Conditions: Cystic Fibrosis
Allocation: NA | Intervention model: SINGLE_GROUP
Enrollment: 2
Healthy volunteers: no

Brief summary:
This postmarketing N of 2 study is designed to evaluate the efficacy and safety of open-label ivacaftor treatment in two sisters with cystic fibrosis and pancreatic sufficiency.

Detailed description:
The two sisters have a splicing mutation that is predicted to respond favorably to ivacaftor therapy. In addition to measurement of usual clinical outcomes (i.e. lung function, nutritional status), there is great interest on the impact on nontuberculous mycobacteria (NTM) airways infection.

Subjects will undergo sputum cultures at baseline and monthly during treatment, initially in the absence of anti-NTM therapy but with the intent to treat with antibiotics if there is persistence of the infection in cultures. Other clinical outcomes will include changes in sweat chloride, lung function and weight. Safety measures will include periodic assessment of liver enzymes. All serious and non-serious adverse events will be collected

Arms:
arm 1: There is only one arm to this study. The two sisters with Cystic Fibrosis will both receive Ivacaftor for 6 months for their treatment.

Interventions: intervention 1: Ivacaftor
Intervention descriptions: intervention 1: Subjects will be treated with ivacaftor for 6 months and followed for 7 months and will undergo assessments along the way to measure sweat chloride and sputum amounts.

Protocol document:
Prot_SAP_000.pdf: 
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1
TITLE PAGE
 
 
 
 
 
 
MEDICAL UNIVERSITY OF SOUTH CAROLINA
 
 
 
 
 
 
Study Protocol
 
 
An Efficacy and Safety Study of Ivacaftor in Patients
With Cystic Fibrosis and Two Splicing Mutations
IND Number: 131831
 
Date and Version of Protocol: 22 June 2015 (Version 1.0) 
 
 
 


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2
PROTOCOL SYNOPSIS
 
Title 
An Efficacy and Safety Study of Ivacaftor in Patients With Cystic Fibrosis 
and Splicing Mutations 
Clinical Phase 
N of 2 Study 
Objective 
To evaluate the efficacy and safety of ivacaftor in two patients (sisters) 
who have a splicing mutation and pancreatic sufficiency 
Endpoints 
Primary 
x
Absolute change in percent predicted forced expiratory volume in 
1 second (FEV1) from baseline through Week 24 
Key Secondary 
x
Relative change in percent predicted FEV1 from baseline through 
Week 24 
x
Achievement of mycobacterial culture conversion (negative 
culture) by Week 24 
Secondary 
x
Safety and tolerability assessments based on adverse events (AEs), 
clinical laboratory values (i.e., liver function tests) 
x
Absolute change in sweat chloride from baseline through Week 24 
x
Absolute change in respiratory symptom scores from baseline at 
Week 24 
Study 
Population 
Sisters with specific mutations 
Number of 
Subjects 
2 
Study 
Duration 
Subjects will be treated for 6 months and followed for 7 months 
Study Design 
This postmarketing N of 2 study is designed to evaluate the efficacy and 
safety of open-label ivacaftor treatment in two sisters with cystic fibrosis 
and pancreatic sufficiency.  They have a splicing mutation that is predicted 
to respond favorably to ivacaftor therapy.  In addition to measurement of 
usual clinical outcomes (i.e. lung function, nutritional status), there is great 
interest on the impact on nontuberculous mycobacteria (NTM) airways 
infection.   
Subjects will undergo sputum cultures at baseline and monthly during 
treatment, initially in the absence of anti-NTM therapy but with the intent 
to treat with antibiotics if there is persistence of the infection in cultures.  
Other clinical outcomes will include changes in sweat chloride, lung 
function and weight.  Safety measures will include periodic assessment of 
liver enzymes. All serious and non-serious adverse events will be collected 
Assessments 
Efficacy: spirometry, sweat chloride testing, CRISS, sputum cultures 
(bacteria and mycobacteria), height, and weight 
Safety: AEs, clinical laboratory assessments (liver function tests), vital 
signs, physical examinations, and pulse oximetry 
Statistical 
Analyses 
Statistical analysis details will be provided in the Statistical Analysis Plan 
(SAP), which will be finalized before the clinical data lock for the study. 
 
