
CF. This study will use GI-symptomatology questionnaires to understand the multiple 
overlapping GI symptoms in people with CF. This would be followed by studies to improve GI 
outcomes through establishing evidence-based algorithms, starting with constipation.  In the 
future, we would also like to evaluate the impact of CF modulators on common GI symptoms 
and evaluate how this might impact the development of symptom-specific algorithms. 
2.1 
Risk / Benefit Assessment 
As an observational study, there is no anticipated direct benefit to subjects.  
3 
STUDY OBJECTIVES 
3.1 
Primary Objective 
 Assess the feasibility of electronic PROs conducted outside-the-clinic.    

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3.2 
Secondary Objectives 
 Estimate the prevalence and variability of GI symptoms occurring in pediatric and adult 
patients with CF 
 Describe current management of GI symptoms in patients with CF  
 Gather information to guide and inform on the design of future algorithm-based approaches 
to treating GI symptoms in people with CF 
4 
STUDY DESIGN 
4.1 
Study Overview 
This is a prospective, multicenter, observational study designed to collect gastrointestinal related 
data in patients with CF. 
Eligible subjects will be consented and enrolled in the study at the Enrollment Visit. At the visit, 
the subject or parent/guardian will complete the PROs using their mobile device (e.g., 
smartphone or tablet). The PROs will consist of four questionnaires: Patient Assessment of 
Constipation-Symptoms (PAC-SYM), Patient Assessment of Gastrointestinal-Symptoms (PAGI-
SYM), Patient Assessment of Constipation Quality of Life (PAC-QOL) and the disease-specific 
questionnaire.  The disease-specific questionnaire will include the Bristol Stool Scale and will 
collect information on presence of fecal incontinence, stool quality and frequency.  At the 
Enrollment Visit, weight and height will be collected in addition to medical history and 
concomitant medication information. The subject or parent/guardian will complete the PROs 
outside-the-clinic setting per the Schedule of Events using their mobile device.   
5 
CRITERIA FOR EVALUATION 
5.1 
Primary Endpoint 
Percentage of scheduled outside-the-clinic assessments with at least one of the four PROs fully 
completed. 
5.2 
Secondary Endpoints 
Assess the feasibility of electronic PRO surveys conducted outside-the-clinic setting: 
1. At each scheduled outside-the-clinic assessment, number (%) of subjects with at least 
one PRO fully completed 
2. For each PRO, number (%) of subjects with fully completed questionnaires at each 
scheduled outside-the-clinic assessment and overall 
3. Number (%) of completed PROs by subject, site, and other demographic and clinical 
features 
Estimate the prevalence and variability of GI symptoms: 
 Evaluate prevalence of protocol-defined constipation: 
4. Number (%) of enrolled subjects with any occurrence of constipation during 1 month 
of follow-up (the period prevalence) 
 Evaluate frequency and severity of each GI symptom at scheduled assessments and overall:  
5. Number (%) of subjects with presence of GI symptom 

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6. Distribution of severity scores of GI symptom 
7. Mean severity score of GI symptom 
8. Distribution of stool frequency and type by Bristol Stool Scale  
9. Change in distribution of GI symptoms and stool frequency/type from enrollment 
visit overall and by whether subjects were receiving treatment 
 Evaluate PRO scores overall and by sub-scale at scheduled assessments: 
10. Mean PRO score 
11. Within and across subject variability of PRO scores 
12. Mean PRO scores (also mean differences and 95% confidence interval) comparing 
subjects with constipation to those without constipation 
 Evaluate alternative CF specific definitions of constipation: 
13. Examine alternative definitions of constipation that are CF specific based on 
correlation with PRO questionnaires and maximizing the area under the receiver 
operating characteristic curve (ROC curve) for PAC-SYM scores 
14. Number (%) reporting constipation based on patient self-assessment. Examine 
concordance of self-reported constipation against protocol/alternate definitions using 
Cohen’s kappa coefficient 
Describe current management of GI symptoms: 
 Evaluate treatment for GI symptoms and constipation at time of enrollment visit: 
15. Number (%) of all subjects receiving treatment 
16. Number (%) of all subjects initiating treatment  
17. Number (%) of all subjects receiving treatment by Medication class/type 
18. Among subjects with GI symptoms and constipation, number (%) receiving treatment 
 Evaluate symptom scores due to treatment: 
19.  Mean PRO scores (also mean differences and 95% confidence interval) comparing 
subjects receiving treatment for GI symptoms to those not receiving treatment  
20. Among subjects receiving treatment for constipation, mean absolute change in PRO 
scores over time overall and by medication type/class 
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. All genders ≥ 2 years of age at time of consent 
2. Documentation of a Cystic Fibrosis (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)  

