CFTR Modulators and Gastrointestinal Complications
Conditions: Cystic Fibrosis, Gastrointestinal System Disease, Distal Intestinal Obstruction Syndrome, Pancreatic Enzyme Abnormality, Pancreatic Disease, Lung Diseases, Digestive System Disease
Sponsor: Nottingham University Hospitals NHS Trust

 
 
 
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CFTR MAGIC Protocol Draft Version  0.1 Final Version 1.0    date 01/09/21 
 
 
This protocol is confidential and the property of the University of Nottingham. No part of it may be 
transmitted, reproduced, published, or used by others persons without prior written authorisation 
from the University of Nottingham 
 
 
 
 
 
 
 
CF Trust and CF Foundation registries  
 
 
Final Version 1.0 
01/09/2021 
 
 
 
Short title:  
 
 CFTR Modulators and Gastrointestinal Complications 
(CFTR MAGIC)  
 
 
Acronym:   
 
CFTR MAGIC 
 
 
IRAS Project ID: 
 
N/A.  
 
 
 
Funding Source: 
NIHR Programme Development Grant. Reference number 
PDG NIHR202952

 
 
 
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CFTR MAGIC Protocol Draft Version  0.1 Final Version 1.0    date 01/09/21 
 
 
This protocol is confidential and the property of the University of Nottingham. No part of it may be 
transmitted, reproduced, published, or used by others persons without prior written authorisation 
from the University of Nottingham 
REGISTRY PERSONNEL AND CONTACT DETAILS 
 
 
Chief investigator:  
 
Professor Alan Smyth  
Professor of Child Health, University of Nottingham 
Room 1702, E Floor East Block, Queen’s Medical Centre 
Nottingham University Hospitals NHS Trust 
Nottingham 
NG7 2UH 
 
Phone: 
01158230612 
Fax: 01158230626 
 
Email:  
alan.smyth@nottingham.ac.uk 
 
 
Co-investigators:  
 
Dr Rebecca Calthorpe 
Clinical Research Fellow,  
University of Nottingham, E Floor East Block, Queen’s Medical Centre,  
Nottingham 
NG7 2UH 
Rebecca.calthorpe@nottingham.ac.uk 
 
Professor Daniel Peckham  
Professor of Respiratory Medicine,  
Leeds Teaching Hospitals NHS Trust,  
St James’s University Hospitals,  
Beckett Street, Leeds,  
LS9 7TF  
D.G.Peckham@leeds.ac.uk 
 
Dr Siobhan Carr  
Paediatric Respiratory Consultant  
Royal Brompton and Harefield NHS Foundation Trust,  
Royal Brompton Hospital, Sydney Street,  
Greater London,  
SW3 6NP  
S.Carr@rbht.nhs.uk 
 
Professor Christopher Goss  
Professor of Paediatrics,  
University of Washington Medical Center,  
Health Sciences Building, 1959 NE Pacific Street 
Campus Box 356522 
Seattle, WA 98195-6522 

 
 
 
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CFTR MAGIC Protocol Draft Version  0.1 Final Version 1.0    date 01/09/21 
 
 
This protocol is confidential and the property of the University of Nottingham. No part of it may be 
transmitted, reproduced, published, or used by others persons without prior written authorisation 
from the University of Nottingham 
CGoss@medicine.washington.edu 
 
Professor Margaret Rosenfeld  
Professor of Paediatrics,  
Seattle Children’s Hospital,  
4800 Sand Point Way, NE,  
Seattle, WA 98105 
margaret.rosenfeld@seattlechildrens.org 
 
 
 
Registry Statistician: 
 
Dr Iain Stewart 
Analytical and statistical lead,  
National Heart and Lung Institute, Imperial College London,  
Guy Scadding Building, Dovehouse Street, London,  
SW3 6LY 
iain.stewart@nottingham.ac.uk 
 
 
Registry database Coordinating Centre: University of Nottingham  
 
 

 
 
 
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CFTR MAGIC Protocol Draft Version  0.1 Final Version 1.0    date 01/09/21 
 
 
This protocol is confidential and the property of the University of Nottingham. No part of it may be 
transmitted, reproduced, published, or used by others persons without prior written authorisation 
from the University of Nottingham 
SYNOPSIS 
 
Title 
CFTR Modulators and Gastrointestinal Complications (CFTR 
MAGIC): a registry study 
Short title 
CFTR MAGIC 
Chief Investigator 
Professor Alan Smyth  
Objectives 
AIM:  To elucidate the similarities and distinctions in non-
pulmonary manifestations of CF including distal intestinal 
obstructive syndrome (DIOS) incidence and Pancreatic 
enzyme replacement therapy (PERT) usage between US and 
UK populations with cystic fibrosis (CF) in a parallel study. To 
assess how CFTR modulators impact upon recorded 
incidence and use.  
OBJECTIVES  
• Describe DIOS events and PERT usage in UK and US 
registries 2007-2017 
• Determine the effect of CFTR modulators on the incidence of 
DIOS and use of PERT: population time series 
• Determine the effect of CFTR modulators on the incidence of 
DIOS and use of PERT: patient-level time series 
 
Registry database 
Configuration 
Parallel study  
Setting 
All people with CF included on the US or UK CF registries    
Number of 
participants 
All patients with CF who are registered on the UK or US CF 
registries from 2007-2017 will be included.   
 
