Assessment of Contraceptive Safety and Effectiveness in Cystic Fibrosis: A Retrospective Analysis
Conditions: Cystic Fibrosis, Contraception
Sponsor: University of Washington

CASE.4.CF Study Protocol 
 
 
 
 
 
 
 
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Title: Assessment of Contraceptive Safety and Effectiveness in Cystic Fibrosis: A Retrospective Analysis 
 
Short title: CASE.4.CF Study (Contraceptive Assessment of Safety and Efficacy) 
Study Protocol Version: 16, 2020.07.20 
ClinicalTrials.gov: NCT04568980, Protocol ID: STUDY00008095 
 
Co-Principal Investigator: Emily Godfrey, MD, MPH 
Departments of Family Medicine and Obstetrics and Gynecology 
University of Washington 
 
Co-Principal Investigator: Moira L. Aitken, MD 
Division of Pulmonary, Critical Care and Sleep Medicine 
Department of Medicine 
University of Washington 
 
 

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Abbreviations: 
ARF=Acute renal failure 
DEXA/DXA=dual-energy x-ray absorptiometry (bone densitometry) 
BMD=bone mineral density 
BMI=Body Mass Index 
CDC-Centers for Disease Control and Prevention 
CFFPR=Cystic Fibrosis Foundation Patient Registry 
CFQ-R=CF questionnaire-revised 
DMPA=depo-medroxyprogesterone acetate 
FDA=Food and Drug Administration 
FEV1= Forced Expiratory Volume in the first second 
ppFEV1=percentage of predicted FEV1 
eGFR=estimated glomerular filtration rate 
OCP=oral contraceptive pills 
OTC=over-the-counter 
IUD=intrauterine device 
LEEP=Loop electrosurgical excision procedure (to treat abnormal cell growth on the surface tissue of the cervix) 
MDR=multi-drug resistant 
MSSA=methicillin-sensitive Staph aureus 
MRSA=methicillin-resistant Staph aureus 
NTM=nontuberculous mycobacteria  
USMEC=United States Medical Eligibility Criteria for Contraceptive Use 
WHO=World Health Organization 
 

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1.0. Summary 
This proposal, originally submitted to the Cystic Fibrosis Foundation (CFF) Spring 2019, has been changed at the 
recommendation of the CFF to reflect a retrospective approach to determine safety and efficacy of contraception among 
up to 625 women of reproductive age with cystic fibrosis (CF). In planning for this retrospective approach, the University 
of Washington (UW) study team determined that the optimal way to collect contraceptive use data would be through 
patient self-respondent approach, since the Cystic Fibrosis Foundation Patient Registry (CFFPR) does not collect 
information on contraception, and electronic medical records (EMR) often have inaccurate information about 
contraceptive use and do not include over-the-counter (OTC) methods. Given the critical nature of collecting exposure 
(contraceptive) data for this retrospective approach, the UW study proposed using the first year to pre-test self-
respondent questions with up to 50 women with CF. The purpose of this pilot survey is to determine the best approach 
to collect reproductive health information due to the sensitive nature of questions on the topics of contraceptive use, 
pregnancy, and menstruation. We will determine if responses about past contraceptive use are more complete when 
the survey is administered or when respondents answer questions on their own at home using an online survey.  
Once the pilot phase is complete, we propose to conduct a retrospective observational cohort study of up to 625 
women with cystic fibrosis aged 18-45 years at time of enrollment. Participants will be recruited from 10 separate CF 
centers. Participants will be recruited for the study from their CF center through email, postal service, or in-person 
contact. CF center research staff will inform interested patients about the study, check that the patient has a CFFPR ID 
number, and pass along the patient names, email addresses, and CFFPR number to the UW study team who will 
determine eligibility. If the potential participants meet enrollment criteria, they will be consented on-line, and continue 
to the online survey that they can complete at home. The self-reported data will be linked with CFFPR objective 
pulmonary data to examine the association of hormonal contraceptive use on pulmonary health, outcomes related to 
CF-liver dysfunction (CFLD), nutritional status, and venous/arterial thromboembolism. The UW study team will work 
with each of the 10 separate CF centers to provide a select number of dual energy X-ray absorptiometry (DXA) scan bone 
mineral density test scores from their center’s EMR, which will be used to validate bone health information in the CFFPR. 
 
2.0. Background/Rationale 
Family planning decisions are increasingly important for women with CF as most reach reproductive age in reasonable 
health. As CF care management and directed therapies advance, the number of women with CF in the US over age 18 
has nearly doubled over the last 15 years: from 4,000 to 7,200. The CFF has an existing comprehensive patient registry, 
the CFFPR, which captures annual data on over 90% of all persons with CF in the US (1). While it is comprehensive 
regarding most aspects of CF patients’ health, the CFFPR currently only asks one question that addresses reproductive 
health for women over 18 living with CF: “Was the patient pregnant during the reporting year?”.  
Reliable information is urgently needed to enable healthcare providers to help CF women understand the effectiveness 
and safety of current contraceptive methods for them. While infertility usually affects men with CF, at least 50% of 
women with CF are estimated to be physiologically capable of becoming pregnant without fertility treatment (2); 
however, that percentage is expected to rise with the use of new life sustaining medications, such as the CFTR 
modulators and especially the newly Food and Drug Administration (FDA)-approved triple-combination modulator, 
TRIKAFTA® (3).   
Our recently completed survey study among 150 women at three CF centers, suggests that only about 60% of 
reproductive–aged women with CF are using contraception (4). Among those who are, oral contraceptive pills (OCPs) 
and condoms are the most commonly reported methods. Gaps in quality contraceptive care for women with CF exist, in 
part because, surprisingly, women with CF prefer to receive their sexual health care within the CF clinics, but many CF 
providers do not feel prepared to deliver safe and detailed contraception care (5). This information gap is exacerbated 
by the limited data which exist to inform contraceptive care provision for women with CF. In fact, most studies 
evaluating contraceptive safety are limited to oral contraceptive pills, even though the number of choices of FDA-