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 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 Patient Registry (subjects may enroll in the 
Registry at Enrollment Visit if not previously enrolled)  
4. Written informed consent (and assent when applicable) obtained from subject or subject's 
legal representative  
5. Willing to complete questionnaires on mobile device 
6. Able to use the Medidata Patient Cloud mobile application for completing the 
questionnaires 
6.3 
Exclusion Criteria 
1. Presence of a condition or abnormality that, in the opinion of the Investigator, would 
complicate interpretation of study outcome data or interfere with achieving the study 
objectives  
2. Presence of a pulmonary exacerbation at the Enrollment Visit  
3. Hospitalization for distal intestinal obstruction syndrome (DIOS) within the 28 days prior 
to the Enrollment Visit  
4. Current gastrointestinal (GI) or abdominal/pelvic malignancy  
5. Abdominal or pelvic surgery within the 28 days prior to the Enrollment Visit  
6. At the time of the Enrollment Visit, planned abdominal or pelvic surgery or bowel 
cleanout in the 28 days after the Enrollment Visit. 
7. Initiation of new CFTR modulator therapy within the 4 weeks prior to the Enrollment 
Visit 
8. Intent to initiate new CFTR modulator therapy within 28 days of the Enrollment Visit 
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 enrollment is considered a screen 
failure. All screen failures must be documented with the reason for the screen failure adequately 
stated.  If a subject screen fails prior to enrollment, they can be rescreened if the site staff feels 
they meet eligibility criteria.  Rescreened subjects will have to complete all screening procedures 
(i.e., data from previous screenings cannot be used).    
7 
CONCURRENT MEDICATIONS 
7.1 
Allowed Medications and Treatments 
Standard therapy for CF is allowed.   

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7.2 
Prohibited Medications and Treatments 
There are no prohibited medications.  
8 
STUDY TREATMENTS 
Not applicable. 
9 
  STUDY PROCEDURES AND GUIDELINES 
The procedures described below will be performed at the visits noted in the Schedule of Events 
(Appendix) and in Section 9. 
Prior to conducting any study-related activities, written informed consent and the Health 
Insurance Portability and Accountability Act (HIPAA) authorization must be signed and dated 
by the subject or subject’s legal representative.  If appropriate, assent must also be obtained prior 
to conducting any study-related activities. 
9.1 
Clinical Assessments 
9.1.1 Concomitant Medications 
Concomitant medications and concurrent therapies will be documented as noted in the Schedule 
of Events.   
9.1.2 Demographics and CFF Registry ID 
Demographic information (date of birth, sex, race) and CF Registry number will be recorded.   
9.1.3 Medical History  
Relevant medical history, including history of current disease, other pertinent gastrointestinal 
history, and information regarding underlying diseases will be recorded. 
9.1.4 CF Diagnosis 
CF diagnostic test date(s) and results will be recorded. 
9.1.5 Weight and Height   
Weight will be measured and recorded as noted in the Schedule of Events. Adults and children 
may remain in clothes (without shoes). A standing height will be measured and recorded as noted 
in the Schedule of Events. 
9.1.6 Subject Questionnaire: Patient Assessment of Gastrointestinal Disorders – 
Symptom Severity Index (PAGI-SYM) 
Subjects will complete the PAGI-SYM questionnaire as noted in the Schedule of Events. The 
PAGI-SYM questionnaire measures specific symptoms of patients with upper gastrointestinal 
disorders, specifically GERD, dyspepsia and gastroparesis. The PAGI-SYM contains 20 
questions scored on a 6-point Likert response scale (0 – 5 range). The questionnaire takes 
approximately 5 minutes to complete. For subjects ≥ 2 years of age to < 12 years of age, the 

