Nutritional Impact of Ivacaftor Treatment in 4 Month to 2 Year Old Children With CF Gating Mutations
Conditions: Cystic Fibrosis
Sponsor: Children's Hospital of Philadelphia

 
18-015299 
                           12/4/2019 
Title: 
Nutritional Impact of Ivacaftor treatment in 6 month to 2 year Old 
Children with CF Gating Mutations  
Short Title 
Ivacaftor in 6 month  to 2 Year Old Children with CF  
Regulatory Sponsor: 
 
eIRB Number 
18-015299 
Protocol Version Date: 
  12/4/19 
Amendment 1 Date:  
Amendment 3 Date:  
Amendment 2 Date: 
Amendment 4 Date: 
 
Sponsor 
Vertex Pharmaceuticals 
50 Northern Ave. 
Boston, MA 02210 
 
Principal Investigator 
Virginia A. Stallings, MD 
2716 South Street, Room 14473 
Philadelphia, PA, 19146 
Phone: 267.425.1633 
email: stallingsv@email.chop.edu 
 

 
  
 
 
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TABLE OF CONTENTS 
Table of Contents............................................................................................................ ii 
Abbreviations and Definitions of Terms ......................................................................... iv 
Abstract ......................................................................................................................... iv 
Protocol Synopsis .......................................................................................................... vi 
1 
BACKGROUND INFORMATION AND RATIONALE ..................................................................................... 1 
1.1 
INTRODUCTION ............................................................................................................................................ 1 
1.2 
COMPLIANCE STATEMENT .............................................................................................................................. 3 
2 
STUDY OBJECTIVES .................................................................................................................................. 3 
2.1 
PRIMARY OBJECTIVE (OR AIM) ....................................................................................................................... 4 
2.2 
SECONDARY OBJECTIVES (OR AIM) .................................................................................................................. 4 
2.3  
EXPLORATORY AIMS…………………………………………………………………………………………………………………………………4 
3 
INVESTIGATIONAL PLAN.......................................................................................................................... 4 
3.1 
GENERAL SCHEMA OF STUDY DESIGN .............................................................................................................. 4 
3.1.1 
Screening Phase ............................................................................................................................... 4 
3.1.2 
Study Enrollment Phase ................................................................................................................... 4 
3.1.3 
Follow-up Phase ............................................................................................................................... 4 
3.2 
STUDY DURATION, ENROLLMENT AND NUMBER OF SITES .................................................................................... 5 
3.2.1 
Duration of Study Participation ....................................................................................................... 5 
3.2.2 
Total Number of Study Sites/Total Number of Subjects Projected ... Error! Bookmark not defined. 
3.3 
STUDY POPULATION ..................................................................................................................................... 5 
3.3.1 
Inclusion Criteria .............................................................................................................................. 5 
3.3.2 
Exclusion Criteria ............................................................................................................................. 5 
4 
STUDY PROCEDURES ............................................................................................................................... 6 
4.1 
SCREENING/CONSENT VISIT (VISIT 1) ............................................................................................................... 6 
4.2 
OBSERVATIONAL PERIOD ................................................................................................................................ 6 
4.2.1 
Visit 1 ............................................................................................................................................... 6 
4.2.2 
Visit 2 ............................................................................................................................................... 7 
4.2.3 
Visit 3……………………………………………………………………………………………………………………………………….…8 
4.3 
UNSCHEDULED VISITS ................................................................................................................................... 8 
4.4 
SUBJECT COMPLETION/WITHDRAWAL ............................................................................................................. 9 
5 
STUDY EVALUATIONS AND MEASUREMENTS .......................................................................................... 9 
5.1 
SCREENING AND MONITORING EVALUATIONS AND MEASUREMENTS ...................................................................... 9 
5.1.1 
Medical Record Review .................................................................................................................... 9 
5.1.2 
Laboratory Evaluations .................................................................................................................... 9 
5.1.3 
Study Assessments ........................................................................................................................... 9 
5.3 
SAFETY EVALUATION................................................................................................................................... 11 
6 
STATISTICAL CONSIDERATIONS ............................................................................................................. 11 
6.1 
STATISTICAL METHODS ................................................................................................................................ 11 
6.1.1 ANALYSIS OF PRIMARY AND SECONDARY ENDPOINTS .......................................................................................... 11 
6.2 
SAMPLE SIZE AND POWER ........................................................................................................................... 12 
7 
STUDY MEDICATION (STUDY DEVICE OR OTHER STUDY INTERVENTION) .............................................. 13 
7.1 
DESCRIPTION ............................................................................................................................................ 13 

 
  
 
 
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8 
SAFETY MANAGEMENT ......................................................................................................................... 12 
8.1 
CLINICAL ADVERSE EVENTS .......................................................................................................................... 12 
8.2 
ADVERSE EVENT REPORTING ........................................................................................................................ 12 
9 
STUDY ADMINISTRATION ...................................................................................................................... 13 
9.1 
DATA COLLECTION AND MANAGEMENT ......................................................................................................... 13 
9.2 
CONFIDENTIALITY ....................................................................................................................................... 14 
9.3 
REGULATORY AND ETHICAL CONSIDERATIONS .................................................................................................. 14 
9.3.1 
Data and Safety Monitoring Plan .................................................................................................. 14 
9.3.2 
Risk Assessment ............................................................................................................................. 15 
9.3.3 
Potential Benefits of Trial Participation ......................................................................................... 15 
9.3.4 
Risk-Benefit Assessment ................................................................................................................ 15 
9.4 
RECRUITMENT STRATEGY ............................................................................................................................. 16 
9.5 
INFORMED CONSENT/ASSENT AND HIPAA AUTHORIZATION .............................................................................. 16 
9.5.1 
Waiver of Documentation of Consent/Assent and Alteration of HIPAA Authorization ................. 16 
9.6 
PAYMENT TO SUBJECTS/FAMILIES ................................................................................................................. 17 
10 
PUBLICATION ...................................................................................................................................... 17 
11 
REFERENCES ........................................................................................................................................ 18 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

 
  
 
 
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ABBREVIATIONS AND DEFINITIONS OF TERMS 
AE 
 
Adverse event 
BMI 
 
Body mass index 
BMIZ 
 
BMI Z score 
CF 
 
Cystic fibrosis 
CFTR 
 
Cystic fibrosis transmembrane conductance regulator 
CHPS 
 
Center for Human Phenomic Science 
CYP 
 
Cytochrome P450 
FFMSEE 
 
Fat free massSleeping energy expenditure 
FMFFM 
 
Fat massFat free mass 
HAZFM 
 
Height Z scoreFat mass 
IvacaftorHAZ 
 
Kalydeco, VX-770Height Z score 
NDS Ivacaftor 
 
Nutrition data systemKalydeco, VX-770 
PHI NDS  
 
Personal health informationNutrition data system 
SAE PHI  
 
Serious adverse eventPersonal health information 
SEESAE  
 
Sleeping energy expenditureSerious adverse event 
ucOC%SEE 
 
Undercarboxylated osteocalcinSleeping energy 
expenditure 
WAZucOC% 
 
Weight Z scoreUndercarboxylated osteocalcin 
WAZ 
 
Weight Z score 
 
 
 

 
 
 
 
 
 
 
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ABSTRACT 
Context: Ivacaftor has been a  novel FDA approved therapy for patients with CF and gating 
mutations who are 2 years and older. The FDA has recently approved Ivacaftor for use in 
children 6 months of age and above. Our Investigator Initiated Study is designed to 
evaluate the nutritional, growth and GI impact of ivacaftor treatment for this unique younger 
(6 months to 2 years) patient cohort and for whom FDA approval for treatment is  now 
approved. This proposal directly extends our previous highly informative nutrition and 
weight gain investigation of ivacaftor treatment in the older patient cohort. 
Objectives: The primary aims of the study are to evaluate the impact of 12 weeks of 
ivacaftor treatment in 6 month  to 2 year old subjects with CF and gating mutations growth 
status and gut health and function in n=18 children with protocol evaluations at baseline 
(pre-treatment) and 6 and 12 weeks after clinically prescribed ivacaftor treatment has 
begun. Other outcomes of significant clinical interest in young patients with CF will be 
explored. All subjects will be evaluated at The Children's Hospital of Philadelphia, and will 
be recruited both regionally and nationally to ensure timely enrollment.  
Study Design: Observational prospective study with evaluations before and after 12 weeks 
of ivacaftor treatment.  An interim assessment at 6 weeks will also be included. 
Setting/Participants: Eighteen subjects ages 6 months  to 2 years of age cystic fibrosis and 
CFTR gating mutations who are in a general state of good health from cystic fibrosis 
centers in US and Canada.  
Study Interventions and Measures: Subjects will be evaluated before and after ivacaftor 
treatment for sleeping energy expenditure, BMI Z score, gut health and function as 
indicated by plasma fatty acids, fecal elastase and fecal calprotectin.  Dietary intake, growth 
status and velocity, and serum fat soluble vitamins, bile acids and calprotectin will also be 
assessed.   
 