Eligibility criteria 
All CF patients of any genotype who are registered on the UK or US 
CF registries from 2007-2017 will be included.   
 
Description of 
interventions 
Registry study. No individual patient interaction.  
Duration of registry 
database 
24 months (1st October 2021 – 30th September 2023)  

 
 
 
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CFTR MAGIC Protocol Draft Version  0.1 Final Version 1.0    date 01/09/21 
 
 
This protocol is confidential and the property of the University of Nottingham. No part of it may be 
transmitted, reproduced, published, or used by others persons without prior written authorisation 
from the University of Nottingham 
ABBREVIATIONS  
 
 
CI 
Chief Investigator overall 
CRF Case Report Form 
GCP Good Clinical Practice 
NHS National Health Service 
PI 
Principal Investigator at a local centre 
REC Research Ethics Committee 
R&D Research and Development department 
UoN University of Nottingham 
 
 
 
 

 
 
 
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CFTR MAGIC Protocol Draft Version  0.1 Final Version 1.0    date 01/09/21 
 
 
This protocol is confidential and the property of the University of Nottingham. No part of it may be 
transmitted, reproduced, published, or used by others persons without prior written authorisation 
from the University of Nottingham 
TABLE OF CONTENTS 
 
 
SYNOPSIS...................................................................................................................... 4 
ABBREVIATIONS .......................................................................................................... 5 
DATABASE BACKGROUND INFORMATION AND RATIONALE ............................. 8 
DATABASE OBJECTIVES AND PURPOSE ............................................................... 9 
PURPOSE 
9 
PRIMARY OBJECTIVE 
9 
SECONDARY OBJECTIVES 
9 
DATABASE DESIGN ..................................................................................................... 9 
DATABASE CONFIGURATION 
9 
DATABASE MANAGEMENT 
10 
DURATION OF THE DATABASE AND PARTICIPANT INVOLVEMENT 
10 
End of the Database 
11 
SELECTION AND WITHDRAWAL OF PARTICIPANTS 
11 
Recruitment 
11 
Eligibility criteria 
11 
Expected duration of participant participation 
11 
Participant Withdrawal 
11 
Informed consent 
11 
DATABASE REGIMEN 
12 
ACCESS TO DATABASE 
12 
Criteria for terminating the database 
12 
STATISTICAL ANALYSES 
12 
Sample size and justification 
12 
ADVERSE EVENTS ..................................................................................................... 15 
ETHICAL AND REGULATORY ASPECTS ................................................................ 16 
ETHICS COMMITTEE AND REGULATORY APPROVALS 
16 
INFORMED CONSENT AND PARTICIPANT INFORMATION 
16 
RECORDS 
16 
Case Report Forms 
16 
Source documents 
16 
Direct access to source data / documents 
17 
DATA PROTECTION 
17 
QUALITY ASSURANCE & AUDIT .............................................................................. 17 
INSURANCE AND INDEMNITY 
17 
DATABASE CONDUCT 
17 
DATABASE DATA 
18 
RECORD RETENTION AND ARCHIVING 
18 
DISCONTINUATION OF THE DATABASE BY THE SPONSOR 
18 
STATEMENT OF CONFIDENTIALITY 
18 
PUBLICATION AND DISSEMINATION POLICY ....................................................... 19 
USER AND PUBLIC INVOLVEMENT ......................................................................... 19 

 
 
 
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transmitted, reproduced, published, or used by others persons without prior written authorisation 
from the University of Nottingham 
DATABASE FINANCES .............................................................................................. 20 
Funding source 
20 
Participant stipends and payments 
20 
SIGNATURE PAGES ................................................................................................... 21 
REFERENCES ............................................................................................................. 22 
 

 
 
 
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CFTR MAGIC Protocol Draft Version  0.1 Final Version 1.0    date 01/09/21 
 
 
This protocol is confidential and the property of the University of Nottingham. No part of it may be 
transmitted, reproduced, published, or used by others persons without prior written authorisation 
from the University of Nottingham 
REGISTRY BACKGROUND INFORMATION AND RATIONALE 
 
BACKGROUND 
Cystic fibrosis (CF) is an autosomal recessive disorder, caused by mutations to the 
cystic fibrosis transmembrane conductance regulator (CFTR) gene encoding for the 
CFTR protein. CF affects around 10,000 people in the UK with a life expectancy of 49 
years in 2019.1 Although CF is a multi-system disorder, its impact on the respiratory 
track and gastrointestinal (GI) system are of particular clinical importance.2 In the gut,  
CFTR mutations result in pancreatic exocrine insufficiency in around 85% infants 
resulting in maldigestion and impaired nutrition,3 with adequate nutrition in CF linked 
to life expectancy.4 Due to the success of the newborn screening programme in the 
UK most people with CF (pwCF) are now identified within the first few weeks of life and 
commenced on pancreatic enzyme replacement therapy (PERT). Cystic fibrosis has a 
high associated treatment burden, with PERT in particular contributing to this, with 
patients often have to take 25-30 capsules per day.5 However, despite this almost all 
pwCF experience GI symptoms including abdominal pain, flatulence, constipation and 
bloating,6 with two thirds missing work or school because of this.7 This is why “How 
can we relieve gastro-intestinal symptoms, such as stomach pain, bloating and nausea 
in people with Cystic Fibrosis?’ was identified as one of the top 10 research priorities 
in a James Lind Alliance Priority Setting Partnership (JLA PSP) in CF conducted by 
our group.8  
 
In addition, other GI manifestations affecting pwCF include distal intestinal obstructive 
syndrome (DIOS), CF related liver disease (CFRD) and pancreatitis. DIOS is a severe 
GI complication in CF defined as a complete intestinal obstruction with an ileo-caecal 
mass and abdominal distension, thought to result from the accumulation of faecal 
material at the ileo-caecal valve.9  It affected 5.7% pwCF in the UK (2.5% in <16 years 
and 7.7% in adults)1 and 2.1% in the US (<18 years 1.7%, adult 2.4%)10 in 2019. 
However, the pathology underlying DIOS and GI symptoms are currently not well 
understood.  
 
