Comparison of Meal-Time Dosing of Rapid Acting Insulin Using Carbohydrate Counting vs. Fixed Doses Utilizing Continuous Glucose Monitoring In Patients With Cystic Fibrosis Related Diabetes
Phase: PHASE4
Conditions: Cystic Fibrosis-related Diabetes
Sponsor: Jagdeesh Ullal

CFRD Meal time Insulin Dosing Study Protocol Version 2.1         Protocol Date: 8/3/2021 12:46 PM 
 
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Title: Comparison of Meal-Time Dosing of 
Rapid Acting Insulin Using Carbohydrate 
Counting vs. Fixed Doses Utilizing 
Continuous Glucose Monitoring In Patients 
with Cystic Fibrosis Related Diabetes 
 
Primary Investigator: Jagdeesh Ullal, MD 
Clinical Associate Professor, UPMC Center for Endocrinology and Diabetes, Division of 
Endocrinology, Department of Medicine 
3601 Fifth Ave Suite 3B 
Pittsburgh PA 15213 
Tel: 412-586-9700,  Fax: 412-586-9724 
Email: ullalj@upmc.edu 
Consultants:  
1. Kara Hughan, MD 
Assistant Professor, Pediatric Endocrinologist, UPMC Children’s Hospital of Pittsburgh 
4401 Penn Ave. 
3rd Floor 
Pittsburgh, PA 15224 United States  
(412) 692-5170 
Email: Kara.Hughan@chp.edu 
 
2. Joseph A. Aloi, MD 
Professor of Internal Medicine 
Chief, Section on Endocrinology and Metabolism 
 Department of Internal Medicine, Section on Endocrinology and Metabolism 
Medical Center Boulevard , Winston-Salem, NC 27157 
Tel: 336-713-6052 , Fax: 336-713-7255   
jaloi@wakehealth.edu   
Sub-investigator   
Joseph M. Pilewski, MD 
University of Pittsburgh Physicians, Department of Medicine 
3601 5th Avenue, 4th Floor Falk, Comprehensive Lung Center 

CFRD Meal time Insulin Dosing Study Protocol Version 2.1         Protocol Date: 8/3/2021 12:46 PM 
 
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Pittsburgh, PA 15213 
Tel: 412-648-6161, Fax: 412-692-2370 
Email: pilewskijm@upmc.edu 
Study Coordinator: 
Shari Reynolds 
Research Coordinator,  
Division of Gastroenterology, Hepatology and Nutrition 
Division of Endocrinology 
University of Pittsburgh 
BST W1140 
Tel: 412-383-0570, Fax: 412-648-4055 
Email: reynoldssl2@upmc.edu 
 
Background and Introduction 
Cystic fibrosis related diabetes (CFRD) is the most common extra-pulmonary comorbidity in 
patients with cystic fibrosis (CF). CFRD is also associated with accelerated decline in pulmonary 
function, increased pulmonary exacerbations and increased mortality. Continuous glucose 
monitoring (CGM) involves the use of a small disposable sensor sited in the subcutaneous 
interstitial fluid that makes frequent glucose measurements. There is data suggesting that the 
Medtronic iPro continuous glucose monitors (CGM) can predict hemoglobin a1c levels in 
patients with CFRD.  
 
The aim of our study is to assess the utility of CGMs to determine the optimal method to dose 
meal-time insulin. We will examine glucose excursions in patients with CF who will dose meal-
time rapid acting insulin by carbohydrate counting versus fixed dose rapid acting insulin.  The 
carbohydrate ratio and fixed doses will be determined by existing doses, total daily insulin 
doses, body weight and insulin sensitivity along with predisposition to hypoglycemia. Bolus 
insulin dosing is an important part of CFRD management due to the high nutritional demands on 
these patients. If dosed incorrectly, this could lead to marked hyperglycemia and could worsen 
nutritional status due to urinary glucose losses. In this project, we will perform a within subjects’ 
comparison of the 2 standard methods of meal-time rapid acting insulin dosing. 
 