 
 
 
 
 
 
 
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PROTOCOL SYNOPSIS 
Study Title 
Nutritional Impact of Ivacaftor Treatment in 6 month  to 2 Year Old 
Children with CF Gating Mutations  
Funder 
Vertex Pharmaceutical and CHOP Center for Human Phenomic 
Science and Nutrition Center 
Study Rationale 
     Cystic fibrosis (CF) is a genetic disease caused by mutations in 
the gene encoding the CF transmembrane conductance regulator 
(CFTR), a chloride channel in many types of cells. Most CF 
mutations either reduce the number of CFTR channels at the cell 
surface (synthesis and processing mutations) or impair channel 
function (gating or conductance mutations). Ivacaftor (Kalydeco®, 
Vertex Pharmaceuticals Inc.) was the first of a new class of drugs 
that improved CFTR gating dysfunction1-3.  For such mutations 
(G551D, G178R, S549N, S549R, G551S, G970R, G1244E, 
S1251N, S1255P, G1349D) that permit CFTR expression at the cell 
membrane but compromise its activity, ivacaftor increases the 
probability that the chloride channel is open and active.  In 
randomized, double-blind, placebo controlled trials, ivacaftor 
treatment in individuals (ages 6 to adulthood) with at least one 
G551D mutation resulted in clinically significant improvements in 
weight and body mass index (BMI), pulmonary function, and patient 
reported quality of life outcomes (QOL)3,4.  Lung function and 
weight changes occurred over eight weeks, then plateaued and 
were sustained over 48 weeks. 
     In the initial trials ivacaftor treatment in individuals with at least 
one G551D mutation resulted in rapid and sustained weight gain, 
increased FEV1%, decreased pulmonary exacerbations, decreased 
sweat chloride concentration reflective of increased CFTR activity, 
and improved patient reported health-related QOL outcomes3-5. 
Ivacaftor has shown similar benefit in younger children and has 
been approved for use in children 6 months of age and older. 
Ivacaftor was found to be safe and effective in 33 children in the 
KIWI study completed 24 weeks of treatment in the KIWI study, 
with significant reductions in sweat chloride concentration, and an 
average increase in weight Z score of 0.2±0.3 and BMI z score of 
0.4±0.46.  Some exocrine pancreatic function restoration was 
demonstrated in these young children, as Davies et al.6 
     In our recent longitudinal observational study of 23 subjects 
(ages 5 to 61 years), we identified several mechanisms for weight 
gain with 3-month ivacaftor treatment including decreased resting 
energy expenditure (REE), gut inflammation and dietary fat 
malabsorption, resulting in a positive energy balance and weight 
gain. Weight gain in this study was 2.5 kg and was associated with 
a significant decrease in REE percent predicted of 5.5%, and in 
fecal calprotectin of 30 ug/g stool, a measure of gut inflammation7-9. 
     Several outcomes related to improved energy balance are 
considered in this proposal. Building on our results in older 

 
 
 
 
 
 
 
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subjects, we will once again focus on the importance of determining 
the effect of ivacaftor treatment on clinically important non-
pulmonary outcomes. Our primary aim in this study of young 6 
month  to 2 year old children is to determine if 12-week ivacaftor 
treatment results in decreased sleeping energy expenditure (REE) 
and improved growth status by BMI Z score. Our secondary aim is 
to determine improvement in gut health and function associated 
with fat digestion, including increased total plasma fatty acids and 
fecal elastase, and decreased fecal calprotectin.  Exploratory aims 
include investigating the impact of ivacaftor treatment on dietary 
intake, length, weight and head circumference status and growth 
velocity, and on serum fat soluble vitamins, bile acids and 
calprotectin.    
Study Objective(s) 
     We propose a longitudinal study design to determine whether 12 
weeks of treatment with ivacaftor results in improvement in sleeping 
energy expenditure (SEE), growth status as BMI Z score, and gut 
health and function in n=18 children ages 6 months  to 2 years with 
at least one CFTR gating mutation. We anticipate that these 
changes will accompany meaningful improvements in dietary 
intake, growth status and growth velocity, and serum fat soluble 
vitamins, bile acids and serum calprotectin in these young children.   
 
PRIMARY AIMS 
H1:  Ivacaftor treatment will result in a significant reduction in SEE 
as percent predicted over 12 weeks compared to baseline, thereby 
increasing the energy available for weight gain and physical 
activity. 
H2: Ivacaftor treatment will result in significantly increased BMI Z 
score over 12 weeks compared to baseline. 
SECONDARY AIMS 
H3:  Ivacaftor treatment will result in significantly improved gut 
health and function resulting in better dietary fat absorption as 
indicated by increased total plasma fatty acids and fecal elastase 
and decreased fecal calprotectin over 12 weeks compared to 
baseline. 
EXPLORATORY AIMS 
To determine the impact of ivacaftor treatment over 12 weeks 
compared to baseline in: 
 
Dietary intake of calories and percent calories from fat 
 
Growth status for length, weight, head circumference and 
growth velocity 
 
Serum fat soluble vitamins A, D, E and K, bile acids, and 
serum calprotectin 
Study Design 
 
We propose a longitudinal study design to assess sleeping energy 
expenditure, improvement in BMI Z score, and improved gut health 
and function in n=18 children ages 6 months  to 2 years with CF 

 
 
 
 
 
 
 
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with a gating mutation (G551D, G178R, S549N, S549R, G551S, 
G970R, G1244E, S1251N, S1255P, G1349D) before treatment 
(baseline) and after 6 and 12 weeks treatment with ivacaftor.   
Inclusion and 
Exclusion: 
Inclusion Criteria 
 
Cystic fibrosis with at least one CFTR gating mutation of these 
ten (G551D, G178R, S549N, S549R, G551S, G1244E, 
S1251N, S1255P, G1439D, or R117H) approved for treatment 
 
Age: 6 months to 2 years of age  
 
In their usual state of good health  
 
A clinical decision has been made for subject to begin 
ivacaftor treatment 
 
Family committed to the 4 to 6 month study protocol with visits 
to CHOP that will last 2 or 3 days for the baseline visit (Visit 1) 
prior to ivacaftor and the 12 week visit (Visit 3) after clinically 
prescribed ivacaftor treatment has begun, and will last 2 days 
for the 6 week visit (Visit 2) after ivacaftor treatment has 
begun. 
 
Note that ivacaftor is now approved by the FDA for 6 month  to 
2 year old children for the additional 28 CFTR mutations 
known to be responsive to ivacaftor potentiation, these will 
also be considered.  With our limited samples size, the 
mutations that have shown the strongest improvement with 
treatment will be given priority for enrollment. 
Exclusion Criteria 
 
On parenteral nutrition 
 
Use of any inhibitors or inducers of cytochrome P450 (CYP) 
3A 
 
Liver function tests elevated above 3x the reference range for 
age and sex 
 
Other illness affecting growth or nutritional status 
 
Other contraindications described for ivacaftor therapy 
 
Number Of Subjects  
18 
Study Duration 
Each subject’s participation will last 4 to 6 months 
The entire study is expected to last 15 months 
Study Phases  
Screening: screening for eligibility and obtaining consent  
Baseline: baseline study visit at CHOP 
Follow up: 6 week visit at CHOP after confirmation of timing of the 
start of clinically prescribed ivacaftor treatment (±2 week window) 
Follow up: 12 week visit at CHOP after confirmation of timing of the 
start of clinically prescribed ivacaftor treatment (±2 week window) 
Safety Evaluations 
As part of safety assessment, a serum comprehensive metabolic 
panel including the ALT and AST liver enzymes, complete blood 

 
 
 
 
 
 
 
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count and serum pre-albumin will be assessed (CHOP Clinical 
Laboratory). 
Dosing will likely be interrupted by the CF clinical care team in 
subjects with ALT or AST of greater than 5 times the upper limit of 
normal (ULN).  
Subjects will be asked about all adverse events at the 6 and 12 
week protocol visits and during the bi-weekly phone calls, and rated 
by intensity (mild, moderate, severe). Serious adverse events will 
be reported as per various policies in a timely manner to CHOP IRB 
and CHPS. 
 