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parent/guardian will complete the questionnaire. For subjects ≥ 12 years of age, the subject will 
complete the questionnaire.   
9.1.7 Subject Questionnaire: Patient Assessment of Constipation – Symptom Severity 
Index (PAC-SYM)  
Subjects will complete the PAC-SYM questionnaire as noted in the Schedule of Events. The 
PAC-SYM questionnaire measures specific symptoms of patients with constipation.  The PAC-
SYM contains 12 questions scored on a 5-point Likert response scale (0 – 4 range). The 
questionnaire takes approximately 5 minutes to complete. For subjects ≥ 2 years of age to < 12 
years of age, the parent/guardian will complete the questionnaire. For subjects ≥ 12 years of age, 
the subject will complete the questionnaire.    
9.1.8 Subject Questionnaire: Patient Assessment of Constipation Quality of Life (PAC-
QOL) 
Subjects will complete the PAC-QOL questionnaire as noted in the Schedule of Events.  The 
PAC-QOL questionnaire measures quality of life of patients with constipation. The PAC-QOL 
contains 28 questions scored on a 5-point Likert response scale (0 – 4 range). The questionnaire 
takes approximately 5 minutes to complete. For subjects ≥ 2 years of age to < 12 years of age, 
the parent/guardian will complete the questionnaire. For subjects ≥ 12 years of age, the subject 
will complete the questionnaire. 
9.1.9 Disease-specific questions 
The Bristol Stool Scale is a visual assessment of stool consistency. In addition, there are 
questions related to stool quality, frequency and presence of fecal incontinence. These will be 
completed as noted in the Schedule of Events. The questionnaire takes approximately 5 minutes 
to complete.  For subjects ≥ 2 years of age to < 12 years of age, the parent/guardian will 
complete these questions. For subjects ≥ 12 years of age, the subject will complete these 
questions. 
10 EVALUATIONS BY VISIT 
10.1 Enrollment Visit (Day 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. Perform review of eligibility criteria. 
4. Record demographics data and CFF Registry ID. 
5. Record medical history, including a history of CF, diagnosis date, gastrointestinal history, 
and prior CF and gastrointestinal treatments. 
6. Record concomitant medications. 
7. Measure and record height and weight. 

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8. Assist with downloading and registering the Medidata Patient Cloud mobile application for 
completing the questionnaires into subject’s mobile device (e.g., smartphone or tablet 
computer). Review and provide the subject with the application and questionnaire completion 
instructions.   
9. Complete electronic PRO questionnaires (PAGI-SYM, PAC-SYM, PAC-QOL, and 
additional disease-specific questions) on mobile device (subject or their parent/guardian). 
11 ADVERSE EXPERIENCE REPORTING AND DOCUMENTATION 
Adverse Events, including Serious Adverse Experiences, will not be collected as part of this 
study.  
12 DISCONTINUATION AND REPLACEMENT OF SUBJECTS 
12.1 Early Withdrawal of Subjects from the Study 
All subjects are free to withdraw from participation at any time, for any reason, specified or 
unspecified, and without prejudice.  This may include subjects who withdraw from completing 
the study visit and who decline to complete the questionnaires.   
If the investigator is able to provide a reason for early subject withdrawals, it will be specified in 
the subject’s source documents.   
12.2 Replacement of Subjects 
Subjects who withdraw from the study will not be replaced.   
13 PROTOCOL VIOLATIONS 
A protocol violation occurs when the subject, investigator, or the Sponsor fails to adhere to 
significant protocol requirements affecting the inclusion, exclusion, subject safety and primary 
endpoint criteria.  Protocol violations for this study include, but are not limited to, the following: 
 Failure to meet inclusion/exclusion criteria 
 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 in accordance 
with their IRB reporting requirements. 
14 DATA SAFETY MONITORING 
Not applicable 