 
 
 


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3
SCHEDULE OF ASSESSMENTS
The Schedule of Assessments is shown in Table 3-1 
 
Visit 1 
Visit 2 
Visit 3 
Visit 4 
Visit 5 
Visit 6 
Visit 7 
Visit 8 
Event/Assessment 
Day 1 
Day 30 
Day 60 
Day 90 
Day 120 
Day 150 
Day 180 
Day 210 
Informed consent 
x 
 
 
 
 
 
 
 
Medical history 
x 
 
 
 
 
 
 
 
Demographicsa 
x 
 
 
 
 
 
 
 
Physical 
examination 
x 
x 
x 
x 
x 
x 
x 
x 
Height and weight 
x 
x 
x 
x 
x 
x 
x 
x 
Sweat test 
x 
x 
 
x 
 
 
x 
x 
Spirometry 
x 
x 
x 
x 
x 
x 
x 
x 
Genetic testingb 
x 
 
 
 
 
 
 
 
Liver function 
testsc 
x 
 
 
x 
 
 
x 
 
Sputum culturesd 
x 
x 
x 
x 
x 
x 
x 
x 
CRISS 
x 
x 
x 
x 
x 
x 
X 
x 
Adverse events 
 
x 
x 
x 
x 
x 
x 
x 
Concomitant 
medications 
x 
x 
x 
x 
x 
x 
x 
x 
Study drug 
dispensed 
x 
x 
x 
x 
x 
x 
 
 
a
Demographics include sex, race, and age. Baseline characteristics include age at CF diagnosis, CFTR genotype
b
Genetic testing will get confirm that the two mutations are not on the same allele (with a cryptic additional mild mutation 
on the other allele)._
c
Safety labs include liver enzymes (ALT, AST, GGT)_
d
Sputum will be tested for bacteria and mycobacteria (including AFB smear and culture).  Susceptibility testing will not 
be performed
 
 
 


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4
TABLE OF CONTENTS
 
1
Title Page
1
2
Protocol Synopsis
2
3
Schedule of Assessments
3
4
Table of Contents
4
List of Tables
6
5
List of Abbreviations
7
6
Introduction
8
Overview of Cystic Fibrosis
8
Overview of Ivacaftor and Rationale for Study
9
7
Study Objective
9
8
Study Endpoints
9
9
Study Design
10
9.1
Overview of Study Design
10
9.1.1
Day 1
10
9.1.2
Months 1-6 and follow up
10
9.2
Rationale for Study Design
10
10 Selection of Study Population
10
10.1
Inclusion Criteria
10
10.2
Exclusion Criteria
11
11 Assessments
11
11.1
Timing of Assessments
11
11.2
Subject and Disease Characteristics
11
11.3
Ivacaftor Exposure
11
11.4
Prior and Concomitant Medications
11
11.5
Safety
11
11.5.1 Adverse Events
11
12 Statistical and Analytical Plans
11
12.1
Sample Size
11
12.2
Analysis Sets
12
12.3
Statistical Analyses
12
12.3.1
General Considerations
12
12.3.2
Background Characteristics
12
12.3.2.1
Subject Disposition
12
12.3.2.2
Demographics and Baseline Characteristics
12
12.3.2.3
Prior and Concomitant Medications
12
12.3.2.4
Ivacaftor Exposure
13
12.3.3
Efficacy Analysis
13
12.3.4
Safety Analysis
13
12.3.4.1
Adverse Events
13
12.4
Interim Analyses
13
13 Procedural, Ethical, Regulatory, and Administrative Considerations
13
13.1
Adverse Event and Serious Adverse Event Documentation and Reporting
13


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13.1.1
Definition of an Adverse Event
13
13.1.2
Definition of a Serious Adverse Event
13
13.1.3
Documentation of Adverse Events
14
13.1.4
Adverse Event Causality
14
13.1.5
Action Taken with Ivacaftor
15
13.1.6
Adverse Event Outcome
15
13.1.7
Reporting Procedure for Adverse Events and Pregnancy
16
13.1.7.1
Reporting Procedure
16
13.1.7.2
Additional Adverse Event Reporting Procedures
16
13.2
Administrative Requirements
16
13.2.1
Ethical Considerations
16
13.2.2
Subject Information and Informed Consent
16
13.2.3
Investigator Compliance
16
13.2.4
Access to Records
16
13.2.5
Subject Privacy
16
13.2.6
Record Retention
17
13.3
Data Quality Assurance
17
13.4
Data Capture
17
13.5
Publications and Clinical Study Report
17
13.5.1
Publication of Study Results
17
13.5.2
Study Report
18
14 References
19
 