Statistical And 
Analytic Plan 
Primary Aims: The goals of the primary aims of this study are to 
determine whether ivacaftor treatment improves SEE and BMI Z 
score. Secondary Aims:  The goal of the secondary aim is to 
determine whether ivacaftor improves gut health and function as 
measured by total plasma fatty acids, fecal elastase and fecal 
calprotectin (ug/g stool). Analysis of efficacy for the primary and 
secondary outcomes will be based on change from baseline (before 
treatment) in SEE% predicted (Schofield), BMI Z scores, total 
plasma fatty acids, fecal elastase and fecal calprotectin. The 
differences between baseline and 12 weeks continuous outcomes 
will initially be compared using paired-t-tests if continuous variables 
are normally distributed and nonparametric tests (Wilcoxon sign 
rank) if they are not. Subsequently, mixed effects longitudinal 
models will be performed to assess change over all three time 
points (baseline, 6 and 12 weeks), adjusting for potential covariates 
such as age, sex, and adherence to treatment. Chi-squared tests 
will be used for comparison of categorical variables before and after 
ivacaftor treatment. Using similar methods, exploratory analyses 
will examine improvement in dietary intake of calories and fat, in 
growth status (weight, length, and head circumference Z scores) 
and growth velocity (both absolute and Z scores), serum fat soluble 
vitamins, bile acids, and calprotectin.   
DATA AND SAFETY 
MONITORING PLAN 
Safety will be formerly monitored weekly by the study team. The 
study protocol will be carried out in accordance with OHRP 
guidelines and requirements. SAEs that are unanticipated, serious, 
and possibly related to the study intervention will be reported to the 
study sponsor, IRB, CHPS, and members of the research and 
clinical teams in accordance with requirements. Anticipated SAEs 
or those unrelated to the study intervention will be reported to the 
same individuals/entities in accordance with requirements. There 
will be ongoing collection of data on adverse events and 
compliance to the treatment protocol throughout the study by 
research staff and which will be summarized and reviewed monthly 
by the study Principal Investigator and the Study Team.  Out of 
range non-clinically significant laboratory data will be reviewed 
continually by the PI and the study team. 

 
  
 
 
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Schedule of Study Procedures & Study Timeline
 
 

 
  
 
  
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1 BACKGROUND INFORMATION AND RATIONALE 
1.1 Introduction 
 Cystic fibrosis (CF) is a genetic disease caused by mutations in the gene encoding the CF 
transmembrane conductance regulator (CFTR), a chloride channel in many types of cells. 
Most CF mutations either reduce the number of CFTR channels at the cell surface 
(synthesis and processing mutations) or impair channel function (gating or conductance 
mutations). Ivacaftor (Kalydeco®, Vertex Pharmaceuticals Inc.) was the first of a new class 
of drugs that improved CFTR gating dysfunction1-3.  For such mutations (G551D, G178R, 
S549N, S549R, G551S, G970R, G1244E, S1251N, S1255P, G1349D) that permit CFTR 
expression at the cell membrane but compromise its activity, ivacaftor increases the 
probability that the chloride channel is open and active.  In randomized, double-blind, 
placebo controlled trials, ivacaftor treatment in individuals (ages 6 to adulthood) with at 
least one G551D mutation resulted in clinically significant improvements in weight and body 
mass index (BMI), pulmonary function, and patient reported quality of life outcomes 
(QOL)3,4.  Lung function and weight changes occurred over eight weeks, then plateaued 
and were sustained over 48 weeks. 
In the initial trials ivacaftor treatment in individuals with at least one G551D mutation 
resulted in rapid and sustained weight gain, increased FEV1%, decreased pulmonary 
exacerbations, decreased sweat chloride concentration reflective of increased CFTR 
activity, and improved patient reported health-related QOL outcomes3-5.   In the STRIVE 
study of 161 adolescents and adults (12+ years old), subjects gained 3.1 kg after 48 weeks 
of treatment compared to 0.4 kg for those on placebo3.  In the ENVISION study of 52 
younger growing children (6 to 11 years old)4, subjects gained 3.7 kg after 24 weeks of 
ivacaftor vs.1.8 kg for placebo. In both studies, weight gain and improved lung function 
occurred rapidly with a weight plateau by 16 weeks or earlier. In people with non-G551 
gating mutations (KONNECTION study, 6+ years old)10, BMI Z scores improved 0.24 after 
eight weeks of treatment compared to -0.04 for placebo.  A long term ivacaftor open-label 
phase that followed the STRIVE and ENVISION studies (PERSIST study)11 as well as 
observational studies have shown persistence and stability of weight gain and improvement 
in nutritional status over two or more years12,13. 
Ivacaftor has shown similar benefit in younger children and has been approved for use in 
children 6 months and older.. Ivacaftor was found to be safe and effective in 33 children in 
the KIWI study completed 24 weeks of treatment in the KIWI study, with significant 
reductions in sweat chloride concentration, and an average increase in weight Z score of 
0.2±0.3 and BMI z score of 0.4±0.46.  Some exocrine pancreatic function restoration was 
demonstrated in these young children, as Davies et al.6 noted an increase in fecal elastase 
concentrations in a small sample of children after 24 weeks ivacaftor treatment.  Prior to 
treatment, 93% were PI with fecal elastase concentrations of <50 µg/g, and after treatment 
this increased 100 µg/g on average.  Furthermore, in the KLIMB study, a long-term follow-
up to the KIWI study, the increased fecal elastase concentrations were sustained with mean 
increase of 129 µg/g after 84 weeks of treatment14.  These results suggest that exocrine 
pancreatic function early in life may be partially restored with ivacaftor6,15.   
In a recent open-label Phase 3 trial (the ARRIVAL study)16,17 in 18 children ages 1 to 2 
years of age with CFTR gating mutations (G551D, G178R, S549N, S549R, G551S, 

 
  
 
  
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G1244E, S1251N, S1255P, G1439D, or R117H) who completed 24-weeks of treatment, 
ivacaftor was safe and effective in significantly reducing sweat chloride concentrations from 
104.1 to 31.5 mmol/L, and improving (restoring) pancreatic function as indicated by 
increasing fecal elastase from 182 to 357 ug/g stool. Ivacaftor’s impact on growth status or 
velocity for weight and BMI in these young children was not reported. Changes in energy 
expenditure with ivacaftor treatment in these young children has also not yet been explored. 
This current application will directly ddress gaps in knowledge related to the important non-
pulmonary outcomes that are clinically very important in very young children.   
     In our recent longitudinal observational study of 23 subjects (ages 5 to 61 years), we 
identified several mechanisms for weight gain with 3-month ivacaftor treatment including 
decreased resting energy expenditure (REE), gut inflammation and dietary fat 
malabsorption, resulting in a positive energy balance and weight gain. Weight gain in this 
study was 2.5 kg and was associated with a significant decrease in REE percent predicted 
of 5.5%, and in fecal calprotectin of 30 ug/g stool, a measure of gut inflammation7-9. For the 
16 subjects with PI, dietary fat absorption as measured by coefficient of fat absorption 
(CFA) improved 3%7,8,18.  Dietary fat intake increased significantly in all subjects7, and 
energy intake increased, particularly in those from Italy8.  In subjects <20 years of age, 
improved weight and BMI status was accompanied by beneficial effects on muscle mass, 
muscle function and QOL. Improvement in pancreatic function (fecal elastase) was seen in 
5 of 7 subjects with PS. Whether a similar improvement in REE, growth status and gut 
health and function related to improved fat absorption in young children with CFTR gating 
mutations is not known. 
     Several outcomes related to improved energy balance are considered in this proposal. 
Building on our results in older subjects, we will once again focus on the importance of 
determining the effect of ivacaftor treatment on clinically important non-pulmonary 
outcomes. Our primary aim in this study of young 6 month  to 2 year old children is to 
determine if 12-week ivacaftor treatment results in decreased sleeping energy expenditure 
(REE) and improved growth status by BMI Z score. Our secondary aim is to determine 
improvement in gut health and function associated with fat digestion, including increased 
total plasma fatty acids and fecal elastase, and decreased fecal calprotectin.  Exploratory 
aims include investigating the impact of ivacaftor treatment on dietary intake, length, weight 
and head circumference status and growth velocity, and on serum fat soluble vitamins, bile 
acids and calprotectin.   
   In addition to reduced dietary fat absorption, altered fatty acid metabolism has been 
shown in CF and PI19,20, and may be linked to CFTR dysfunction, and little is known of 
changes with CFTR modulator treatment. In the GOAL study, change in serum fatty acid 
concentrations with ivacaftor treatment were explored. Serum arachidonic acid levels 
decreased while linoleic and docosahexenoic acid levels did not change in 40 subjects with 
G551D CFTR mutation21. We previously demonstrated a significant increase in total plasma 
fatty acids from 8.5±1.6 to 10.2±3.6 mmol/L (P<0.01) with 3-month treatment of a fat-based 
nutritional supplement: linoleic, lauric, palmitoleic, oleic and docosatetraenoic acids all 
significantly increased as well19. We propose to assess a plasma fatty acid panel that 
includes concentrations for 22 individual fatty acids as well as total fatty acids, as an 
indicator of change in fat absorption.  
   Serum calprotectin is a marker for whole body inflammation including lung and gut 
inflammation in CF, and other chronic inflammatory diseases22-24, and will be assessed 
along with fecal calprotectin. Improvements in length, weight and head circumference 
status will likely result from an expected reduction in SEE in these children associated with 