Advances in CF care has seen the development and introduction of CFTR modulator 
drugs, capable of targeting the basic defect of CF rather than the consequences of 
CFTR failure. Ivacaftor was first introduced in 2012 suitable for patients with gating 
mutations. Since then, a number of CFTR modulators have been developed the most 
recent being the CFTR modulator Ivacaftor/Tezacaftor/Elexacaftor: KaftrioTM (UK) or 
TrikaftaTM (US). This is indicated for 508del homozygote patients and patients with one 
copy of 508del combined with a minimal function mutation which comprises 90% of the 
UK CF population. Kaftrio was induced in the UK in 2020. CFTR modulators have 
already demonstrated dramatic improvements in respiratory outcome measures in 
CF,11 however the impact of other aspects of the disease, such as within the gut are 
less well understood. A registry study in 2014 using US and UK data showed a lower 
prevalence of GI complications in patients receiving Ivacaftor although this was not 
significant. However, the average length of ivacaftor exposure in this study was short 
(2 years US, 1.3 year UK).12 
 
Although our JLA PSP demonstrated that reducing GI symptoms was a research 
priority7 there is currently a disconnect between this and ongoing clinical trials, with 
only three ongoing trials investigating GI symptoms.13 In addition, there is no agreed, 

 
 
 
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This protocol is confidential and the property of the University of Nottingham. No part of it may be 
transmitted, reproduced, published, or used by others persons without prior written authorisation 
from the University of Nottingham 
validated outcome measures such as biomarkers or patient reported outcome 
measures in CF for GI symptoms that can be used as a primary end point14 or agreed 
core outcome sets for trials. Finally, we do not yet know the impact of CFTR modulators 
on GI burden of the disease such as GI symptoms, PERT usage and the development 
of severe complications such as DIOS. 
 
 
RATIONALE  
The overall study name is “A Comprehensive Approach To Relief Of Digestive 
Symptoms In Cystic Fibrosis: CARDS-CF”. This will consist of 3 workstreams. We will 
complete a systematic review of the literature for outcomes and endpoints for studies 
of interventions to relieve GI symptoms in CF (workstream 3). This will help guide the 
development of the initial conceptual framework as part of the PROM development 
(workstream 1). A registry study will compare the trends in PERT usage and DIOS in 
the US and UK and will investigate the effects of the introduction of CFTR modulator 
drugs on PERT usage and the development of DIOS (workstream 2).  This protocol 
relates specifically to workstream 2; CFTR MAGIC study.  
 
 
OBJECTIVES AND PURPOSE 
PURPOSE 
To elucidate the similarities and distinctions in non-pulmonary manifestations of CF 
including DIOS incidence and PERT usage between US and UK populations with 
cystic fibrosis in a parallel study. To assess how CFTR modulators impact upon 
recorded incidence and use. 
 
PRIMARY OBJECTIVE 
1. Describe DIOS events and PERT usage in UK and US registries 2007-2017 
2. Determine the effect of CFTR modulators on the incidence of DIOS and use of 
PERT: population time series 
3. Determine the effect of CFTR modulators on the incidence of DIOS and use of 
PERT: patient-level time series 
 
SECONDARY OBJECTIVES 
To use objectives 1 to 3 above to generate a hypothesis regarding the effect of the 
newer CFTR modulators such as Symdeko/Symkevi and Tricaftor/Kaftrio of PERT 
usage and DIOS incidence in CF registry data post 2018. This will form the basis of 
future studies.  
 
DESIGN 
REGISTRY CONFIGURATION 
STUDY DESIGN  

 
 
 
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This protocol is confidential and the property of the University of Nottingham. No part of it may be 
transmitted, reproduced, published, or used by others persons without prior written authorisation 
from the University of Nottingham 
This is a parallel data registry study using data from the UK and US CF registries. 
Application for data from the CF Foundation registry and UK CF Trust has been 
approved. Data will be obtained for 2007-2017 in both cohorts to allow for a minimum 
of 4 years of annualised data prior to the introduction of the first CFTR modulator drug, 
Ivacaftor, in 2012.  
 