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15 STATISTICAL METHODS AND CONSIDERATIONS 
15.1 General Considerations 
Prior to the analysis of the final study data, a detailed Statistical Analysis Plan (SAP) will be 
written, describing all analyses that will be performed.  The SAP will contain any modifications 
to the analysis plan described below.  
The endpoints of this study are mostly descriptive, with all continuous outcomes such as 
symptom severity and PRO scores evaluated using descriptive statistics such as mean, median, 
standard deviation and 95% confidence intervals. Presence/absence of symptoms will be shown 
as percentages and corresponding 95% confidence intervals calculated using the Wilson method. 
Group comparisons will be made via the two-sample t-test for continuous outcomes or Fisher’s 
exact test for categorical outcomes. Except where otherwise noted, all tests will be two-sided and 
statistical significance will be determined at the 0.05 level. No adjustment for multiple 
comparisons will be made.  
15.1.1 Data Sets Analyzed 
The analysis population consists of all eligible subjects who enroll into the study – the Full 
Analysis Set.  For select endpoints, stratification of study results by age group, CF genotype, 
pancreatic status, and whether sites were DIGEST awardees will also be considered.  
15.2 Demographic and Baseline Characteristics 
The enrolled study population will be described with respect to baseline demographic and 
clinical characteristics such as age, gender, race, ethnicity, genotype, height, weight, pancreatic 
status, body mass index, and use of concomitant medications. Demographics of subjects 
comparing completers (those who completed all questionnaires at all assessments) to those that 
are not completers will also be included. To evaluate the representativeness of the enrolled study 
population, the demographics of enrolled subjects will be compared against the general CF 
population (from the CFF Patient registry). 
15.3 Analysis of Primary Endpoint 
The primary endpoint is the percentage of scheduled outside-the-clinic assessments with at least 
one PRO fully completed out of the four questionnaires administered (the PAC-SYM, PAGI-
SYM, PAC-QOL and the disease-specific questionnaire). The denominator for the percentage is 
the expected number of outside-the-clinic assessments (# of enrolled subjects x 3 outside-the-
clinic assessments/subject).   
15.4 Analysis of Secondary Endpoints 
Constipation is defined as <3 bowel movements in the past week and/or Bristol Stool type 1 or 2. 
The secondary endpoint upon which the sample size is based is the number (%) of enrolled 
subjects with any occurrence of constipation during 1 month of follow-up (the period 
prevalence). Treatment for GI symptoms and constipation will be summarized based on the 
percentage of enrolled subjects receiving and initiating treatment at time of enrollment visit. To 
evaluate whether CF subjects are adequately treated, the number and percentage of subjects with 
GI symptoms and constipation on treatment will be reported. All GI related treatments will be 
classified by medication type/class. 

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Individual GI symptoms will be extracted from the PAC-SYM and PAGI-SYM questionnaires. 
For each GI symptom, frequency and severity will be summarized at each assessment as follows: 
number (%) of subjects with GI symptom, severity of GI symptom (mean score and distribution 
of severity score) and change in severity scores from the enrollment visit by whether subjects 
were receiving treatment. 
Mean overall (and by sub-scale) PRO scores for PAC-SYM, PAGI-SYM and PAC-QOL at 
scheduled assessments will be reported including evaluation of within and between subject 
variability.  Group comparisons of mean scores by subjects receiving/not receiving treatment and 
by those with/without constipation will also be made. Absolute change in PRO scores from 
enrollment visit to scheduled assessments will be reported based on subjects receiving/not 
receiving treatment for constipation. To examine these effects, figures displaying mean PRO 
scores by scheduled assessment will be created. Additionally, mixed effects models for repeated 
measures will be fit with PRO scores as the outcome and covariates for visit, treatment, 
pancreatic status, age group and the interaction between treatment and visit. 
Alternative definitions of constipation that are CF specific will be created based on different 
frequencies of bowel movement and Bristol stool type evaluated individually or in combination. 
Spearman correlations of stool frequency with the PAC-SYM score and Bristol stool type with 
PAC-SYM scores will be examined. The different constipation definitions will be evaluated by 
comparing against the area under the curve of receiver operating characteristic curve (ROC 
curve) for PAC-SYM scores. The percentage of subjects reporting constipation based on self-
assessment and the concordance to the protocol definition/alternate definitions will be made 
using Cohen’s kappa coefficient. 
15.5 Analysis of Missing Data  
Detailed summaries of missing data including the number and percentage of scheduled 
assessments with at least one of the four PROs completed will be provided. For each PRO, the 
percentage of scheduled assessments with fully completed PROs will also be provided. Other 
missing data methods to examine sensitivity and robustness of study results for the primary and 
key secondary endpoints will be described in the SAP. To minimize missing data, subjects will 
receive reminder notifications to complete their scheduled assessment. 
15.6 Interim Review 
When 100 subjects have enrolled, an interim review will be conducted by an External Advisory 
Committee to determine whether the study should continue or stop. The Advisory Committee 
decision to continue to enroll or stop will be made in consideration of several factors including 
but not limited to: overall rate of enrollment, adequate representation of sub-populations, missing 
PRO data, and prevalence of constipation as well as estimates of PRO variability. The two-stage 
enrollment strategy will allow for enriching enrollment based on either under-enrolled sub-
populations or on the observed variability of GI symptoms for demographics-related factors such 
as age-group (pediatric/adult), modulator use or pancreatic status. In addition to the interim 
review, the TDNCC will continuously monitor enrollment and provide the Advisory Committee 
quarterly reports of enrollment demographics. 
15.7 Sample Size  
 Sample size estimates for this study are based on two criteria: 