 


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List of Tables
Table 3-1
Schedule of Assessments
4
Table 13-1
Classifications for Adverse Event Causality
15
Table 13-2
Classifications for Ivacaftor Action Taken With Regard
to an Adverse Event
15
Table 13-3
Classifications for Outcome of an Adverse Event
15


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5
LIST OF ABBREVIATIONS
 
Abbreviation
Definition
ALT
Alanine transaminase
AST
Aspartate transaminase
BMI
body mass index
CF
cystic fibrosis
CFF
Cystic Fibrosis Foundation
CFTR
CF transmembrane conductance regulator gene
CFTR
CF transmembrane conductance regulator protein
CRF
case report form
EDC
electronic data capture
EU
European Union
FEV1
Forced expiratory volume in one second
G551D
CFTR missense gene mutation that results in the replacement of a glycine residue at 
position 551 of CFTR with an aspartic acid residue
G551D
CFTR protein with a replacement of a glycine residue at position 551 with an aspartic 
acid residue
GCP
Good Clinical Practice
GGT
Gamma-glutamyl transaminase
HIPAA
Health Insurance Portability and Accountability Act
ICF
informed consent form
IEC
independent ethics committee
IRB
institutional review board
MAC
Mycobacteria avium complex
MedDRA
Medical Dictionary for Regulatory Activities
NTM
Non-tuberculous mycobacteria
SAE
serious adverse event
SAP
statistical analysis plan
SD
standard deviation
US
United States
WHO-DD
World Health Organization Drug Dictionary
 
 
 


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6
INTRODUCTION
 
Overview of Cystic Fibrosis
 
Cystic fibrosis (CF) is a chronically debilitating autosomal recessive disease with high
morbidity and premature mortality that affects approximately 30,000 individuals in the
United States (US)1 and 36,000 individuals in the European Union (EU).2 The disease is 
caused by mutations in the CF transmembrane conductance regulator gene (CFTR),
which results in absent or deficient function of the CF transmembrane conductance
regulator protein (CFTR) at the cell surface.4 CFTR is an epithelial chloride channel
responsible for helping to regulate salt and water absorption and secretion in various 
tissues. The failure to regulate chloride transport in these organs results in the
multisystem pathology associated with CF.5 In the lungs, obstruction of airways with 
thick mucus, establishment of a chronic bacterial infection in the airways, and damaging 
inflammatory responses are all thought to play a role in causing irreversible structural
changes in the lungs and, ultimately, respiratory failure. Progressive loss of lung
function is the leading cause of mortality.1,3 Currently there is no cure for CF, and,
despite adjunctive treatments with nutritional supplements, antibiotics, and mucolytics6,
the median predicted age of survival of individuals born today with CF is approximately
40 years of age.1,7
 
More than 1800 mutations in the CFTR gene have been identified.8 Mutations in the CFTR
gene have been classified based on the molecular and functional consequence of the mutation 
on the CFTR protein9,10,11 and can be generally considered to reduce the quantity of functional
CFTR protein that reaches the epithelial cell surface or reduce the function of CFTR protein 
located at the cell surface. CFTR gene mutations that affect the quantity of functional cell
surface CFTR protein include defects that reduce CFTR protein synthesis and defects that
impede the cellular processing and delivery of CFTR proteins to the cell surface.
CFTR gene mutations associated with minimal CFTR function include
x
mutations associated with severe defects in the ability of the CFTR channel to open
and close, known as defective channel gating or “gating mutations”;
x
defects in the cellular processing and delivery to the cell surface;
x
no (or minimal) CFTR synthesis; and
x
severe defects in channel conductance.
One approach to increasing the level of chloride transport through the CFTR channels is to 
treat with a potentiator, a compound that increases the channel gating activity of CFTR 
protein located at the cell surface, resulting in increased chloride transport.10,12 Potentiators
represent a therapeutic strategy to treat CF. A modest restoration of chloride secretion 
through the action of a potentiator could prevent the hyperabsorption of water across the 
apical surface of epithelial cells, allowing for proper maintenance of airway hydration. 
Adequate airway hydration could alleviate the cycle of mucus plugging, infection, and
inflammation that leads to irreversible structural changes in the lungs, and eventually
respiratory failure for patients with CF. There is a supposition that potentiators can facilitate
chloride secretion in patients with CF who express at least some amount of residual CFTR
protein at the cell surface.13