 
  
 
  
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ivacaftor treatment. Furthermore, comparisons of metabolic profiles in children with CF and 
their healthy counterparts, showed that the children with CF had profiles indicating bile acid 
processing abnormalities25.  Whether ivacaftor treatment results in improved fatty acid 
profiles, gut and systemic inflammation (fecal and serum calprotectin), bile acids and fat 
soluble vitamin status as markers of improved fat absorption in young children with CFTR 
gating mutations is not known and represent novel and clinically meaningful outcomes in 
young children with CF. 
We propose a longitudinal study design to determine whether 12 weeks of treatment with 
ivacaftor results in improvement in SEE, growth status as BMI Z score, and gut health and 
function in 18 children ages 6 months  to 2 years with at least one CFTR gating mutation. 
There will be a mid-treatment evaluation at 6 weeks to explore the pace of the change in 
the primary and secondary outcomes. To plan the study, we assume that 1/3 of subjects 
will be recruited locally within a 150 mile radius of Philadelphia and the remaining 2/3 from 
other CF Centers in North America and will travel to Children’s Hospital of Philadelphia 
(CHOP) for three protocol visits, each visit lasting 2 or 3 days, conducted at our Center for 
Human Phenomic Science (CHPS) and Nutrition and Growth Laboratory. 
The primary aims of this study are to determine whether ivacaftor treatment reduces SEE 
and increases BMI Z score.  Secondary aims are to determine if ivacaftor treatment 
improves gut health and function resulting in better fat absorption as indicated by increased 
total plasma fatty acids and fecal elastase, and decreased fecal calprotectin. Exploratory 
aims are to examine the impact on dietary intake, growth status and velocity, serum fat 
soluble vitamins, serum bile acids, and serum calprotectin as a measure of systemic 
inflammation.   
 
1.2 Compliance Statement 
This study will be conducted in full accordance all applicable Children’s Hospital of 
Philadelphia Research Policies and Procedures and all applicable Federal and state laws 
and regulations including 45 CFR 46.  All episodes of noncompliance will be documented. 
The investigators will perform the study in accordance with this protocol, will obtain consent 
and will report unanticipated problems involving risks to subjects or others in accordance 
with The Children’s Hospital of Philadelphia IRB Policies and Procedures and all federal 
requirements. Collection, recording, and reporting of data will be accurate and will ensure 
the privacy, health, and welfare of research subjects during and after the study. 
2 
STUDY OBJECTIVES 
We propose a longitudinal study design to determine whether 12 weeks of treatment with 
ivacaftor results in improvement in sleeping energy expenditure (SEE), growth status as 
BMI Z score, and gut health and function in n=18 children ages 6 months  to 2 years with at 
least one CFTR gating mutation. We anticipate that these changes will accompany 
meaningful improvements in dietary intake, growth status and growth velocity, and serum 
fat soluble vitamins, bile acids and serum calprotectin in these young children.   
   
 
 

 
  
 
  
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2.1 Primary Aims 
H1:  Ivacaftor treatment will result in a significant reduction in SEE as percent predicted 
over 12 weeks compared to baseline, thereby increasing the energy available for weight 
gain and physical activity. 
H2: Ivacaftor treatment will result in significantly increased BMI Z score over 12 weeks 
compared to baseline. 
2.2 Secondary Aims 
H3:  Ivacaftor treatment will result in significantly improved gut health and function resulting 
in better dietary fat absorption as indicated by increased total plasma fatty acids and fecal 
elastase and decreased fecal calprotectin over 12 weeks compared to baseline.To 
determine if treatment with Ivacaftor results in increased dietary fat absorption using three 
methods: 
2.3 Exploratory Aims 
1) To determine the impact of ivacaftor treatment over 12 weeks compared to baseline in: 
a) Dietary intake of calories and percent calories from fat 
b) Growth status for length, weight, head circumference and growth velocity 
c) Serum fat soluble vitamins A, D, E and K, bile acids, and calprotectin 
3 
INVESTIGATIONAL PLAN 
3.1 General Schema of Study Design 
3.1.1 Screening Phase 
Subjects (n=18) will be recruited to participate in the study from a pool of subjects with at 
least one CFTR gating mutation.  Given our previous success in enrolling subjects with CF 
from both local CF Centers and more distant Centers who traveled considerable distances 
to participate in our research protocols, we expect that enrollment will be achieved in a 
timely fashion. The plan to initiate treatment and the clinical eligibility for treatment is 
determined by the subject’s family and the CF care team. 
Potential subjects will be screened using the protocol inclusion and exclusion criteria.  The 
CF Centers around the country and Canada will provide the study with resources that will 
aide in recruitment efforts (i.e. to help to identify subjects with “gating” mutations). The 
subject’s CF care team will be contacted to confirm eligibility for the study and this will 
include obtaining medical information from the team and subject’s medical record. To 
collect medical data for screening purposes, a verbal or in person consent from 
parents/guardians will be obtained. 
Parental/guardian permission (informed consent) will be obtained prior to any study related 
procedures being performed.  
3.1.2 Study Enrollment Phase  
Eligible subjects will be enrolled into the study and come to CHOP for the study visits. Refer 
to Table 1 for list of assessments and the study timeline for the pace of recruitment.  
3.1.3 Follow-up Phase 
Their initial baseline visit (Visit 1) will occur before clinically prescribed ivacaftor treatment 
has begun. The exact date of the start of medication will vary for families as they obtain 

 
  
 
  
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their medication. Subjects will return to CHOP for the 6 week visit (Visit 2) and the 12 week 
visit (Visit 3 and final) after subject/family has confirmed the timing of the start of ivacaftor 
treatment. There may be a delay between the baseline visit and the 6 week visit based 
upon when treatment begins. For most families, the total duration of the study will be from 4 
to 6 months. The duration of the study from start of ivacaftor treatment until last study visit 
will be 12 weeks.  For each of the 6 and 12 week visits following the start of ivacaftor 
treatment, there will be a window of ±2 weeks for the visit to occur (i.e. 6 week visit may 
occur between 4 and 8 weeks, and 12 week visit between 10 and 14 weeks post ivacaftor 
treatment).  
Refer to Table 1 for list of assessments and the study timeline for the visit schedule.  
3.2 Study Duration, Enrollment and Number of Sites 
3.2.1 Duration of Study Participation 
The study duration for subject participation from enrollment to the last study visit will range 
from 4 to 6 months. The baseline visit will occur prior to the start of ivacaftor treatment. 
From the start of the clinically prescribed ivacaftor treatment to the last study visit will be 12 
weeks with a window of ±2 weeks. 
3.2.2 Total Number of Study Sites/Total Number of Subjects Projected 
The study will be conducted at one investigative site in the United States. 
Recruitment will stop when 18 subjects are enrolled. It is expected that 18 subjects will be 
enrolled to produce 16 evaluable subjects.  
3.3 Study Population 
3.3.1 Inclusion Criteria 
 
Cystic fibrosis with at least one CFTR gating mutation of these ten (G551D, G178R, 
S549N, S549R, G551S, G1244E, S1251N, S1255P, G1439D, or R117H).  
 
Age: 6 months to 2 years of age  
 
In their usual state of good health  
 
A clinical decision has been made for subject to begin ivacaftor treatment. 
 
Family committed to the 4 to 6 month study protocol with visits to CHOP that will last 
2-3 days for the baseline visit (Visit 1) prior to ivacaftor treatment and the 12 week 
visit (Visit 3) after clinically prescribed ivacaftor treatment has begun, and will last up 
to 2 days for the 6 week visit (Visit 2) after ivacaftor treatment has begun. 
 