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a. To assess feasibility and ensure representativeness of the enrolled CF subjects  
b. To estimate prevalence of GI symptoms (specifically constipation) 
Period prevalence is defined as the proportion of subjects with symptom over an interval of time.  
Estimates of constipation prevalence in CF patients varies in the literature. A recent 2017 
publication (7) showed the period prevalence of constipation over 3 months was 31% (32% 
adults; 30% children). Another 2010 publication (3) estimated prevalence of constipation in CF 
patients age ≤ 18 years in the Netherlands at 20% (annual assessment) using the ESPGHAN 
definition. Note that an epidemiologic review of constipation prevalence in the general 
population (non-CF) in North America ranged from 1.9% to 27.2% with most estimates from 
12%-19% (19). Therefore, 10% will serve as the lower bound estimate of constipation 
prevalence. The sample size estimate for CF patients in the GALAXY study is based on a 
prevalence of constipation over a 1 month period in the 20% - 30% range (25% average). 
Sample size estimates are based on 95% confidence intervals (C.I.) half-widths (i.e., width of 
one arm of the 95% CI) for proportions. While constipation is one symptom of interest, it is 
difficult to specify an exact prevalence estimate over a 1 month period utilizing the study 
specific definition of constipation. In addition, the occurrence of other GI symptoms is also of 
interest and will occur at varying rates. Therefore, the figure below shows what the sample size 
(y-axis) is for varying half-width sizes (x-axis) when prevalence estimates range between 10% to 
50% (maximum). Approximately 400 subjects are needed to estimate a prevalence of 
constipation of 25% with a 95% C.I.  half-width of 4.5% (95% C.I. = 20.5%, 29.5%) and 
assuming a 12% missing data rate. 

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With 400 subjects, this study will allow estimation of variability (between and within subject) in 
160 pediatric subjects and 240 adult subjects.  A recent publication (20) reported PAC-SYM 
variability from 2884 adult patients with chronic constipation from six randomized clinical trials 
(scores range from 0 to 4 per subject).  The study reported a baseline variance of 0.52. With 240 
adult subjects and between-subject variance of 0.52, the 95% confidence interval for variance is 
0.44, 0.63 (width = 0.19). 
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 
and subject number. 
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.   

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The Investigator is responsible for all information collected on subjects enrolled in this study.  
All data collected during the course of this study must be reviewed and verified for completeness 
and accuracy by the Investigator.  At the completion of the study, a copy of the CRF data will be 
provided to the site to be retained at the Investigator’s site. 
16.2 Data Management Procedures 
TDNCC utilizes Medidata Solutions, Inc. (Medidata) Rave for their study database. 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 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.  TDNCC also utilizes 
the Medidata Rave eCOA/ePRO system, a regulatory compliant system which allows subjects in 
a study using Medidata Rave EDC to complete and submit forms and data for patient-reported 
outcomes electronically on a mobile device to the Medidata Rave EDC System. Study personnel 
at each site will register study subjects using their unique subject identification number which 
generates an activation code unique to that subject. Study site personnel provide the subject with 
their activation code. The study subject downloads the Medidata Rave eCOA/ePRO app to their 
mobile device and uses their unique activation code to create their ePRO login and password.   
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 clinical trials.   
16.3 Data Quality Control and Reporting 
After data have been entered into the study database, data validation checks will be applied on a 
regular basis. Queries are entered, tracked, and resolved through the EDC system directly.  The 
study database will be updated in accordance with the resolved queries. All changes to the study 
database will be documented in an audit trail. 
16.4 Security and Archival of Data 
The Rave EDC and Rave eCOA/ePRO systems are 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. 