Data will be requested on the following patient-level variables;  
• Year  
• Current age/birth year  
• Age at diagnosis  
• Sex  
• Ethnicity  
• Height and weight or BMI  
• Centre pseudoID  
• Genotype  
• CFTR modulator status (with date commenced and any treatment interruptions).  
o ivacaftor  
o lumacaftor/ivacaftor  
o tezacaftor/ivacaftor  
o elexacaftor/tezacaftor/ivacaftor  
• DIOS events (with any date/encounter/timing variable available)  
• Medication (with date commenced and any treatment interruptions).  
o Laxatives (including Movicol / Laxido)  
o PERT dosage/usage  
o Proton pump inhibitors  
o Azithromycin 
• History of meconium ileus  
• Disease status: FEV1 (with any date/encounter/timing variable available)  
• Comorbidities  
o CF related liver disease (including raised transaminases and cirrhosis).  
o CF related diabetes  
o Pseudomonas colonisation  
• Gut complications (with any date/encounter/timing variable available)  
o Constipation 
o Intestinal obstruction  
o Acute pancreatitis 
 
REGISTRY DATA MANAGEMENT 
A full data management plan is included separately. The Chief Investigator has overall 
responsibility for the registry data and shall oversee all data management. The data 
custodian will be the Chief Investigator. 
 
DURATION OF THE STUDY AND PARTICIPANT INVOLVEMENT 
Registry database Duration: 24 months 
 
 
Participant Duration: This is a registry study therefore no individual participant 
interaction. However, registry data from the US and UK CF registries will be used from 
2007 to 2017.  

 
 
 
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This protocol is confidential and the property of the University of Nottingham. No part of it may be 
transmitted, reproduced, published, or used by others persons without prior written authorisation 
from the University of Nottingham 
End of the registry study 
Data will be destroyed in line with the UK and US CF registry requirements at the end 
of the study period. A detailed description of this is outlined in the data management 
plan. The end of the study will be 31/09/2023.  
 
SELECTION AND WITHDRAWAL OF PARTICIPANTS 
Recruitment 
This is a registry study using data from 2007-2017 from the UK and US CF registries. 
As such no individual participants will be recruited to the study. PwCF have given 
explicit consent to their usual CF teams for their demographic, clinical care, and health 
outcomes data to be submitted to either the UK or US CF registries.  
 
Eligibility criteria 
 
Inclusion criteria  
All CF patients of any genotype who are registered on the UK or US CF registries from 
2007-2017 will be included.   
 
4.2.2 Exclusion criteria  
Patients whose CFTR modulator status is unknown or only have one year of CFTR 
data recorded on the registry will be excluded from the analysis of the effects of CFTR 
modulators. This is to account for the fact that DIOS data is annualised on the registry, 
therefore there is no certainty at what time of year DIOS was diagnosed in relation to 
commencing CFTR modulatory therapy.  
 
Expected duration of participant participation 
No individual participant interaction. The CFTR MAGIC study will take place over 24 
months, from 1/10/2021 to 30/9/2023.  
 
Participant Withdrawal  
Not applicable – no individual participant involvement.  
 
Informed consent 
PwCF have given explicit consent to their usual CF teams for their demographic, 
clinical care, and health outcomes data to be submitted to either the UK or US CF 
registries.15, 16  Written consent is gained from pwCF or their parent/ legal guardian and 
as part of this they are made aware that the information may be used for research and 
to plan and improve the quality of clinical care. For the UK CF Trust the use of any 
data from the registry requires the approval of the Registry Steering Committee.15 In 
the US, the request for registry data is reviewed and approved by the Patient 
Registry/Comparative Effectiveness Research Committee. The project has received 
approval from both the US and UK registries for patient data to be released to be used 
for this project. Data is released by the registries as anonymised forms of the data to 
maintain patient confidentiality. Additional patient specific consent for CFTR MAGIC is 
therefore not required.  

 
 
 
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CFTR MAGIC Protocol Draft Version  0.1 Final Version 1.0    date 01/09/21 
 
 
This protocol is confidential and the property of the University of Nottingham. No part of it may be 
transmitted, reproduced, published, or used by others persons without prior written authorisation 
from the University of Nottingham 
 
DATA COLLECTION REGIMEN 
No new data collection will be necessary within this project. Existing data will be 
provided by the US and UK CF registries. Requests for the data was approved by the 
UK CF Trust Registry Steering Committee after reviewing the programme development 
grant aims, statistical analysis and plan for publication of results. In the US, the request 
for registry data was reviewed and approved by the Patient Registry/Comparative 
Effectiveness Research Committee and was subject to peer review. Data will be 
provided as anonymised data so the individuals cannot be identified and analysed 
using Stata software.  
 
ACCESS TO REGISTRY DATA  
Data will be in the form of registry data provided from the US and UK CF registries 
from the period 2007-2017. These datasets will be provided as encrypted data via the 
registries preferred data sharing platform (Box.com or similar). Both registries have 
already reviewed and approved the sharing of their data for use within this project.  
 
Criteria for terminating the registry data 
No data will be archived in a data repository following project completion due to the 
requirements of the CF Foundation and CF Trust registries. The CF foundation 
considers the project to be completed after 3 years. After this time data files and any 
copies of the files will be destroyed. The CF Foundation will be provided with written 
confirmation of destruction of the data and completion of the project or alternatively 
provided with a sufficient justification for continuation of the project if required. The CF 
Foundation maintains copies of all data sets sent to researchers and can provide the 
data again if required for auditing purposes. The CF Trust requires all data to be 
destroyed at the end of the project and that all data forms must be permanently 
destroyed within 12 months of the date of supply unless approval has been granted by 
the UK CF Registry Research Committee for an extension.  
 