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approved contraceptives has increased significantly since 2001, especially with the FDA-approval of hormonal long-
acting reversible contraceptive methods. In today’s U.S. market, two types of hormonal contraceptives exist: estrogen-
and-progestin-containing methods (a.k.a. combined hormonal methods) and progestin-only methods. Within the 
estrogen-containing methods, contraceptive choices include oral pills and non-oral methods, such as the transdermal 
patch and vaginal ring. Within the progestin-only methods, contraceptive choices include four different hormonal 
intrauterine devices (IUD), a subdermal implant, a 3-month injectable depo-medroxyprogesterone acetate (DMPA), and 
progestin-only oral pills  
The most recent edition of the national contraceptive guidance for women with medical conditions called the United 
States Medical Eligibility Criteria for Contraceptive Use (USMEC), was released in 2016 by the Centers for Disease Control 
and Prevention (CDC), which lists CF as a chronic health condition (6). The USMEC lists all hormonal methods safe to 
prescribe without restrictions (USMEC = 1), except the 3-month injectable, depot-medroxyprogesterone acetate 
(DMPA). DMPA is listed as USMEC = 2, in which the advantages of using the method in a woman with CF generally 
outweighs the theoretical or proven risks because of concerns about DMPA on bone health. Despite these national 
recommendations, the data for women with CF and hormonal contraception are limited. Potential complications for CF 
patients include decreased pulmonary function, CF-related diabetes (CFRD), CFLD, increased gallbladder disease, 
decreased nutritional status, increased venous thromboembolism and poor bone health. There are theoretical concerns 
that hormonal contraception may adversely impact these complications. Another concern is the reduced efficacy of 
hormonal contraception, specifically oral contraceptive pills with concomitant use of CFTR modulators.  
The definitions for normal bone, osteopenia, and osteoporosis are based on bone mineral density (BMD) scores. BMD is 
measured by dual energy X-ray absorptiometry (DXA), which provides both T-scores and Z-scores. These scores are used 
to define whether a person is categorized as having osteoporosis, osteopenia, or normal bone. According to the World 
Health Organization (WHO), the T-score is the number of standard deviations (SD) above (+) or below (-) the mean BMD 
in a young, normal, sex-matched population and is preferred for postmenopausal women. The Z-score is the number of 
standard deviations (SD) above (+) or below (-) the mean bone density in a normal, sex- and age-matched population 
and is preferred in females prior to menopause (7). In contrast to WHO criteria, the CFF uses Z-scores for children less 
than 18 years, considers T- and Z-scores as nearly equivalent for persons between ages 18-30 years, and uses T-score 
findings for persons with CF ages 30 years and older (8).  
Our project is specifically designed to collect more information on these critically important issues by expanding our 
pilot contraceptive CFFPR study and further assess the safety and efficacy of contraception among patients with CF. 
With pilot funding from the Society of Family Planning, Drs. Godfrey, Aitken, and Heltshe collaborated with two other CF 
centers to assess feasibility, data completeness, and data accuracy of a pilot contraceptive registry. Having successfully 
linked women with CF’s self-reported information on current and prior contraceptive use with clinical data information 
obtained from the CFFPR, we are now ready to expand our work to include seven additional CF Centers for a total of ten 
centers (see Table 2).  
The research questions we aim to answer for women with CF, aged 18-45 years in this retrospective study include:  
(1) Are estrogen-containing or progestin-only hormonal contraceptives associated with improved objective 
pulmonary symptoms compared to women with CF who use non-hormonal methods (control)?  
(2) Are estrogen-containing or progestin-only hormonal contraceptives associated with increased incidence of CF-
related liver disease (as noted with increasing trend of liver enzyme tests), gallbladder disease or 
thromboembolism? 
(3) Are estrogen-containing or progestin-only hormonal contraceptives associated with increased serum glucose 
trends (as measured by oral glucose tolerance testing) compared to women using non-hormonal methods?  
(4) Does hormonal contraceptive use affect nutritional status for women with low body mass index? 

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(5) What is the percent agreement between CF Clinic DXA scan T-scores and CFFPR data about osteoporosis, 
osteopenia and bone fracture? 
(6) Are women who use CFTR modulators and more likely to become pregnant unintentionally while taking 
hormonal contraception (compared to women on non-hormonal contraception)?  
(7) Does use of hormonal contraception result in a higher proportion of patients with mucoid vs. non-mucoid 
Pseudomonas aeruginosa compared to non-hormonal contraceptive users? 
 
3.0. Hypothesis 
• 
Estrogen-containing methods, but not progestin-only methods, reduce the annual rate of pulmonary 
exacerbations, the microorganisms associated with a more rapid decline in lung function, and improve ppFEV1 
(or absolute FEV1) of women with CF when compared to women with CF who use non-hormonal contraception 
(control group).  
• 
Estrogen-containing oral methods of birth control are associated with higher incidence of gallbladder disease 
(defined as gallstones, requiring surgery), increased liver function enzyme values, and/or increased incidence of 
thromboembolism among women with CF.  
• 
Both estrogen-containing and progestin-only hormonal methods improve BMI among women with CF, which is 
linked to nutritional status. 
• 
The strength of agreement between DXA scan T-scores and CFFPR data about osteoporosis, osteopenia and 
bone fracture will be “substantial.” 
• 
The effectiveness of oral birth control is reduced compared to other methods of hormonal birth control in the 
presence of CFTR modulator use.  
• 
Hormonal birth control use results in a greater proportion of patients with mucoid Pseudomonas aeruginosa, in 
patients who are P. aeruginosa positive, compared to non-hormonal contraceptive users. 
 
4.0. Study Objectives  
4.1. Primary Study Objective 
• 
To assess the association of hormonal contraceptive use on frequency of pulmonary exacerbations, compared to 
non-hormonal contraceptive users (primary control) and non-contraceptive users (secondary control). 
4.2. Secondary Study Objectives/Endpoints 
• 
To assess the association of hormonal contraceptive use on trends in lung function (FEV1) over time, compared 
to non-hormonal contraceptive users (primary control) and non-contraceptive users (secondary control). 
• 
To assess the association of hormonal contraceptive use on the incidence of venous or arterial 
thromboembolism. 
• 
To assess the association of hormonal contraceptive use on prevalence of liver dysfunction, defined as 
gallstones (requiring surgery), hepatic steatosis, hepatic cirrhosis, and/or incidence of increased liver enzyme 
test values (ALT/GGT). Increased liver enzymes is defined as exceeding upper limit of normal on at least 3 
occasions over 12-month period. 
• 
To assess the association of hormonal contraceptive use on serum glucose trends, incidence of insulin resistance 
or time to CF-related diabetes (requiring insulin treatment). 

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• 
To assess association of hormonal contraceptive use on nutritional status through the evaluation of BMI trends. 
• 
To validate bone health information in CFFPR with chart data obtained from one CF center (limited due to need 
for data use agreements between institutions for EMR data). 
• 
To determine if those using hormonal contraception while using CFTR modulators report higher rates of 
unintended pregnancy compared to those taking non-hormonal contraception.  
• 
To assess proportion of mucoid P. aeruginosa, in patients who are P. aeruginosa positive, among hormonal 
contraception users compared to non-hormonal contraceptive users. 
 
5.0. Trial Design  
This is a non-randomized, non-interventional, observational cohort design among reproductive-aged women (ages 18-45 
years) with CF. This protocol describes a pilot phase, as well as a larger retrospective approach.  
We intend to ask about 625 female participants to provide information about their types of past contraceptive use from 
2008 through the most recent data available from CFFPR (2018 or 2019). Before initiating our trial among up to 625 
respondents, we intend to pre-test the survey questions on our self-respondent questionnaire among as many as 50 
women with and without CF through CFF Community Voice, the Cystic Fibrosis Research, Inc. (CFRI), and the Cystic 
Fibrosis Reproductive and Sexual Health Collaborative (CFReSHC). Pre-testing our survey questions will help ensure 
contraceptive, pregnancy, and other reproductive health data from respondents for the larger phase of this study are as 
complete and accurate as possible. 
Once the survey has been piloted and revised accordingly, we will collect past contraceptive, pregnancy and other 
reproductive health data from up to 625 women at 10 different CF centers. We may over-sample by 25 participants 
because it is possible that some participants from UW, UTSW and National Jewish may have participated in our earlier 
published study related to contraceptive use and CFFPR (4). Recruiting through the CF centers will help ensure that 
women with a confirmed diagnosis of CF respond to the finalized survey. We will link respondent self-reported 
contraceptive and reproductive health data with CFFPR clinical data. We will ask for EMR data from the 10 different CF 
centers to validate DXA scan results with findings regarding osteoporosis, osteopenia, and bone fracture in the CFFPR. 
We plan to randomly select about 10 consented subjects from each of the centers for the EMR DXA scan chart review. 
Because of our need to link questionnaires and clinical case report forms correctly to the same women with CF in the 
CFFPR clinical data, we need to request identifiable information, including the CFFPR member ID number.  
 