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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 Seattle Children’s.  Data is backed up regularly 
according to the Information Services group’s procedures.  
16.5 Availability and Retention of Investigational Records 
The Investigator must make study data accessible to the monitor, other authorized 
representatives of the Sponsor (or designee), IRB, and Regulatory Agency (e.g., FDA) inspectors 
upon request.  A file for each subject must be maintained that includes the signed Informed 
Consent, 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, 
Essential Document and Study Reference Binders) must be kept secured for a period of five 
years after 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.  Monitoring visits will be conducted by representatives of the Sponsor 
according to the U.S. CFR 21 Part 312 to ensure investigator compliance to 21 CFR Parts 50, 56 
and 312.   
16.7 Subject Confidentiality 
In order to maintain subject confidentiality, only a site number and subject number will identify 
all study subjects on CRFs and other documentation submitted to the Sponsor.  The subject’s 
CFF patient registry number will also be collected. Additional subject confidentiality issues (if 
applicable) are covered in the Clinical Study Agreement. 
17 ADMINISTRATIVE, ETHICAL, REGULATORY CONSIDERATIONS 
The study will be conducted according to the Declaration of Helsinki, Protection of Human 
Volunteers (21 CFR 50), Institutional Review Boards (21 CFR 56), and Obligations of Clinical 
Investigators (21 CFR 312). 
Clinical information will not be released without written permission of the subject, except as 
necessary for monitoring by the FDA.  The Investigator must also comply with all applicable 
privacy regulations (e.g., Health Insurance Portability and Accountability Act of 1996, EU Data 
Protection Directive 95/46/EC). 
17.1 Protocol Amendments 
Any amendment to the protocol will be written by the Sponsor.  Protocol amendments cannot be 
implemented without prior written IRB approval except as necessary to eliminate immediate 
safety hazards to patients.  A protocol amendment intended to eliminate an apparent immediate 

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hazard to patients may be implemented immediately, provided the IRBs are notified within five 
working days. 
17.2 Institutional Review Boards and Independent Ethics Committees 
The protocol and consent form will be reviewed and approved by the IRB on record prior to 
study initiation.  The Investigator will keep the IRB informed as to the progress of the study.  
The Investigator will obtain assurance of IRB compliance with regulations. 
Any documents that the IRB may need to fulfill its responsibilities (such as protocol, protocol 
amendments, consent forms, information concerning patient recruitment, payment or 
compensation procedures, or other pertinent information) will be submitted to the IRB.  The 
IRB’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’s unconditional 
approval statement will be transmitted by the Investigator to the Sponsor or 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 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 and written verification that the modification was 
submitted and subsequently approved should be obtained.   
The IRB must be informed of revisions to other documents originally submitted for review; 
serious and/or unexpected adverse experiences occurring during the study in accordance with the 
standard operating procedures and policies of the IRB; new information that may affect 
adversely the safety of the patients of the conduct of the study; an annual update and/or request 
for re-approval; and when the study has been completed. 
17.3 Informed Consent Form  
Informed consent will be obtained in accordance with the Declaration of Helsinki, US Code of 
Federal Regulations for Protection of Human Subjects (21 CFR 50.25[a,b], CFR 50.27, and CFR 
Part 56, Subpart A), the Health Insurance Portability and Accountability Act (HIPAA, if 
applicable), and local regulations. 
The Investigator will prepare the informed consent form, assent and HIPAA authorization and 
provide the documents to the Sponsor or designee for approval prior to submission to the IRB.  
The consent form generated by the Investigator must be acceptable to the Sponsor and be 
approved by the IRB.  The written consent document will embody the elements of informed 
consent as described in the 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 (or their legal representatives) must be given ample opportunity to inquire about details 
of the study.  If appropriate and required by the IRB, assent from the subject will also be 
obtained.  If a subject is unable to sign the informed consent form (ICF) and the HIPAA 
authorization, a legal representative may sign for the subject.   A copy of the signed consent form 