STATISTICAL ANALYSIS 
Data will be provided from the UK and US registries as an encrypted file and analysis 
will be performed using Stata software. Statistical analysis will be completed by 
members of the research team, led by Prof Iain Stewart. A full plan for statistical  
analysis is described below.  
 
Objective 1: Assess the rate of PERT use and the incidence of DIOS in UK and 
US registries 2007-2017 
1. Descriptive analysis 2007-2017 to include: 
• Yearly cumulative incidence of DIOS and prevalence of PERT usage in the UK 
and US (2007-2017) 
o PERT use will be dichotomised (i.e use/no use) 
o Incidence of DIOS (event/no event) 
o Plotted by year, separated by registry  
o Stratification by age range (<6, 6-11, 12+) 
 

 
 
 
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CFTR MAGIC Protocol Draft Version  0.1 Final Version 1.0    date 01/09/21 
 
 
This protocol is confidential and the property of the University of Nottingham. No part of it may be 
transmitted, reproduced, published, or used by others persons without prior written authorisation 
from the University of Nottingham 
• Patient demographics of DIOS and PERT reporting 
o The distribution of yearly reported incidence events and use prevalence 
(%) will be addressed according to age groups, sex, BMI, ethnicity, 
antibiotic use, comorbidities (including Pseudomonas colonisation, GI 
complication history, GI co-morbidities such as CFRD and CFRLD), 
FEV1 lung function, centre (where available, pseudo ID). 
 
Trends in the registries will be described, however no statistical tests will be used to 
directly similarities and differences between the registries over time due to the 
distinctions between the two registries.  
 
2. The patient demographics lists above will be used for demographic propensity 
matched controls 
• Patient-level data will be used to create registry-based control groups with 
similar demographic features to those taking CFTR modulators.  Due to the 
restricted genotype eligibility criteria for the earliest CFTR modulator, Ivacaftor, 
the CFTR user group may have distinct features compared to the overall 
registry. In addition the restrictive indications for the use of Ivacaftor and 
limited number of DIOS events on the registry will therefore mean the number 
of events within exposed individuals may be low. Therefore propensity scores 
will be used to define a control group of non-eligible non-users that are 
otherwise representative at the year CFTR modulator exposure was 
commenced. See directed acyclic graph (DAG) below.  
• Nearest neighbour matching, caliper 0.2 standard deviation, 3:1 ratio of 
unexposed to exposed will be used for propensity matching. Matching will be 
performed according to first year of exposure using all pre-exposure 
information in wide format. Standardised mean difference will be used to 
check covariate balance between matched and unmatched populations. 
Average treatment effect of treated will be used to assess matching 
specification with alternates. 
 
 
 
Directed acyclic graph (DAG) for the potential relationship of CFTR modulator and 
DIOS  
 
 
Objective 2: Determine the effect of CFTR modulators on DIOS and PERT, 
using an population-level controlled interrupted time series   

 
 
 
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CFTR MAGIC Protocol Draft Version  0.1 Final Version 1.0    date 01/09/21 
 
 
This protocol is confidential and the property of the University of Nottingham. No part of it may be 
transmitted, reproduced, published, or used by others persons without prior written authorisation 
from the University of Nottingham 
Objective 2 will investigate the effect of CFTR modulator intervention on the rate on 
PERT use and DIOS incidence.  
 
We will test the hypotheses that;  
a) Ivacaftor introduction (2012) in patients with gating mutations lowered the rate 
of PERT use and the incidence of DIOS in both registries, and that 
b) The introduction of Orkambi (Ivacaftor/Lumacaftor) for those homozygous for 
F508del mutations in the US (2015) lowered the rate of PERT use and the 
incidence of DIOS. Specifically, we hypothesise a downward trend, no lag. 
 
Hypothesis 2b will be explored in the US population only given that introduction of 
Orkambi was delayed in the UK until 2019.  
 
ITS will explore proportion of DIOS events at population level in the CFTR modulator 
population and the propensity score defined comparator population. ITS will explore 
proportion of overall PERT usage (user/non user), and the proportion of individuals 
with a reduction in weight standardised PERT dose (decrease/no decrease)  
• Sensitivity will include distributed lag of 1-3 (years) to account for the 
possibility that exposure time in the first year was not sufficient for a change in 
outcome, compared to non-lagged, and to explore PERT usage status change 
to non-user.  
• Autoregression will be visually assessed and effects will also be compared 
with those from autoregressive model (Prais-Winsten).  
 
Analysis will be performed overall and stratified by 1) Age group (<6, 6-11, 12+) to 
account for clinical distinctions in pre-schoolers, school age children and adults, 2) 
History of meconium ileus, as these individuals are at higher risk of DIOS events.  
 