Hypothesis: 
1. We hypothesize that postprandial interstitial fluid glucose levels in patients who utilize 
carbohydrate counting to dose mealtime rapid acting insulin will have improved control as 
defined as area under the curve and time in target compared to patients who used fixed dose 
mealtime insulin 
2. Our second hypothesis is that patients who utilize carbohydrate counting will have fewer 
hypoglycemia events compared to patients who use fixed dose meal-time insulin  
 

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Specific Aims: 
1. To compare within-subject glucose excursions defined as percentage of time in target glucose 
level, percentage of glucose in target and peak post prandial glucose with fixed insulin dosing 
versus carbohydrate count based insulin dosing. 
2. To compare the frequency and duration of hypoglycemia (defined as daily, weekly and average 
duration of event) between insulin delivery methods described above. 
3. To test the use of ‘rule of 500’ for carb counting estimation in CFRD patients. 
4. To compare the effect of two methods of rapid acting insulin delivery on fasting glycemia 
 
Research Design and Methods 
Subject population:   
Adult patients with a diagnosis of CFRD will be recruited from the CF Center at the University of 
Pittsburgh. Sample size will be 20 patients. Inclusion criteria will be adults >18 age of years with 
diagnosis of CFRD (as defined by standard 2-hour oral glucose tolerance test (OGTT) Patients 
who are being evaluated for transplant and patients who already use CGM will be excluded. 
Stable lung transplant patients who are more than 1 year from transplantation will be included. 
The patients will be individually followed in the adult CF Endocrine clinic. Downloads and data 
gathering will be performed at the clinic during follow up visits. 
 
Methods 
CGM involves the use of a small sensor sited in the subcutaneous interstitial fluid that makes 
frequent glucose measurements. The Wake Forest School of Medicine Endocrinology Division 
(WFBSM) will provide us with Abbott Freestyle Libre CGM patches to use in our CF patients. All 
patients will be recruited from the UPMC adult CF Center and the CF Endocrine Clinic. The CGMs 
will be placed in our clinic on patients recruited from the Cystic Fibrosis center. Downloads and 
data gathering will be performed at our center. The project will be performed in collaboration 
with partners from WFBSM. There will be study design input from collaborators at WFBSM as 
well as statistical support if needed.  
 
Each sensor is valid for a 2-week period of use and these sensors automatically stop gathering 
data beyond 14 days. Each participant will be provided carbohydrate counting education and 
training prior to their participation by certified diabetes educators at UPMC. During the first 
seven days of wear, the participants will be asked to dose their meal time rapid acting insulin by 
fixed dose and the next 7 days, participants will be asked to dose their meal time rapid acting 
insulin by carbohydrate counting. Patients will be required to maintain a paper log of their 
carbohydrates consumed at every meal and snacks and insulin doses given during the 2-week 
time frame. The CGM will record blood sugars once every minute in a blinded fashion and 
participants will not be aware of the CGM recording data. At the completion of the 14-day 
period, participants will return their CMG devices for analysis and interpretation.  If they live at a 
distance from our office and are unable to visit us to return the device, they will be permitted to 
mail in the sensor along with the food and glucose logs. The data will be summarized and 

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communicated to the patients once analyzed.  Patient will be required maintain fingerstick 
blood sugar logs. The figure below describes the various study periods: 
 
 
 
 
 
 
 
 
Measurement: 
Thorough literature search found only one other study examining inpatient carbohydrate counting.  
Three other studies were identified that examined other insulin regimens inpatient and their effect on 
hypoglycemia and hyperglycemia rates.  The statistical analysis methods of those studies were used as a 
benchmark for this study    
Data Points:  
Primary: We will be measuring postprandial excursions on continuous glucose monitoring data 
and the instances of hypoglycemia during the two-week timeframe of the study period 
Secondary: Total carbohydrates consumed each day during the two-week time frame, total daily 
dose of insulin per 24 hour period (midnight to midnight) will be secondary endpoints 
 