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(and assent) will be given to the subject or legal representative 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  
To facilitate the inclusion of retrospective and prospective information from all patients enrolled 
in this study, the subject’s CFF Registry ID number will be collected.  The Cystic Fibrosis 
Foundation Patient Registry (CFFPR) collects data on all CF patients who consented to 
participate in the CFFPR registry and who are followed at CFF-accredited care centers.  The 
registry data includes information from clinical encounters, hospitalizations courses of 
antibiotics, and year-end surveys.  Data also include microbiology results, spirometry results, CF 
genotype and other information. The patient’s CF registry number will be recorded in the CRF. 
17.5 Publications  
The preparation and submittal for publication of manuscripts containing the study results shall be 
in accordance with a process determined by mutual written agreement among the study Sponsor 
and participating institutions.  The publication or presentation of any study results shall comply 
with all applicable privacy laws, including, but not limited to, the Health Insurance Portability 
and Accountability Act of 1996. 
17.6 Investigator Responsibilities 
By signing the Agreement of Investigator form, the Investigator agrees to: 
1 Conduct the study in accordance with the protocol and only make changes after notifying 
the Sponsor (or designee), except when to protect the safety, rights or welfare of subjects. 
2 Personally conduct or supervise the study (or investigation). 
3 Ensure that the requirements relating to obtaining informed consent and IRB review and 
approval meet federal guidelines, as stated in § 21 CFR, parts 50 and 56. 
4 Report to the Sponsor or designee any AEs that occur in the course of the study, in 
accordance with §21 CFR 312.64. 
5 Ensure that all associates, colleagues and employees assisting in the conduct of the study 
are informed about their obligations in meeting the above commitments. 
6 Maintain adequate and accurate records in accordance with §21 CFR 312.62 and to make 
those records available for inspection with the Sponsor (or designee). 
7 Ensure that an IRB that complies with the requirements of §21 CFR part 56 will be 
responsible for initial and continuing review and approval of the clinical study. 
8 Promptly report to the IRB and the Sponsor (or designee) all changes in the research 
activity and all unanticipated problems involving risks to subjects or others (to include 
amendments and IND safety reports). 
9 Seek IRB approval before any changes are made in the research study, except when 
necessary to eliminate hazards to the patients/subjects. 

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10 Comply with all other requirements regarding the obligations of clinical investigators and 
all other pertinent requirements listed in § 21 CFR part 312. 
18 REFERENCES 
1. Tack J, Camilleri M, Dubois D, Vandeplassche L, Joseph A, Kerstens R. Association between 
health-related quality of life and symptoms in patients with chronic constipation: an 
integrated analysis of three phase 3 trials of prucalopride. Neurogastroenterology and 
motility : the official journal of the European Gastrointestinal Motility Society 2015; 27: 
397-405. 
2. Rubinstein S, Moss R, Lewiston N. Constipation and meconium ileus equivalent in patients 
with cystic fibrosis. Pediatrics 1986; 78: 473-479. 
3. van der Doef HP, Kokke FT, Beek FJ, Woestenenk JW, Froeling SP, Houwen RH. 
Constipation in pediatric cystic fibrosis patients: an underestimated medical condition. J 
Cyst Fibros 2010; 9: 59-63. 
4. Gelfond D, Borowitz D. Gastrointestinal complications of cystic fibrosis. Clin Gastroenterol 
Hepatol 2013; 11: 333-342; quiz e330-331. 
5. Bali A, Stableforth DE, Asquith P. Prolonged small-intestinal transit time in cystic fibrosis. Br 
Med J (Clin Res Ed) 1983; 287: 1011-1013. 
6. Corral JE, Dye CW, Mascarenhas MR, Barkin JS, Salathe M, Moshiree B. Is Gastroparesis 
Found More Frequently in Patients with Cystic Fibrosis? A Systematic Review. 
Scientifica 2016; 2016: 2918139. 
7. Tabori H, Arnold C, Jaudszus A, Mentzel HJ, Renz DM, Reinsch S, Lorenz M, Michl R, 
Gerber A, Lehmann T, Mainz JG. Abdominal symptoms in cystic fibrosis and their 
relation to genotype, history, clinical and laboratory findings. PLoS One 2017; 12: 
e0174463. 
8. Spiegel BM, Hays RD, Bolus R, Melmed GY, Chang L, Whitman C, Khanna PP, Paz SH, 
Hays T, Reise S, Khanna D. Development of the NIH Patient-Reported Outcomes 
Measurement Information System (PROMIS) gastrointestinal symptom scales. Am J 
Gastroenterol 2014; 109: 1804-1814. 
9. Lewis SJ, Heaton KW. Stool form scale as a useful guide to intestinal transit time. Scand J 
Gastroenterol 1997; 32: 920-924. 
10. Benezech A, Desmazes-Dufeu N, Baumstarck K, Bouvier M, Coltey B, Reynaud-Gaubert M, 
Vitton V. Prevalence of Fecal Incontinence in Adults with Cystic Fibrosis. Dig Dis Sci 
2018; 63: 982-988. 
11. Lacy BE, Mearin F, Chang L, Chey WD, Lembo AJ, Simren M, Spiller R. Bowel Disorders. 
Gastroenterology 2016; 150: 1393-1407.e1395. 
12. Rentz AM, Kahrilas P, Stanghellini V, Tack J, Talley NJ, de la Loge C, Trudeau E, Dubois 
D, Revicki DA. Development and psychometric evaluation of the patient assessment of 
upper gastrointestinal symptom severity index (PAGI-SYM) in patients with upper 
gastrointestinal disorders. Qual Life Res 2004; 13: 1737-1749. 
13. Frank L, Kleinman L, Farup C, Taylor L, Miner P, Jr. Psychometric validation of a 
constipation symptom assessment questionnaire. Scand J Gastroenterol 1999; 34: 870-
877. 
14. Marquis P, De La Loge C, Dubois D, McDermott A, Chassany O. Development and 
validation of the Patient Assessment of Constipation Quality of Life questionnaire. Scand 
J Gastroenterol 2005; 40: 540-551. 