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Overview of Ivacaftor and Rationale for Study
Ivacaftor, a compound developed by Vertex Pharmaceuticals Incorporated, is classified as a 
CFTR potentiator. Commercially-available ivacaftor (KalydecoTM; 150-mg tablets) was 
approved in the US and the EU in 2012 for the treatment of CF in patients 6 years of age and
older who have the G551D mutation in the CFTR gene. The indication for ivacaftor has since 
been expanded to include additional mutations (G1244E, G1349D, G178R, G551S, S1251N, 
S1255P, S549N, S549R, and R117H) based on the demonstration of clinical efficacy. 
Ivacaftor is an orally bioavailable small molecule CFTR potentiator that targets the underlying
defect in CF. As such, ivacaftor is a member of a new class of drugs, known in the literature
as CFTR modulators, that provides a new therapeutic approach to the treatment of CF.
Since ivacaftor has been made available there are a growing number of reports of its 
successful use outside of the labeled indications.  These include demonstration of pulmonary 
efficacy in patients with the indicated mutations but whose lung function is more severe than 
treated in the clinical trials, but also for patients with mutations that are predicted to respond 
to CFTR potentiation but are not in the label as an indicated mutations. For example, there is 
a report of successful treatment of sinus disease in a patient with the mutations F508del and 
2585delT and the highly publicized account of a patient with F508del and 3849+10kb, C—T
in which United Healthcare initially declined coverage of the medication but eventually 
reversed the decision.  He was seen to complete a marathon not long after.
In addition, since ivacaftor is delivered systemically there is an expectation there could be 
clinical benefits outside of its primary indication (i.e. improvement in pulmonary function).  
There are growing reports of non-pulmonary benefits of CFTR potentiation including the 
sinus disease noted above.  The GOAL study, an observational study of a treated cohort of 
patients with the G551D mutation, demonstrated increased nutritional parameters (i.e. weight 
and BMI) likely because of normalization of the intestinal pH resulting in improved digestion 
and absorption of calories (REF).  There are reports of pregnancy in female patients who had 
previously been unable to conceive, presumed because of changes to the cervical mucus 
thought to cause a mechanical barrier to fertility (REF).  Finally, the GOAL study has also 
shown a reduction in the prevalence of Pseudomonas infection in treated patients (REF).  This 
could be because of improved mucociliary clearance and a mechanical reduction in the 
bacterial load but an additional hypothesis is that enhanced mucociliary clearance causes an 
increase of local production of nitric oxide, known to have an antimicrobial effect and to be a 
key part of host defense against infection (REF).
This study is intended to assess the effects of ivacaftor in two related patients with a CFTR 
splicing mutation (3120 G>A).  A splicing mutation results in a reduction in functional CFTR 
present at the cell surface because of inefficient splicing of the final mRNA product, but the 
protein product is presumed to be normal.  Ivacaftor is known to potentiate normal CFTR and 
would then be expected to potentiate the product of a splicing mutation. The question is 
whether there is sufficient protein present in the apical membrane in a patient with a splicing 
mutation such that treatment with ivacaftor could result in a clinical benefit. The patients of 
interest for this study have a splicing mutation and have a reasonable probability of response 
given a milder manifestation of initial clinical presentation and evidence of residual CFTR 
function (i.e. pancreatic sufficiency). The first patient is a 36 year old female with CF, who 


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was first diagnosed at the age of 18 years with hemoptysis. Her genotype is 3120 G>A and 
3659delC. The first mutation is a splicing mutation so there should be some protein at the cell 
surface; the other is a premature stop codon so little CFTR should be present. She has a sweat 
chloride of 85 mmol/L (1997) and a fecal elastase >500 (12-2-13). She has moderately severe 
lung disease with a history of lobar resection prior to her diagnosis of CF. She has chronic 
sinus disease. Her sputum cultures had previously grown Pseudomonas but this has not been 
present since 2010. Currently she has Mycobacterium abscessus in her sputum cultures with 
positive smears despite antibiotic therapy. It is hypothesized there could be better response to 
antibiotic therapy if there was adequate CFTR potentiation. The purpose of six months of 
treatment is to measure a change in the microbiology in the presence of antibiotics. The 
second patient is her older sister, who was diagnosed only after the first patient had been 
diagnosed. Her symptoms have predominantly been sinusitis, but she has mild obstructive 
airways disease, chronic infection with Pseudomonas, pancreatic sufficiency, and suffered a 
bout of acute pancreatitis due to a pancreatic stone (not from the gallbladder). She also had a 
mycobacterial infection (MAC) that appears to have been eradicated with antibiotic therapy.
However, this is based on culture conversion (persistently negative cultures) while on therapy 
and she is being monitored now off antibiotic therapy.
 