6.0. Pilot Survey Phase 
Given the critical nature of collecting exposure (contraceptive) data for this retrospective approach, the UW study 
proposed using part of the first year of this grant to pre-test the self-respondent questions with up to 50 women with 
and without CF. The purpose of this pilot survey is to determine the best approach to collection reproductive health 
information due to the sensitive nature of question on the topics of contraceptive use, pregnancy and menstruation. 
Because this phase may affect how we collect the data in the larger phase of this work, we will simultaneously be 
refining our analysis plan as we collect, summarize, and analyze our findings during this pre-test/pilot phase.  
6.1. Pilot Recruitment 
We intend to recruit up to 50 participants through the CFF Community Voice program, CFRI, and CFReSHC. We intend to 
enroll women between the ages 18-45 years with or without CF. We have chosen the CFF Community Voice program 
because participants have already agreed to participate in research and we believe they will be forthcoming about their 
thoughts about the understandability and format of our questions seeking to gather information about past 
contraceptive use. Inclusion/Exclusion criteria for the pilot phase are listed below: 

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Table 1: Pilot phase inclusion and exclusion criteria 
Pilot inclusion criteria 
Female 
Aged between 18-45 years. 
Functional email address  
Has device capable of using Zoom 
Pilot exclusion criteria 
Receives CF care at one of the 10 collaborating CF centers 
 
6.2. Pilot Process: Please see Pilot Pre-test Survey Protocol for Details 
We will not be able to validate responses against the EMR because of research suggesting that EMR data are not 
accurate with regards to contraceptive information (9).  
6.3. Pilot Duration 
This phase is expected to take up to 5 months, depending on the number of interviewees needed for question pre-
testing. During this phase, the research coordinator (RC) will schedule and enroll participants, pre-test the questions, 
and implement feedback. We will be working closely with the Washington State University (WSU) Social and Economic 
Sciences Research Center who will provide survey development guidance, as well as the UW Social Development 
Research Group (SDRG) who will provide expertise on cognitive interviewing.  
 
7.0. Methods: Participants, Interventions, and Outcomes of Final Questionnaire Phase 
Once the questionnaire is pretested (anticipated end date of pre-testing is July 2020), the final questionnaire will be 
revised accordingly prior to initiating the full, larger study. 
7.1. Study Setting  
We intend to enroll up to 625 women, aged 18-45 years, at 10 separate CF centers. We may over-enroll the sample by 
25 women to account for women who may have participated in the prior contraceptive study in 2017. This will allow us 
to perform a sensitivity analysis excluding women who participated in the pre-study, while maintaining study power.  
Table 2: Study sites and anticipated number of eligible participants 
Name of Institution 
Institution PI(s) 
Number of women with 
CF aged 18-45 years 
University of Washington 
Emily Godfrey, MD, MPH 
Moira Aitken, MD 
141 
University of Texas Southwestern 
Raksha Jain, MD, MS 
140 
National Jewish Hospital 
Jennifer Taylor-Cousar, MD, MS 
233 
University of California San Diego 
Douglas Conrad, MD 
Sheila Mody, MD, MPH 
120 
University of Pittsburgh 
Traci Kazmerski, MD, MS 
106 
University of Pennsylvania 
Denis Hadjiliadis, MD 
Andrea Roe, MD, MPH 
128 
John’s Hopkins University 
Natalie West, MD, MPH 
159 
University of Alabama 
Marty Solomon, MD 
Sigrid Ladores, RN 
Leigh Ann Bray RN 
135 

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Name of Institution 
Institution PI(s) 
Number of women with 
CF aged 18-45 years 
Harvard U/Boston 
Ahmet Uluer, MD 
189 
Mount Sinai 
Patricia Walker, MD 
51 
 
We anticipate that each site will be able to enroll 50% of eligible women ages 18-45 years into the study. We have 
chosen the lower age range because of estimated age of sexual debut among young women with CF is between ages 
16-17 years (5) and it is expected that some women aged 18 will have started using contraception. We have chosen the 
upper age range of 45 years because of the lower life expectancy of women with CF compared to the general 
population and inherent bias that adults with CF who live past the currently life expectancy are most likely healthier 
than younger adults with CF (10). 
Table 3: Age distribution goals for study enrollment 
Age Distribution of Women with CF 
Age Range (years) 
Approximate number of subjects planned 
18-35 
383 
36-45  
192 
 
7.1.1. Study Duration 
Participant enrollment will take approximately 15 months for the finalized survey phase.  
7.2. Eligibility Criteria  
The study population will be women with CF who have used any form of contraception for protection against pregnancy 
or for treatment of dysmenorrhea, pelvic pain, abnormally heavy or prolonged menstrual bleeding, excessive uterine 
bleeding, endometriosis, acne, or amenorrhea.  
Table 4: Full study inclusion and exclusion criteria 
Inclusion Criteria 
Females ages ≥ 18 and < 46 years at enrollment 
Confirmed patients at one of the 10 participating CF centers (has been seen at least one time for a face-to-face 
office visit at the CF center in the last 2 years) 
CFFPR participant (noted as having a CFFPR ID number) 
Has internet access  
Has a functioning email addresses or may create a functioning email address at enrollment 
Willing to consent to obtain request of their identified data from CFFPR  
Willing to consent to their CF center to provide data related to contraceptive medication and DXA scan test results 
as far back as 2013 in clinic EMR  
Exclusion Criteria 
Not in CFFPR 
Non-functioning email address 
History of organ transplant 
Participant in pre-test phase of this study 
 
7.2.1. Informed Consent 
By obtaining informed consent from participants, the UW study team shall: 

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• 
Avoid any coercion of or undue influence to participate 
• 
Sustain the candidate’s legal rights 
• 
Provide complete, detailed description of study, intent to link survey information with participant’s clinical 
information in the CFFPR, follow up and costs/reimbursements using language that is non-technical and 
understandable to the participant 
• 
Ensure the participant understands the risks and responsibilities 
• 
Include contact information of the principal investigator and study site investigator 
• 
Ensure protection of the participant’s confidentiality 
7.2.2. Enrollment 
The participant is considered enrolled into the study after providing written consent and is found eligible based on 
history, eligibility screening questions, and confirmation as a participant in the CFFPR. Eligible consented participants 
who withdraw consent for any reason before completing the survey are considered screen failures. Eligible consented 
participants who cannot be verified as a participant in the CFFPR with a CFFPR ID number (confirmed by respective CF 
center) will be considered a screen failure.  
 