Note that ivacaftor is now approved by the FDA for 6 month  to 2 year old children 
for the additional 28 CFTR mutations known to be responsive to ivacaftor 
potentiation, these will also be considered. With our limited sample size, the 
mutations that have shown the strongest improvement with treatment will be given 
priority for enrollment. 
3.3.2 Exclusion Criteria 
 
On parenteral nutrition 
 
Use of any inhibitor or inducer medications of cytochrome P450 (CYP) 3A 
 
Liver function tests elevated above 3x the reference range for age and sex 
 
Other illness affecting growth or nutritional status 
 
Other contraindications described for ivacaftor therapy 

 
  
 
  
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4 STUDY PROCEDURES 
4.1 Screening  
Subjects will be screened using the protocol inclusion and exclusion criteria.  Written (in 
person) or verbal (via phone) parental/guardian permission will be obtained prior to 
scheduling any study screening related procedures. Informed written consent will be 
obtained at the baseline visit prior to conducting any research procedures.  
All subjects will be enrolled in their usual state of good health defined as no 
hospitalizations, emergency room or unscheduled acute illness clinic visits, and with activity 
levels and food intake considered typical by the subject and their care provider for two or 
four weeks prior to the baseline visit.    
4.2 Observational Period  
Many of the protocol assessments could occur on any of the visit days (i.e. questionnaires, 
spot stool sample). Below is the best estimate of how each day will proceed. The baseline 
(Visit 1) and the 12 week (Visit 3) visit after ivacaftor treatment has begun are nearly 
identical with the exception of obtaining informed consent which will occur at Visit 1 Day 1 
prior to any assessments being done or specimens being collected.  For the 6 week (Visit 
2) and 12 week (Visit 3) visits that will occur after confirmation of the timing of the start of 
clinically prescribed ivacaftor treatment, there will be a ±2 week window for the visit. (i.e. 6 
week visit may occur between 4 and 8 weeks, and 12 week visit between 10 and 14 weeks 
post ivacaftor treatment).  
The description provided here applies to subjects who are not local to CHOP and who will 
be traveling to Philadelphia from other regions of the US and Canada and staying at a local 
hotel for one or two nights depending on the time of their scheduled research procedures. 
For non-regional families, Day 1 of each Visit is the day of arrival to CHOP and first night of 
their hotel stay.  
If the subject is local to CHOP, we will still require a Day 1 visit for in-person written consent 
for Visit 1, however, for Visits 2 and 3, Days 1 and 2 can be combined to complete study 
protocol procedures, and they will come in to CHOP from home for the major study protocol 
days: Day 2 for Visit 2 and Day 2 and again on Day 3 (if needed) for Visit 3.   
4.2.1 Baseline visit (Visit 1)
 
Day 1 
 
 
Informed Consent/Assent will be completed in at CHOP Main CHPS  
 
Instructions in preparation for study procedures will be given 
 
Spot stool sample will be collected for Fecal Elastase I and fecal calprotectin 
(collected anytime) 
 
Questionnaires may occur on this day (see Day 2 for details) 
 
Day 2 
 

 
  
 
  
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 
Sleeping energy expenditure with morning nap (or afternoon nap if 
necessary). Time and amount of food and beverage intake will be recorded 
prior to the procedure. 
 
Blood draw for CBC, CMP, pre-albumin, bile acids, fatty acids, serum 
calprotectin, vitamin A (retinol), vitamin D (25(OH)D), vitamin E (a-
tocopherol) and  vitamin K (ucOC) 
 
Spot stool sample for fecal elastase and fecal calprotectin (if not collected on 
Day 1) 
 
Questionnaires: Health History 
 
Anthropometry: Length, weight, head circumference, skinfolds, 
circumferences   
 
 
 
Day 3 (if needed and expected for half of subjects)  
 
 
 Sleeping energy expenditure test– if it was not performed on Day 2 
 
Post Visit Follow Up 
 
 
3-day weighed food records  
 
Begin clinically prescribed ivacaftor treatment after food records have been 
completed, and document the date that ivacaftor treatment was started 
 
 
In Between Visits 1 & 2 
 
 
Maintain adverse events  calendar 
 
 
4.2.2 6 week visit (Visit 2) after ivacaftor treatment has begun
 
Day 1 
 
 
Instructions in preparation for study procedures will be given 
 
Spot stool sample will be collected for Fecal Elastase I and fecal calprotectin 
(collected anytime) 
 
Questionnaires may occur on this day 
 
Day 2 
 
 
Sleeping energy expenditure with morning nap (or afternoon nap if 
necessary). Time and amount of food and beverage intake will be recorded 
prior to the procedure. 
 
Anthropometry: Length, weight, head circumference, skinfolds, 
circumferences   

 
  
 
  
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 
Blood draw for fatty acids and serum calprotectin 
 
Spot stool sample for fecal elastase and fecal calprotectin (if not collected on 
Day 1) 
 
Questionnaires regarding interval health history, Adherence to ivacaftor, 
enzymes, medications, and Adverse events  
 
Post Visit Follow Up 
 
 
3-day weighed food records  
 
Maintain adverse events  calendar 
 
In Between Visits 2 & 3 
 
 
Maintain adverse events  calendar 
. 
  
4.2.3 12 week visit (Visit 3) after ivacaftor treatment has begun
 
Day 1 
 
 
Instructions in preparation for study procedures will be given 
 
Spot stool sample will be collected for Fecal Elastase I and fecal calprotectin 
(collected anytime) 
 
Questionnaires may occur on this day 
 
Day 2 
 
 
Sleeping energy expenditure with morning nap (or afternoon nap if 
necessary). Time and amount of food and beverage intake will be recorded 
prior to the procedure.  
 
Blood draw for CBC, CMP, pre-albumin, bile acids, fatty acids, serum 
calprotectin, vitamin A (retinol), vitamin D (25(OH)D), vitamin E (a-
tocopherol) and  vitamin K (ucOC) 
 
Spot stool sample for fecal elastase and fecal calprotectin (if not collected on 
Day 1) 
 
Questionnaires about interval health history, Adherence to ivacaftor, 
enzymes, medications, and Adverse events  
 
Anthropometry: Length, weight, head circumference, skinfolds, 
circumferences   
 
Day 3 (if needed and expected for half of subjects)  
 
 
Sleeping energy expenditure test– if it was not performed on Day 2 

 
  
 
  
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Post Visit Follow Up 
 
 
3-day weighed food records  
 
Maintain adverse events  calendar until 3-day food records are completed 
 
4.3 Unscheduled Visits 
Due to the complexity of the study, no unscheduled visits will be permitted. 
4.4 Subject Completion/Withdrawal 
Subjects may withdraw from the study at any time without prejudice to their care.  They may 
also be discontinued from the study at the discretion of the Investigator for lack of 
adherence to study treatment or visit schedules, or AEs. The Investigator or the Sponsor 
may also withdraw subjects who violate the study plan, or to protect the subject for reasons 
of safety or for administrative reasons.  It will be documented whether or not each subject 
completes the clinical study. If the Investigator becomes aware of any serious, related 
adverse events after the subject completes or withdraws from the study, they will be 
recorded in the source documents and on the CRF.  
5 STUDY EVALUATIONS AND MEASUREMENTS 
5.1.1 Medical Record Review 
Variables that may be abstracted from the medical chart (paper or electronic): 
 
Date of birth 
 
Sex 
 
CF genotype 
 
Medications 
 
History of liver disease, CF related diabetes, GI disease or abdominal surgery  
5.1.2 Laboratory Evaluations 
Plasma Total Fatty Acids: A total plasma fatty acid panel will be assessed (ARUP 
Laboratories) to measure change in status of 22 fatty acids. 
Fat Soluble Vitamins: Serum vitamin A and vitamin E assessed at Craft Technologies 
Laboratories. Serum vitamin D determined using Liquid Chromatography-Tandem Mass 
Spectrometry (CHOP).  As a measure of vitamin K status, % undercarboxylated osteocalcin 
(Gundberg Lab, Yale University) will be assessed.  
Serum Bile Acids: Total serum bile acids and 14 bile acid concentrations will be assessed 
by liquid chromatography tandem mass spectrometry (ARUP Laboratories) 
Serum Calprotectin: Serum calprotectin will be obtained as a marker of lung and gut 
inflammation22,23 using a Buhlmann MRP8/14 ELISA kit (Alpco, Salem, NH)).  
Safety Assessment: As part of safety assessment, a comprehensive metabolic panel 
including the ALT and AST liver enzymes, complete blood count and serum pre-albumin will 
be assessed (CHOP Clinical Laboratory). 