7
STUDY OBJECTIVE
 
To evaluate the efficacy and safety of ivacaftor in two sisters known to have a splicing 
mutation of CFTR.
 
8
STUDY ENDPOINTS
 
x
The primary measures of efficacy will include spirometry and sweat chloride compared 
to baseline.
x
Secondary measures of efficacy will include change in weight (BMI), respiratory 
symptoms (CRISS), and sputum microbiology with particular interest in mycobacterial 
cultures, including semi-quantitative smear and culture results.
 
9
STUDY DESIGN
 
9.1
Overview of Study Design
This postmarketing N of 2 study is designed to evaluate the efficacy and safety of open-label 
ivacaftor treatment in two sisters with cystic fibrosis and pancreatic sufficiency.  They have a 
splicing mutation that is predicted to respond favorably to ivacaftor therapy.  In addition to 
measurement of usual clinical outcomes (i.e. lung function, nutritional status), there is great 
interest on the impact on nontuberculous mycobacteria (NTM) airways infection.  
Subjects will undergo sputum cultures at baseline and monthly during treatment, initially in the 
absence of anti-NTM therapy but with the intent to treat with antibiotics if there is persistence 
of the infection in cultures.  Other clinical outcomes will include changes in sweat chloride, 
lung function, respiratory symptoms (CRISS), and weight.  Safety measures will include 
periodic assessment of liver enzymes. All serious and non-serious adverse events will be 
collected
9.1.1
Day 1


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The investigator will obtain informed consent from the subjects (Note: they have already 
expressed interest in participation prior to protocol development but are aware of planned 
study procedures). Subjects will have blood drawn for genetic testing and undergo a physical 
examination, including height and weight, and measurement of baseline measures for efficacy 
and safety (i.e. sweat test, spirometry, respiratory symptoms (CRISS), sputum cultures for 
bacteria and mycobacteria, and liver enzyme testing). The subjects will commence dosing of 
ivacaftor on this day.
9.1.2
Months 1, 2, 3, 4, 5, and 6
Patients will be evaluated for any changes in health or medications.  They will undergo 
physical examination, including height and weight.  They will undergo measurement of 
efficacy outcomes (sweat test, spirometry, CRISS, sputum cultures) and safety (liver enzyme 
tests) as per the Study Assessment Schedule (Table 3-1).
9.2
Rationale for Study Design
The primary efficacy measures (changes in sweat chloride, respiratory symptoms, and 
spirometry) are expected to change in the short term (i.e. 2-4 weeks) as shown in clinical 
trials, but measurement through the duration of the study will demonstrate persistence of 
effect with chronic therapy.  The other key assessment will be the change in sputum culture 
results, especially related to mycobacteria.  It is expected that these changes will take more 
time to be realized, accounting for the planned 6 months of therapy and monitoring.
As this is an n-of-2 study, there is no value to a blinded aspect for the study.  Treatment will 
be open-label and clinical outcomes will be assessed by the individuals.
 
10
SELECTION OF STUDY POPULATION
 
10.1
Inclusion Criteria
 
Subjects include two identified sisters with CF gene mutations expected to respond to ivacaftor.
They fulfill the following criteria:
x
Subjects are >18 years of age and able to provide informed consent.
x
Subjects reside in the US and are willing to be treated with ivacaftor.
x
Subjects have the splicing mutation of interest.
x
Subjects are willing and able to perform requirements of the study.
10.2
Exclusion Criteria
There are no relevant exclusion criteria for this n-of-2 study.
 
11
ASSESSMENTS
 
11.1
Timing of Assessments
The timing of assessments is shown in Table 3-1.


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11.2
Subject and Disease Characteristics
Subject and disease characteristics include the following: CFTR genotype, sex, race, age, 
weight, height, body mass index (BMI), age at CF diagnosis, and relevant medical history.
Supplemental medical history may be collected from the Cystic Fibrosis Foundation (CFF)
Patient Registry.
11.3
Ivacaftor Exposure
The start and stop dates of all ivacaftor treatment will be recorded; all unique dosing intervals 
will be recorded during the study.
11.4
Prior and Concomitant Medications
Information regarding all medications administered before study enrollment and through
the last study visit will be recorded.
11.5
Safety
11.5.1
Adverse Events
All serious and non-serious adverse events will be assessed and documented. 
 