7.3. Interventions 
We will provide an online questionnaire to give to female participants in order to obtain exposure data (past 
contraceptive use). We will have participants complete the survey on their own, either in clinic or at home. The survey 
will include pictures, brand names, and descriptions to help respondents remember birth control method used 
retrospectively.  
We will ask each CF center to provide DXA scan results for 10 participants (selected at random) from their respective 
EMRs in order to validate osteoporosis, osteopenia and bone fracture information in the CFFPR.  
7.3.1. Treatment  
N/A 
7.4. Interventions: Modifications  
N/A.  
7.5. Outcomes (include DAG diagrams to show relationships between exposure and outcomes) 
Table 5: Outcomes and associated confounders and covariates 
Exposure of 
interest  
Outcome 
Confounders/Covariates 
Rationale 
Combined 
hormonal 
contraception 
(CHC) 
 
&  
 
Progestin-only 
contraception 
 
Pulmonary outcomes 
• 
Annual pulmonary 
exacerbation rate (PEx) 
(defined as episodes 
requiring intravenous 
antibiotic use at home or in 
hospital) 
• 
Absolute change in FEV1 (in 
liters) 
Prevalence of micro-organism 
(defined as 1 or greater sputum 
culture within a 12-month period) 
•  P. aeruginosa 
Smoking 
Affects lung function 
Insurance status (reflection of 
SES) 
Will be used as 
socioeconomic 
indicator. Less access to 
meds may mean less 
compliance 
Age 
Lung function worsens 
as one ages 
Education (reflection of SES) 
Affects contraceptive 
knowledge decision 
making 
BMI 
Associated with better 
or worse health status in 
general 

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Exposure of 
interest  
Outcome 
Confounders/Covariates 
Rationale 
• MDR P. aeruginosa  
• Staph aureus 
• MSSA  
• MRSA  
Secondary infections: 
• Burkholderia cepacia 
• Burkholderia cenocepacia  
• Mycobacterial species –includes 
M. tuberculosis and NTM species  
Exercise 
May reduce pulmonary 
exacerbation rates 
CF genotype class 
Associated with severity 
of disease 
CFTR modulator treatment 
Likely preserves 
pulmonary decline 
Comorbidity with CFRD (defined 
as requiring chronic insulin 
therapy) (11) 
Associated with worse 
disease (reduced 
immunity) 
 
Length of hormonal 
contraceptive use (person-year 
of exposure) 
 
 
 
 
Venous/arterial thromboembolism 
(VTE) 
BMI ≥ 30 
 
• 
Noted on self-respondent 
survey (defined as blood clot 
requiring anticoagulation 
treatment) 
Age > 35 years 
 
PMHx for thrombophilia 
 
Arterial/venous lines or ports 
 
Pmhx cancer 
 
Smoking 
 
 
 
 
Liver outcomes 
• 
Liver disease, non-cirrhosis 
• 
Gallstone, requiring 
surgery/procedure (defined 
as present or absent as 
recorded in CFFPR) 
 
BMI 
Obesity contributes to 
liver dysfunction 
Comorbidity with diabetes 
Associated with worse 
disease (reduced 
immunity) 
Hepatitis 
Risk factor for liver 
dysfunction 
CF genotype class 
 
Length of hormonal 
contraceptive use (person-year 
of exposure) 
 
• 
Serum ALT, GGT (meets 
criteria if hepatic 
transaminases and GGT 
levels exceed upper limit of 
normal on at least 3 
consecutive occasions over 
12-month period) (12) 
 
Will track meeting 
criteria annually over 
time 
 
 
 
CF-related diabetes 
 
 
• 
Serum ogtt trends 
 
 
• 
New onset insulin resistance 
or diabetes (defined as 
 
 

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Exposure of 
interest  
Outcome 
Confounders/Covariates 
Rationale 
present or absent as 
recorded in CFFPR) 
 
 
 
Nutritional status 
• 
Change in BMI 
CF genotype class 
 
CF-specific vitamins (Fat 
soluable A, D and E) (defined as 
present or absent as recorded in 
CFFPR) 
 
Taking any pancreatic enzyme 
replacement therapy (noted 
under medications in CFFPR) 
 
CFTR modulator use (will stratify 
by type of modulator) 
 
 
 
 
Bone outcomes 
• 
Osteoporosis, fragile bone 
fracture 
Length of oral steroid use 
(person-months of use) 
Contributes to bone 
weakening 
Comorbidity with pancreatic 
insufficiency 
Reduced Vit D/Calcium 
absorption 
Exercise 
Help prevents 
osteoporosis 
Age 
Known risk factor for 
osteoporosis 
BMI 
Reduced BMI is a risk 
factor for osteoporosis 
CF genotype class 
 
Length of hormonal 
contraceptive use (person-year 
of exposure) 
 
Smoking 
Known risk factor for 
osteoporosis 
 
7.6. Participant Timeline – Full Study  
7.6.1. Time 0: Invitation to inquire about enrolling in the study 
Each CF center will contact eligible patients by whichever means approved by their IRB (email, phone), inviting all 
current female patients, ages 18-45 years who are participants in the CFFPR to participate in the study. Eligible patients 
will also be approached at their clinic visits. For CF centers who want the UW research team to contact eligible patients, 
they will send a list of eligible patients, email, and CFFPR member ID to the study team. 
7.6.2. Time 1 (V0): Enrollment procedure  
1. Each CF center will identify all female patients with CF, ages 18-45 years who have a CFFPR patient registry ID 
number.  
2. Each CF center will send an email with information about the study to all female patients identified in step #1. If 
they prefer the UW research team to contact eligible patients, they will send a list of eligible patients, email, and 

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CFFPR member ID to the UW, and the UW research team will send an email with information about the study to 
eligible patients. 
3. Each CF center also approach female patient identified in Step #1 when they are seen in the clinic with written 
information about the study. 
4. Interested potential participants will receive the link the online survey to complete the eligibility questions and 
consent form via email. This link will come from either the UW research team or CF center staff, depending on 
CF center preference. 
5. The potential participant will answer screening questions via the online portal to ensure eligibility.  
6. If the participant qualifies for the study, they will be consented to participate via the online portal.  
7. Once consented, the participant will move forward to the online survey itself. To help reduce recall bias, pictures 
of most birth control pill packages as well as other birth control methods will be accessible as the participant 
completes the survey. 
8. In order to maximize response rates, participants will be sent automatic reminders to complete their survey 
using REDCap reminder features. 
9. Compensation to the participant will be provided by the UW research team once survey is complete and the UW 
research team has verified that they are in the CFFPR (about 2 weeks after completion of the survey). 
10. The UW research team will receive CFFPR data, which includes whether patients have a diagnosis of osteopenia 
or osteoporosis. Among those with a positive diagnosis, the research team will randomly select 10 participants 
from each CF center, in order to compare CFFPR data to DXA scan results from CF centers. 
11. Providing DXA scan results: Once the 100 participants have been confirmed as having completed the enrollment, 
consent form, and survey by the UW research team, and CFFPR data indicates a diagnosis of osteopenia or 
osteoporosis, the UW research team will provide the appropriate CF center with a case report form (CRF), 
labelled with the participant’s survey study ID number only. The CF Center research staff will have access to a 
password protected database in REDCap that links the survey ID number with participant name and date of birth 
(for patients at their CF center only). The name and date of birth will be used for the CF Center to complete the 
case report form using the participant’s electronic medical record (EMR) data.  
12. The CF center research staff will complete the CRF that asks for DXA scan scores (from 2013 to 2018).  
a. CF research staff will report T-scores from 3 anatomical sites: femoral neck, lumbar spine and total hip.  
b. Verification with CFFPR: We will take the lowest BMD T-score reported for either the femoral neck, 
lumbar spine, or total hip when categorizing a participant as osteoporotic, osteopenia, or normal for a 
given DXA test within a given year and compare to the diagnosis of record in the CFFPR. Scores provided 
at other anatomical sites (forearm, heel, etc.) will not be considered.  
Table 6: Outline of responsibilities of clinic  
Clinic responsibilities 
 