Analysis of hypothesis 2a: Controlled interrupted time series: ivacaftor analysis in 
G551D criteria  
• Segmented regression (with and without lag term), and Prais-Winsten 
regression for serial correlation.  
• Impact model: downward trend (no/minimal level change)  
• Model includes: pre intervention, level change, post intervention: interaction 
with covariates (age, gender, disease status). 
o Pre intervention: no CFTR modulator (time control)  
o Post intervention: ivacaftor (minimum 6 months)  
• US 2007-2011:2012-2017  
• UK 2007-2011:2012-2017  
• Propensity score matched controls (demographic control)  
 
Analysis hypothesis 2b. Interrupted time series: lumacaftor/ivacaftor analysis in US 
F508del subgroup.  
• Hypothesis, downward trend no lag.  
• Pre intervention no CFTR modulator: (time control)  
• Post intervention: lumacaftor/ivacaftor, minimum 6 months  
• US 2007-2014:2015-2017  
• Propensity score matched controls (demographic control)  

 
 
 
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This protocol is confidential and the property of the University of Nottingham. No part of it may be 
transmitted, reproduced, published, or used by others persons without prior written authorisation 
from the University of Nottingham 
• Parallel plot of UK F508del homozygous subgroup (indirect genotype control) 
 
 
Objective 3: Determine the effect of CFTR modulators on DIOS and PERT: 
patient-level time series 
This will focus on patient level associations to complement the registry level findings. 
We will specify explore associations in the incidence of PERT usage and DIOS 
events between 2012 and 2017 in individuals with CFTR modulators, compared to 
propensity matched controls. 
• UK 2012-2017 & US 2012-2017 separately  
o Exposure: ivacaftor (minimum 6 months) vs No modulator (matched) 
• Secondary comparator: ivacaftor alone and lumacaftor/ivacaftor 
(US only)  
• DIOS events:  
o Outcome: Patient-level annualised DIOS event counts  
o Multilevel Poisson Regression model for count data (or negative 
binomial) by year  
• Incidence rate ratio (frequency of DIOS events)  
• Adjusted analysis for main covariates (DAG – Fig 2), also include 
history of DIOS as pre-exposure time will not be modelled. 
o Contingency table with χ²/fisher if insufficient events for modelling. 
• PERT usage:  
o Outcome: Patient-level annualised PERT dosage standardised by weight  
• Secondary: decreased PERT usage vs continued/increased 
o Multilevel linear regression for continuous data  
• Secondary: multilevel logistic regression for dichotomised data 
• Adjusted for main covariates (DAG – Fig 2), also include history of 
DIOS as pre-exposure time will not be modelled.  
• Sensitivity analyses  
o CFTR modulator start year excluded, finite distributed lag (1-3 years).  
o Long run propensity (cumulative 0-3 years), cumulative modulator 
exposure. 
 
 
Sample size and justification 
N/A.- registry study  
 
 
 
ADVERSE EVENTS 
 
This is a registry study therefore there is no individual participant interaction and as 
such no associated risk or burden for participants in the study. Patient’s data will be 
provided as anonymised data and therefore patient confidentiality will be maintained.  
 

 
 
 
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CFTR MAGIC Protocol Draft Version  0.1 Final Version 1.0    date 01/09/21 
 
 
This protocol is confidential and the property of the University of Nottingham. No part of it may be 
transmitted, reproduced, published, or used by others persons without prior written authorisation 
from the University of Nottingham 
ETHICAL AND REGULATORY ASPECTS 
ETHICS COMMITTEE AND REGULATORY APPROVALS 
Requests for the data required the approval of the UK CF Trust Registry Steering 
Committee after reviewing of the programme development grant aims, analysis and 
plan for publication of results. In the US, the request for registry data was reviewed 
and approved by the Patient Registry/Comparative Effectiveness Research 
Committee and was subject to peer review. 
The data will be provided from the registries as anonymised data so the individuals 
cannot be identified. Specifically, the CF Foundation requires that no individually 
identifiable information from the CF Foundation Patient Registry shall be included in 
publications and other written products and data must be presented in the aggregate. 
Both US and UK registries require that all tables or presentation of the data generated 
from registry data should include a patient count of five or more in each cell and any 
values less than 5 should be represented as <5. 
 
The registry study will not be initiated before the protocol, data management plan and 
application form have received approval / favourable opinion from the University of 
Nottingham ethics committee. Should a protocol amendment need to be made that 
requires ethical approval, the changes in the protocol will not be instituted until the 
amendment have been reviewed and received approval / favourable opinion from the 
REC. Minor protocol amendments only for logistical or administrative changes may be 
implemented immediately; and the REC will be informed. 
 
 
INFORMED CONSENT AND PARTICIPANT INFORMATION 
N/A – individual informed consent as part of the CFTR MAGIC study is not required. 
As described in detail in the Consent Section above PwCF have given explicit consent 
to their usual CF teams for their demographic, clinical care, and health outcomes data 
to be submitted to either the UK or US CF registries.15, 16  Written consent is gained 
from pwCF or their parent/ legal guardian and as part of this they are made aware that 
the information may be used for research purposes.   
 
 
RECORDS  
Case Report Forms  
N/A – this is a registry study therefore no individual participant involvement or 
requirement for CRFs.  
 
Source documents  
No new data collection will be necessary within this project. Existing data will be 
provided by the US and UK CF registries. Data for the registry study will be provided 
by the CF Trust (UK) and CF Foundation (US). Requests for the data required the 
approval of the UK CF Trust Registry Steering Committee Patient 

 
 
 
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This protocol is confidential and the property of the University of Nottingham. No part of it may be 
transmitted, reproduced, published, or used by others persons without prior written authorisation 
from the University of Nottingham 
Registry/Comparative Effectiveness Research Committee in the US. Only research 
staff involved in the study shall have access to the registry data and analysis.  
 
Direct access to source data / documents 
The study data and associated documents shall made be available at all times for 
review by the Chief Investigator and inspection by relevant regulatory authorities.  
 