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15. Blake MR, Raker JM, Whelan K. Validity and reliability of the Bristol Stool Form Scale in 
healthy adults and patients with diarrhoea-predominant irritable bowel syndrome. Aliment 
Pharmacol Ther 2016; 44: 693-703. 
16. Lusman SS, Grand R. Approach to chronic abdominal pain in Cystic Fibrosis. J Cyst Fibros 
2017; 16 Suppl 2: S24-S31. 
17. Houwen RH, van der Doef HP, Sermet I, Munck A, Hauser B, Walkowiak J, Robberecht E, 
Colombo C, Sinaasappel M, Wilschanski M, Group ECFW. Defining DIOS and 
constipation in cystic fibrosis with a multicentre study on the incidence, characteristics, 
and treatment of DIOS. J Pediatr Gastroenterol Nutr 2010; 50: 38-42. 
18. Freeman AJ, Kowalcyk M, Borowitz D, Schwarzenberg S. Management of Constipation in 
patients with cystic fibrosis: Cystic Fibrosis Foundation Clinical Guidance Statement 
Bethesda, MD: Cystic Fibrosis Foundation; 2015. 
19. Higgins PD, Johanson JF. Epidemiology of constipation in North America: a systematic 
review. Am J Gastroenterol 2004; 99: 750-759. 
20. Yiannakou Y, Tack J, Piessevaux H, Dubois D, Quigley EMM, Ke MY, Da Silva S, Joseph 
A, Kerstens R. The PAC-SYM questionnaire for chronic constipation: defining the 
minimal important difference. Aliment Pharmacol Ther 2017; 46: 1103-1111. 

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APPENDIX. SCHEDULE OF EVENTS 
 
ENROLLMENT VISIT 
(DAY 1) 
DAY 7
 A 
(+ 1 day) 
DAY 14
 A 
(+ 1 day) 
DAY 28
 A 
(+ 1 day) 
Informed Consent 
X 
 
 
 
Review Eligibility  
X  
 
 
 
CFF Registry ID, CF Diagnosis, and 
Demographics 
X  
 
 
 
Medical History/GI History 
X 
 
 
 
Concomitant Medication Review  
X  
 
 
 
Height 
X 
 
 
 
Weight 
X 
 
 
 
Assist with downloading mobile 
application for completing questionnaires 
X  
 
 
 
Complete PAC-SYM and PAGI-SYM 
questionnaires and disease-specific 
questions on mobile device 
X 
X 
X 
X 
Complete PAC-QOL on mobile device 
X 
 
 
X 
A The Questionnaire(s) will be completed outside-the-clinic.