 
 
 
Pre-enroll 
Enrollment 
Post-enroll 
Month 
0 
1-12 months 
13-15 months 
• Send invitations to participate in study, followed by phone call, and 
approach women in clinic to participate 
X 
 
 
• CF center research staff to give patient’s unique CFFPR ID number, 
name, DOB, and contact information to UW research team 
 
X 
 
• CF clinic research staff to complete case report form: 
 
 
X 

CASE.4.CF Study Protocol 
 
 
 
 
 
 
 
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Table 7: Outline of responsibilities of Study Participant (Patient) 
Participant responsibilities 
 
 
 
Pre-enroll 
Enrollment 
Month 
0 
1-15 months 
• Enroll in study 
 
X 
• Be willing to be contacted by UW research team staff member 
 
X  
• Complete smoking and blood clot questions 
 
X 
• Complete CFTR modulator questions 
 
X 
• Complete surgical history questions 
 
X 
• Complete contraception questions 
 
X 
• Complete menstrual questions  
 
X 
• Complete pregnancy history questions 
 
X 
7.6.4. Interim or Off-cycle Visits  
Because this is an online observational study, we do not anticipate any interim visits to occur that are related to 
participating in the study. 
7.6.5. Early Discontinuation  
Incomplete surveys will be excluded from the analysis. Persons who are not verified as participants in the CFFPR 
between 2010 and 2018 will be excluded.  
7.7. Sample Size 
During the pilot phase, the study team will further discuss the statistical plan to ensure adequate numbers of 
participants are enrolled in the study. Based on information from participating centers, we expect to enroll 
approximately 600 women and expect about half of them to be on hormonal contraceptives based on our pilot study. 
The following table shows the power for detecting different RRs of non-hormonal to hormonal contraceptives in women 
and baseline proportion of outcome in the non-hormonal contraceptives group.  
Table 8: Sample size calculation 
 
 
 
Total Sample Size 
Using Poisson Regression Power 
to detect a Rate Ratio 
 (hormonal / non-hormonal) 
RR=0.70 
450 
0.77 
475 
0.80 
500 
0.82 
525 
0.83 
550 
0.85 
575 
0.86 
 
o DXA scan results: dates and results as far back as 2013. Results 
will include T-scores from 3 sites: femoral neck, lumbar spine and 
total hip and year that DXA scan was performed.  

CASE.4.CF Study Protocol 
 
 
 
 
 
 
 
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Recent data following the U.S. FDA approval of genetic modulators, show that in this population (mean age 25 years) 
there are approximately 0.8 PEx/year (13). Using Poisson regression, this study will have 80% power to detect a rate 
ratio of 0.70 between the progestin-only and combined hormonal groups with 575 enrolled women with CF (assuming 
alpha 0.05 and an estimated attrition rate of 15%). Although triple therapy has already been FDA approved, we do not 
anticipate this will affect our retrospective study design since we are evaluating years prior to FDA approval of triple 
modulator therapy. 
7.8. Recruitment 
We aim to recruit up to 625 female patients ages 18-45 years across 10 CF Centers. We may enroll an additional 25 
participants to off-set participants who participated in a prior contraceptive study (4). The UW research team will ask 
each participating CF center research staff to invite all women ages 18-45 years who have been seen at their clinic 
within the last 2 years to participate in this retrospective contraceptive study. By inviting all potential qualified 
participants, we reduce selection bias of only those who physically come to the CF center on a regular basis. CF center 
research staff will send an email to all eligible women in their clinic and follow up with a phone call to recruit potential 
participants. In addition, women who come to the clinic for routine visits with their CF clinician during the first year of 
the study will be asked to enroll in the study by the CF center research staff member.  
7.8.1. Participant Incentives  
Participants will be paid for enrolling into the study and completing the questionnaire ($30). We have based this amount 
on the CFF hourly rate for research subjects of $30/hour.  
 
8.0. Methods: Assignment of interventions 
8.1. Allocation  
Participants will belong to a group based on their choice of contraception. Women with CF will be allocated to hormonal 
group (intervention), non-hormonal groups (control), and never used contraception.  
8.2. Blinding  
This is a retrospective, observational study. This trial is not blinded.  
 
9.0. Methods: Data Collection, Management, and Analysis 
9.1. Data Collection Methods 
The women with CF who are enrolled at any of the 10 CF centers will complete the contraceptive and reproductive 
health questionnaire. We will ask for exposure data as far back as 2008. One way we will improve exposure data will be 
to reduce recall bias with pictures of most birth control pill packages and other birth control methods. Exposure 
questions will be piloted as described in 6.0 above. Survey responses will be entered directly into a REDCap database 
which will be developed at UW. REDCap is HIPAA compliant and securely accessible from anywhere with Internet access, 
and feasibly merges data from separate REDCap databases into a single database. Next, UW will send the CFFPR a list of 
patient names, their birthdates, and CFFPR ID. The CFF will provide UW with their CFFPR ID and requested registry data. 
UW will assign a central ID number for each participant, so that data from each of the databases can be connected for 
analysis. We will import data from CFFPR using Excel into a REDCap database housed at UW. 
Data will be collated at the UW. When a computer is available, participants will answer directly into the database, which 
leaves less room for transposing errors. In case of technical difficulty with computer access to the REDCap website, the 
clinical site will receive paper source documents. Each survey (online and paper) will be identified by the participant's 
study number.  

CASE.4.CF Study Protocol 
 
 
 
 
 
 
 
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9.1.1. CFFPR Data Elements  
A complete list of data points being requested from CFFPR are in the Appendix. 
9.1.2. Clinic Case Report Forms (CRF) 
We are requesting CRFs from each of the 10 CF centers in order to verify DXA scan findings with bone data reported in 
the CFFPR.  
Table 9: Information sought on CRF  
EMR Data Request 
• DXA scan results: dates and results as far back as 2013. Results will include T-scores and Z-scores from 3 sites: 
femoral neck, lumbar spine, and total hip and date that DXA scan was performed. 
 