12
STATISTICAL AND ANALYTICAL PLANS
 
Data analysis will be performed by the investigator.
12.1
Sample Size and Power
This study is based upon the call for n-of-1 trials in clinical medicine; that is, single subject clinical 
trials that consider an individual patient as the sole unit of observation in a study investigating eth 
efficacy of an intervention (Lillie et al 2011), which is the heart of individualized medicine.  As 
the patients of interest are sisters with the same mutation and similar clinical issues, this will be an 
n-of-2 trial.  No power analysis is necessary.
 
12.2
Analysis Sets
There is only one set of data to be analyzed, consisting of the 2 subjects enrolled in this 
study.  They will comprise both the Enrolled Set and the Safety Set.
12.3
Statistical Analyses
This section presents a summary of the planned statistical analyses of safety. Analysis details 
will be provided in the Statistical Analysis Plan (SAP) for this study, which will be finalized
before study database lock.
12.3.1
General Considerations


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Continuous data variables (e.g., FEV1) will be summarized using descriptive summary
statistics. Categorical data (e.g., sex) will be summarized. All subject data, including those
derived, will be presented in the subject data listings.
12.3.2
Background Characteristics
12.3.2.1
Subject Disposition
The number of subjects in each disposition category (e.g., enrolled; prematurely discontinued
from the study; and completed the study) will be summarized.
12.3.2.2
Demographics and Baseline Characteristics
The following demographic and baseline characteristics will be captured: CFTR genotype,
sex, race, age, weight, height, BMI, sweat chloride, spirometry, CRISS, and sputum culture 
results.
 
12.3.2.3
Prior and Concomitant Medications
Only prior and concomitant corticosteroids and ivacaftor will be collected. Medications taken 
during the collection period specified in Section 11.4 will be summarized by preferred term 
using the World Health Organization Drug Dictionary (WHO-DD) for the Safety Set as 
frequency tables in 2 parts:
x
Prior medication: medication that started before the first dose of ivacaftor, regardless
of when dosing of the medication ended.
x
Concomitant medication: medication received at or after the first dose of ivacaftor,
medication that was received before initial dosing of ivacaftor and continued after
initial dosing, or medication with missing stop date.
Medications that started before the first dose of ivacaftor and continued after the first dose of
ivacaftor will be summarized separately as prior medications and concomitant medications, 
respectively. Medications with a missing start date will be considered to have a start date 
before the first dose of ivacaftor.
12.3.2.4
Ivacaftor Exposure
Exposure to ivacaftor (i.e., duration of treatment) will be summarized for the Safety Set in 
terms of duration of treatment a subject received (in days). Duration of treatment will be
summarized by descriptive summary statistics.
12.3.3
Efficacy Analysis
Change (absolute change) from baseline will be calculated as post-baseline value - baseline
value. Relative change from baseline will be calculated as (post-baseline value - baseline
value)/baseline value.
12.3.4
Safety Analysis


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Safety analyses will be based on the Safety Set. All safety data will be presented in individual
subject data listings.
12.3.4.1
Adverse Events
All adverse events with start date on or after enrollment date through the last study visit will 
be summarized. Adverse events are defined in Section 13.1.1. Adverse event summary tables
will include the following:
•
all adverse events;
•
related (identified as related to ivacaftor by the investigator) adverse events;
•
adverse events leading to treatment discontinuation;
•
serious adverse events (SAEs); and
•
adverse events by relationship.
 
Summaries will be presented by MedDRA system organ class and preferred term using 
frequency counts and percentages. A subject with multiple occurrences of the same adverse 
event or a continuing adverse event will be counted only once, by relationship.
12.4
Interim Analyses
 
No interim analyses will be performed but safety will be monitored throughout.
 
13
PROCEDURAL, ETHICAL, REGULATORY, AND ADMINISTRATIVE 
CONSIDERATIONS
 
13.1
Adverse Event and Serious Adverse Event Documentation and
Reporting
 
13.1.1
Definition of an Adverse Event
 
For this study, an adverse event is defined as any untoward medical occurrence in a subject
during the study, including any newly-occurring event or previous condition that has
increased in severity or frequency after the informed consent form is signed.
 