 
  
 
  
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5.1.3 Study Assessments 
Sleeping Energy Expenditure: The primary outcome for the assessment of energy 
expenditure is sleeping energy expenditure (SEE). Using indirect calorimetry, SEE and 
respiratory quotient will be assessed using a computerized metabolic cart Vmax ENCORE 
at each protocol visit while the child is asleep. SEE will be assessed in the morning if 
possible and careful note of previous feeding of the child, including the time of day, amount 
of food, and feeding interval prior to test.  SEE is compared to predicted values derived 
from the World Health Organization that adjust for age, sex and weight26 and Schofield 
equations that adjust for age, sex, weight and length27.  SEE as kcal/d will also be assessed 
by adjusting for both fat free mass (FFM) and fat mass (FM) obtained from skinfold 
measurements. Anthropometric Assessment: The outcomes for weight gain, growth and 
nutritional status will be length, weight, BMI, and head circumference Z scores. Measures of 
body composition will also be conducted to determine relative muscle and fat stores. All 
anthropometric techniques will follow those described by Lohman et al28. Weight (0.1 kg) 
will be measured on a digital electronic scale (Seca, Munich, Germany), length (0.1 cm) on 
an infantometer, (Holtain, Crymych, UK), and head circumference (0.1 cm) using an 
insertion tape. Skinfold thickness will be measured (0.1 mm) at the triceps, biceps, 
subscapular, and supra-iliac sites with a skinfold caliper (Holtain, Crymych, UK) to assess 
subcutaneous fat stores. Mid upper arm circumference measured with a non-stretchable 
fiberglass tape (0.1 cm) (McCoy, Maryland Heights, MO). All measurements will be used to 
generate age-sex-specific Z scores for length,  weight, BMI, head circumference, arm 
circumference, triceps and subscapular skinfolds using WHO reference data29,30.  Z scores 
for growth velocity will also be calculated for the 12 week period using the WHO reference 
data31, and will provide a novel approach to growth response. 
Body Composition: Total body composition, total FFM and FM and percent body fat (%FAT) 
and regional fat deposition, will be assessed by skinfold measurements.  
Fecal Elastase I:  Pancreatic function will be assessed at both visits by obtaining spot stool 
samples with fecal elastase 1 to determine the level of pancreatic enzyme activity32,33. 
Subjects will be provided with the stool collection kit and proper instructions and supplies, 
and will bring a stool sample back the next day. The stool sample will be stored at -20oC, 
and analyzed with an enzyme-linked immunosorbent assay kit sent to ARUP Laboratory 
(Salt Lake City, UT). 
Fecal Calprotectin: Spot stool samples will be obtained to determine fecal calprotectin, a 
marker for gut inflammation (CHOP Laboratories), determined using a QUANTA Lite® 
ELISA kit. 
Dietary Intake: Three day weighed food record will be obtained and calories, macro- and 
micro-nutrient content averaged over the three days. Families will be trained by staff and 
provided with scales, spoons and all supplies necessary for the collection of the dietary 
data.  Detailed verbal and written instructions will be provided to ensure that the recording 
procedures are clearly understood. Also assisting with this will come from the Center for 
Human Phenomic Science (CHPS) staff and Bionutrition Unit system34,35. Dietary intake of 
all nutrients will be analyzed using Nutrition Data System for Research software version 
2012 developed by the National Coordinating Center (NCC, University of Minnesota. 
Minneapolis, MN)36.   
Health Questionnaire: The questionnaire will be administered by interview by the research 
staff, and will consist of two sections. The Health History section has general questions 
about the subject’s health history including documentation of medical history, recent 
hospital admissions and illnesses, medications, and nutrient supplement use. A section 
describes aspects of environment such household size, insurance for child and whether on 

 
  
 
  
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Medicaid. In addition to family contact information (name, address, phone numbers), 
contact information from two non-household contacts will be collected to maintain contact 
with the subject in the event that the family cannot be contacted at their primary residence. 
Adherence: Questionnaire at the 6 and 12 week in person visit regarding adherence to 
treatment will be administered. Phone calls will be made to all families at the 3 and 9 week 
time points and at the 12-week in person visit after ivacaftor treatment has begun to 
assess adherence to treatment, to trouble-shoot any barriers to adherence, and also to 
collect information on adverse events experienced within the past four weeks.  Adherence 
to treatment with ivacaftor treatment and pancreatic enzyme medication use will be 
assessed. 
Adverse Events Calendar: Families will be asked about all adverse events for their child at 
the 12 week protocol visit and during the phone calls at 3 and 9 weeks, and rate by intensity 
(mild, moderate, severe). Serious adverse events will be reported as per various policies in 
a timely manner to CHOP IRB, and CHPS.  
5.2 Safety Evaluation 
As part of safety assessment, a comprehensive metabolic panel including the ALT and AST 
liver enzymes, complete blood count and serum pre-albumin will be assessed (CHOP 
Clinical Laboratory). 
Dosing will likely be interrupted by the CF clinical care team in subjects with ALT or AST of 
greater than 5 times the upper limit of normal (ULN).  
Subjects will be asked about all adverse events at the 6 and 12 week protocol visits and 
during the phone calls at 3 and 9 weeks, and rate by intensity (mild, moderate, severe). 
Serious adverse events will be reported as per various policies in a timely manner to CHOP 
IRB, and CHPS. 
6 STATISTICAL CONSIDERATIONS 
6.1 Statistical Methods 
Analysis will begin with descriptive analyses of the study sample using means, standard 
deviations, medians, and ranges for continuous variables, and frequency distributions for 
categorical variables. Descriptive statistics and exploratory graphing such as frequencies, 
means, standard deviations, box plots, and scatter plots will be used to assess the 
normality of the data in terms of the presence of skew and/or outliers.  
6.1.1 Analysis of Primary & Secondary Aims 
Data Analysis:  Analysis will begin with descriptive analyses of the study sample using 
means, standard deviations, medians, and ranges for continuous variables, and frequency 
distributions for categorical variables. Descriptive statistics and exploratory graphing such 
as frequencies, means, standard deviations, box plots, and scatter plots will be used to 
assess the normality of the data in terms of the presence of skew and/or outliers. Primary 
Aims: The goals of the primary aims of this study are to determine whether ivacaftor 
treatment improves SEE and BMI Z score. Secondary Aims:  The goal of the secondary aim 
is to determine whether ivacaftor improves gut health and function as measured by total 
plasma fatty acids, fecal elastase and fecal calprotectin (ug/g stool). Analysis of efficacy for 
the primary and secondary outcomes will be based on change from baseline (before 
treatment) in SEE% predicted (Schofield), BMI Z scores, total plasma fatty acids, fecal 
elastase and fecal calprotectin. The differences between baseline and 12 weeks continuous 

 
  
 
  