9.1.3. Patient Surveys 
Table 10: Information in online, self-respondent surveys 
Survey Once Enrolled 
• Demographics: marital status, race/ethnicity, and education  
• Past medical history: ever smoked, ever had a blood clot requiring anticoagulation, # PICC lines placed, PORT in 
place (dates) 
• Medication history: ever taken CFTR modulator (with start and stop dates)  
• Surgical history: Tubal ligation, hysteroscopic sterilization, hysterectomy, bilateral oophorectomy, other operation 
that has made it impossible to get pregnant 
• Menstrual history: menarche, regularity of menstruation, menopause 
• Contraception questionnaire 
• 
Questions regarding types of contraception used since 2008, start and stop dates of each method or age at 
first/last use. Questions are based off of the National Survey of Family Growth (NSFG) 
• Pregnancy history questionnaire  
o Includes number of pregnancies in lifetime, year(s) pregnant, outcome of pregnancy, whether pregnancy 
was planned or not 
o Additional questions to include for funded study (Taylor-Cousar and Jain): times visited CF center during 
pregnancy and type of provider who cared for participant during pregnancy, ART 
 
9.2. Data Management 
The University of Washington will have the overall responsibility of this project and will serve as the Data Coordinating 
Center. As the Data Coordinating Center, UW will create the source documents for the study and be responsible for 
creating and managing the web-based, password-protected database. Any paper copies of the survey responses will be 
maintained in locked files in a locked room.  
Participants will enter responses to the questionnaires directly into a UW Web-based program (REDCap). In case of 
technical difficulty with computer access to the REDCap website, participants will complete paper source documents. In 
order to ensure that surveys are being completed only by eligible participants, patients will be sent unique survey links 
that are connected to their email address. Therefore, if patients share the survey link with others, they can be contacted 
if there are multiple survey responses connected to their email address. 
Case Report Forms (CRFs) will be de-identified, with only the participant study ID number, and entered into REDCap, a 
web-based, password-protected database managed by UW. CF centers will have access to a separate password-

CASE.4.CF Study Protocol 
 
 
 
 
 
 
 
Page 16 of 24 
 
protected database that links the participant survey ID number with the name and birthdate of the participant, so that 
the selected CF center that is providing EMR data can complete the CRF with their institution’s EMR.  
The self-respondent contraception and reproductive history questionnaire will be entered into a separate REDCap 
database from the CRF information entered by the respective CF centers. 
The UW will create a webpage for the study where CF centers can log in and view real-time, prepared reports that show 
response rates for patients at their CF center. 
UW will send the CFFPR a list of participants and their birthdates, and CFFPR ID number. The CFF will provide UW with 
their CFFPR ID and requested registry data in Excel format. The UW will assign a central ID number for each participant, 
so that data from each of the databases can be connected for analysis.  
9.3. Statistical Methods  
Because this is a retrospective cohort study, we are most interested in determining whether this exposure (to hormonal 
contraception) is associated with our primary outcome (counting the number of pulmonary exacerbations requiring 
additional IV in a given year) and/or our secondary outcomes (new respiratory microbiology, liver disease/non-cirrhosis, 
gallstone, requiring surgery/procedure, improved BMI, incidence of VTE, osteoporosis and fragile bone fracture). 
Women on hormonal contraception will be compared to the primary control group of women on non-hormonal 
contraception. We will also compare to women on no contraception, as the secondary control group. We will exclude 
persons with these existing diagnosis at the start of the follow up period for outcome data (January 1, 2010). Within this 
objective we will be able to calculate incidence rates, relative risks and confidence intervals. We will use Poisson 
regression to calculate progestin-only and combined hormonal method to non-hormonal method pulmonary 
exacerbation rate ratios and 95% confidence intervals. This allows for adjustment of follow-up time of each individual.  
(Objective 1a): We will evaluate lab values over time (ppFEV1%, serum AST, ALT, alkaline phosphatase) to determine if 
trends between hormonal contraceptive users and non-hormonal contraceptive users differ. See Table 5 for 
confounders and covariates that we will use to adjust for the primary and secondary outcomes. 
We will model ppFEV1 via generalized estimating equations (GEE), allowing for correlation within a subject, and 
compare via a fixed effect for exposure. Among women who change or stop contraception, we will estimate and 
compare within-participant difference in outcomes via the model (if numbers allow). We will censor women who switch 
method types or become pregnant, and for 6 months post pregnancy, for the primary analysis and subsequently follow 
them to leverage within-patient data and analyze changes in pulmonary status and contraception. Presence of 
respiratory microbiology will be estimated longitudinally via GEE with a logit link function. Graphic displays and summary 
statistics will be used; all p values will be two-sided.  
We will assess the strength of agreement between CFFPR reported data on osteoporosis, osteopenia and bone fracture 
compared to gold standard clinic DXA scan T-scores. We calculate the percent overall level of agreement between the 
CFFPR and clinical BMD scores using Cohen’s kappa statistic calculation. Level of absolute agreement represents the 
proportion of participants for whom the CFFPR and clinic DXA scan T-score were correct. We will also report on 
proportion of scores entered within the year or year after DXA scan was completed, versus scores entered 3-5 years 
after DXA scan completed.  
Missing Data 
We will plan to impute missing data as our primary analysis. Should we discover large amounts of missing data, we will 
perform a sensitivity analysis excluding women with missing data to explore how findings differ from those without 
missing data.  
Computer Facilities 
Appropriate computer facilities are readily available for data analysis. REDCap will be used for entry and preparation of 
data for statistical analysis. Statistical analysis will be performed using STATA 12. 

CASE.4.CF Study Protocol 
 
 
 
 
 
 
 
Page 17 of 24 
 
 
10.0. Methods: Monitoring 
10.1. Disposition 
The study ends for the participants once participants complete the survey and the CF center research staff complete the 
case report forms.  
10.2. Safety Assessment Methods  
Because this is an observational study, we do not anticipate any adverse events on account of this study. Participants 
may feel uncomfortable answering questions about their medical history, birth control and pregnancy history. They may 
decline to answer any of the online survey questions at any time. Participants may feel uncomfortable with the research 
team accessing their data from CFFPR. The research team will do their best to protect your privacy during this process. 
10.3. Adverse Event Management and Reporting  
An adverse event for this study may include a breach of confidentiality. Should a confidentiality breach occur, it will be 
reported to the Institutional Review Board by the investigator (according to the local policies). No Data Safety 
Monitoring Board will be used for this study.  
Participants will also be provided the site PI and study PIs contact information should a participant believe they have a 
medical problem or illness related to this research. The principal investigators at each site will be responsible for 
monitoring participant confidentiality.  
10.4. Duration of Project (see Table 11) 
• 
The duration of the project is expected to be about 36 months.  
• 
Recruitment is expected to take 12 months. 
• 
Merging of the data and cleaning the database is expected to take up to 4 months.  
• 
Data analysis will take 3 months. 
• 
Creation of the web-based REDCap database for data entry will occur before enrollment begins, and data entry 
will be ongoing throughout the study.  
 
11.0. Ethics and Dissemination Plan 
All of the information participants and clinics provide for this study will be kept confidential. When participants open the 
online survey, they will automatically be assigned a subject ID number. Based on the assigned ID number, centers will be 
able to identify which of their patients have already enrolled in the study. This number will be connected to the 
identifying information provided by participants to locate their records in the CFFPR. After participants complete their 
online survey, UW will send the identifying information (CFFPR ID or name, date of birth, and zip code) along with the 
subject ID number assigned by UW to the CFFPR team. They will use this information to pull participant data from 2010-
year as recent as possible. They will provide us with this data attached to the subject ID number. The link between 
participant identifiers and the research data will be destroyed after the records retention period required by state 
and/or federal law. 
Government or university staff sometimes review studies such as this one to make sure they are being done safely and 
legally. If a review of this study takes place, participant records may be examined. The reviewers will protect the 
subjects’ privacy. The study records will not be used to put participants at legal risk of harm. 
We plan to present our data at the North American CF Conference and the Society of Family Planning Conference. We 
will develop a summary paper from this feasibility study consistent with “Strengthening the Reporting of Observational 
Studies in Epidemiology” (STROBE) guidelines for reporting observational studies for publication (14).