A subset of adverse events may meet serious criteria. The definition of an SAE and reporting
procedures for SAEs are detailed in Section 13.1.2. The definitions below apply to both 
adverse events and SAEs.
 
Planned hospital admissions or surgical procedures for an illness or disease that existed before
the subject was enrolled in the study are not to be considered adverse events unless the 
condition deteriorated in an unanticipated manner during the study (e.g., surgery was performed
earlier than planned).
13.1.2
Definition of a Serious Adverse Event
An SAE is any adverse event that meets any of the following criteria:
•
Fatal (death, regardless of cause, that occurs during participation in the study, or occurs
after participation in the study and is suspected of being possibly related to ivacaftor).
•
Life-threatening, such that the subject was at immediate risk of death from the reaction as
it occurred.


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•
Inpatient hospitalization or prolongation of hospitalization, with the exception of
planned or elective hospitalization.
•
Persistent or significant disability/incapacity (disability is defined as a
substantial disruption of a person's ability to conduct normal life functions).
•
Congenital anomaly or birth defect.
•
Important medical event that, based upon appropriate medical judgment, may
jeopardize the subject or may require medical or surgical intervention to prevent 1 of the
outcomes listed above (e.g., an allergic bronchospasm requiring intensive treatment in an
emergency room or at home).
13.1.3
Documentation of Adverse Events
From the time informed consent is signed through the last study visit all adverse events will 
be collected. The following data should be documented for each adverse event:
•
Description of the event
•
Classification of "serious" or "not serious"
•
Date of first occurrence and date of resolution (if applicable)
•
Causal relationship to ivacaftor exposure
•
Action taken
•
Outcome
•
Concomitant medication or other treatment given
For all other adverse events considered related to ivacaftor, see Section 13.1.7.2.
13.1.4
Adverse Event Causality
Every effort should be made by the investigator to assess the relationship of the adverse
event, if any, to ivacaftor exposure. Causality should be classified using the categories 
presented in Table 13-1.
 
Table 13-1  Classification for Adverse Event Causality 
Classification 
Definition 
Related 
There is a suspected association between the event and the administration of 
ivacaftor, a plausible mechanism for the event to be related to ivacaftor and 
causes other than the ivacaftor have been ruled out, and/or the event re-
appeared on re-exposure to ivacaftor 
Not related 
The event is believed related to an etiology other than the ivacaftor. (The 
alternative etiology should be documented in the study subject's medical record) 
 
13.1.5
Action Taken with Ivacaftor
The investigator will classify the action taken with regard to ivacaftor due to the adverse
event. The action taken should be classified according to the categories shown in Table 13-2.
Table 13-2  Classification for Ivacaftor Action Taken With Regard to an Adverse Event  
Classification 
Definition 
Dose Not Changed 
Ivacaftor treatment not changed in response to an adverse event 
Drug Interrupted 
Ivacaftor administration interrupted in response to an adverse event 
Drug Withdrawn 
Ivacaftor administration permanently discontinued in response to an adverse 
event 
Not Applicable 
Action taken regarding ivacaftor administration does not apply. 
"Not applicable" should be used in circumstances such as when the ivacaftor 


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treatment had been completed before the adverse event began and no 
opportunity to decide whether to continue, interrupt, or withdraw treatment is 
possible 
 
13.1.6
Adverse Event Outcome
An adverse event should be followed until the investigator has determined and provided the 
final outcome. The outcome should be classified according to the categories shown in Table
13-3.
 
Table 13-3  Classifications for Outcome of an Adverse Event 
Classification 
Definition 
Recovered/Resolved 
Resolution of an adverse event with no residual signs or 
symptoms 
Recovered/Resolved with Sequelae 
Resolution of an adverse event with residual signs or symptoms 
Not Recovered/Not resolved (Continuing) 
Either incomplete improvement or no improvement of an 
adverse event, such that it remains ongoing 
Fatal 
Outcome of an adverse event is death. "Fatal" should be used 
when death is at least possibly related to the adverse event 
Unknown 
Outcome of an adverse event is not known (e.g., a subject lost 
to follow-up). 
 