 
CGM devices can be connected to desktop machines and downloaded via a receiver.  The 
baseline characteristics that will be collected are age, sex, race, exocrine pancreatic function 
status, CFTR genotype, duration of CFRD, hemoglobin A1c, renal function tests, weight and BMI. 
From the log, insulin doses and fingerstick glucoses will be collected. The outcome measures 
that will be extracted from the CGM devices to assess the effectiveness of our intervention in 
improving glycemic control and nutritional status will include daily glucose trends calculated by 
percentage of time in target interstitial fluid glucose levels level and percentage of target 
interstitial fluid glucose levels readings, hypoglycemia episodes, and average glucose from the 2 
comparison periods. This data will be compared for statistical significance using student t-test 
with significance assigned to p-value less than 0.05.  
The clinical endocrine fellow will collect data from each included patient by performing a Cerner 
and Epic (EHR) chart review. Data will be recorded on an encrypted UPMC OneDrive Microsoft 
excel spreadsheet with password restricted access. A list of collected data points are as follows: 
1. Age 
2. Sex 
Lead in 
Carbohydrate and 
CGM use Training 
by Diabetes 
Educator 
 
WEEK 1: PARTICIPANTS WILL 
DOSE MEALTIME INSULIN WITH 
FIXED DOSE SCHEDULE 
 
WEEK 2: PARTICIPANTS WILL 
DOSE MEALTIME INSULIN WITH 
CARBOHYDRATE COUNTING 

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3. Race 
4. Exocrine pancreatic function status (sufficient vs. insufficient) 
5. CFTR genotypes 
6. Duration of CFRD 
7. Weight and BMI at the most recent office visit or on the day of the placement 
8. Labs: serum creatinine and eGFR (most recent value in the last 12 months), hemoglobin 
a1c (the most recent value in the last 3 months, or will be performed by point of care 
testing at the time of the CGM device placement) 
9. Modulator use: ivacaftor (Kalydeco), lumacaftor/ivacaftor (Orkambi), 
tezacaftor/ivacaftor (Symdeko), elexacaftor/tezacaftor/ivacaftor (Trikafta); start date 
and duration of use 
10. Meal /snack time insulin doses from log  
11. CGM glycemic control data (percentage of time within glycemic target)  
12. Data from fingerstick before and after intervention 
13. Nutritional information with carbohydrates consumed per meal/snack in grams 
Study power: This is a proof-of-concept study and we plan to include 20 patients in this study which we 
expect will be adequately powered to demonstrate a trend and compared intrasubject variation 
between the 2 study periods.  
Controls/patient demographics: Patient demographics are shown in table 1, while variables to be 
measured are shown in table 2.  
 
Data safety: 
Data for individual patients will be deidentified without names, addresses, DOB, or SSN.  Individual 
patients will be classified as patient 001, 002, 003 etc.  
A subject identifier key will be used to match the medical record number with a subject ID number.  The 
subject identifier key will be maintained in a password protected Excel file.  Collected information on the 
data collection tool will be entered into a separate password protected Excel file.  One year after the 
conclusion of the study, all collected data will be destroyed by permanently deleting electronic copies.  
The principal investigator and study team members will not disclose PHI to any other person or entity.    
All individuals involved in the completion of this study will take every precaution to ensure the 
safety and confidentiality of all patient information. This will include the use of an encrypted 
UPMC OneDrive Microsoft excel spreadsheet with restricted access. No patient information will 
ever be stored on personal devices or on an external hard drive/flash drive. 
 
Statistical Analysis: 
We will perform a within subjects statistical comparison using student t-test to compare CGM 
glucose values, time in target  glucose level, percent of glucose values in target and 
hypoglycemia events during each week using the 2 standard methods of meal-time rapid acting 
insulin dosing. The data will be analyzed by SPSS statistical software package.