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outcomes will initially be compared using paired-t-tests if continuous variables are normally 
distributed and nonparametric tests (Wilcoxon sign rank) if they are not. Subsequently, 
mixed effects longitudinal models will be performed to assess change over all three time 
points (baseline, 6 and 12 weeks), adjusting for potential covariates such as age, sex, and 
adherence to treatment. Chi-squared tests will be used for comparison of categorical 
variables before and after ivacaftor treatment. Using similar methods, exploratory analyses 
will examine improvement in dietary intake of calories and fat, in growth status (weight, 
length, and head circumference Z scores) and growth velocity (both absolute and Z scores), 
serum fat soluble vitamins, bile acids, and calprotectin.   
6.2 Sample Size and Power 
Sample Size and Power: This is a longitudinal study of the effects of ivacaftor treatment on 
outcomes before and after 12-week treatment.  The sample size of 16 subjects to complete 
the study has been determined as adequate to have the power to test the primary 
outcomes of decrease in SEE percent predicted value (7% change), an increase in BMI Z 
score of 0.3, and secondary outcomes of measures of gut health and function; an increase 
in plasma total fatty acids from 8.5 to 10.5 mmol/L, an increase in fecal elastase of 120 ug/g 
stool, and a decrease in fecal calprotectin (-30 ug/g stool change). Using STATA, power 
calculations were generated, with α=0.05, for paired data (n=16) within the same sample 
(before and after 12 weeks of treatment) using the changes described above for the primary 
outcomes and secondary outcomes.  
Primary outcomes: A sample size of 16 subjects results in 86% power to see a decrease of 
7% in SEE (i.e. from 115 to 108) with a standard deviation of the change of 9%, using a 
paired t-test two-sided significance level. We demonstrated a change of similar magnitude 
in REE in 24 subjects with CF gating mutation after 3-mo treatment with ivacaftor7,9. For 
growth status, 16 subjects will provide 85% power to detect an increase in BMI Z score of 
0.3 with a standard deviation of 0.4. In the KIWI study of 2 to 5 year old children with CFTR 
gating mutation treated with ivacaftor for 24 weeks, a BMIZ score increase of 0.4±0.4 was 
demonstrated6. We showed a BMI Z score increase over 12 weeks of 0.3±0.4 in our recent 
study of 18 children (5 to 19 years) with 12-week ivacaftor treatment7. 
Secondary outcomes: A sample of 16 subjects will provide 80% power to detect an 
increase in total plasma fatty acids from 8.5 to 10.5 mmol/L with a standard deviation of 
2.8%, will provide 88% power to detect an increase in fecal elastase of 120 ug/g stool with 
a standard deviation of 150 ug/g stool, and will provide 85% power to detect a decrease in 
fecal calprotectin of 30 ug/g stool with a standard deviation of the change of 40 ug/g stool.  
We previously demonstrated a 3-month increase in plasma total fatty acids of this 
magnitude in subjects with CF receiving a fat-based nutritional supplement19. Davies et al6 
demonstrated a change of 100 ug/g stool in fecal elastase with 24-week ivacaftor treatment 
in for 2 to 5 year old children with CFTR gating mutations in the KIWI study, and an even 
greater increase of 164 ug/g stool fecal elastase was shown in 1 to 2 year old children 
participating in the ARRIVAL study16. We have previously demonstrated a 3-month 
decrease of 30 ug/g stool in fecal calprotectin with ivacaftor treatment in 5 to 61 year old 
people with CFTR gating mutations7. The standard deviations of 9% for SEE, 40 ug/g stool 
for fecal calprotectin, 150 ug/g stool for fecal elastase and 0.4 for BMI Z score are 
reasonable estimates of the variability expected in changes for these variables from our 
experience with 3-12 month changes in these measures in previous longitudinal clinical 
trials we have conducted for changes in children and adults with CF7,18,19,37,38.  In addition, 
our recent experience with SEE measures in 1 year old healthy children showed a standard 
deviation of 8% in SEE percent predicted values39 (personal communication). 

 
  
 
  
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     We plan for up to 12% attrition over the 12 weeks. By enrolling 18 subjects we can 
account for attrition and also allow for the possibility of greater variability in the SEE, BMI Z 
scores and gut health and function measures. 
7 STUDY MEDICATION (STUDY DEVICE OR OTHER STUDY INTERVENTION) 
7.1 
Description 
This is an observational study of subjects who will be assessed before and after ivacaftor 
use.  The study will not provide the ivacaftor to the subjects.  It will be clinically prescribed 
by the subject’s home CF care provider and the subject will not begin the ivacaftor 
treatment until after all Baseline (Visit 1) study visit procedures have been completed.  
8 SAFETY MANAGEMENT 
8.1 
Clinical Adverse Events 
Clinical adverse events (AEs) will be monitored throughout the study.  
8.2 
Adverse Event Reporting 
Since the study procedures are not greater than minimal risk, SAEs are not expected. If any 
unanticipated problems related to the research involving risks to subjects or others happen 
during the course of this study (including SAEs) these will be reported to the IRB in 
accordance with CHOP IRB SOP 408: Unanticipated Problems Involving Risks to Subjects. 
AEs that are not serious but that are notable and could involve risks to subjects will be 
summarized in narrative or other format and submitted to the IRB at the time of continuing 
review. 
9 
STUDY ADMINISTRATION 
9.1 Data Collection and Management 
Data Management: The CHPS will work with the study team to create case report forms, 
set up REDcap database, and provide training for data entry and quality assurance. 
REDcap, a secure, web-based database, provides real time calculations, error detection 
and an automated export procedure for seamless data downloads to Excel, SAS and Stata. 
REDcap and all study computers are password protected and allow for storage of direct 
identifiers and de-identified data in a single database. Subjects will be assigned a unique 
identification number to insure confidentiality. Biological specimens are stored, identified 
using unique numbers in locked CHPS freezer. Routine backup to a secure server, 
including images of forms, the main study database, and files created for analysis, and 
analysis programs will be archived daily. Source documents will be stored in locked 
cabinets in secure research facilities with locked doors and security alarm with 24 hour 
security guard response. 
We will establish a database to store study data using standard software (e.g. RedCap). 
The database will be designed to perform automatic computations, such as exact age 
based upon birth date and date of exam, and averaging anthropometric measures, which 
are recorded in triplicate. Reports containing the number of subjects enrolled and data 
entered for each subject are generated and reviewed each month by the PI.  The PI, or 
study staff, will review all data collection forms on an ongoing basis for data completeness 
and accuracy as well as protocol compliance. Following data entry, all primary and 

 
  
 
  
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secondary endpoint data will be verified against original source documents.  Data 
verification will be performed by someone other than the individual originally collecting and 
entering the data.  
All subjects will be assigned a unique identification number that will be used to insure strict 
confidentiality. The databases are secured with password protection to insure 
confidentiality and security. The informatics manager receives only coded information 
which is entered into the database under those identification numbers. Electronic 
communication with outside collaborators involves only unidentifiable information.  A 
master list containing PHI and subject ID number will be kept separate from the data forms 
and the database that will only have a study ID number. The master list will be on a 
separate password protected file on CHOP’s secured server. All source documents 
including case report forms, laboratory results, and subject study binders will be kept in 
secured locations on the 14th floor of the Roberts Center for pediatric Research.  The file 
cabinets and the study-specific room will be locked with access to study personnel only, 
and the outer hallway is also locked with limited access to CHOP research personnel. 
Routine backup to the main study database, files created for analyses, and analysis 
programs will be completed. The main study database will be archived on a daily basis and 
stored on a CHOP secured server. The Informatics Core of the CHPS will create case 
report forms, set up the database in RedCap, and provide oversight for data entry and 
quality assurance for this study. 
There is no set time for destroying the information that will be collected for this study.  
9.2 Confidentiality 
Medical history information will be obtained at baseline.  All of the materials collected are 
for research purposes only, and data will be kept in strict confidence. No information will be 
given to anyone without permission from the subject or parent/guardian of the subject. This 
will be stated in the consent form.  Confidentiality is assured by use of identification codes. 
All data, whether generated in the laboratory or at the bedside, will be identified with a 
identification code unique to the subject.  
To maintain confidentiality, private health information will be collected, accessed and stored 
in accordance with Institutional policies and HIPAA guidelines, including the use of 
multilevel password protection and enforcement of system user privileges on the database. 
To minimize the risk of disclosure, all direct identifiers will be removed as soon as possible 
and codes will be substituted for personal identifiers. Records of individuals are stored with 
ID numbers and a code with no discernible personal identifiers. Code lists and data files will 
be stored in separate, secure locations. Data will be accessed and stored on password-
protected computers on the CHOP network. To maintain confidentiality, codes will be used 
in the database, presentations and publications. The Investigator and other site personnel 
will not use such data and records for any purpose other than conducting the study. 
9.3 Regulatory and Ethical Considerations 
9.3.1 Data and Safety Monitoring Plan 
Safety will be formerly monitored weekly by the study team and PI. The IRB and CHPS will 
also monitor safety. The study protocol will be carried out in accordance with OHRP and 
NIH guidelines and requirements. SAEs that are unanticipated, serious, and possibly 
related to the study will be reported to the IRB, CHPS, all members of the research team, 
the clinical care team, and sponsor in accordance with requirements.  