CASE.4.CF Study Protocol 
 
 
 
 
 
 
 
 
 
Page 18 of 24 
Table 11: Project Timeline 
Activities & Timeline 
Pre-
Award 
Period 
YEAR 1 
YEAR 2 
2019 
2020 
2021 
Aug - 
Sep 
Oct - 
Nov 
Dec 
Jan-
Feb 
Mar - 
Apr 
May - 
Jun 
Jul 
Aug - 
Oct 
Nov - 
Dec 
Jan - 
Feb 
Mar - 
Apr 
May - 
Jun 
Jul 
IRB application submission and approval  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Institutional subcontract finalization 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Interdisciplinary Team meetings (Zoom for 
remote participants) 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Progress report due to CFF (due 90 days 
before start of next award period) 
 
 
 
 
 
 
Due 
5/1/20 
 
 
 
 
 
Due 
5/1/21 
 
Financial report due to CFF (due 90 days 
after completion of prior award period) 
 
 
 
 
 
 
 
 
 
Due 
11/1/20 
 
 
 
 
CFFPR Data Application submission and 
approval 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
CFF Confidentiality Agreement and 
Information Use Agreement  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Create recruitment letters for clinical sites 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Pilot and finalize patient questionnaire 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Set up questionnaire in REDCap 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Recruit patients from CF Centers (on-
going)  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Database design and setup 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Data control quality checks for patient 
questionnaire 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Self-respondent and CF Center CRF 
database cleaning 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Prepare and submit NACFC and NAPCRG 
abstracts 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Prepare manuscript on pilot study for 
publication 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Submit manuscript for publication (journal 
TBD) 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

CASE.4.CF Study Protocol 
 
 
 
 
 
 
 
 
 
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Activities & Timeline 
YEAR 3 
 
2021 
2022 
Aug - 
Sep 
Oct - Nov 
Dec 
Jan - 
Feb 
Mar - 
Apr 
May - 
Jun 
Jul 
Post Award 
Period 
Progress report due to CFF (due 90 days 
before start of next award period) 
 
 
 
 
 
Due 
5/1/22 
 
 
Financial report due to CFF (due 90 days 
after completion of prior award period) 
 
Due 
11/1/21 
 
 
 
 
 
 
Final project/scientific report and final 
report of expenditures due to CFF 
 
 
 
 
 
 
 
Due no later 
than 11/1/22 
Interdisciplinary Team meetings (Zoom for 
remote participants) 
 
 
 
 
 
 
 
 
Import and merge data from CFFPR 
 
 
 
 
 
 
 
 
Determine randomized group of women 
from each of the 10 CF centers whose EMR 
will be reviewed for DXA results 
 
 
 
 
 
 
 
 
CF centers do EMR data pull 
 
 
 
 
 
 
 
 
Additional database cleaning post merging 
of databases 
 
 
 
 
 
 
 
 
Conduct analysis 
 
 
 
 
 
 
 
 
Prepare manuscripts for publication and 
abstracts to NACFC 
 
 
 
 
 
 
 
 
Submit manuscript to CFF for review 
 
 
 
 
 
 
 
 
Submit revised manuscript to peer-
reviewed journal (J of CF) 
 
 
 
 
 
 
 
 
 

CASE.4.CF Study Protocol 
 
 
 
 
 
 
Page 20 of 24 
References 
 
1. Marshall BC, Faro A, Fink A, et al. Cystic Fibrosis Foundation Patient Registry 2017 Annual Data Report. 
Bethesda, MD: Cystic Fibrosis Foundation; 2018. 
2. Ahmad A, Ahmed A, Patrizio P. Cystic fibrosis and fertility. Curr Opin Obstet Gynecol. 2013;25:167-72. 
3. Jones GH, Walshaw MJ. Potential impact on fertility of new systemic therapies for cystic fibrosis. Paediatr Respir 
Rev. 2015;16 Suppl 1:25-27. 
4. Godfrey EM, Mody S, Schwartz MR, et al. Contraceptive use among women with cystic fibrosis: A pilot study 
linking reproductive health questions to the Cystic Fibrosis Foundation National Patient Registry. Contraception. 
2020;101(6):420-426. 
5. Kazmerski TM, Hill K, Prushinskaya O, et al. Perspectives of adolescent girls with cystic fibrosis and parents on 
disease-specific sexual and reproductive health education. Pediatr Pulmonol. 2018;53(8):1027-1034. 
6. Curtis KM, Tepper NK, Jatlaoui TC, et al. U.S. Medical Eligibility Criteria for Contraceptive Use, 2016. MMWR 
Recomm Rep. 2016;65(No. RR-3):1–104. 
7. World Health Organization. WHO scientific group on the assessment of osteoporosis at primary health care 
level. Summary meeting report; 2004. p. 5-7. 
8. Rayas MS, Aris RM. Bone disease in CF clinical care guidelines. 2017 [cited 2019 March 22]; Available from: 
https://www.cff.org/Care/Clinical-Care-Guidelines/Other-CF-Related-Conditions-Clinical-Care-Guidelines/Bone-
Disease-in-CF-Clinical-Care-Guidelines/.  
9. Godfrey EM, West II, Holmes J, et al. Use of an electronic health record data sharing system for identifying 
current contraceptive use within the WWAMI region Practice and Research Network. Contraception. 
2018;98(6):476-481. 
10. Cystic Fibrosis Foundation Patient Registry. 2018. Annual Data Report Technical Summary. Bethesda, Maryland. 
Available from: https://www.cff.org/Research/Researcher-Resources/Patient-Registry/Patient-Registry-Annual-
Data-Report-Technical-Supplement.pdf.  
11. Quon BS, Mayer-Hamblett N, Aitken ML, et al. Risk factors for chronic kidney disease in adults with cystic 
fibrosis. Am J Respir Crit Care Med. 2011;184(10):1147-1152. 
12. Ronan NJ, Elborn JS, Plant BJ. Current and emerging comorbidities in cystic fibrosis. Presse Med. 2017;46(6 Pt 
2):e125-e138. 
13. Wainwright CE, Elborn JS, Ramsey BW, et al. Lumacaftor-Ivacaftor in Patients with Cystic Fibrosis Homozygous 
for Phe508del CFTR. N Engl J Med. 2015;373(18):1783-1784. 
14. von Elm E, Altman DG, Egger M, et al. The Strengthening the Reporting of Observational Studies in Epidemiology 
(STROBE) Statement: guidelines for reporting observational studies. Int J Surg. 2014;12(12):1495-9. 