13.1.7
Reporting Procedure for Adverse Events and Pregnancy
All serious and non-serious vision-related events (as defined in Section 13.1.1) that occur
after obtaining informed consent and assent (where applicable) through the last study visit, 
regardless of causality, must be reported to the MUSC IRB within 24 hours of their
awareness.
13.1.7.1
Additional Adverse Event Reporting Procedures
Investigators are encouraged to report any adverse reactions suspected due to ivacaftor to the
FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.
Investigators should also report any suspected adverse reactions related to ivacaftor, other
than those being collected as part of the study, as well any pregnancies, to Vertex 
Pharmaceuticals Incorporated at 1-877-752-5933.
13.2
Administrative Requirements
13.2.1
Ethical Considerations
The study will be conducted in accordance with the ethical principles founded in the 
Declaration of Helsinki, and according to local applicable laws and regulations. The 
institutional review board (IRB) will review all appropriate study documentation to safeguard
the rights, safety, and well-being of the subjects. The study will only be conducted at MUSC.
 
13.2.2
Subject Information and Informed Consent
Subjects must also be informed that participation is voluntary and that they may withdraw


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from the study at any time, without prejudice to their current or future care. Documentation of
the discussion and the date of informed consent must be recorded in the subject's medical
record or a study/clinic chart. Once all of their questions have been answered and they have
voluntarily agreed to participate in the study, each subject will be asked to sign and date the
ICF. Informed consent must be obtained from each subject before the performance of any
study-related activity.
13.2.3
Investigator Compliance
No modifications to the protocol should be made without the approval of the IRB, except 
where the modification is necessary to eliminate an apparent immediate hazard to human
subjects. Any departures from protocol must be fully documented in the source
documentation and in a protocol deviation log.
13.2.4
Access to Records
The records must also be available for direct inspection, verification, and copying, as required
by applicable laws and regulations, by officials of the regulatory health authorities (FDA and
others). The investigator must comply with applicable privacy and security laws for use and
disclosure of information related to the research set forth in this protocol.
13.2.5
Subject Privacy
To maintain subject confidentiality, all case report forms (CRFs), study reports, and
communications relating to the study will identify subjects by assigned subject numbers. The
FDA (or other regulatory authority) may also request access to all study records, including
source documentation, for inspection.
 
As applicable, in accordance with the Health Insurance Portability and Accountability Act
(HIPAA) and associated privacy regulations, a subject authorization to use personally
identifiable health information may be required from each subject before research activities 
begin. This authorization document must clearly specify which parties will have access to a
subject's personal health information, for what purpose, and for how long.
13.2.6
Record Retention
The investigator will maintain all study records according to ICH GCP guidelines and/or 
applicable local regulatory requirement(s), whichever is longest
13.3
Data Quality Assurance
The investigator will prepare and maintain adequate and accurate case histories designed to
record all observations and other data pertinent to the study for each study participant. Study
data for each enrolled subject will be entered into a CRF by site personnel using a secure,
electronic data capture (EDC) application. Any changes to study data will be made to the
CRF and documented in an audit trail, which will be maintained within the study database.
13.4
Data Capture


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It is the investigator's responsibility to ensure the accuracy, completeness, clarity, and
timeliness of the data reported in the subject's CRF. Source documentation supporting the
CRF data should indicate the subject's participation in the study and should document the 
dates and details of study procedures, adverse events, other observations, and subject
status.
The investigator will retain the CRF data and corresponding audit trails that show all updates
to data, with user identification, date, and time.
13.5
Publications and Clinical Study Report
13.5.1
Publication of Study Results
Any and all scientific, commercial, and technical information in this protocol or elsewhere
should be considered the confidential and proprietary property of the investigator. The
investigator shall not disclose private information to any third party except to such of the
investigator's employees and staff as have been made aware that the information is confidential
and who are bound to treat it as such and to whom disclosure is necessary to evaluate that
information. The investigator shall not use such information for any purpose other than
determining mutual interest in performing the study and, if the parties decide to proceed with 
the study, for the purpose of conducting the study.
 
The investigator understands that the information developed from this postmarketing treatment
study will be considered the property of the investigator but may be disclosed as required to 
other clinical investigators, the FDA, and other government agencies.
 
The investigator will be responsible for publication and/or disclosure of study results but 
will review the data under the terms and conditions of a separate written agreement between
Vertex and the investigator and/or the investigator's institution.
13.5.2
Study Report
A clinical study report will be written by the investigator. Vertex will review the report and 
submit the study report to the FDA.
 
 


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Commented [F1]: May not need this reference