 
  
 
  
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9.3.2 Risk Assessment 
There is minimal risk to the subject associated with delaying clinically prescribed ivacaftor 
treatment until all procedures for the baseline visit (Visit 1) have been completed. 
The procedures in this study involve the potential risks related to the drawing of blood.  
The risks of drawing blood are rare, and minimal. There is a small risk of pain, infection 
and local irritation associated with the blood draw. However, this is considered a minimal 
risk and skilled pediatric research nursing staff will perform phlebotomy. Each subject will 
have approximately 18cc (approximately 1.2 tablespoons) of blood drawn at baseline (Visit 
1) and 12 week (Visit 3) study visit, and 5 cc( 1 teaspoon) at the 6 week visit (Visit 2), and 
no more than 5mL/kg over an eight week period.   
The sleeping energy expenditure assessment using the metabolic cart poses minimal risk 
to the subjects. There is minimal risk associated with anthropometric measurements, 
sharing dietary intake, demographic information, health history and medical information.   
Collection and storage of stool is associated with a small risk of fecal contamination. 
However, for safety and convenience, subjects will be provided with proper stool collection 
instructions and supplies (gloves, disposable collection containers, storage freezer 
container). 
Private health information will be collected, accessed and stored according to HIPAA 
guidelines, including the use of multilevel password protection and enforcement of system 
user privileges on the database. To minimize the risk of disclosure, all direct identifiers will 
be removed as soon as possible and codes will be substituted for personal identifiers. 
Records of individuals are stored with ID numbers and a code with no discernible personal 
identifiers. Code lists and data files will be stored in separate, secure locations. Data will 
be accessed and stored on password-protected computers. To maintain confidentiality, 
codes will be used in the database, presentations and publications.  
If clinically significant results are found as a results of this research study, subjects/families 
will be informed and consent to share findings with their clinical care team will be obtained.  
Once consent to share medical information is obtained, the subject’s clinical care team will 
be contacted by the study team and the results transferred for appropriate follow-up. 
In the event of a serious adverse event during the study protocol, it will be reported to Dr. 
Stallings (Principal Investigator), the IRB and CHPS, all study team members and sponsor 
as directed by policies and procedures and in accordance with requirements. With the 
approval of families, the information will be provided to their care providers as directed. 
9.3.3 Potential Benefits of Study Participation 
We cannot ensure a direct benefit to the subjects or their families as a result of 
participating in this study. Participants and their families may benefit from knowing that 
they will contribute to a clinical research study that is important to the health of people with 
CF in the U.S. and around the world. 
9.3.4 Risk-Benefit Assessment 
The research we propose is justified, considering that the risk associated with participation 
is minimal compared to the potential and anticipated benefits. The benefits of participation 
clearly outweigh the risks, in view of the positive and long-lasting benefits of the study to 
the larger population of people living with CF. 

 
  
 
  
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9.4 Recruitment Strategy 
It is expected that all subjects will be recruited by word of mouth and at the 
recommendation of the subjects’ CF Care Team. The CF Foundation, CF Centers and CF 
support organizations around the country and Canada will provide the study with resources 
that will aide in recruitment efforts (i.e. to help to identify young subjects with “gating” 
mutations). Subjects will be recruited after introduction by the subject’s CF Care Team. In 
this initial discussion of the study, we plan to have the subject’s CF Care Team use the 
Family Recruitment Flyer, which leaves them with information about the study as well as 
contact information for the study team. The Family Recruitment Flyer will be used as a tool 
that explains the study in easier terminology, since the flyer sent to other CF Centers has a 
lot more complicated and confusing information that could potentially be overwhelming for 
families. The flyer explains to the family why they and their child are being recruited and 
what the purpose of the study is, and leaves the family with contact information for our 
study team if they want to reach out. Once a family has expressed interest in participating a 
CHOP-based research team member will contact the family via telephone or in person and 
continue the introduction of the study to families. Written (in person) or verbal (via phone) 
consent will be acquired to collect medical information to determine eligibility. For verbal 
screening consent, a waiver of documentation of consent, a waiver of assent and an 
alteration of HIPAA to obtain verbal consent and HIPAA authorization for screening over the 
phone will be in place.  A waiver of verbal assent is requested due to the fact that the child 
is too young to provide it.In the event that a non-English speaking family is approached for 
screening, an interpreter will be used either by phone or in person depending upon whether 
the screening takes place verbally over the phone or in person to present the study in a 
language understandable to the subjects/families. The interpreter can be conferenced into 
the phone call for the consent process. The screening consent will include the Study 
Summary Document for interpreter documentation attesting to statements on the summary 
document. This document will be faxed or emailed (using secure email) to the interpreter to 
sign and sent back electronically if the process takes place by phone. All members of the 
team will be available to discuss the details and answer any study related questions as they 
arise. Once interest and eligibility are determined, procedures to set up enrollment will 
begin. 
9.5 Informed Consent/Assent and HIPAA Authorization 
At entry into the study, parent(s) or legal guardian of the subjects will be asked to review 
the study informed consent form (ICF).  The Project Coordinator or other member of the 
clinical research team will meet with the family on Day 1 of Visit 1 to review the form, to 
confirm the subject understands the study, and to answer any questions that the subject or 
parent/guardian might have.  After all study-related questions are answered and subjects 
and families have had time to consider their decision, the Project Coordinator or member of 
the clinical research team will obtain fully informed, written consent from parent(s) or legal 
guardian of the subjects. Again, in the event of enrollment of a non-English speaking 
subject/family, an interpreter will be used to present the study and the consent document in 
a language understandable to the family. The main ICF will include a Study Summary 
Document for interpreter documentation attesting to statements on the summary document,  
If the interpreter is not in person but is instead conferenced in by phone, then a copy of this 
attestation document will be faxed or emailed (using secure email) to the interpreter to sign 
and return to the team electronically. The consent will be signed in the presence of a team 
member. The families will be given a printed copy of the signed, informed consent.  The 
subjects will be too young to assent to this study. 

 
  
 
  
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9.5.1 Waiver of Documentation of Consent/Assent and Alteration of HIPAA 
Authorization 
Full waivers of consent will only be sought for the verbal screening component of the study. 
The rights and welfare of the subject will not be adversely affected because during the 
verbal consent process it is explained to the subject that we are recording their health 
information to determine eligibility for the study. Study staff stress during the verbal consent 
that the screening is voluntary, but necessary if they wish to participate, and that they can 
decline and stop the process at any point. A written informed consent will be obtained upon 
study entry before any study procedures are performed. 
9.6 Payment to Subjects/Families 
We will compensate subjects/families via bank card (ClinCard) at a standard rate of $150 
per research visit day to offset incurred expenses, including compensation for time, food, 
and babysitting expenses. The baseline and 12-week visits will require 2 or 3 days and one 
or two overnight stays to complete the protocol. For the baseline (Visit 1) and 12 week (Visit 
3) visits, we have assumed that half the families will receive $150 to complete the visit and 
study protocol procedures and half will require an additional day to complete procedures, 
and will receive $300. For the 6-week visit (Visit 2), all families will receive $150 as an 
additional day will not be an option. The average compensation to complete the study is 
$600, with a minimum of $450 and maximum compensation of $750.  If the subject/family 
total compensation exceeds $600 in one calendar year, they will be provided with a W9 
form. 
Summary of Range of Payment 
 
      Each Visit 
 If Additional day required 
Visit 1 (Baseline) 
$150 
$300 
Visit 2 (6-weeks) 
$150 
$150* 
Visit 3 (12 weeks) 
$150 
$300 
 
           $450 (minimum) 
            $750 (maximum) 
*The compensation for Visit 2 (6 weeks) will always be $150 as there is no additional day 
option. 
Subjects/Families will be compensated $150 for each visit for your time and effort 
associated with the study protocol procedures. Since one important test (sleeping energy 
expenditures [SEE]) for this Baseline Visit 1 requires you to be very still, it is planned to be 
conducted during a nap. If the SEE is not completed in one day than an additional day may 
be needed.   
If subjects are not local to CHOP, they will stay in a nearby hotel for either 1 or 2 nights 
depending upon time of research procedures and whether a Day 3 is needed to complete 
the SEE.  Subjects will also be reimbursed to cover the costs of travel and parking 
Subjects/ families will provide official receipts for these items. The 12-week Visit 3 plan is 
the same as Visit 1. The 6-week Visit 2 requires one day of research study procedures.  
For all subjects not from the Philadelphia area, we have assumed that the cost of travel will 
paid for the subject and one family member to accompany the subject for about half of the 
subjects and for two people to accompany the subject for the other half of subjects. The 
overnight stays will also be paid for the family at a hotel nearby to CHOP.  

 
  
 
  
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Travel expenses that are considered reimbursable are: miles to/from CHOP for subjects 
who are traveling regionally (miles to/from the airport or train station, parking at the airport 
or train station (at a rate of $20/day), cab to and from the airport or train station, checked 
bags.  All expenses will be reimbursed with official receipts by bank card (ClinCard) 
payment request.  
 
10 PUBLICATION 
The research data obtained through the study outlined in this protocol will be shared with 
the research community, both through oral presentation at scientific meetings, and in 
written form, as published manuscripts.  Reported factual material (primary data on which 
summary statistics and tables are based), commonly accepted in the scientific community 
as necessary to document and support research findings, will be provided in a timely 
fashion upon request by members of the scientific community to the principal investigator 
for a period of 3 years following acceptance for publication. The CHOP investigators will 
have access to the complete study data.  
 

 
  
 
  
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