CASE.4.CF Study Protocol 
 
 
 
 
 
 
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APPENDIX: List of CFFPR cariables that will be requested from the CFF once recruitment of up to 625 
respondents is complete. Data will include years 2010-to most recent year available.  
I. DEMOGRAPHICS 
• 
Birth characteristics 
o Date of birth (mm/dd/yyyy) [PHI] 
• 
Race/Ethnicity  
o Race includes 'White' 
o Race includes 'Black or African American' 
o Race includes 'American Indian or Alaska Native' 
o Race includes 'Asian' 
o Race includes 'Native Hawaiian or Other Pacific Islander' 
o Race includes 'Some other race' 
o Patient is Hispanic 
• 
Health insurance 
o Health insurance policy (i.e. private insurance) 
o Medicare 
o Medicaid 
o State special needs program (BCMH, CCS, CRS, GHPP...) 
o TriCare or other military health plan 
o Indian Health Service 
o Other health insurance  
o Patient has no health insurance for the entire year 
o Patient covered on their parents' insurance plan 
o Receives free medicine/assistance from patient assistance program 
• 
Socioeconomic characteristics 
o Patient's education 
• 
Smoking 
o Patient smokes cigarettes during the reporting year 
• 
Research involvement 
o Patient participated in interventional (drug) studies 
• 
Patient pregnancy 
o Patient was pregnant during the reporting year 
o Outcome of patient's pregnancy 
II. DIAGNOSIS 
• 
Diagnosis date 
o First year in the CFF Patient Registry 
o Research involvement 
o Patient participated in interventional (drug) studies  
• 
Genotyping 
o Has this patient been genotyped 
o Mutation classification 
o Name of the first mutation 
o Mutation 1 Class 
o Name of the second mutation 
o Mutation 2 Class 
o Delta F508 
III. CLINIC VISITS 
• 
Visit details 

CASE.4.CF Study Protocol 
 
 
 
 
 
 
Page 22 of 24 
o Date of Encounter [PHI] 
o Encounter age [PHI] 
• 
Pulmonary exacerbation - encounter level 
o Assessment of potential pulmonary exacerbation 
• 
Pulmonary exacerbation - summarized by calendar year 
o Any pulmonary exacerbation assessment in the year 
o Any pulmonary exacerbation assessment positive in the year 
o # encounters with pulmonary exacerbation assessments: absent 
o # encounters with pulmonary exacerbation assessments: mild exacerbations 
o # encounters with pulmonary exacerbation assessments: moderate exacerbations 
o # encounters with pulmonary exacerbation assessments: severe exacerbations 
o Encounter exacerbation treatment: Incr. airway clearance 
o Encounter exacerbation treatment: Oral NON-quinolone antibiotic 
o Encounter exacerbation treatment: Oral quinolone antibiotic 
o Encounter exacerbation treatment: Inhaled Antibiotic 
o Encounter exacerbation treatment: Inhaled + Oral NON-quinolone antibiotic 
o Encounter exacerbation treatment: Inhaled + oral quinolone antibiotic 
o Encounter exacerbation treatment: None of the above 
IV. CLINICAL MEASUREMENTS 
• 
Anthropometric measures - encounter level 
o Patient's height 
o BMI Value 
o BMI Percentile 
o Weight of Patient 
• 
Pulmonary function tests - encounter level 
o Measure of FVC 
o Percent predicted relative to predicted FVC 
o Predicted Value for FVC using GLI reference equations 
o Measure of FEV1 
o Percent predicted relative to predicted FEV1 
o Predicted Value for FEV1 using GLI reference equations 
• 
Lab values - encounter level 
o Alanine Aminotransferase (ALT or SGPT), IU/L 
o Fecal elastase value (microg/g of stool) 
o Alkaline phosphatase 2 hour blood glucose (mg/dL) 
o Total bilirubin, mg/dL 
o Hgb A1C value, % 
o Liver enzymes drawn (pre-2010) Aspartate aminotransferase 
o GGTP (gamma glutamyl transpeptidase), IU/L 
o Fasting glucose level (mg/dL) 
o OGTT Fasting glucose level (mg/dL) 
• 
Lab values - summarized by calendar year 
o Fasting glucose level (mg/dL) 
o OGTT fasting glucose level (mg/dL) 
o 2-hour blood glucose (mg/dL) 
• 
Screening tests 
o Liver function tests performed 
o DEXA scan for bone density performed in the reporting year 
o DEXA scan result is normal 

CASE.4.CF Study Protocol 
 
 
 
 
 
 
Page 23 of 24 
o DEXA scan result is osteopenia 
o DEXA scan result is osteoporosis 
o DEXA scan result is other 
o DEXA scan result is unknown 
V. MICROBIOLOGY 
• 
Bacteria - encounter level 
o Was bacterial culture done? 
o Date of bacterial culture [PHI] 
o Culture results 
o Staphylococcus aureus 
o MRSA 
o Any Burkholderia Complex species 
o Multidrug-Resistant P. aeruginosa (MDR-PA) Infection 
o Stenotrophomonas 
o MSSA 
o Pseudomonas aeruginosa found in the culture 
o Mucoid Pseudomonas aeruginosa 
o Non-mucoid Pseudomonas aeruginosa 
o Mucoid Pseudomonas aeruginosa status unknown 
• 
Mycobacteria - encounter level 
o Was mycobacterial culture done? 
o Date of myco culture [PHI] 
o Myco culture results 
o Mycobacterial tuberculosis 
o Mycobacterium terrae 
o Mycobacterium other 
o Mycobacterium abscessus/chelonae 
o Mycobacterium avium complex 
o Mycobacterium fortuitum group 
o Mycobacterium gordonae 
o Mycobacterium kansasii 
VI. TREATMENTS 
• 
Antibiotics - encounter level 
o Chronic oral macrolide antibiotic 
o Azithromycin 
o Clarithromycin 
o Sulfa 
o Amoxicillin 
o Tetracycline 
o Other oral antibiotic 
o Other chronic oral antibiotic 
o Quinolone 
o Cephalosporin 
• 
CFTR modulators - encounter level 
o On Ivacaftor medication (VX-770) 
o VX770 (Ivacaftor) dosage 
o Ivacaftor/Lumacaftor (i.e., Orkambi) 
o Ivacaftor/Lumacaftor (i.e., Orkambi) dosage 
• 
Other treatments - encounter level 

CASE.4.CF Study Protocol 
 
 
 
 
 
 
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o Patient is taking enzymes 
o CF-specific vitamins (i.e. vitamins A, D, E and K) 
o Exercise 
• 
Other treatments - annual 
o Was the patient started on treatment for NTM 
VII. COMPLICATIONS 
• 
CF related diabetes - encounter level 
o CFRD Status 
o Chronic renal insufficiency 
o Chronic renal failure requiring dialysis 
• 
Liver disease - encounter level 
o Gall stones 
o Gall stones, requiring surgery/procedure 
o Liver disease, cirrhosis 
o Acute hepatitis 
o Acute hepatitis - infectious 
o Acute hepatitis - non-infectious 
o Acute hepatitis - unknown 
o Liver disease, non-cirrhosis 
o Hepatic Steatosis 
o Liver disease, other Acute liver failure 
• 
Other complications - encounter level 
o Bone fracture 
o Osteopenia 
o Osteoporosis 
o Cancer confirmed by histology 
VIII. CARE EPISODES (HOSPITALIZATIONS/HOME IV) 
• 
Care episodes 
o Start date for care episode [PHI] 
o End date for care episode [PHI] 
o # home IV nights with reason pulmonary exacerbation 
o # hospitalization nights with reason pulmonary exacerbation 
• 
Care episodes - summarized by calendar year 
o Total # pulmonary exacerbations treated by IV antibiotics 
o # nights in hospital for pulmonary exacerbations 
o # nights on home IV for pulmonary exacerbations 
o Total # pulmonary exacerbation treated by IV antibiotics (incl unknown) 
o # nights hospital for pulmonary exacerbation (incl unknown) 
o # nights home IV for pulmonary exacerbation (incl unknown)