DATA PROTECTION  
All data will be stored on a secure dedicated web server. Access will be restricted by 
user identifiers and passwords (encrypted using a one way encryption method). 
Information about the registry will be treated confidentially in the same way as all other 
confidential medical information. Electronic data will be backed up every 24 hours to 
both local and remote media in encrypted format. 
 
Access to data file locations on university servers is granted only by written request 
from a senior manager and limited to research staff and PhD students where required. 
Access to secure data file locations is managed by University of Nottingham IT services 
and accessed by university username and password. The Chief Investigator and 
researchers will be aware of their professional duty to maintain confidentiality at all 
times. All data stored on University Servers is backed up by University of Nottingham 
I.T. Services on a daily basis.  
 
The University of Nottingham licences Microsoft OneDrive, an ISO 27001 information 
security management compliant service for storage of working data. We will use this 
for the storage and backing up of data. Both registries require the data to be stored on 
a secure encrypted network.  OneDrive will allow for the secure and controlled sharing 
of data amongst relevant members of the research team. Any off site working with the 
data will be backed up and stored on the University of Nottingham OneDrive as soon 
as possible.  
 
 
QUALITY ASSURANCE & AUDIT  
 
INSURANCE AND INDEMNITY 
N/A – registry study  
 
DATA CONDUCT 
Procedures for the collection and analysis of data for the registry may be subject to 
systems audit for inclusion of essential documents; permissions to conduct the study; 
CVs of registry staff and training received; local document control procedures; 
adherence to procedures defined in the protocol (e.g. inclusion / exclusion criteria) and 
accountability of registry materials.  
 

 
 
 
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This protocol is confidential and the property of the University of Nottingham. No part of it may be 
transmitted, reproduced, published, or used by others persons without prior written authorisation 
from the University of Nottingham 
REGISTRY DATA  
The chief investigator, or where required, a nominated designee shall carry out 
monitoring of the data as an ongoing activity. Evidence of monitoring and systems 
audits will be made available for inspection by the REC as required. 
Monitoring of registry data shall include source data verification; data storage and data 
transfer procedures; local quality control checks and procedures, back-up and disaster 
recovery of any local data and validation of data manipulation.  
 
 
RECORD RETENTION AND ARCHIVING 
In compliance with the ICH/GCP guidelines, regulations and in accordance with the 
University of Nottingham Code of Research Conduct and Research Ethics, the Chief 
or local Principal Investigator will maintain all records and documents regarding the 
conduct of the registry data. Specific requirements from both registries require that 
data be destroyed at the end of the study period and therefore will not be archived.  
 
Specific requirements are as follows;  
The CF foundation requirements;  
The CT Foundation considers the project to be complete after 3 years. After this time 
data files and any copies of the files must be destroyed and the CF foundation provided 
with written confirmation of destruction of the data and completion of the project or 
provide sufficient justification for continuation of the project. The CF Foundation 
maintains copies of all data sets sent to researchers, and can provide the data again 
if required for auditing purposes. The US registries requires the following statement to 
be included when submitting a manuscript to a journal.  
 
Data are available upon request through the Cystic Fibrosis Foundation Patient 
Registry/ Comparative Effectiveness Research Committee. You can contact the 
committee at datarequests@cff.org. Restrictions on access to data are to ensure 
patient privacy for all persons in the CF Foundation Patient Registry. 
 
 
 
The CF Trust requires all data to be destroyed at the end of the project and that all 
data forms must be permanently deleted/destroyed within 12 months of the date of 
supply unless approval has been granted by the UK CF Registry Research Committee.  
 
DISCONTINUATION OF THE DATABASE BY THE SPONSOR  
N/A 
 
STATEMENT OF CONFIDENTIALITY  
There is no individual participant recruitment or involvement in this study and as such 
the risk of participant identification if low. Both US and UK registries require that all 
tables or presentation of the data generated from registry data should include a patient 
count of five or more in each cell and any values less than 5 should be represented as 
<5 to prevent patients being identified through the data. The data custodian is the Chief 

 
 
 
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CFTR MAGIC Protocol Draft Version  0.1 Final Version 1.0    date 01/09/21 
 
 
This protocol is confidential and the property of the University of Nottingham. No part of it may be 
transmitted, reproduced, published, or used by others persons without prior written authorisation 
from the University of Nottingham 
Investigator. Data will not be shared outside the research team without prior approval 
from the US and UK registries.  
 
 
PUBLICATION AND DISSEMINATION POLICY 
 
On completion of the study, the data will be analysed, tabulated and a Final Study 
Report prepared. Funders will be acknowledged within the publications but do not 
have any rights for review or approval of data for publication.   As research data will 
be provided by the UK and US CF registries, these will be cited in any future 
publications as directed by the registries as follows;  
 
CF Trust specific requirements;  
The CF Trust will be acknowledged in publications using the following citation “UK CF 
Registry. Cystic Fibrosis Trust, 2019” and a copy of the publication also shared with 
them. On completion of the study we will provide outputs of the study to the CF Trust.  
 
CF foundation requirements;  
The CF foundation require annual updates on the project until completion and 
encourages dissemination of the work at professional conferences. Prior to the 
submission of abstracts, poster presentations, and manuscripts, a copy will be sent to 
datarequests@cff.org for review and approval by the CF Foundation and/or members 
of the Patient Registry/CER Committee. Seven days for review of abstracts or poster 
presentations, and 30 days to review manuscripts is required. In addition, once the 
manuscript is accepted by a scientific organisation, a copy of the paper shall be 
forwarded to datarequests@cff.org on notice of such acceptance, along with the name 
of the publication. When abstracts, exhibits, invited papers, or manuscripts are 
prepared using CFFPR data, the work must include the following acknowledgment:  
 
The authors would like to thank the Cystic Fibrosis Foundation for the use of CF 
Foundation Patient Registry data to conduct this study. Additionally, we would like to 
thank the patients, care providers, and clinic coordinators at CF centres throughout the 
United States for their contributions to the CF Foundation Patient Registry. 
 
At the end of the study we will also hold an online dissemination event for pwCF in 
addition to preparing a lay summary of outcomes and also disseminating the results 
via social media accounts. 
 
USER AND PUBLIC INVOLVEMENT 
 
This study is in response to a James Lind Alliance Priority Setting Partnership for CF.8  
“How can we relieve gastrointestinal symptoms, such as stomach pain, bloating and 
nausea in people with Cystic Fibrosis” was ranked the 2nd most important research 
priority amongst pwCF, their families and healthcare professionals. CARDS-CF has 
had patient and public involvement throughout its design process. A co-applicant 
central in the development of CARDS-CF is a person with CF.  She will have continued 
involvement and will sit on the management group for CFTR MAGIC as well as 
workstream 1.   

 
 
 
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CFTR MAGIC Protocol Draft Version  0.1 Final Version 1.0    date 01/09/21 
 
 
This protocol is confidential and the property of the University of Nottingham. No part of it may be 
transmitted, reproduced, published, or used by others persons without prior written authorisation 
from the University of Nottingham 
 
REGISTRY FINANCES 
 
Funding source  
This study was funded by the NIHR programme development grant. Reference 
number PDG NIHR202952 
 
Participant stipends and payments 
n/a – registry study  
 
 
 
 

 
 
 
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CFTR MAGIC Protocol Draft Version  0.1 Final Version 1.0    date 01/09/21 
 
 
This protocol is confidential and the property of the University of Nottingham. No part of it may be 
transmitted, reproduced, published, or used by others persons without prior written authorisation 
from the University of Nottingham 
SIGNATURE PAGES 
 
Signatories to Protocol: 
 
Chief Investigator: (name) Prof Alan Smyth 
 
 
Signature: 
 
 
 
Date: 1/9/21 
 
 
 

 
 
 
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CFTR MAGIC Protocol Draft Version  0.1 Final Version 1.0    date 01/09/21 
 
 
This protocol is confidential and the property of the University of Nottingham. No part of it may be 
transmitted, reproduced, published, or used by others persons without prior written authorisation 
from the University of Nottingham 
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Elborn JS. Cystic fibrosis. Lancet. 2016. 388(10059):2519-31,  
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Singh VK, Schwarzenberg SJ. Pancreatic insufficiency in Cystic Fibrosis. J Cyst 
Fibros. 2017. 16 Suppl 2:S70-s8,  
4. 
Corey M, McLaughlin FJ, Williams M, Levison H. A comparison of survival, 
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Davies G, Rowbotham NJ, Smith S, Elliot ZC, Gathercole K, Rayner O, et al. 
Characterising burden of treatment in cystic fibrosis to identify priority areas for 
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Tabori H, Arnold C, Jaudszus A, Mentzel HJ, Renz DM, Reinsch S, et al. Abdominal 
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Smith S, Rowbotham N, Davies G, Gathercole K, Collins SJ, Elliott Z, et al. How can 
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Rowbotham NJ, Smith S, Leighton PA, Rayner OC, Gathercole K, Elliott ZC, et al. 
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Houwen RH, van der Doef HP, Sermet I, Munck A, Hauser B, Walkowiak J, et al. 
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Cystic Fibrosis Foundation Patient Registry. 2019 Annual Data Report2019. Available 
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Middleton PG, Mall MA, Dřevínek P, Lands LC, McKone EF, Polineni D, et al. 
Elexacaftor-Tezacaftor-Ivacaftor for Cystic Fibrosis with a Single Phe508del Allele. N 
Engl J Med. 2019. 381(19):1809-19,  
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Bessonova L, Volkova N, Higgins M, Bengtsson L, Tian S, Simard C, et al. Data 
from the US and UK cystic fibrosis registries support disease modification by CFTR 
modulation with ivacaftor. Thorax. 2018. 73(8):731-40,  
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Kalaitzis IS, Rowbotham NJ, Smith SJ, Smyth AR. Do current clinical trials in 
cystic fibrosis match the priorities of patients and clinicans? A systematic review. J Cyst 
Fibros. 2020. 19(1):26-33,  
14. 
European Medicines Agency. Report on Enpr-EMA workshop on gastrointestinal (GI) 
outcome measures to evaluate CFTR modulators for the treatment of cystic fibrosis 
(CF).2016. Available from: https://www.ema.europa.eu/en/documents/report/report-european-
network-paediatric-research-european-medicines-agency-workshop-gastrointestinal-
gi_en.pdf. 
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Cystic Fibrosis Trust. UK CF Registry privacy notice: Cystic Fibrosis Trust,; 2021 
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Cystic Fibrosis Foundation. Privacy Statement: Cystic Fibrosis Foundation, ; 2021 
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